Daily oral iron supplementation during pregnancy

Abstract

Background

Iron and folic acid supplementation have been recommended in pregnancy for anaemia prevention, and may improve other maternal, pregnancy, and infant outcomes.

Objectives

To examine the effects of daily oral iron supplementation during pregnancy, either alone or in combination with folic acid or with other vitamins and minerals, as an intervention in antenatal care.

Search methods

We searched the Cochrane Pregnancy and Childbirth Trials Registry on 18 January 2024 (including CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, conference proceedings), and searched reference lists of retrieved studies.

Selection criteria

Randomised or quasi‐randomised trials that evaluated the effects of oral supplementation with daily iron, iron + folic acid, or iron + other vitamins and minerals during pregnancy were included.

Data collection and analysis

Review authors independently assessed trial eligibility, ascertained trustworthiness based on pre‐defined criteria, assessed risk of bias, extracted data, and conducted checks for accuracy. We used the GRADE approach to assess the certainty of the evidence for primary outcomes.

We anticipated high heterogeneity amongst trials; we pooled trial results using a random‐effects model (average treatment effect).

Main results

We included 57 trials involving 48,971 women. A total of 40 trials compared the effects of daily oral supplements with iron to placebo or no iron; eight trials evaluated the effects of iron + folic acid compared to placebo or no iron + folic acid.

Iron supplementation compared to placebo or no iron

Maternal outcomes: Iron supplementation during pregnancy may reduce maternal anaemia (4.0% versus 7.4%; risk ratio (RR) 0.30, 95% confidence interval (CI) 0.20 to 0.47; 14 trials, 13,543 women; low‐certainty evidence) and iron deficiency at term (44.0% versus 66.0%; RR 0.51, 95% CI 0.38 to 0.68; 8 trials, 2873 women; low‐certainty evidence), and probably reduces maternal iron‐deficiency anaemia at term (5.0% versus 18.4%; RR 0.41, 95% CI 0.26 to 0.63; 7 trials, 2704 women; moderate‐certainty evidence), compared to placebo or no iron supplementation. There is probably little to no difference in maternal death (2 versus 4 events, RR 0.57, 95% CI 0.12 to 2.69; 3 trials, 14,060 women; moderate‐certainty evidence). The evidence is very uncertain for adverse effects (21.6% versus 18.0%; RR 1.29, 95% CI 0.83 to 2.02; 12 trials, 2423 women; very low‐certainty evidence) and severe anaemia (Hb < 70 g/L) in the second/third trimester (< 1% versus 3.6%; RR 0.22, 95% CI 0.01 to 3.20; 8 trials, 1398 women; very low‐certainty evidence). No trials reported clinical malaria or infection during pregnancy.

Infant outcomes: Women taking iron supplements are probably less likely to have infants with low birthweight (5.2% versus 6.1%; RR 0.84, 95% CI 0.72 to 0.99; 12 trials, 18,290 infants; moderate‐certainty evidence), compared to placebo or no iron supplementation. However, the evidence is very uncertain for infant birthweight (MD 24.9 g, 95% CI ‐125.81 to 175.60; 16 trials, 18,554 infants; very low‐certainty evidence). There is probably little to no difference in preterm birth (7.6% versus 8.2%; RR 0.93, 95% CI 0.84 to 1.02; 11 trials, 18,827 infants; moderate‐certainty evidence) and there may be little to no difference in neonatal death (1.4% versus 1.5%, RR 0.98, 95% CI 0.77 to 1.24; 4 trials, 17,243 infants; low‐certainty evidence) or congenital anomalies, including neural tube defects (41 versus 48 events; RR 0.88, 95% CI 0.58 to 1.33; 4 trials, 14,377 infants; low‐certainty evidence).

Iron + folic supplementation compared to placebo or no iron + folic acid

Maternal outcomes: Daily oral supplementation with iron + folic acid probably reduces maternal anaemia at term (12.1% versus 25.5%; RR 0.44, 95% CI 0.30 to 0.64; 4 trials, 1962 women; moderate‐certainty evidence), and may reduce maternal iron deficiency at term (3.6% versus 15%; RR 0.24, 95% CI 0.06 to 0.99; 1 trial, 131 women; low‐certainty evidence), compared to placebo or no iron + folic acid. The evidence is very uncertain about the effects of iron + folic acid on maternal iron‐deficiency anaemia (10.8% versus 25%; RR 0.43, 95% CI 0.17 to 1.09; 1 trial, 131 women; very low‐certainty evidence), or maternal deaths (no events; 1 trial; very low‐certainty evidence). The evidence is uncertain for adverse effects (21.0% versus 0.0%; RR 44.32, 95% CI 2.77 to 709.09; 1 trial, 456 women; low‐certainty evidence), and the evidence is very uncertain for severe anaemia in the second or third trimester (< 1% versus 5.6%; RR 0.12, 95% CI 0.02 to 0.63; 4 trials, 506 women; very low‐certainty evidence), compared to placebo or no iron + folic acid.

Infant outcomes: There may be little to no difference in infant low birthweight (33.4% versus 40.2%; RR 1.07, 95% CI 0.31 to 3.74; 2 trials, 1311 infants; low‐certainty evidence), comparing iron + folic acid supplementation to placebo or no iron + folic acid. Infants born to women who received iron + folic acid during pregnancy probably had higher birthweight (MD 57.73 g, 95% CI 7.66 to 107.79; 2 trials, 1365 infants; moderate‐certainty evidence), compared to placebo or no iron + folic acid. There may be little to no difference in other infant outcomes, including preterm birth (19.4% versus 19.2%; RR 1.55, 95% CI 0.40 to 6.00; 3 trials, 1497 infants; low‐certainty evidence), neonatal death (3.4% versus 4.2%; RR 0.81, 95% CI 0.51 to 1.30; 1 trial, 1793 infants; low‐certainty evidence), or congenital anomalies (1.7% versus 2.4; RR 0.70, 95% CI 0.35 to 1.40; 1 trial, 1652 infants; low‐certainty evidence), comparing iron + folic acid supplementation to placebo or no iron + folic acid.

A total of 19 trials were conducted in malaria‐endemic countries, or in settings with some malaria risk. No studies reported maternal clinical malaria; one study reported data on placental malaria.

Authors' conclusions

Daily oral iron supplementation during pregnancy may reduce maternal anaemia and iron deficiency at term. For other maternal and infant outcomes, there was little to no difference between groups or the evidence was uncertain. Future research is needed to examine the effects of iron supplementation on other maternal and infant health outcomes, including infant iron status, growth, and development.

Plain language summary

Effects of daily oral iron supplementation during pregnancy

Key messages

Women taking daily iron supplements may have reduced anaemia and iron deficiency when they give birth around their due date, compared with placebo or no iron.

From the evidence in this review, we are less certain about the impact of iron supplements on other outcomes for the woman and her baby.

What is anaemia?

Anaemia is a condition with fewer red blood cells or less haemoglobin (a red substance found in blood that combines with oxygen and carries it around the body) in each red blood cell than normal. Iron deficiency is the leading cause of anaemia; additional factors such as micronutrient deficiencies of folate and vitamin B₁₂ also cause anaemia. If pregnant women develop anaemia or become deficient in iron or other nutrients, they are unable to supply them in sufficient quantities to their baby. Low iron and folate levels in women can cause anaemia, which can make women tired, faint, and at increased risk of infection.

What did we want to find out?

We wanted to find out if taking daily iron supplements (either alone or with folic acid or other vitamins and minerals) during pregnancy would improve the health and nutrition of pregnant women and their babies.

What did we do?

We searched for studies that examined the effects of daily iron supplementation during pregnancy (either alone or with folic acid or other vitamins and minerals). We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We included 57 trials involving 48,971 women in this review (40 studies on daily oral iron supplementation compared to placebo/no iron and eight comparing iron with folic acid compared to placebo/no iron and folic acid).

The largest study was amongst 18,775 participants and the smallest study was amongst 13 participants. The trials were conducted in 27 countries around the world; most studies were done in the United Kingdom (14) and United States of America (eight). Studies were mainly funded by government agencies, universities, health ministries within countries, and pharmaceutical companies.

Iron supplementation compared to placebo or no iron

Women taking iron supplements during pregnancy may have reduced anaemia, iron deficiency, and probably reduced iron‐deficiency anaemia when they give birth around their due date. There is probably little to no difference in the risk of other maternal outcomes, including maternal death; however, the evidence is very uncertain for adverse effects, or severe anaemia in the second or third trimester. No trials reported maternal clinical malaria or infection during pregnancy.

Women taking iron supplements during pregnancy were probably less likely to have infants with low birthweight (less than 2500 g), but the evidence is very uncertain for infant birthweight. There was probably little to no difference between groups for preterm birth and little to no difference in birth defects or death of a baby in the first 28 days of life.

Iron + folic acid compared to placebo or no iron + folic acid

Women taking daily iron + folic acid supplements probably had reduced anaemia or may have reduced iron deficiency when they gave birth around their due date; however, the evidence is very uncertain for iron‐deficiency anaemia, or maternal death. The evidence is uncertain for any adverse effects, and the evidence is very uncertain for severe anaemia in the second or third trimester. No maternal deaths were reported, and no trials reported maternal clinical malaria.

Women taking iron + folic acid supplements during pregnancy probably had infants with increased birthweight, but there may be little to no difference between groups for other outcomes, including low infant birthweight (less than 2500 g), preterm birth, death of a baby in the first 28 days of life, or birth defects.

What are the limitations of the evidence?

Few studies reported the main outcomes, including maternal deaths, adverse effects, severe anaemia, maternal clinical malaria, or infection during pregnancy, and other infant outcomes, including birth defects, and infant iron status, growth, and development. In addition, studies included pregnant women at different iron levels and gestational age at enrolment with different doses of iron, and timing of outcome assessments, which constrains the comparability of evidence for some outcomes in pregnant women and children.

How up‐to‐date is this evidence?

This review is an update of the previous review. The evidence is up‐to‐date as of 18 January 2024.

Summary of findings

Summary of findings 1. (Comparison 1: Maternal outcomes) Any supplements containing iron compared with the same supplements without iron or no treatment/placebo (no iron or placebo) for pregnant women.

(Comparison 1: Maternal outcomes) Any supplements containing iron compared with the same supplements without iron or no treatment/placebo (no iron or placebo)
Patient or population: pregnant women of any gestational age and parity Settings: hospital or community‐based antenatal clinics Intervention: any supplements containing iron Comparison: same supplements without iron or no treatment/placebo (no iron or placebo)
Outcomes	Anticipated absolute effects * (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with same supplements without iron or no treatment/placebo (no iron or placebo)	Risk with any supplements containing iron
Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL) Assessed with: cyanmethemoglobin method (Hb less than 110 g/L) Follow‐up: range 37 weeks' gestation to 8 weeks postpartum	74 per 1000	22 per 1000 (15 to 35)	RR 0.30 (0.20 to 0.47)	13,543 (14 RCTs)	⊕⊕⊝⊝ lowa,b	—
Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL) Assessed with: chemiluminescent immunoassay (serum ferritin < 15 µg/L) Follow‐up: range 37 weeks' gestation to 6 weeks postpartum	660 per 1000	337 per 1000 (251 to 449)	RR 0.51 (0.38 to 0.68)	2873 (8 RCTs)	⊕⊕⊝⊝ lowa,b	—
Maternal iron deficiency anaemia at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL) Assessed with: cyanmethemoglobin method and chemiluminescent immunoassay (Hb less than 110 g/L and serum ferritin < 15 µg/L) Follow‐up: range 37 weeks' gestation to 6 weeks postpartum	184 per 1000	75 per 1000 (48 to 116)	RR 0.41 (0.26 to 0.63)	2704 (7 RCTs)	⊕⊕⊕⊝ moderatea	—
Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL) Assessed with: surveillance system, or medical records for clinic or hospital deliveries Follow‐up: first trimester to 8 weeks postpartum	1 per 1000	1 per 1000 (0 to 3)	RR 0.57 (0.12 to 2.69)	14,060 (3 RCTs)	⊕⊕⊕⊝ moderatec	1 trial reported no maternal deaths (Eskeland 1997)
Adverse effects (any reported throughout the intervention period) (ALL) Assessed with: self‐reported questionnaires Follow‐up: first trimester to term	180 per 1000	232 per 1000 (149 to 364)	RR 1.29 (0.83 to 2.02)	2423 (11 RCTs)	⊕⊝⊝⊝ very lowa,b,d	—
Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL) Assessed with: cyanmethemoglobin method Follow‐up: 8 weeks' gestation to 3 months postpartum	36 per 1000	8 per 1000 (0 to 115)	RR 0.22 (0.01 to 3.20)	1398 (8 RCTs)	⊕⊝⊝⊝ very lowa,b,e	—
Maternal clinical malaria (ALL) Assessed with: placental histopathologic analysis or quantitative polymerase chain reaction Follow‐up: 18 weeks' gestation to 6 weeks postpartum	65 per 1000	67 per 1000 (42 to 107)	RR 1.03 (0.65 to 1.65)	1003 (1 RCT)	⊕⊕⊕⊝ moderatef	Authors reported placental malaria
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

^aDowngraded one level due to study design: most studies contributing data have design limitations.

^bDowngraded one level due to inconsistency: statistical heterogeneity I² > 60%.

^cDowngraded one level due to imprecision: wide confidence intervals crossing the line of no effect and few events but a sufficiently large sample size to not downgrade further.

^dDowngraded one level due to imprecision: wide confidence intervals crossing the line of no effect.

^eDowngraded one level due to imprecision: wide confidence intervals crossing the line of no effect and few events.

^fDowngraded one level for imprecision: only one study contributed to the effect estimate.

Summary of findings 2. (Comparison 1: Infant outcomes) Any supplements containing iron compared with the same supplements without iron or no treatment/placebo (no iron or placebo) for pregnant women.

(Comparison 1: Infant outcomes) Any supplements containing iron compared with the same supplements without iron or no treatment/placebo (no iron or placebo)
Patient or population: pregnant women of any gestational age and parity Setting: hospital or community‐based antenatal clinics Intervention: any supplements containing iron Comparison: same supplements without iron or no treatment/placebo (no iron or placebo)
Outcomes	Anticipated absolute effects * (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with same supplements without iron or no treatment/placebo (no iron or placebo)	Risk with any supplements containing iron
Low birthweight (less than 2500 g) (ALL) Assessed with: electronic scale Follow‐up: immediately after birth or within 1 to 72 hours post‐delivery	61 per 1000	51 per 1000 (44 to 60)	RR 0.84 (0.72 to 0.99)	18,290 (12 RCTs)	⊕⊕⊕⊝ moderatea	—
Birthweight (g) (ALL) Assessed with: electronic scale Follow‐up: immediately after birth or within 1 to 72 hours post‐delivery	The mean birthweight (g) (ALL) ranged across control groups from 2652 g to 3740 g	The mean birthweight (g) (ALL) in the intervention group was 24.9 g higher (‐125.81 g lower to 175.6 g higher)	—	18,554 (16 RCTs)	⊕⊝⊝⊝ very lowb,c,d	—
Preterm birth(less than 37 weeks of gestation) (ALL) Assessed with: medical records for clinic or hospital deliveries, or self‐report Follow‐up: 11 weeks' gestation to less than 37 weeks' gestation	82 per 1000	76 per 1000 (69 to 78)	RR 0.93 (0.84 to 1.02)	18,827 (11 RCTs)	⊕⊕⊕⊝ moderatea	—
Neonatal death (within 28 days after delivery) (ALL) Assessed with: medical records for clinic or hospital deliveries, or self‐report Follow‐up: 18 weeks to 3 months postpartum	15 per 1000	15 per 1000 (12 to 19)	RR 0.98 (0.77 to 1.24)	17,243 (4 RCTs)	⊕⊕⊝⊝ lowb,d	—
Congenital anomalies (ALL) Assessed with: medical records for clinic or hospital deliveries, or self‐report Follow up: 13 weeks' gestation to 12 weeks postpartum	8 per 1000	7 per 1000 (5 to 11)	RR 0.88 (0.58 to 1.33)	14,377 (4 RCTs)	⊕⊕⊝⊝ lowb,d	—
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

^aDowngraded one level due to study design: more than half of the studies (five to six) contributing data had serious concerns due to selection bias, and attrition bias.

^bDowngraded one level due to study design: most studies contributing data have design limitations.

^cDowngraded one level due to inconsistency: high heterogeneity between studies (I² > 60%).

^dDowngraded one level due to imprecision: wide confidence intervals crossing the line of no effect.

Summary of findings 3. (Comparison 2: Maternal outcomes) Any supplements containing iron and folic acid compared with the same supplements without iron or folic acid (no iron or folic acid or placebo) for pregnant women.

(Comparison 2: Maternal outcomes) Any supplements containing iron and folic acid compared with the same supplements without iron or folic acid (no iron or folic acid or placebo)
Patient or population: pregnant women of any gestational age and parity Settings: hospital or community‐based antenatal clinics Intervention: any supplements containing iron and folic acid Comparison: same supplements without iron or folic acid (no iron or folic acid or placebo)
Outcomes	Anticipated absolute effects * (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with same supplements without iron or folic acid (no iron no folic acid or placebo)	Risk with any supplements containing iron and folic acid
Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL) Assessed with: cyanmethemoglobin method or automated haematology analyser (Hb less than 110 g/L) Follow‐up: range 37 weeks' gestation to 3 days postpartum	255 per 1000	112 per 1000 (77 to 163)	RR 0.44 (0.30 to 0.64)	1962 (4 RCTs)	⊕⊕⊕⊝ moderatea	—
Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL) Assessed with: immunoradiometric assay (serum ferritin < 15 µg/L) Follow‐up: range 9 weeks' gestation to 39 weeks' gestation	150 per 1000	36 per 1000 (9 to 149)	RR 0.24 (0.06 to 0.99)	131 (1 RCT)	⊕⊕⊝⊝ lowa,b	—
Maternal iron deficiency anaemia at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL) Assessed with: automated haematology analyser and immunoradiometric assay (Hb less than 110 g/L and serum ferritin < 15 µg/L) Follow‐up: range 9 weeks' gestation to 39 weeks' gestation	250 per 1000	108 per 1000 (43 to 273)	RR 0.43 (0.17 to 1.09)	131 (1 RCTs)	⊕⊝⊝⊝ very lowa,c,d	—
Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL) Assessed with: medical records for clinic or hospital deliveries Follow‐up: range 9 weeks' gestation to 39 weeks' gestation	—	—	Not estimable	131 (1 RCT)	⊕⊝⊝⊝ very lowa,e,f	—
Adverse effects (any reported throughout the intervention period) (ALL) Assessed with: self‐reported by participating women Follow‐up: first trimester to term	0 per 1000	0 per 1000 (0 to 0)	RR 44.32 (2.77 to 709.09)	456 (1 RCT)	⊕⊕⊝⊝ lowa,c
Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL) Assessed with: cyanmethemoglobin method Follow‐up: 12 weeks' gestation to 3 months postpartum	56 per 1000	7 per 1000 (1 to 35)	RR 0.12 (0.02 to 0.63)	506 (4 RCTs)	⊕⊝⊝⊝ very lowa,g	—
Maternal clinical malaria (ALL)	—	—	—	— (0 RCTs)	—	No trial reported this outcome
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

^aDowngraded one level due to study design: studies contributing data had design limitations.

^bDowngraded one level due to imprecision: wide 95% CI and one study contributed to the effect estimate.

^cDowngraded one level due to inconsistency: only one study contributed data.

^dDowngraded one level for imprecision: small sample size, low event rate, and wide CI crossing the line of no effect.

^eDowngraded one level due to imprecision: small sample size and no events.

^fDowngraded one level due to inconsistency: only one study contributed data and it was not estimable.

^gDowngraded two levels due to imprecision: very wide 95% CI and low event rate.

Summary of findings 4. (Comparison 2: Infant outcomes) Any supplements containing iron and folic acid compared with the same supplements without iron or folic acid (no iron or folic acid or placebo) for pregnant women.

(Comparison 2: Infant outcomes) Any supplements containing iron and folic acid compared with the same supplements without iron or folic acid (no iron or folic acid or placebo)
Patient or population: pregnant women of any gestational age and parity Settings: hospital or community‐based antenatal clinics Intervention: any supplements containing iron and folic acid Comparison: same supplements without iron or folic acid (no iron or folic acid or placebo)
Outcomes	Anticipated absolute effects * (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with same supplements without iron or folic acid (no iron or folic acid or placebo)	Risk with any supplements containing iron and folic acid
Low birthweight (less than 2500 g) (ALL) Assessed with: electronic scale Follow‐up: immediately after birth to 72 hours post‐delivery	402 per 1000	430 per 1000 (125 to 1503)	RR 1.07 (0.31 to 3.74)	1311 (2 RCTs)	⊕⊕⊝⊝ lowa,b	—
Birthweight (g) (ALL) Assessed with: electronic scale Follow‐up: immediately after birth to 72 hours post‐delivery	The mean birthweight (g) (ALL) ranged across control groups from 2587 g to 3502 g	The mean birthweight (g) (ALL) in the intervention group was 57.73 g higher (7.66 g higher to 107.79 g higher)	—	1365 (2 RCTs)	⊕⊕⊕⊝ moderatea	—
Preterm birth (less than 37 weeks of gestation) (ALL) Assessed with: medical records for clinic or hospital deliveries, or self‐report Follow‐up: first trimester to 3 months postpartum	192 per 1000	298 per 1000 (77 to 1152)	RR 1.55 (0.40 to 6.00)	1497 (3 RCTs)	⊕⊕⊝⊝ lowb,c	—
Neonatal death (within 28 days after delivery) (ALL) Assessed with: medical records for clinic or hospital deliveries, or self‐report Follow‐up: first trimester to 3 months postpartum	42 per 1000	34 per 1000 (21 to 55)	RR 0.81 (0.51 to 1.30)	1793 (3 RCTs)	⊕⊕⊝⊝ lowb,c	—
Congenital anomalies (ALL) Assessed with: medical records for clinic or hospital deliveries, or self‐report Follow‐up: first trimester to 3 months postpartum	24 per 1000	17 per 1000 (8 to 34)	RR 0.70 (0.35 to 1.40)	1652 (1 RCT)	⊕⊕⊝⊝ lowb,d	—
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

^aDowngraded one level due to study design: both studies contributing data had design limitations.

^bDowngraded one level due to imprecision: wide 95% CI crossing the line of no effect.

^cDowngraded one level due to study design: all studies contributing data had design limitations.

^dDowngraded one level due to study design: study contributing data had design limitations.

Background

Description of the condition

Anaemia is an important public health problem that affects more than 1.9 billion people globally (Chaparro 2019; WHO 2021). The prevalence of anaemia is highest in pregnant women and children, with the highest burden in resource‐limited settings (Chaparro 2019; Goodarzi 2020; WHO 2011; WHO 2021). Anaemia affects approximately 30% of women 15 to 49 years of age, and 37% of pregnant women have anaemia globally (WHO 2021; WHO 2023).

Iron deficiency is the most common nutritional deficiency worldwide (ACC/SCN 2000; Haider 2013; Stelle 2019; Stoltzfus 1998), and is the main cause of anaemia globally (Petry 2016; WHO 2001; WHO 2015; Williams 2019). It has been estimated that approximately 50% of anaemia cases are attributable to iron deficiency (WHO 2015); however, this may be lower (non‐pregnant women 15 to 49 years: 37.0% (95% confidence interval (CI) 28.0 to 46.0); children five to 59 months: 25.0% (95% CI 18.0 to 32.0)) (Petry 2016), particularly in settings with high prevalence of anaemia, and increased burden of infections and inflammation (Petry 2016). In addition to iron deficiency, other micronutrient deficiencies (e.g. folate, vitamin B₁₂), infections (e.g. hookworm), inflammation, and genetically inherited traits (e.g. thalassaemias, sickle‐cell anaemia) are important causes of anaemia (WHO 2015a).

The burden of anaemia and iron deficiency in women of reproductive age, including pregnant women, is particularly high, due to low dietary intake or bioavailability, menstrual blood loss, increased requirements for iron during pregnancy (WHO 2015; WHO 2017; WHO 2020; Wirth 2017), and physiological changes during pregnancy such as blood volume expansion (WHO 2020).

Assessment of anaemia and iron deficiency during pregnancy

Anaemia in pregnancy is defined as haemoglobin (Hb) concentrations less than 110 g/L (at sea level) (WHO 2011a). Additional trimester‐specific cut‐offs have also been proposed (i.e. Hb < 110 g/L, Hb < 105 g/L, Hb < 110 g/L, respectively) (WHO 2017). Cyanmethaemoglobin is the recommended method for haemoglobin assessment and has been used to validate methods including automated haematology analysers (Prakash 1972). The World Health Organization (WHO) recommends assessment of haemoglobin in venous blood via automated haematology analysers when available (WHO 2020a). However, national surveys and population‐based data on anaemia prevalence are often based on analysis of capillary blood using portable haemoglobinometers, due to the comparatively lower cost, availability, personnel, and infrastructure requirements (Neufeld 2019; Whitehead 2019).

For iron status, the WHO recommends assessment of haemoglobin, ferritin, soluble transferrin receptor, and C‐reactive protein and/or alpha‐1 acid glycoprotein (WHO 2020; WHO 2020a). However, haemoglobin is often assessed as a proxy indicator of iron status (McLean 2009; Zimmermann 2007). Iron deficiency is defined as low ferritin concentrations (e.g. < 15.0 µg/L) (WHO 2020) to reflect depleted iron stores, although higher cut‐offs may be considered in the context of inflammation or pregnancy.

The WHO recently updated haemoglobin thresholds for anaemia assessment (Addo 2019; Garcia‐Casal 2019; Karakochuk 2019; Pasricha 2018; Sharma 2019), cut‐offs for serum/plasma ferritin for iron status in different populations (Daru 2017; Garcia‐Casal 2014; WHO 2020), and cut‐offs for biomarkers of iron status in the context of inflammation and infection (Suchdev 2017; WHO 2020a), emphasising harmonisation of laboratory methods for assessment of iron status (Garcia‐Casal 2018; WHO 2020a) and methods for adjustment of biomarkers of iron status in the presence of infection or inflammation (Suchdev 2016; WHO 2020a). In pregnancy, iron deficiency has been commonly defined as serum ferritin concentrations less than 15.0 µg/L, although recent assessments highlighted the need for review of cut‐off points (Garcia‐Casal 2014; Garcia‐Casal 2021; WHO 2020) and establishment of unified thresholds for iron deficiency in pregnancy (Daru 2017; WHO 2020a).

Anaemia and iron status and perinatal outcomes

Anaemia and iron deficiency during pregnancy have been linked to risk of adverse perinatal outcomes (Athe 2020; De‐Regil 2016; Iglesias 2018; Iqbal 2019; Janbek 2019; Lynch 2018; Means 2020; Oh 2020; Peña‐Rosas 2012; Peña‐Rosas 2015; WHO 2011; WHO 2012), including maternal mortality (Means 2020), preterm birth (Athe 2020; Means 2020; Peña‐Rosas 2015), neonatal and infant mortality (Means 2020), low birthweight (< 2500 g) (Anand 2014; Athe 2020; Brabin 2001; Daru 2018; Geelhoed 2006; Iqbal 2019; Lone 2004; Means 2020; Oh 2020; Peña‐Rosas 2015; Rahman 2016; Rahman 2020), and lower infant iron status (Bothwell 1981; Shukla 2019). Iron deficiency has been associated with impaired neurodevelopment (Iglesias 2018; Janbek 2019), and deficits in cognitive function in childhood (Black 2011; Congdon 2012; Lozoff 2006; McClung 2013; Murray‐Kolb 2007; Pivina 2019; Santos 2018; Wenger 2017) and reduced physical work capacity in adulthood (Blakstad 2020; Haas 2001; McClung 2013).

Anaemia and lower haemoglobin concentrations have been associated with an increased risk of adverse pregnancy outcomes. The lowest rates of low birthweight and premature birth appear to occur when maternal haemoglobin levels are between 95 and 105 g/L during the second trimester of gestation (Murphy 1986; Steer 2000), and between 95 and 125 g/L at term (Hytten 1964; Hytten 1971). However, findings from several studies suggest that near‐term haemoglobin levels below 95 g/L or even below 110 g/L may be associated with low birthweight, heavier placentas, and increased frequency of premature births (Bukhari 2022; Carpenter 2022; Detlefs 2022; Jessani 2021; Mitsuda 2020; Parks 2019). There is evidence that maternal haemoglobin levels below 95 g/L before or during the second trimester of gestation are associated with an increased risk of premature delivery and low birthweight (Burke 2014). During pregnancy, low haemoglobin levels, indicative of moderate (70 to 90 g/L) or severe (< 70 g/L) anaemia, are associated with increased risk of maternal and infant mortality and infectious diseases (INACG 2002b). It is estimated that infants born to women with anaemia have less than one‐half of normal iron reserves (Bothwell 1981). For example, infants born to women with anaemia had lower mean haemoglobin and ferritin levels at birth and 14 weeks of life compared to women without anaemia (Shukla 2019).

Delayed umbilical cord clamping (one to three minutes) has been shown to improve infant iron reserves (Busarira 2019; Kc 2017; McDonald 2013; Rabe 2012), and is recommended to prevent maternal postpartum haemorrhage (WHO 2012b) and other perinatal outcomes (WHO 2014b). However, the timing between birth and umbilical cord clamping has not been considered in the estimates of the impact of maternal iron status and anaemia on infant iron reserves.

Higher haemoglobin concentrations during early and late gestation have also been associated with increased risk of adverse maternal and infant outcomes in observational studies, including gestational diabetes mellitus, pre‐eclampsia, preterm birth, low birthweight, small for gestational age, and fetal death (Burden 2023). Findings from systematic reviews (Dewey 2017; Young 2023), population‐based cohort studies (Ali 2020; Carpenter 2022; Mitsuda 2020; Ohuma 2023; Sun 2021; Wang 2018; Wu 2022), and secondary analyses of a cluster‐randomised trial (Liu 2022) have suggested a U‐shaped association between maternal haemoglobin concentrations and adverse pregnancy outcomes for both low (< 110 g/L) and high (≥ 130 g/L) haemoglobin concentrations during pregnancy.

Findings from observational studies have indicated that in pregnant women receiving iron supplementation (and particularly, women with anaemia early in pregnancy), a failure of haemoglobin and/or ferritin levels to decline during the second and third trimesters (i.e. blood volume expansion) and high ferritin levels during pregnancy (not due to infection) are associated with adverse pregnancy outcomes (Bukhari 2022; Jessani 2021; Kohli 2021; Ray 2020). However, in these observational studies, biomarkers of iron status were not adjusted for inflammation, which constrains interpretation of findings.

Description of the intervention

Iron requirements increase during pregnancy from approximately 18 mg/day prior to conception to 27 mg/day during gestation (Sangkhae 2023). The Institute of Medicine (now National Academy of Medicine) in the United States recommends that women consume 27 mg of iron per day during pregnancy (IOM 2001).

Iron supplementation (30 to 60 mg of elemental iron) is currently recommended during pregnancy for prevention of anaemia, along with 400 μg of folic acid for prevention of anaemia and neural tube defects (Haider 2017; WHO 2015; WHO 2016a). In settings where the prevalence of anaemia is high (i.e. > 40%, severe public health problem), 60 mg of elemental iron daily is recommended during pregnancy. If a woman is diagnosed with anaemia during pregnancy, a higher dose of iron (120 mg of elemental iron) is recommended along with folic acid (400 μg or 0.4 mg) supplementation until haemoglobin concentrations rise to normal levels (WHO 2012a). Data from national surveys (2006 to 2012) conducted in 22 countries (162,958 women) estimated that 81% of women had received iron and folic acid tablets during pregnancy, and adherence was low (Sununtnasuk 2016). Daily iron and folic acid supplementation is currently recommended by the World Health Organization as part of standard of care (WHO 2020b). There is also some evidence that iron supplementation in combination with other vitamins and minerals may be associated with improved infant health outcomes (Ballestín 2021;Keats 2019;Oh 2020).

Daily iron and folic acid supplementation is currently recommended by WHO as part of antenatal care. The recommended dose of 60 mg of elemental iron was established based on estimated iron requirements for women during pregnancy (WHO 1959). Folic acid supplementation (400 μg (0.4 mg) per day) is recommended based on the demonstrated benefits of periconceptional folic acid in prevention of risk and recurrence of neural tube defects (INACG 1998). The 400 µg daily dose of folic acid was recommended to continue beyond the first trimester of pregnancy (i.e. the window for prevention of neural tube defects, which occur in the first 28 days from conception), to provide a safe and healthy intake for women during pregnancy and lactation, although a dose of more than 400 µg folic acid was likely required to produce an optimal haemoglobin response in pregnancy (INACG 1998).

The tolerable upper limit for iron during pregnancy of 45 mg/day of iron was set by the Institute of Medicine (now National Academy of Medicine) in the United States based on gastrointestinal symptoms such as nausea and constipation (IOM 2001). High‐dose iron supplements are commonly associated with gastrointestinal effects including nausea, vomiting, constipation, and diarrhoea, with frequency and severity varying according to the amount of elemental iron released in the stomach (Tolkien 2015). This tolerable upper limit for iron established by the Institute of Medicine in the United States is considerably lower than the dose of 60 mg of elemental iron recommended internationally (IOM 2001). In the United States, preventive iron supplementation involves smaller daily iron doses (i.e. 30 mg/day), but therapeutic doses of up to 120 mg of elemental iron daily are recommended for treatment of anaemia (CDC 1998). However, recommendations for iron supplementation in other countries vary: for example, in the United Kingdom, the British Committee for Standards in Haematology does not recommend routine iron supplementation for all women in pregnancy (BCSH 2019; Pavord 2019).

How the intervention might work

Iron supplementation in pregnancy is aimed at prevention of anaemia and improving maternal iron status and maternal and infant outcomes (Keats 2021). Iron is essential for growth, development, and cellular metabolism (Ganz 2013), due to its role in DNA synthesis, and metabolic processes involved in oxygen transport (Abbaspour 2014). Iron requirements during pregnancy are increased to support maternal metabolism, placental development, and transport of iron to the growing fetus, and enhanced erythropoiesis in response to an increased maternal red blood cell mass and plasma volume in pregnancy (Fisher 2017; Georgieff 2020). Evidence from laboratory and observational studies suggest that lower iron status in pregnancy is associated with adverse pregnancy outcomes (Nemeth 2021; Sangkhae 2020; Young 2023). In addition to prevention of anaemia and iron deficiency, iron supplementation during pregnancy (alone or in combination with folic acid or with other vitamins and minerals) may also confer longer‐term benefits for maternal and child health outcomes (Carine 2012; Kawai 2011; Keats 2019; Keats 2021).

Why it is important to do this review

Several studies have been conducted to evaluate the efficacy of prenatal iron supplementation on maternal haematological status, and demonstrated that iron supplementation, with or without folic acid during pregnancy, helps improve maternal iron status, and reduces the risk of anaemia in late pregnancy, at delivery, and six weeks postpartum (Bumrungpert 2022; Fawzi 2010; Næss‐Andresen 2023). Iron and folic acid supplementation during pregnancy has also been associated with reduced risk of adverse pregnancy outcomes in observational studies, including stillbirth, preterm birth, very preterm birth, neonatal death, low birthweight, and very low birthweight (Caniglia 2022). Data from secondary analyses of randomised trials also indicated that iron supplementation with or without folic acid may reduce the risk of low birthweight (Passerini 2012), and improve infant developmental outcomes (Zhu 2023), compared to no iron (or no iron + folic acid).

Evidence from public health programmes and other observational studies suggest that the effectiveness of iron supplementation interventions may be more limited (Beaton 2000). This has been attributed to constrained infrastructure and low adherence (Fouelifack 2019; Gonzalez‐Casanova 2017), although recent studies have focused on improving coverage of antenatal iron and folic acid supplementation in resource‐limited settings (Koné 2023; Saragih 2022). The evaluation of the efficacy, safety, and effectiveness of iron (or iron + folic acid) supplementation during pregnancy has primarily focused on maternal haemoglobin concentrations (Garcia‐Casal 2023; Georgieff 2019); the evaluation of other maternal, pregnancy, or infant health outcomes has been more limited. Additionally, the safety and efficacy of iron (and folic acid) supplementation is important to evaluate in the context of malaria (NIH 2011), as approximately half of the world's population is at risk of malaria (247 million estimated cases of malaria), and malaria is currently endemic in 84 countries (WHO 2022).

This review updates previous Cochrane reviews on iron supplementation in pregnancy (Peña‐Rosas 2012; Peña‐Rosas 2015), which clearly demonstrated improvements in maternal haematological parameters, and evaluates the issues related to dose and the efficacy and safety of daily iron supplementation during pregnancy on maternal and infant outcomes.

The present review is not only an update since the previous review was published in 2015, but it is also part of a pilot project assessing Cochrane Pregnancy and Childbirth’s screening tool for scientific integrity/trustworthiness (Alfirevic 2023). This trustworthiness screening was implemented to ensure that high‐quality, relevant, and accessible systematic reviews are produced in response to the increase in the number of publications from untrustworthy and potentially fraudulent trials. This is important as these reviews are used for evidence‐informed health decision‐making for pregnant women and their infants. The use of this trustworthiness screening resulted in the removal of 10 trials from the previous version of the review. As a result of the update from 2015, a total of six trials that were included also passed the trustworthiness screening.

The effects of supplementation with iron and vitamin A during pregnancy (McCauley 2015; Van den Broek 2010) and the effectiveness of different iron treatments for anaemia amongst pregnant women in clinical practice (Reveiz 2011) are covered in other Cochrane reviews. The effects and safety of periconceptional folic acid supplementation for preventing birth defects (De‐Regil 2010; De‐Regil 2015), the effectiveness of oral folic acid supplementation alone during pregnancy on haematological and biochemical parameters during pregnancy and on pregnancy outcomes (Lassi 2013), and the effects of multiple vitamin and mineral supplements during pregnancy have also been reviewed elsewhere (Haider 2012; Haider 2017; Keats 2019; Ramakrishnan 2013). A separate Cochrane review addresses the efficacy of intermittent iron and folic acid supplementation regimens for women during pregnancy (Peña‐Rosas 2015a).

Objectives

To examine the effects of daily oral iron supplementation during pregnancy, either alone or in combination with folic acid (or with other vitamins and minerals), as an intervention in antenatal care.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised, cluster‐randomised, and quasi‐randomised trials (i.e. where the intervention was allocated by a predictable method such as date of birth, medical record number, or alternation) comparing the effects of daily oral prenatal supplements of iron, or iron + folic acid or iron + other vitamins and minerals supplements amongst pregnant women.

We excluded studies that assessed the effects of multiple combinations of vitamins and minerals, except studies that examined the 'additional effect' of iron or iron + folic acid supplements, i.e. when women in all arms of the trial were provided with the same micronutrient supplements (except iron or iron + folic acid).

We have not reviewed the effects of supplementation with multiple micronutrients containing iron or iron + folic acid in comparison to supplementation with iron or iron + folic acid or in comparison to placebo or no treatment. We have excluded studies dealing specifically with iron supplementation as a medical treatment. We also excluded trials addressing the effects of intermittent (i.e. weekly, twice‐weekly) iron supplementation regimens in comparison to daily supplementation regimens.

Types of participants

Pregnant women of any gestational age and parity. We included studies that provided iron supplementation to women during pregnancy. Studies that provided iron supplementation to women of reproductive age (preconception) and to women and their offspring were considered for inclusion, provided that women were also administered iron supplementation during pregnancy; if study authors reported stratified outcomes for pregnant women, we extracted data for pregnant women only.

Types of interventions

We have included a range of interventions providing daily oral supplementation (e.g. tablets, capsules) containing iron alone, iron + folic acid or iron + other vitamins and minerals.

The oral supplement forms include tablets or capsules (WHO 2008). Tablets (soluble tablets, effervescent tablets, tablets for use in the mouth, and modified‐release tablets) are solid dosage forms containing one or more active ingredients. They are obtained by single or multiple compression (in certain cases they are moulded) and may be coated or uncoated. Capsules are solid dosage forms with hard or soft shells, various shapes and sizes, that contain a single dose of one or more active ingredients. Capsules may be hard, soft, and modified‐release and are generally intended for oral administration.

Where data were available we planned to compare the following:

1. Any supplements containing iron versus the same supplements without iron or no treatment/placebo (no iron or placebo).

2. Any supplements containing iron and folic acid versus the same supplements without iron or folic acid (no iron + folic acid or placebo).

3. Supplementation with iron alone versus no treatment/placebo.

4. Supplementation with iron + folic acid versus no treatment/placebo.

5. Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation.

6. Supplementation with iron + other vitamins and minerals supplementation versus the same other vitamins and minerals (without iron) supplementation.

7. Supplementation with iron + folic acid + other vitamins and minerals versus folic acid + the same other vitamins and minerals (without iron) supplementation.

8. Supplementation with iron + folic acid + other vitamins and minerals versus the same other vitamins and minerals (without iron + folic acid) supplementation.

Comparisons 3, 5, 6, and 7 are summarised in comparison 1. Comparisons 4 and 8 are summarised in comparison 2. Comparisons 1 and 2 are used in the summary of findings tables; we have produced separate tables for infant and maternal outcomes (Table 2; Table 1; Table 4; Table 3).

Interventions that combined daily oral iron or iron + folic acid supplementation with co‐interventions such as education or other approaches were included, only if the other co‐interventions were the same in both the intervention and comparison groups. Studies examining supplemental iron alone or vitamins and minerals provided from supplementary food‐based interventions (i.e. interventions with multiple micronutrient powders, lipid‐based supplements, fortified complementary foods, and other fortified foods) were excluded. Likewise, regimens providing iron supplements in intermittent regimens were excluded from this review.

Types of outcome measures

Maternal perinatal and postpartum clinical and laboratory outcomes and infant clinical and laboratory outcomes are described below.

Primary outcomes

Maternal

1. Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more).

2. Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more).

3. Maternal iron‐deficiency anaemia at term (as defined by trialists at 37 weeks' gestation or more).

4. Maternal death (death while pregnant or within 42 days of termination of pregnancy).

5. Adverse effects (any reported throughout the intervention period)*.

6. Severe anaemia at any time during second or third trimester (Hb less than 70 g/L).

7. Clinical malaria (as defined by trialists).

8. Infection during pregnancy (including urinary tract infections and others as specified by trialists).

Infant

1. Low birthweight (less than 2500 g).

2. Birthweight (g).

3. Preterm birth (less than 37 weeks' gestation).

4. Neonatal death (within 28 days after delivery).

5. Congenital anomalies, including neural tube defects (as defined by trialists).

Secondary outcomes

Maternal

1. Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more).

2. Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more).

3. Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more).

4. Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more).

5. Maternal Hb concentration within six weeks postpartum (in g/L).

6. Maternal high Hb concentrations at any time during second or third trimester (defined as Hb greater than 130 g/L).

7. Maternal high Hb concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more).

8. Moderate anaemia at postpartum (Hb between 80 and 109 g/L).

9. Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more).

10. Severe anaemia postpartum (Hb less than 80 g/L).

11. Puerperal infection (as defined by trialists).

12. Antepartum haemorrhage (as defined by trialists).

13. Postpartum haemorrhage (intrapartum and postnatal, as defined by trialists).

14. Transfusion given (as defined by trialists).

15. Diarrhoea (as defined by trialists).

16. Constipation (as defined by trialists).

17. Nausea (as defined by trialists).

18. Heartburn (as defined by trialists).

19. Vomiting (as defined by trialists).

20. Maternal well‐being/satisfaction (as defined by trialists).

21. Placental abruption (as defined by trialists).

22. Premature rupture of membranes (as defined by trialists).

23. Pre‐eclampsia (as defined by trialists).

Infant

1. Very low birthweight (less than 1500 g).

2. Very premature birth (less than 34 weeks' gestation).

3. Hb concentration in the first six months (in g/L, counting the last reported measure after birth within this period).

4. Ferritin concentration in the first six months (in μg/L, counting the last reported measure after birth within this period).

5. Development and motor skills (as defined by trialists).

6. Admission to a special care unit.

*For trials reporting individual adverse effects separately but not specifying the number of women reporting any adverse effects, for our primary outcome, we selected the adverse effect with the greatest number of women (in the intervention and control groups combined) reporting that particular problem. We did this to avoid double counting any individuals reporting more than one adverse effect.

Search methods for identification of studies

The following methods section of this review is based on a standard template used by Cochrane Pregnancy and Childbirth.

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Trials Register on 18 January 2024.

The Cochrane Pregnancy and Childbirth Trials Register is a database containing over 34,000 reports of controlled trials in the field of pregnancy and childbirth. It represents the contemporary results of over 30 years of searching, including handsearched journals and conference proceedings, and journals reviewed via a current awareness service. For the detailed search strategies used to populate Cochrane Pregnancy and Childbirth's Trials Register for the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and CINAHL, see Appendix 1; Appendix 2; Appendix 3; Appendix 4.

Briefly, Cochrane Pregnancy and Childbirth’s Trials Register was maintained by their Information Specialist and contains trials identified from the following.

• Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL). CENTRAL contains Cochrane's centralised searches of PubMed, Embase, CINAHL, ClinicalTrials.gov, and WHO's International Clinical Trials Registry Platform (ICTRP).

• Weekly searches of MEDLINE (Ovid).

• Weekly searches of Embase (Ovid).

• Monthly searches of CINAHL (EBSCO).

• Regular scanning of 30 journals and the proceedings of major conferences.

• Weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Search results are screened and the full text of all relevant trial reports identified through the search activities described above is reviewed. Based on the intervention described, each trial report is assigned a number that corresponds to a specific Pregnancy and Childbirth review topic (or topics), and is then added to the Register. The Information Specialist searches the Register for each review using this topic number rather than keywords. This results in a more specific search set that has been fully accounted for in the relevant review sections (Included, Excluded, Awaiting Classification, or Ongoing).

In addition, we searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (18 January 2024) for unpublished, planned, and ongoing trial reports using the search methods detailed in Appendix 5.

We did not apply any language or date restrictions.

Searching other resources

We searched the reference lists of retrieved studies.

Data collection and analysis

For methods used when assessing trials identified in previous versions of this review, see Peña‐Rosas 2015 and Peña‐Rosas 2012.

For this review update, we used the following methods when assessing the trials identified by the updated search. These methods are based on a standard template used by Cochrane Pregnancy and Childbirth.

Selection of studies

Two review authors (AC, JW) independently assessed for inclusion all the references identified through the search. All records were evaluated in duplicate, and we resolved any disagreements through discussion and consultation with the senior author. For studies that were published only as abstracts or study reports that contained little information on methods, we attempted to contact the authors to obtain further details of study design and results. We were able to screen all the potentially eligible studies. We created a study flow diagram to map out the number of records identified, included, and excluded (Figure 1).

1.

Study flow diagram.

Screening eligible studies for scientific integrity/trustworthiness

The Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool had four criteria, or domains, at the time of our screening process (Alfirevic 2023). These were on governance, baseline data, feasibility, and results. We refined the tool by developing its list of questions for each criterion, to facilitate the screening process, and to allow for historical changes in the expectations for research methods. All studies meeting our inclusion criteria were evaluated by at least two authors using the tool (consulting another author in cases where the decision was not immediately clear) to select studies that, based on available information, were deemed to be sufficiently trustworthy to be included in the analysis. Data from abstracts were only included if, in addition to the trustworthiness assessment, the study authors confirmed in writing that the data to be included in the review came from the final analysis and would not change. If such information was not available or provided, the study remained in ‘Awaiting classification’. The detailed criteria are described below and in Figure 2.

2.

Process for using the Cochrane Pregnancy and Childbirth criteria for assessing the trustworthiness of a study (Produced with permission from the Cochrane Pregnancy and Childbirth Group)

1. Research governance: Are there any retraction notices or expressions of concern listed on the Retraction Watch Database relating to this study? Was the study prospectively registered (for those studies submitted during or after 2010)? And have the authors provided a plausible reason? Did the trial authors provide/share the protocol and/or ethics approval letter? For the authors that were reached out to, did they engage in communication with Cochrane Pregnancy and Childbirth within the agreed timelines? Did the trial authors provide IPD data? If not, was there a plausible reason?

2. Baseline characteristics: Is the study free from characteristics of the study participants that appear too similar, e.g. the distribution of the mean (SD) excessively narrow or excessively wide, as noted by Carlisle 2017?

3. Feasibility: Is the study free from characteristics that could be implausible (e.g. large numbers of women with a rare condition recruited from a single centre within 12 months)? In cases with (close to) zero losses to follow‐up, is there a plausible explanation?

4. Results: Is the study free from results that could be implausible? (e.g. massive risk reduction for main outcomes with small sample size, evidence of copying). Compared with other studies in the review, is the study free from very different results? (e.g. huge benefits with no complications or side effects, but others show that the benefits are not so pronounced and there are complications)

5. Cases of insufficient data: Data from abstracts or posters were only included if, in addition to the trustworthiness assessment, the study authors confirmed in writing that the data to be included in the review came from the final analysis and would not change.

6. Allowing for historical changes in methodological/reporting expectations: Studies submitted before 1990 were judged to have passed the trustworthiness criteria even if study dates, ethics approval, a clear description of randomisation and blinding process, and dropout rates were not explicitly stated. For studies submitted before 2010, mention of the trial registration was not required and either the study dates or the ethics/consent information could be missing from the write‐up. For studies submitted before 1980, we did not try to contact the authors because of the age of the publications and the age of the authors; rather, trustworthiness/GRADE decisions were made on what information was available in the public domain.

Data extraction and management

Four review authors (AC, JW, SV, DYL) independently extracted data from eligible studies. We designed a form to facilitate the process of data extraction and to request additional (unpublished) information from the authors of the original reports. We resolved any disagreements amongst us by discussion, and consultation with the senior author, if necessary, and we sought clarification from the authors of the original reports. We extracted data relating to the setting and cadre from all the included studies, specifying whether the intervention was reported as being done by a physician, obstetrician, lay health worker, birthing specialist, dietitian, or a combination of health professionals. We also extracted the type of healthcare facility and the geographical location of the intervention, when this information was available.

We entered data into Review Manager Web (RevMan 2024) and checked for accuracy.

Assessment of risk of bias in included studies

Four review authors (AC, JW, SV, DYL) independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion and consultation with the senior author.

(1) Sequence generation (checking for possible selection bias)

We have described for each included study the method used to generate the allocation sequence. We assessed the method as:

• low risk of bias (any truly random process, e.g. random number table; computer random number generator);

• high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);

• unclear.

(2) Allocation concealment (checking for possible selection bias)

We have described for each included study the method used to conceal the allocation sequence and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

• low risk of bias (e.g. telephone or central randomisation; consecutively numbered, sealed, opaque envelopes);

• high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);

• unclear.

(3.1) Blinding of participants and personnel (checking for possible performance)

We have described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. For this type of intervention, where different regimens were compared, it would be theoretically possible to blind study participants and staff by providing both active and placebo tablets to women allocated to intermittent regimens and placebo tablets to women in no supplementation arms of trials.

Blinding was assessed separately for different outcomes or classes of outcomes, and we have noted where there was partial blinding.

We assessed the methods as:

• low, high, or unclear risk of bias for participants;

• low, high, or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We have described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods used for blinding outcome assessment as:

• low, high, or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We assessed lost to follow‐up and post‐randomisation exclusions systematically for each trial.

We have described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We have noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition and exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. We assessed the methods as:

• low risk of bias;

• high risk of bias; or

• unclear.

We considered follow‐up to be adequate if more than 80% of participants initially randomised in a trial were included in the analysis and any loss was balanced across groups, unclear if the percentage of initially randomised participants included in the analysis was unclear, and inadequate if less than 80% of those initially randomised were included in the analysis or if loss was imbalanced in different treatment groups.

(5) Selective reporting bias

We have described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

• low risk of bias (where it is clear that all the study’s pre‐specified outcomes and all expected outcomes of interest in the review had been reported);

• high risk of bias (where not all the study’s pre‐specified outcomes had been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest were reported incompletely and so could not be used; the study failed to include results of a key outcome that would have been expected to have been reported);

• unclear.

(6) Other sources of bias

For cluster‐randomised trials, we considered additional criteria for possible sources of bias, i.e. recruitment to the trial after randomisation of clusters (recruitment bias), incomparability of baseline characteristics amongst clusters (baseline imbalance), loss of complete clusters, exclusion of clusters from analyses, or missing outcomes for individuals within clusters (loss of clusters), inappropriate analyses to adjust for clustering (incorrect analysis), or possible differential intervention effect estimates in individually randomised compared to cluster‐randomised trials (comparability with individually randomised trials).

We assessed whether each study was free of other problems that could put it at risk of bias. We have noted for each included study any important concerns we had about other possible sources of bias.

We assessed whether each study was free of other problems that could put it at risk of bias:

• low risk of further bias;

• high risk of further bias;

• unclear whether there is a risk of further bias.

(7) Overall risk of bias

We have made explicit judgements about whether studies are at high risk of bias, according to the criteria given in the CochraneHandbook (Higgins 2011) and, for primary outcomes, have explored the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis.

Measures of treatment effect

For dichotomous data, we present results as a summary risk ratio (RR) with 95% confidence interval (CI).

For continuous data, we have used the mean difference (MD) if outcomes were measured in the same way between trials. We planned to use the standardised mean difference (SMD) to combine trials measuring the same outcome, but using different scales or methods.

Unit of analysis issues

Cluster‐randomised trials

We included cluster‐randomised trials in the analyses along with individually randomised trials. Cluster‐randomised trials are labelled with a (C). Where possible, we estimated the intra cluster correlation coefficient (ICC) from trials' original data sets and reported the design effect. On the basis of this information we used the methods set out in the CochraneHandbook to calculate the adjusted sample sizes (Higgins 2011).

We included four cluster‐randomised trials (Christian 2003 (C); Hoa 2005 (C); Menendez 1994 (C); Zeng 2008 (C)). One of these trials did not contribute data to the analysis (Hoa 2005 (C)). For the remaining three cluster‐randomised trials (Christian 2003 (C); Menendez 1994 (C); Zeng 2008 (C)), data have been adjusted to take account of the design effect. In the study by Christian 2003 (C), adjusted data were provided by the author using outcome‐specific ICCs. For the Zeng 2008 (C) trial, we adjusted the published results and calculated an effective sample size by dividing figures by the design effect calculated using the ICC for the trial’s primary outcome: birthweight ICC = 0.03. We used the same sample adjustment for all outcomes. We used the same method for the Menendez 1994 (C) trial. However, in this case there was insufficient information in the study reports to allow us to calculate the design effect, and so we estimated it using the ICC for Hb at term (ICC = 0.03) reported in another study with similar average cluster sizes (Winichagoon 2003). We used this same ICC for all outcomes.

Where we have identified both cluster‐randomised trials and individually randomised trials reporting data for the same outcome, we considered that it was reasonable to combine the results from both if there was little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit was considered to be unlikely.

Cross‐over trials

Cross‐over trials were not included.

Studies with more than one intervention group

When studies were identified with more than two intervention groups (i.e. multi‐arm studies), where possible, we combined groups to create a single pair‐wise comparison and used the methods described in the Cochrane Handbook to avoid double‐counting study participants (Higgins 2023). For subgroup analyses, when the control group was shared by two or more study arms, we planned to divide the control group (i.e. events and total population) over the number of relevant subgroups to avoid double‐counting participants. The studies included in this review had only two treatment groups (i.e. one intervention arm and one comparison group) that met the criteria for inclusion in this review. We reported detailed information on included pair‐wise groups in the Characteristics of included studies tables.

Dealing with missing data

For the included studies, we noted levels of attrition in the Characteristics of included studies tables. We explored the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

When possible, we conducted an available case analysis and reinstated previously excluded cases, i.e. we attempted to include all participants randomised to each group in the analyses. The denominator for each outcome in each trial is the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We examined the forest plots for the analyses visually to assess any obvious heterogeneity in terms of the size or direction of treatment effect between studies. We used I² and Tau² statistics, and the P value of the Chi² test for heterogeneity to quantify heterogeneity amongst the trials in each analysis. The I² statistic quantifies inconsistencies and describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance).

Assessment of reporting biases

For our primary outcomes, we investigated publication bias on outcomes in more than 10 trials by examining the funnel plots for signs of asymmetry, although we gave consideration to reasons other than publication bias that could explain the asymmetry, when present.

Data synthesis

We carried out statistical analysis using Review Manager Web (RevMan 2024).

We anticipated high heterogeneity amongst trials. We pooled trial results using a random‐effects model and were cautious in our interpretation of the pooled results. We have indicated in the text that the random‐effects model gives the average treatment effect. For statistically significant results where there are high levels of heterogeneity (I² greater than 50%), we have given the values of I², Tau², and the P value of the Chi² test for heterogeneity and have provided an estimate of the 95% range of underlying intervention effects (prediction interval (PI)).

Subgroup analysis and investigation of heterogeneity

Where more than one trial was included in a comparison, we conducted both overall analysis of the effects of various supplementation regimens on primary outcomes and subgroup analysis on the primary outcomes based on the following criteria:

1. by gestational age: early, if supplementation started before 20 weeks' gestation or prior to pregnancy; late if supplementation started at 20 weeks of gestation or later; or, unspecified or mixed gestational ages at the start of supplementation;

2. by anaemic status at start of intervention: anaemic when Hb below 110 g/L during first and third trimesters or below 105 g/L in second trimester; non‐anaemic if Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester; or unspecified/mixed anaemic status;

3. by dose of iron: ≤ 30 mg; > 30 mg to < 60 mg; and ≥ 60 mg of elemental iron;

4. by type of formulation: slow release iron supplement (as defined by trialists) or normal release iron supplement/not specified;

5. by iron compound bioavailability in comparison to ferrous sulphate: higher bioavailability: NaFeEDTA; equivalent or lower relative bioavailability: ferrous sulphate, ferrous fumarate, ferrous gluconate; other/not specified;

6. by malaria risk setting: study carried out in malaria risk‐free countries or study carried out in countries with some malaria risk or explicitly described as a malaria risk study site.

In the subgroup analyses, we provided totals and subtotals and assessed subgroup differences by using the interaction tests available in Review Manager (RevMan 2024). Where there was evidence of a difference between subgroups, we have reported this in the text and presented the results for the subgroup analyses quoting the Chi² statistic and P value, and the interaction I² value. However, for some outcomes, few studies contributed data, and for some outcomes, all the trials were in the same subgroup. As more data become available, in updates of the review, we will explore possible subgroup differences as a means of exploring heterogeneity.

Sensitivity analysis

In previous versions of the review for primary outcomes, we conducted sensitivity analysis based on the risk of bias. We considered a study to be of high quality if it was assessed as low risk of bias in both the randomisation and allocation concealment and in either blinding or loss to follow‐up. In this updated version of the review, for our main comparisons (comparisons 1 and 2) for primary outcomes, we have now graded the overall certainty of the evidence (taking into account risk or bias, heterogeneity, imprecision of findings and possible publication bias); we considered that this would give a better indication of the overall certainty of evidence at the outcome level. The certainty of the evidence is noted both in the text (Effects of interventions) and in tables (Table 1; Table 2; Table 3; Table 4).

For comparisons 3 onwards, we conducted planned sensitivity analysis because for these comparisons the overall certainty of the evidence was not graded.

Summary of findings and assessment of the certainty of the evidence

For the assessment across studies, we used the GRADE approach to interpret findings (Langendam 2013) and the GRADE profiler (GRADEpro 2014) to import data from Review Manager (RevMan 2024) to create summary of findings (SoF) tables (set out in Table 1; Table 2; Table 3; Table 4). We listed the primary outcomes for each comparison with estimates of effects along with the number of participants and studies contributing data on those outcomes. These tables provide outcome‐specific information concerning the overall certainty of evidence from studies included in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on the outcomes we considered. Primary outcomes were included in the summary of findings tables, with the exception of infection during pregnancy, which was summarised in detail in the results section. For each individual outcome, two review authors independently assessed the certainty of the evidence using the GRADE approach (Balshem 2010).

For assessments of the overall certainty of evidence for each outcome that included pooled data from included trials, we downgraded the evidence from 'high certainty' by one level for serious (or by two for very serious) study limitations (risk of bias), indirectness of evidence, serious inconsistency, imprecision of effect estimates, or potential publication bias. This assessment was limited only to the trials included in this review; as we did not consider there was a serious risk of indirectness or publication bias, we did not downgrade in these domains.

Results

Description of studies

The results of the updated search for this review update are presented in the study flow chart (Figure 1). See Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies.

Results of the search

The updated search for this review was conducted on 18 January 2024. The Cochrane Pregnancy and Childbirth Trials Registry was searched and a total of 57 trials with 48,971 women were included; 194 trials (263 reports) were excluded. Six new trials were included in this review update (Bloxam 1989; Dawson 1989; Fawzi 2010; Li 2020; Parisi 2017; Zhao 2014). A total of 20 trials were assigned to awaiting classification (Akyol 2014; Alizadeh 2016; Corrigan 1936; CTRI/2016/10/007373 (first received 2016); Dixit 2023; Hamzehgardeshi 2009; Han 2011; Hankin 1963; Jafarbegloo 2010; Korkmaz 2014; Liu 2000; Ma 2010; NCT04101461 (first received 2019 Sep 24); NCT04810546 (first received 2021 Mar 23); NCT05423249 (first received 2022); Ouladsahebmadarek 2011; PACTR201804003188338 (first received 2018); Sun 2010; Ziaei 2007; Ziaei 2008), and we confirmed that one study from a trials registry is ongoing (ISRCTN16425597 2023). A total of 41 trials contributed quantitative data for the comparisons in this review.

We assessed a total of 115 new reports for eligibility from the updated search, and evaluated eight additional records that were identified in the previous review (Peña‐Rosas 2015), including seven ongoing trials and one study that was awaiting classification. We applied the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (CPC‐TST) to evaluate 61 trials from the previous version of the review, and 16 new trials identified in this review update (see Screening eligible studies for trustworthiness below for details).

Sixteen studies that were included as eligible trials did not contribute data on outcomes for this review (Butler 1967; Chanarin 1965; Dommisse 1983; Fenton 1977; Fleming 1974; Fleming 1985; Foulkes 1982; Freire 1989; Groner 1986; Hoa 2005 (C); Kuizon 1979; Li 2020; Simmons 1993; Suharno 1993; Svanberg 1975; Tholin 1993). These studies did not report data on the review's prespecified outcomes, or results were not reported in a manner that could be included in meta‐analyses (e.g. results for outcomes were not reported separately for randomised groups, or standard deviations or standard errors were not reported for continuous outcomes). In addition, two of these trials that were otherwise eligible for inclusion (Butler 1967; Kuizon 1979) had such high attrition (up to 80% for some outcomes) that they were excluded from previous meta‐analyses (Peña‐Rosas 2015), including in this review update. The included trials are described in detail in the Characteristics of included studies tables.

In addition to published papers, abstracts, and reports identified in the search, trial authors provided additional unpublished information for inclusion in this review, including: additional information on study design for clarification of risk of bias assessment and description of included studies (Cogswell 2003; Freire 1989; Harvey 2007; Siega‐Riz 2001; Zeng 2008 (C)), individual patient datasets for statistical analyses (Butler 1967; Eskeland 1997; Lee 2005), and additional re‐analysed data for inclusion in this review (Christian 2003 (C); Makrides 2003; Paintin 1966).

In meta‐analyses, we treated one study conducted collaboratively in two different sites (i.e. Rotterdam (Wallenburg 1983) and Antwerp (Buytaert 1983)) as two different trials. Some trials included more than two intervention arms and may be included in more than one comparison (Batu 1976; Charoenlarp 1988; Chisholm 1966; Christian 2003 (C); Willoughby 1967).

Screening eligible studies for trustworthiness

We applied the CPC‐TST to evaluate the 61 trials from the previous version of the review (Peña‐Rosas 2015) and 16 new trials from the review update.

Of the 61 trials that were included in the previous version of this review (Peña‐Rosas 2015), 51 trials met CPC‐TST criteria, and were included in this review update: 45 trials met the trustworthiness criteria on first assessment (Barton 1994; Batu 1976; Butler 1967; Buytaert 1983; Cantlie 1971; Chan 2009; Chanarin 1965; Chanarin 1971; Charoenlarp 1988; Chisholm 1966; De Benaze 1989; Dommisse 1983; Eskeland 1997; Fenton 1977; Fleming 1974; Fleming 1985; Foulkes 1982; Freire 1989; Groner 1986; Harvey 2007; Hoa 2005 (C); Holly 1955; Hood 1960; Kerr 1958; Kuizon 1979; Lee 2005; Meier 2003; Menendez 1994 (C); Paintin 1966; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983; Siega‐Riz 2001; Simmons 1993; Suharno 1993; Svanberg 1975; Taylor 1982; Tholin 1993; Tura 1989; Van Eijk 1978; Wallenburg 1983; Willoughby 1967; Wills 1947; Zeng 2008 (C)), and six studies met the criteria after communication with study authors (Christian 2003 (C); Cogswell 2003; Falahi 2010; Liu 2012; Makrides 2003; Milman 1991). A total of 10 trials were moved to 'Awaiting classification' (Corrigan 1936; Han 2011; Hankin 1963; Korkmaz 2014; Liu 2000; Ma 2010; Ouladsahebmadarek 2011; Sun 2010; Ziaei 2007; Ziaei 2008). Four of these trials did not meet CPC‐TST criteria (i.e. lack of registration information) and the authors did not respond to queries (Han 2011; Korkmaz 2014; Ma 2010; Sun 2010). Six trials did not meet CPC‐TST criteria (i.e. lack of information on ethics or consent of participants, no trial dates, baseline characteristics not provided, unclear randomisation methods, or no dropouts) and we were unable to contact the study authors (Corrigan 1936; Hankin 1963; Liu 2000; Ouladsahebmadarek 2011; Ziaei 2007; Ziaei 2008).

We applied the CPC‐TST to evaluate 16 new trials in this review update. A total of six new trials met CPC‐TST criteria and were included in this review (Bloxam 1989; Dawson 1989; Fawzi 2010; Li 2020; Parisi 2017; Zhao 2014). A total of 10 trials were included in 'Awaiting classification'. Five trials did not meet the trustworthiness criteria (i.e. inconsistency in number of participants reported in the trial registry compared to the published report, equal number of randomised participants in groups at baseline, unclear randomisation method, only abstract was available, no published papers were available) and the authors did not respond to queries (Akyol 2014; Alizadeh 2016; Dixit 2023; Hamzehgardeshi 2009; Jafarbegloo 2010). Five studies from trial registries were also identified and included under 'Awaiting classification' (i.e. no published papers) because we were unable to find contact information for study authors (CTRI/2016/10/007373 (first received 2016); NCT04101461 (first received 2019 Sep 24); NCT04810546 (first received 2021 Mar 23); NCT05423249 (first received 2022); PACTR201804003188338 (first received 2018)).

In total, 57 trials met CPC‐TST criteria, and 20 studies were categorised as 'Awaiting classification' in this review update.

Included studies

Settings

The trials included in the review were conducted beginning in 1947, in 27 countries across the globe. A total of 27 trials were conducted in Europe: 14 trials in the United Kingdom (Bloxam 1989; Butler 1967; Chanarin 1965; Chisholm 1966;.Chanarin 1971; Dawson 1989; Fenton 1977; Foulkes 1982; Harvey 2007; Kerr 1958; Paintin 1966; Taylor 1982; Willoughby 1967; Wills 1947), two trials in Norway (Eskeland 1997; Romslo 1983), one trial in Finland (Puolakka 1980), two trials in Sweden (Svanberg 1975; Tholin 1993), two trials in The Netherlands (Van Eijk 1978; Wallenburg 1983), two trials in Italy (Parisi 2017; Tura 1989), and one trial each in Denmark (Milman 1991), Ireland (Barton 1994), Belgium (Buytaert 1983), and France (De Benaze 1989).

A total of 11 trials were conducted in the Americas: eight trials were conducted in the United States of America (Cogswell 2003; Dawson 1989; Groner 1986; Holly 1955; Hood 1960; Meier 2003; Pritchard 1958; Siega‐Riz 2001), one in Canada (Cantlie 1971), one in Ecuador (Freire 1989), and one in Jamaica (Simmons 1993). Five trials were conducted in Africa, with one trial each in Tanzania (Fawzi 2010), South Africa (Dommisse 1983), Nigeria (Fleming 1985), the Gambia (Menendez 1994 (C)), and Niger (Preziosi 1997). One trial was conducted in Iran (Falahi 2010). Seven trials were conducted in Asia, including one trial each in Myanmar (Burma) (Batu 1976), Thailand (Charoenlarp 1988), Nepal (Christian 2003 (C)), Vietnam (Hoa 2005 (C)), the Philippines (Kuizon 1979), South Korea (Lee 2005), and Indonesia (Suharno 1993). Three trials were conducted in China (Li 2020; Zeng 2008 (C); Zhao 2014), and one trial was conducted in Hong Kong (Chan 2009). Two trials were conducted in Australia (Fleming 1974; Makrides 2003).

Most included trials were published between 1980 and 1989 (Bloxam 1989; Buytaert 1983; Charoenlarp 1988; Dawson 1989; De Benaze 1989; Dommisse 1983; Fleming 1985; Foulkes 1982; Freire 1989; Groner 1986; Puolakka 1980; Romslo 1983; Taylor 1982; Tura 1989; Wallenburg 1983) and 2000 to 2009 (Chan 2009; Christian 2003 (C); Cogswell 2003; Harvey 2007; Hoa 2005 (C); Lee 2005; Makrides 2003; Meier 2003; Siega‐Riz 2001; Zeng 2008 (C)). One trial was published in the 1940s (Wills 1947); three trials in the period 1950 to 1959 (Holly 1955; Kerr 1958; Pritchard 1958); and six trials between 1960 and 1969 (Butler 1967; Chanarin 1965; Chisholm 1966; Hood 1960; Paintin 1966; Willoughby 1967). A total of seven trials were published between 1970 and 1979 (Batu 1976; Cantlie 1971; Chanarin 1971; Fenton 1977; Fleming 1974; Kuizon 1979; Van Eijk 1978), 15 trials in the 1980s (Bloxam 1989; Buytaert 1983; Charoenlarp 1988; Dawson 1989; De Benaze 1989; Dommisse 1983; Fleming 1985; Foulkes 1982; Freire 1989; Groner 1986; Puolakka 1980; Romslo 1983; Taylor 1982; Tura 1989; Wallenburg 1983), eight trials between 1990 and 1999 (Barton 1994; Eskeland 1997; Menendez 1994 (C); Milman 1991; Preziosi 1997; Simmons 1993; Suharno 1993; Tholin 1993), 10 trials between 2000 and 2009 (Chan 2009; Christian 2003 (C); Cogswell 2003; Harvey 2007; Hoa 2005 (C); Lee 2005; Makrides 2003; Meier 2003; Siega‐Riz 2001; Zeng 2008 (C)), and six trials were published since 2010 (Falahi 2010; Fawzi 2010; Li 2020; Liu 2012; Parisi 2017; Zhao 2014).

In this review, malarial endemicity was defined based on the World Health Organization classification for the setting at the time that the studies were conducted (WHO 2014c; WHO 2011b; WHO 2022). A total of 19 trials were conducted in countries that were classified as malaria endemic (Batu 1976; Chan 2009; Charoenlarp 1988; Christian 2003 (C); Dommisse 1983; Falahi 2010; Fawzi 2010; Fleming 1985; Freire 1989; Hoa 2005 (C); Kuizon 1979; Lee 2005; Li 2020; Menendez 1994 (C); Preziosi 1997; Simmons 1993; Suharno 1993; Zeng 2008 (C); Zhao 2014). Three of these trials reported malaria‐related outcomes (Fawzi 2010; Fleming 1985; Menendez 1994 (C)). In many countries, malaria has a seasonal pattern (WHO 2022) and in some settings, malaria is present only in certain areas or below a specific altitude. Information on malaria was extracted for trials, including: malarial endemicity, seasonal variation, predominant malaria species, and available data for resistance to antimalarial medications at the time that trials were conducted (WHO 2014c; WHO 2011b; WHO 2022); this information is included in the Characteristics of included studies tables. A total of 18 trials were conducted in malaria‐endemic areas, and 38 trials were conducted in settings classified as not malaria‐endemic (WHO 2014c; WHO 2011b; WHO 2022).

Participants

A total of 24 trials were conducted amongst pregnant women who were not anaemic at the start of supplementation (Barton 1994; Bloxam 1989; Buytaert 1983; Cantlie 1971; Chisholm 1966; Cogswell 2003; Dawson 1989; De Benaze 1989; Eskeland 1997; Falahi 2010; Harvey 2007; Li 2020; Makrides 2003; Meier 2003; Liu 2012; Parisi 2017; Puolakka 1980; Romslo 1983; Siega‐Riz 2001; Svanberg 1975; Tholin 1993; Tura 1989; Wallenburg 1983; Zhao 2014). In the remaining trials, anaemia status of participants at enrolment was not reported or was not clearly described. In some studies, pregnant women with mild or moderate anaemia were eligible for inclusion, so the study samples were heterogeneous in terms of anaemia status at the start of supplementation. In some of these trials, women with severe anaemia were excluded (Batu 1976; Butler 1967; Chan 2009; Charoenlarp 1988; Fawzi 2010; Kerr 1958; Paintin 1966; Willoughby 1967). Two trials recruited women with mild or moderate anaemia (i.e. Hb ≥ 80 to < 110 g/L) (Simmons 1993; Suharno 1993), but these trials did not contribute data to meta‐analyses in this review.

Timing of supplementation was defined as early (i.e. prior to 20 weeks' gestation), later (i.e. at 20 weeks of gestation or later), or unspecified or heterogeneous at the start of supplementation. In most of the included trials, iron supplementation was initiated before 20 weeks' gestation and continued through delivery. In 12 trials, supplementation started at or after 20 weeks' gestation (Batu 1976; Chanarin 1965; Chisholm 1966; Eskeland 1997; Fleming 1974; Freire 1989; Hood 1960; Kerr 1958; Makrides 2003; Menendez 1994 (C); Paintin 1966; Preziosi 1997). In 12 trials, the timing for initiation of supplementation was not reported or was not clearly defined, or was heterogeneous (i.e. the study sample included participants who started taking supplements before or after 20 weeks' gestation) (Cantlie 1971; Charoenlarp 1988; Fawzi 2010; Fleming 1985; Holly 1955; Kuizon 1979; Lee 2005; Meier 2003; Pritchard 1958; Simmons 1993; Suharno 1993; Willoughby 1967).

Interventions

Daily iron dose

The daily dose of iron in the included trials ranged from 9 to 900 milligrams of elemental iron.

The daily doses of iron included in interventions were categorised as: ≤ 30 mg, > 30 mg to < 60 mg, and ≥ 60 mg of elemental iron. A total of 10 trials provided a dose of ≤ 30 mg of elemental iron daily, ranging from 9 mg to 30 mg of elemental iron per day: one trial provided 12 mg of elemental iron (Paintin 1966), one trial provided 18 mg elemental iron (Dawson 1989), one trial provided 20 mg of elemental iron (Makrides 2003), six trials provided 30 mg of elemental iron (Chanarin 1971; Cogswell 2003; Lee 2005; Parisi 2017; Siega‐Riz 2001; Zeng 2008 (C)), and one trial provided 9 mg of elemental iron daily to one intervention arm, and 27 mg to another arm (Eskeland 1997).

Three trials provided iron at doses of > 30 mg to < 60 mg of elemental iron per day, including: 40 mg of elemental iron (Tura 1989), 45 mg of elemental iron (De Benaze 1989), and 55 mg of elemental iron (Hood 1960) per day.

A total of 44 trials provided iron at a dose of ≥ 60 mg of elemental iron per day. Seventeen trials administered a dose of 60 mg elemental iron daily (Barton 1994; Batu 1976; Chan 2009; Christian 2003 (C); Falahi 2010; Fawzi 2010; Fenton 1977; Fleming 1974; Fleming 1985; Groner 1986; Hoa 2005 (C); Li 2020; Meier 2003; Menendez 1994 (C); Suharno 1993; Zeng 2008 (C); Zhao 2014).

A total of 27 trials provided iron at a dose of > 60 mg of elemental iron per day, ranging from 65 mg to 900 mg of elemental iron daily. The doses of elemental iron administered daily included: 65 mg (Kuizon 1979; Taylor 1982), 66 mg (Milman 1991), 78 mg (Cantlie 1971; Freire 1989), 80 mg (Wills 1947), 100 mg (Foulkes 1982; Harvey 2007; Preziosi 1997; Simmons 1993; Tholin 1993; Van Eijk 1978), 105 mg (Buytaert 1983; Kerr 1958; Paintin 1966; Wallenburg 1983; Willoughby 1967), 94 mg (Bloxam 1989), 112 mg (Pritchard 1958), 120 mg (Charoenlarp 1988; Dommisse 1983), 122 mg (Butler 1967), 200 mg (Puolakka 1980; Romslo 1983; Svanberg 1975), 220 mg (Hood 1960), 240 mg (Charoenlarp 1988), and 900 mg (Chisholm 1966) of elemental iron daily.

In addition, in one trial, intervention groups received 12 mg or 105 mg of elemental iron daily (Paintin 1966). One trial administered a dose of 1 g of iron salt daily (Holly 1955).

Folic acid dose

In trials that provided folic acid daily (in addition to iron supplementation), the dose of folic acid administered ranged from 10 μg to 5000 μg (5.0 mg) of folic acid per day. In nine of the included trials, the dose of folic acid administered ranged from 10 μg to 350 μg per day, including: 10 μg (Chanarin 1965), 30 μg (Chanarin 1965), 100 μg (Willoughby 1967), 175 μg (Lee 2005), 250 μg (Hoa 2005 (C)), 300 μg (Willoughby 1967), and 350 μg (Foulkes 1982; Lee 2005; Taylor 1982) of folic acid daily. In 20 of the included trials, the daily doses of folic acid provided to participants ranged from 400 μg (0.4 mg) to 5.0 mg, including: 400 μg (Christian 2003 (C); Dawson 1989; Simmons 1993; Zeng 2008 (C); Zhao 2014), 450 μg (Willoughby 1967), 500 μg (Chisholm 1966; Fleming 1974; Siega‐Riz 2001), 1000 μg (1.0 mg) (to some intervention groups) (Barton 1994; Batu 1976; Bloxam 1989; Fleming 1985; Meier 2003), 3400 μg (3.4 mg) (Butler 1967), and 5000 μg (5.0 mg) (Charoenlarp 1988; Chisholm 1966; Fawzi 2010; Fleming 1974; Menendez 1994 (C)) of folic acid daily.

Type of iron compounds

In five of the included trials, the iron supplements administered were slow or sustained release (Buytaert 1983; Hood 1960; Simmons 1993; Svanberg 1975; Wallenburg 1983); the other 51 included trials administered standard preparations of iron supplementation (e.g. ferrous sulphate or ferrous fumarate), or the type of preparation was not described.

In seven of the included trials, the type of iron compound administered was not reported, and was described in terms of dose of elemental iron provided daily (Barton 1994; Dawson 1989; Fleming 1985; Foulkes 1982; Makrides 2003; Paintin 1966; Zeng 2008 (C)).

In most of the included trials, iron supplements were administered as ferrous sulphate (34 trials) (Batu 1976; Bloxam 1989; Butler 1967; Buytaert 1983; Chan 2009; Charoenlarp 1988; Cogswell 2003; Dommisse 1983; Falahi 2010; Fawzi 2010; Fenton 1977; Fleming 1974; Freire 1989; Hoa 2005 (C); Holly 1955; Hood 1960; Kerr 1958; Kuizon 1979; Lee 2005; Li 2020; Meier 2003; Menendez 1994 (C); Parisi 2017; Puolakka 1980; Romslo 1983; Siega‐Riz 2001; Simmons 1993; Suharno 1993; Svanberg 1975; Taylor 1982; Tholin 1993; Van Eijk 1978; Wallenburg 1983; Zhao 2014) or ferrous fumarate (six trials) (Chanarin 1965; Chanarin 1971; Christian 2003 (C); Eskeland 1997; Groner 1986; Milman 1991). Ferrous iron was administered in one of the included trials (Cantlie 1971).

A total of 10 of the included studies used alternate higher bioavailability iron compounds, including: ferrous gluconate (five trials) (Chisholm 1966; Harvey 2007; Kerr 1958; Pritchard 1958; Wills 1947) and ferrous betainate hydrochloride (two trials) (De Benaze 1989; Preziosi 1997). Additional formulations included haem iron from porcine blood (Eskeland 1997), ferritin in a micro‐granulated gastric resistant capsule (Tura 1989), and chelated iron aminoates (Willoughby 1967).

Supervision and co‐interventions

In most of the included trials, supplements were provided to women without direct observation or supervision. In three of the trials, intake of the supplements was supervised in all or some of the intervention groups (Batu 1976; Charoenlarp 1988; Preziosi 1997). In one study, Christian 2003 (C), intake was not directly observed, but trial staff visited women twice each week to monitor supplement intake.

Some of the studies included co‐interventions in addition to the iron (or iron + folic acid) supplement. For example, in one trial (Cantlie 1971), participants in both intervention groups received one tablet containing vitamins and minerals daily (i.e. containing 2 mg copper citrate, 6 mg magnesium stearate, 0.3 mg manganese carbonate, 1000 IU vitamin A, 500 IU vitamin D, 130 mg bone flour, 1 mg vitamin B₁, 1 mg vitamin B₂, 50 mg brewer yeast concentrate, 5 mg niacinamide, 25 mg vitamin C, 0.2 mg sodium iodide, and 0.049 μg folate (naturally occurring)). In another trial (Christian 2003 (C)), all participants were offered vitamin A supplementation (1000 μg retinol equivalents) daily and antihelminthic medication (albendazole 400 mg as a single dose) during the second and third trimester of pregnancy.

In Fleming 1974, all participants received vitamin C supplementation (50 mg of ascorbic acid) daily from enrolment until 20 weeks of gestation. In Menendez 1994 (C), all pregnant women also received a weekly tablet of folic acid (5000 μg or 5.0 mg) beginning at 23 to 24 weeks' of gestation until delivery. In the study by Siega‐Riz 2001, folic acid supplements were prescribed for all women who received a positive pregnancy test until their first prenatal visit.

In Fleming 1985, participants in the intervention groups included in this review received intermittent preventive therapy (IPT) for malaria prophylaxis (i.e. 600 mg chloroquine as a single dose, followed by 100 mg proguanil per day). In the Fawzi 2010 trial, women received folic acid (5000 μg or 5.0 mg) supplementation daily, and malaria prophylaxis (i.e. 1500 mg sulfadoxine and 75 mg pyrimethamine) in the second and third trimesters. In one trial, all participating women received folic acid 400 µg/day before pregnancy and early in gestation (Li 2020).

Intervention settings and health worker cadre

In 52 of the included trials (91%), the intervention was delivered in hospitals or community‐based antenatal clinics, and administered by physicians or other healthcare professionals, including nurses, midwives, dietitians, or social workers. In five of the trials, the intervention was delivered by community health or village workers (Charoenlarp 1988; Christian 2003 (C); Hoa 2005 (C); Suharno 1993) or village‐based traditional birth attendants (Menendez 1994 (C)), administered in women's homes or in local settings in the community.

Comparisons

Comparison 1: A total of 40 trials contributed data to the overall comparison of daily iron supplementation compared to placebo or no iron (i.e. comparison of any daily oral supplements containing iron versus the same supplements without iron (or placebo or no supplementation)). This included data from 30 trials that compared the effects of daily iron supplementation to placebo or no iron supplements (Batu 1976; Buytaert 1983; Chan 2009; Chanarin 1971; Charoenlarp 1988; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Falahi 2010; Fawzi 2010; Harvey 2007; Holly 1955; Hood 1960; Kerr 1958; Makrides 2003; Meier 2003; Menendez 1994 (C); Milman 1991; Paintin 1966; Parisi 2017; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983; Tura 1989; Van Eijk 1978; Wallenburg 1983; Willoughby 1967; Wills 1947). Six studies contributed data to the comparison of daily iron + folic acid supplementation versus folic acid supplementation alone (without iron) (Batu 1976; Chisholm 1966; Christian 2003 (C); Liu 2012; Zeng 2008 (C); Zhao 2014). Additionally, one trial evaluated daily iron + folic acid supplementation compared to folic acid (without iron), along with vitamin A supplementation as co‐intervention in both arms (Christian 2003 (C)). Four of the included trials compared daily supplementation with iron + other vitamins and minerals versus vitamins and minerals alone (without iron) (Bloxam 1989; Cantlie 1971; Dawson 1989; Siega‐Riz 2001). No studies evaluated the effects of iron + folic acid + other vitamins and minerals, compared to folic acid + the same vitamins and minerals alone (without iron) supplementation. Some of the included trials contributed data from some intervention arms to different comparisons. Of the 40 trials that contributed data for this comparison, 14 trials were rated high quality, based on a priori criteria (Bloxam 1989; Buytaert 1983; Christian 2003 (C); Cogswell 2003; Eskeland 1997; Fawzi 2010; Harvey 2007; Liu 2012; Makrides 2003; Preziosi 1997; Siega‐Riz 2001; Tura 1989; Wallenburg 1983; Zeng 2008 (C)).

Comparison 2: A total of eight trials contributed data to the overall comparison of the effects of daily supplementation with iron + folic acid versus placebo or no iron + folic acid (i.e. comparison of any daily oral supplements containing iron + folic acid versus the same supplements without iron + folic acid or placebo or no supplementation). Eight trials compared the effects of daily iron + folic acid supplementation with no treatment (Barton 1994; Batu 1976; Charoenlarp 1988; Chisholm 1966; Christian 2003 (C); Lee 2005; Taylor 1982; Willoughby 1967). One of these trials included a comparison of daily iron + folic acid supplementation versus no treatment, with vitamin A supplementation and deworming administered as co‐interventions in both groups (Christian 2003 (C)). No trials compared daily supplementation with iron + folic acid + other vitamins and minerals versus the same supplements without iron + folic acid.

Comparison 3: A total of 30 trials compared the effects of daily iron supplementation (alone) to no iron or placebo (Batu 1976; Buytaert 1983; Chan 2009; Chanarin 1971; Charoenlarp 1988; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Falahi 2010; Fawzi 2010; Harvey 2007; Holly 1955; Hood 1960; Kerr 1958; Makrides 2003; Meier 2003; Menendez 1994 (C); Milman 1991; Paintin 1966; Parisi 2017; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983; Tura 1989; Van Eijk 1978; Wallenburg 1983; Willoughby 1967; Wills 1947). Of these, 11 trials met a priori criteria for high quality (Buytaert 1983; Chisholm 1966; Cogswell 2003; Christian 2003 (C); Eskeland 1997; Fawzi 2010; Harvey 2007; Makrides 2003; Preziosi 1997; Tura 1989; Wallenburg 1983).

Comparison 4: Eight trials compared the effects of daily iron + folic acid supplementation to no supplementation (Barton 1994; Batu 1976; Charoenlarp 1988; Chisholm 1966; Christian 2003 (C); Lee 2005; Taylor 1982; Willoughby 1967). Three of these trials were rated high quality, based on a priori criteria (Barton 1994; Chisholm 1966; Christian 2003 (C)). One study included intervention arms of daily iron + folic acid supplementation versus no supplementation, along with vitamin A supplementation and deworming as co‐interventions in both groups (Christian 2003 (C)).

Comparison 5: Six studies were conducted to evaluate daily iron + folic acid supplementation compared to folic acid alone (without iron) (Batu 1976; Chisholm 1966; Christian 2003 (C); Liu 2012; Zeng 2008 (C); Zhao 2014). Five of these trials met pre‐determined criteria for high quality (Chisholm 1966; Christian 2003 (C); Liu 2012; Zeng 2008 (C)). One of these trials included a comparison of daily iron + folic acid supplementation versus folic acid alone, considering the vitamin A supplementation and deworming as co‐interventions in both groups (Christian 2003 (C)).

Comparison 6: Four trials compared iron supplementation + other vitamins and minerals, versus the same vitamins and minerals alone (Bloxam 1989; Cantlie 1971; Dawson 1989; Siega‐Riz 2001). Two of these trials met a priori criteria for high quality (Bloxam 1989; Siega‐Riz 2001).

Comparison 7: No trials contributed data to the comparison of supplementation with iron + folic acid + other vitamins and minerals versus folic acid + other vitamins and minerals alone (without iron).

Comparison 8: No studies compared women receiving daily oral supplements with iron + folic acid + other vitamins and minerals versus the same other vitamins and minerals (without iron + folic acid).

Dates of the studies

Trials included in the review were conducted beginning in 1947. Two of the included trials were conducted in the 1950s (Kerr 1958) and 1960s (Paintin 1966). One trial was conducted between 1977 and 1984 (Fleming 1985). Four of the included trials were conducted in the 1980s (Freire 1989; Groner 1986; Milman 1991; Tura 1989), and six studies were conducted between 1990 and 1999 (Cogswell 2003; Eskeland 1997; Hoa 2005 (C); Makrides 2003; Siega‐Riz 2001; Suharno 1993). One study took place between 1999 and 2000 (Christian 2003 (C)). Five of the included trials were conducted in the 2000s (Chan 2009; Harvey 2007; Lee 2005; Liu 2012; Zeng 2008 (C)). One study took place between 2009 and 2010 (Falahi 2010), and one trial was conducted between 2009 and 2011 (Zhao 2014). Two trials were conducted from 2010 to date (Fawzi 2010; Li 2020; Parisi 2017). A total of 33 of the included trials did not report the dates that the study was conducted (Barton 1994; Batu 1976; Bloxam 1989; Butler 1967; Buytaert 1983; Cantlie 1971; Chanarin 1965; Chanarin 1971; Charoenlarp 1988; Chisholm 1966; Dawson 1989; De Benaze 1989; Dommisse 1983; Fenton 1977; Fleming 1974; Foulkes 1982; Holly 1955; Hood 1960; Kuizon 1979; Meier 2003; Menendez 1994 (C); Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983; Simmons 1993; Svanberg 1975; Taylor 1982; Tholin 1993; Van Eijk 1978; Wallenburg 1983; Willoughby 1967; Wills 1947).

Funding sources

A total of 42 trials reported sources of funding (Bloxam 1989; Butler 1967; Cantlie 1971; Chan 2009; Chanarin 1965; Chanarin 1971; Charoenlarp 1988; Chisholm 1966; Christian 2003 (C); Cogswell 2003; Dommisse 1983; Fawzi 2010; Fenton 1977; Fleming 1974; Fleming 1985; Groner 1986; Harvey 2007; Hoa 2005 (C); Holly 1955; Kerr 1958; Kuizon 1979; Lee 2005; Li 2020; Liu 2012; Makrides 2003; Meier 2003; Menendez 1994 (C); Milman 1991; Paintin 1966; Parisi 2017; Preziosi 1997; Pritchard 1958; Romslo 1983; Siega‐Riz 2001; Simmons 1993; Suharno 1993; Svanberg 1975; Taylor 1982; Tholin 1993; Willoughby 1967; Zeng 2008 (C); Zhao 2014). Fifteen studies did not report sources of funding (Barton 1994; Batu 1976; Buytaert 1983; Dawson 1989; De Benaze 1989; Eskeland 1997; Falahi 2010; Foulkes 1982; Freire 1989; Hood 1960; Puolakka 1980; Tura 1989; Van Eijk 1978; Wallenburg 1983; Wills 1947).

Declarations of interest

Nine of the included trials reported that the authors had no conflicts of interest (Cogswell 2003; Fawzi 2010; Harvey 2007; Lee 2005; Li 2020; Liu 2012; Makrides 2003; Parisi 2017; Zhao 2014). One trial reported that the study authors had a conflict of interest (Zeng 2008 (C)). In the remaining 47 included trials, study authors did not report declarations of interest (Barton 1994; Batu 1976; Bloxam 1989; Butler 1967; Buytaert 1983; Cantlie 1971; Chan 2009; Chanarin 1965; Chanarin 1971; Charoenlarp 1988; Chisholm 1966; Christian 2003 (C); Dawson 1989; De Benaze 1989; Dommisse 1983; Eskeland 1997; Falahi 2010; Fenton 1977; Fleming 1974; Fleming 1985; Foulkes 1982; Freire 1989; Groner 1986; Hoa 2005 (C); Holly 1955; Hood 1960; Kerr 1958; Kuizon 1979; Meier 2003; Menendez 1994 (C); Milman 1991; Paintin 1966; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983; Siega‐Riz 2001; Simmons 1993; Suharno 1993; Svanberg 1975; Taylor 1982; Tholin 1993; Tura 1989; Van Eijk 1978; Wallenburg 1983; Willoughby 1967; Wills 1947).

Detailed information regarding funding sources and declarations of interest in trials is reported in Characteristics of included studies. All the included trials met a priori inclusion criteria for funding and declarations of interest.

Excluded studies

A total of 194 trials (263 reports) were excluded in this review.

Nine trials were conducted amongst non‐pregnant women (Angulo‐Barroso 2016; Compaore 2017; Cook 1990; Gunaratna 2015; Khambalia 2009; Lozoff 2016; Mitra 2012; NCT04363905 (first received 2020 Apr 27); Picha 1975).

Thirteen trials were excluded due to inappropriate route of administration (Adhikari 2009; Ahamed 2018; Antonia 2023; Bencaiova 2007; Breymann 2015; Kumar 2005; Marin 2012; Sinha 2011; Sood 1979; Swain 2011; Wali 2002; Wasim 2023; Zutschi 2004).

A total of 25 trials were excluded due to inappropriate study design (Abel 2000;Angeles‐Agdeppa 2003;Berger 2003;Chawla 1995;Dawson 1962;Edgar 1956;Gopalan 2004;Iyengar 1970;Jones 2021;Kinnunen 2016;Kulkarni 2010;Menon 1962;Morgan 1961;Ortega‐Soler 1998;Osifo 1970;Powers 1985;Rabindrakumar 2021;Ramakrishnan 2016;Roztocil 1994;Sandstad 2003;Schoorl 2012;Tange 1993;Willoughby 1966;Wu 1998;Young 2010).

A total of 35 trials were excluded due to inappropriate intervention (Adaji 2019; Agrawal 2011; Bhatla 2009; Bokhari 2011; Bokhari 2012; Callaghan‐Gillespie 2017; Casanueva 2003a; Chew 1996a; Chew 1996b; ChiCTR1800017574 (first received 2018); CTRI/2017/10/010057 (first received 2017); Gomber 2002; Goonewardene 2001; Goshtasebi 2012; Grover 1998; Iglesias‐Vazquez 2022; Khangura 2021; Liu 1996; McKenna 2002; Mukhopadhyay 2004; Mumtaz 2000; Peña‐Rosas 2003; Pita Martin 1999; Quintero 2004; Ridwan 1996; Robinson 1998; Rukhsana 2006; Shaheen 2020; Shankar 2016; Winichagoon 2003; Xu 2022; Yecta 2011; Young 2000; Yu 1998; Zamani 2008).

A total of 105 trials were excluded due to inappropriate comparator (Afifi 1978; Babior 1985; Balmelli 1974; Bhatt 2020; Burslem 1968; Buss 1981; Carrasco 1962; Castren 1968; Chanarin 1968; Coelho 2000; CTRI/2019/09/021372 (first received 2019); Aaseth 2001; Ahn 2006; Alaoddolehei 2012; Ali 2016; Arija 2014; Bah 2019; Blot 1980; Brown 1972; CTRI/2019/08/020917 (first received 2019); CTRI/2020/09/028053 (first received 2020); CTRI/2021/03/032434 (first received 2021); CTRI/2021/09/036960 (first received 2021); CTRI/2022/02/040426 (first received 2022); Dawson 1987; Dewey 2019; Dijkhuizen 2004; Eeesha 2022; Ekstrom 1996; Ekstrom 2002; EUCTR2012‐005480‐28‐ES (first received 2013); EUCTR2022‐001815‐25‐IE (first received 2022); Fletcher 1971; Giles 1971; Glosz 2018; Gringras 1982; Guldholt 1991; Hanieh 2013; Hartman‐Craven 2009; Hemminki 1991; Hemminki 2016; Horgan 1966; Hosokawa 1989; Hossain 2014; Huda 2018; ISRCTN77724888 (first received 2017); Itam 2003; Kaestel 2005; Kann 1988; Khan 2017; Kone 2020; Lee 2022; Lira 1989; Ma 2008; Madan 1999; Mbaye 2006; Metz 1965; Milman 2005; Milman 2014; Morrison 1977; Mwangi 2015; Nadimin 2019; Nadimin 2020; NCT03836703 (first received 2019 Feb 11); NCT04250428 (first received 2020 Jan 31); Nguyen 2008; Nguyen 2012; Nguyen 2012a; Nogueira 2002; Nur 2020; Nwaru 2015; Ogunbode 1984; Ogunbode 1992; Osrin 2005; Pandey 2015; Parkkali 2013; Payne 1968; Priliani 2019; Rae 1970; Ramakrishnan 2003; Rayado 1997; Reddaiah 1989; Reddy 2016; Rolschau 1979; Roth 1980; Rybo 1971; Sachdeva 1993; Saha 2007; Salma 2021; Seck 2008; Shatrugna 1999; Sjostedt 1977; Srisupandit 1983; Stone 1975; Suhartatik 2020; Thane‐Toe 1982; Thomsen 1993; Tofail 2008; Trigg 1976; Vazquez 2019; Vogel 1963; Weil 1977; West 2014; Willoughby 1968; Zhou 2009).

Other reasons for exclusion included: trial non‐completion (Bergsjo 1987; Steer 1992), and insufficient or inappropriate reporting (Hampel 1974; Hawkins 1987; Hermsdorf 1986; Tampakoudis 1996; Tan 1995).

See Characteristics of excluded studies for detailed information on reasons for study exclusion.

Risk of bias in included studies

The assessment of the risk of bias for each included trial is summarised in the risk of bias tables (Characteristics of included studies) and the overall summary of the risk of bias for all included trials is presented in Figure 3 and Figure 4. In the text below, the risk of bias assessment is summarised for the 41 trials that contributed quantitative outcome data to the review.

3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

4.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

In the summary of findings tables, the risk of bias for each outcome is reported separately, for trials that contributed data for each of the primary outcomes.

Allocation

Sequence generation

A total of 22 of the included trials had adequate methods for generation of the randomisation sequence (Barton 1994; Bloxam 1989; Buytaert 1983; Chan 2009; Charoenlarp 1988; Christian 2003 (C); Cogswell 2003; Eskeland 1997; Fawzi 2010; Harvey 2007; Kerr 1958; Lee 2005; Li 2020; Liu 2012; Makrides 2003; Meier 2003; Preziosi 1997; Siega‐Riz 2001; Tura 1989; Wallenburg 1983; Zeng 2008 (C); Zhao 2014). In 19 trials, the methods for sequence generation were not reported or the randomisation methods used were not adequately described (Batu 1976; Cantlie 1971; Chisholm 1966; Dawson 1989; De Benaze 1989; Falahi 2010; Holly 1955; Hood 1960; Menendez 1994 (C); Milman 1991; Paintin 1966; Parisi 2017; Pritchard 1958; Puolakka 1980; Romslo 1983; Svanberg 1975; Taylor 1982; Van Eijk 1978; Willoughby 1967). Two studies were quasi‐randomised trials and used alternate sequence allocation (Chanarin 1971; Wills 1947).

Four of the included studies were cluster‐randomised trials (Christian 2003 (C); Li 2020; Menendez 1994 (C); Zeng 2008 (C)).

Allocation concealment

A total of 20 trials had adequate methods for allocation concealment (Bloxam 1989; Buytaert 1983; Chan 2009; Chisholm 1966; Christian 2003 (C); Cogswell 2003; De Benaze 1989; Eskeland 1997; Falahi 2010; Fawzi 2010; Harvey 2007; Liu 2012; Makrides 2003; Paintin 1966; Preziosi 1997; Siega‐Riz 2001; Tura 1989; Wallenburg 1983; Zeng 2008 (C); Zhao 2014). Five trials did not use adequate methods for concealment or did not use any allocation concealment (Chanarin 1971; Menendez 1994 (C); Parisi 2017; Van Eijk 1978; Wills 1947). In 18 studies, the methods used for allocation concealment were not clear (Barton 1994; Batu 1976; Cantlie 1971; Charoenlarp 1988; Dawson 1989; Holly 1955; Hood 1960; Kerr 1958; Lee 2005; Li 2020; Meier 2003; Milman 1991; Pritchard 1958; Puolakka 1980; Romslo 1983; Svanberg 1975; Taylor 1982; Willoughby 1967).

Blinding

Blinding of participants and staff (performance bias)

In 19 trials, blinding of participants and staff was attempted by using placebos, supplements that were similar in appearance to the active intervention and/or were stored in opaque or coded bottles (Barton 1994; Batu 1976; Bloxam 1989; Chanarin 1971; Chisholm 1966; Christian 2003 (C); Cogswell 2003; De Benaze 1989; Eskeland 1997; Falahi 2010; Fawzi 2010; Liu 2012; Makrides 2003; Meier 2003; Paintin 1966; Preziosi 1997; Siega‐Riz 2001; Svanberg 1975; Zhao 2014). In the remaining 27 trials, blinding was not attempted, methods used were not reported, or it was not clear if the methods used were adequate for blinding participants and staff (e.g. placebo and active treatment were not identical).

Blinding of outcome assessors (detection bias)

We assessed a total of 36 trials as being at low risk of detection bias. This assessment was irrespective of whether a placebo was used (which was identical in appearance), as for many of the primary outcomes (e.g. haemoglobin concentrations, anaemia), lack of blinding of laboratory or clinical staff or outcome assessors was unlikely to impact their evaluation. One study was an unblinded trial and was determined to be at high risk of detection bias (Parisi 2017). In the remaining eight trials, the extent to which lack of blinding could lead to detection bias was not clear (Buytaert 1983; Chan 2009; Chanarin 1971; Charoenlarp 1988; Dawson 1989; Hood 1960; Kerr 1958; Li 2020; Zeng 2008 (C)). In some cases, a lack of blinding may have led to a change in clinical management for some participants (e.g. women who developed anaemia were identified and provided additional treatment or were withdrawn from trials), or if there was heterogeneity in blinding of outcome assessors (e.g. certain outcomes were blinded but others such as adverse effects were not).

Incomplete outcome data

We assessed a total of 16 trials as having high risk of bias for incomplete outcome data (Batu 1976; Bloxam 1989; Cantlie 1971; Chan 2009; Christian 2003 (C); Cogswell 2003; Eskeland 1997; Fleming 1985; Groner 1986; Kerr 1958; Meier 2003; Menendez 1994 (C); Parisi 2017; Siega‐Riz 2001; Simmons 1993; Zhao 2014), due to high levels of attrition (> 20%) or unbalanced or differential loss to follow‐up by intervention arms of a trial (e.g. if pregnant women were withdrawn from trials if they experienced adverse effects).

Selective reporting

Selective reporting bias was not formally evaluated; for many of the included trials, we did not have access to trial registries or study protocols required to evaluate potential outcome reporting bias. However, we described potential issues relating to outcome reporting in the Characteristics of included studies tables where relevant. In most cases, there were not sufficient studies contributing data for specific outcomes to examine potential publication bias via funnel plots; however, we arranged studies in meta‐analyses by weight to allow us to visually examine plots for evidence of a greater effect size in smaller studies.

Other potential sources of bias

Information for other potential sources of bias in the included studies is described in the risk of bias section of the Characteristics of included studies tables. Two of the included trials were determined to be at high risk for other potential sources of bias (Kuizon 1979; Tholin 1993).

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4

The results for primary and secondary outcomes are described in further detail in the Data and analyses section. See Table 1; Table 2; Table 3; Table 4.

A total of 41 trials contributed quantitative data for the comparisons in this review: 40 trials compared the effects of daily oral supplements with iron to placebo or no iron, and eight trials evaluated the effects of iron + folic acid compared to placebo or no iron + folic acid. Some trials with more than two treatment arms are included in more than one comparison. The number of studies contributing data and the number of participants from included studies are indicated for each outcome. For most outcomes, a small proportion of studies included in the comparison reported estimable data. For outcomes including data from cluster‐randomised trials, the number reported is the effective sample size (i.e. sample sizes and event rates have been adjusted for cluster‐trials to account for the design effect). In subgroup analyses, there were not sufficient data reported to form evaluation of primary outcomes by: type of formulation (i.e. slow release iron supplement (as defined by trialists) or normal release iron supplement/not specified) or iron compound bioavailability in comparison to ferrous sulphate (i.e. higher bioavailability: NaFeEDTA; equivalent or lower relative bioavailability: ferrous sulphate, ferrous fumarate, ferrous gluconate; other/not specified).

(1) Any supplements containing iron versus the same supplements without iron, or placebo or no treatment (40 trials)

Maternal primary outcomes

Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more)

Iron supplementation during pregnancy may reduce anaemia at term, compared to placebo or no iron supplementation (4.0% versus 7.4%; risk ratio (RR) 0.30, 95% confidence interval (95% CI) 0.20 to 0.47; low‐certainty evidence), based on data from 14 trials with 13,543 women (Batu 1976; Chanarin 1971; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Holly 1955; Liu 2012; Makrides 2003; Milman 1991; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983) (Analysis 1.1). However, due to heterogeneity in study results (heterogeneity: Tau² = 0.39, Chi² = 76.02, df =13 (P < 0.00001); I² = 83%), the findings should be interpreted with caution (Analysis 1.1). There was no evidence of differences between subgroups in most of the analyses (Analysis 1.2; Analysis 1.3; Analysis 1.4; Analysis 1.5), although trials with higher doses of iron supplementation and studies conducted in settings where malaria was not endemic appeared to have more pronounced treatment effects (test for subgroup differences: Analysis 1.4: Chi² = 8.18, df = 2 (P = 0.02), I² = 75.5%; Analysis 1.5: Chi² = 6.46, df = 1 (P = 0.01), I² = 84.5%). Visual inspection of the funnel plot for this outcome suggested that the treatment effect was more pronounced in smaller studies (not shown), but we did not downgrade this outcome due to publication bias.

1.1. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 1: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)

1.2. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 2: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation

1.3. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 3: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

1.4. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 4: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron

1.5. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 5: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting

Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more)

A total of eight trials, including 2873 women, reported data for this outcome (Cogswell 2003; Eskeland 1997; Falahi 2010; Makrides 2003; Milman 1991; Preziosi 1997; Tura 1989; Zhao 2014). Iron supplementation during pregnancy may reduce iron deficiency at term, compared to placebo or no iron supplementation (44.0% versus 66.0%; RR 0.51, 95% CI 0.38 to 0.68; low‐certainty evidence) (heterogeneity: Tau² = 0.11; Chi² = 44.40, df = 7 (P < 0.00001); I² = 84%) (Analysis 1.6). In subgroup analyses, trials with higher doses of iron or studies with mixed or unspecified anaemia status at the start of supplementation were associated with more pronounced treatment effects (test for subgroup differences: Chi² = 14.56, df = 1 (P = 0.0001), I² = 93.1%, and Chi² = 9.75, df = 2 (P = 0.008), I² = 79.5%, respectively), compared to placebo or no iron supplementation (Analysis 1.8; Analysis 1.9). There was little to no difference by gestational age at the start of supplementation or malaria endemicity (Analysis 1.7; Analysis 1.10).

1.6. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 6: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)

1.8. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 8: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

1.9. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 9: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron

1.7. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 7: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation

1.10. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 10: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting

Maternal iron‐deficiency anaemia at term (Hb below 110 g/L and at least one additional indicator of iron deficiency at 37 weeks' gestation or more)

Data from seven trials, with 2704 women, contributed data for iron‐deficiency anaemia (Cogswell 2003; Eskeland 1997; Falahi 2010; Makrides 2003; Milman 1991; Tura 1989; Zhao 2014). Iron supplementation during pregnancy probably reduces iron‐deficiency anaemia at term, compared to placebo or no iron supplementation (5.0% versus 18.4%; RR 0.41, 95% CI 0.26 to 0.63; moderate‐certainty evidence) (heterogeneity: Tau² = 0.11; Chi² = 8.43, df = 5 (P = 0.13); I² = 41%) (Analysis 1.11). There was little to no difference between subgroups (Analysis 1.12; Analysis 1.13; Analysis 1.14; Analysis 1.15).

1.11. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 11: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more) (ALL)

1.12. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 12: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation

1.13. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 13: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

1.14. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 14: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron

1.15. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 15: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting

Maternal death (death while pregnant or within 42 days of termination of pregnancy)

A total of three studies, with 14,060 women, evaluated maternal death (Eskeland 1997; Fawzi 2010; Liu 2012), although two trials contributed estimable data to meta‐analyses (Fawzi 2010; Liu 2012); no maternal deaths were reported in Eskeland 1997. Iron supplementation probably results in little to no difference between iron and placebo groups for maternal mortality (2 versus 4 events) (RR 0.57, 95% CI 0.12 to 2.69; moderate‐certainty evidence) (heterogeneity: Tau² = 0.00; Chi² = 0.14, df = 1 (P = 0.71); I² = 0%) (Analysis 1.16).

1.16. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 16: Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)

Adverse effects (any) reported throughout the intervention period

Data from 12 trials, involving 2423 women, reported on this outcome (Charoenlarp 1988; Cogswell 2003; De Benaze 1989; Eskeland 1997; Harvey 2007; Hood 1960; Kerr 1958; Liu 2012; Makrides 2003; Paintin 1966; Siega‐Riz 2001; Zhao 2014). Adverse effects include abdominal discomfort, vomiting (Charoenlarp 1988; Siega‐Riz 2001), dizziness (Charoenlarp 1988), loss of appetite (Siega‐Riz 2001), and fatigue (Charoenlarp 1988; Eskeland 1997). The evidence is uncertain about the number of women who reported any adverse effects, between groups that received iron supplements compared to placebo or no iron supplements (21.6% versus 18.0%; RR 1.29, 95% CI 0.83 to 2.02; very low‐certainty evidence) (Analysis 1.17). Due to the substantial heterogeneity in analyses, findings should be interpreted with caution (heterogeneity: Tau² = 0.30; Chi² = 46.77, df = 9 (P < 0.00001); I² = 81%). There was little to no difference between subgroups (Analysis 1.18; Analysis 1.19; Analysis 1.20; Analysis 1.21) or funnel plot asymmetry for this outcome (not shown). In one trial, over two‐thirds of women from both intervention and control groups reported adverse effects, although quantitative data were not reported for inclusion in meta‐analyses (i.e. 68.4% and 68.2% of women, respectively, reported adverse effects such as nausea, vomiting, diarrhoea, or constipation) (Zhao 2014).

1.17. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 17: Adverse effects (any reported throughout the intervention period) (ALL)

1.18. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 18: Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by gestational age at the start of supplementation

1.19. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 19: Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

1.20. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 20: Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by dose of iron

1.21. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 21: Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by malarial status of setting

Severe anaemia (Hb < 70 g/L) at any time during the second or third trimester

Eight trials, with 1398 women, reported this outcome (Batu 1976; Christian 2003 (C); Cogswell 2003; Eskeland 1997; Harvey 2007; Holly 1955; Makrides 2003; Milman 1991), although only three trials contributed estimable data for inclusion in quantitative analyses (Batu 1976; Christian 2003 (C); Makrides 2003). There was little to no difference between groups for severe anaemia during the second or third trimester, comparing women who received iron supplementation to placebo or no iron (< 1% versus 3.6%; RR 0.22, 95% CI 0.01 to 3.20; very low‐certainty evidence), although the evidence is very uncertain (heterogeneity: Tau² = 3.87; Chi² = 6.43, df = 2 (P = 0.04); I² = 69%) (Analysis 1.22). There was little to no difference between subgroups (Analysis 1.23; Analysis 1.24; Analysis 1.25; Analysis 1.26). In the included trials that reported this outcome, there were very few cases of severe anaemia (< 1% versus 3.6%), as women who became anaemic during follow‐up were treated and excluded from analyses, independent of the intervention group.

1.22. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 22: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)

1.23. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 23: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestational age at the start of supplementation

1.24. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 24: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

1.25. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 25: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron

1.26. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 26: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting

Clinical malaria

No studies reported data on maternal clinical malaria. In one trial, including 1003 women (Fawzi 2010), iron supplementation probably results in little to no difference between groups for placental malaria cases (6.7% versus 6.5%; RR 1.03, 95% CI 0.65 to 1.65; moderate‐certainty evidence) (Analysis 1.27), defined based on placental histopathology.

1.27. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 27: Maternal clinical malaria

Infection during pregnancy (including urinary tract infections)

No studies reported data on this outcome.

Infant primary outcomes

Low birthweight (less than 2500 g)

Overall, iron supplementation probably reduces infant low birthweight (less than 2500 g), compared to placebo or no iron supplementation. In analyses of data from 12 trials with 18,290 participants (Christian 2003 (C); Cogswell 2003; Dawson 1989; Eskeland 1997; Falahi 2010; Fawzi 2010; Liu 2012; Makrides 2003; Meier 2003; Menendez 1994 (C); Siega‐Riz 2001; Zeng 2008 (C)), women who took daily iron supplementation during pregnancy were probably less likely to have an infant with low birthweight (less than 2500 g), compared to women who received placebo or no iron supplementation (5.2% versus 6.1%; RR 0.84, 95% CI 0.72 to 0.99; moderate‐certainty evidence) (heterogeneity: Tau² = 0.01; Chi² = 12.91, df = 10 (P = 0.23); I² = 23%) (Analysis 1.28). There was little to no difference between subgroups (Analysis 1.29; Analysis 1.30; Analysis 1.31; Analysis 1.32) or asymmetry in funnel plots (Figure 5).

1.28. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 28: Low birthweight (less than 2500 g) (ALL)

1.29. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 29: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation

1.30. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 30: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

1.31. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 31: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron

1.32. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 32: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting

5.

Funnel plot of comparison: 1 Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), outcome: 1.1 Low birthweight (less than 2500 g) (ALL).

Birthweight (g)

A total of 16 trials, including 18,554 participants, reported data on infant birthweight (Bloxam 1989; Christian 2003 (C); Cogswell 2003; Dawson 1989; Eskeland 1997; Falahi 2010; Fawzi 2010; Harvey 2007; Liu 2012; Makrides 2003; Milman 1991; Paintin 1966; Preziosi 1997; Puolakka 1980; Siega‐Riz 2001; Zeng 2008 (C)). There may be little to no difference in birthweight amongst infants born to women who received iron supplementation during pregnancy, compared to placebo or no iron supplementation (mean difference (MD) 24.90 g, 95% CI ‐125.81 to 175.60; very low‐certainty evidence) (heterogeneity: Tau² = 86658.56; Chi² = 2922.20, df = 15 (P < 0.00001); I² = 99%) (Analysis 1.33), however, the evidence is very uncertain. There was little to no evidence of subgroup differences (Analysis 1.34; Analysis 1.35; Analysis 1.36; Analysis 1.37) or funnel plot asymmetry (Figure 6). One‐third of studies had study design limitations due to high attrition (45%: Bloxam 1989; > 20%: Christian 2003 (C); Cogswell 2003; Eskeland 1997; Siega‐Riz 2001) and non‐blinding of participants and trial personnel (Puolakka 1980). In sensitivity analyses of data from 15 trials (Christian 2003 (C); Cogswell 2003; Dawson 1989; Eskeland 1997; Falahi 2010; Fawzi 2010; Harvey 2007; Liu 2012; Makrides 2003; Milman 1991; Paintin 1966; Preziosi 1997; Puolakka 1980; Siega‐Riz 2001; Zeng 2008 (C)), there was no evidence of differences in intervention groups for birthweight (MD 16.08 g, 95% CI ‐17.05 to 49.21); however, there was a decrease in heterogeneity (Tau² = 1461.02; Chi² = 32.63, df = 14 (P = 0.003); I² = 57%).

1.33. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 33: Birthweight (g) (ALL)

1.34. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 34: Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation

1.35. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 35: Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

1.36. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 36: Birthweight (g): SUBGROUP ANALYSIS by dose of iron

1.37. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 37: Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting

6.

Funnel plot of comparison: 1 Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), outcome: 1.6 Birthweight (g) (ALL).

Preterm birth (less than 37 weeks' gestation)

A total of 11 trials, with 18,827 participants, contributed data on preterm birth (less than 37 weeks' gestation) (Chan 2009; Christian 2003 (C); Cogswell 2003; Eskeland 1997; Falahi 2010; Fawzi 2010; Harvey 2007; Liu 2012; Makrides 2003; Siega‐Riz 2001; Zeng 2008 (C)). There was probably little to no difference in preterm birth amongst women who received iron supplementation during pregnancy, compared to placebo or no iron supplementation (7.6% versus 8.2%; RR 0.93, 95% CI 0.84 to 1.02; moderate‐certainty evidence) (heterogeneity: Tau² = 0.00; Chi² = 8.36, df = 9 (P = 0.50); I² = 0%) (Analysis 1.38). There was no evidence of a difference between subgroups (Analysis 1.39; Analysis 1.40; Analysis 1.41; Analysis 1.42). Visual inspection of the funnel plot for this outcome suggested that smaller studies tended to report more pronounced treatment effects (Figure 7).

1.38. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 38: Preterm birth (less than 37 weeks of gestation) (ALL)

1.39. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 39: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation

1.40. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 40: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

1.41. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 41: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron

1.42. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 42: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting

7.

Funnel plot of comparison: 1 Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), outcome: 1.11 Preterm birth (less than 37 weeks of gestation) (ALL).

Neonatal death (within 28 days after delivery)

Four trials, with 17,243 participants, reported data on neonatal mortality (Christian 2003 (C); Fawzi 2010; Liu 2012; Zeng 2008 (C)). There may be little to no difference between groups in neonatal death, comparing iron supplementation to placebo or no iron supplementation (1.4% versus 1.5%; RR 0.98, 95% CI 0.77 to 1.24; low‐certainty evidence) (heterogeneity: Tau² = 0.00; Chi² = 1.77, df = 3 (P = 0.62); I² = 0%) (Analysis 1.43). We did not find evidence of differences between subgroups for this outcome (Analysis 1.44; Analysis 1.45; Analysis 1.46; Analysis 1.47).

1.43. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 43: Neonatal death (within 28 days after delivery) (ALL)

1.44. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 44: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at the start of supplementation

1.45. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 45: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

1.46. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 46: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron

1.47. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 47: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting

Congenital anomalies (including neural tube defects)

Four studies, with 14,377 participants, provided data on congenital anomalies, including neural tube defects (Chan 2009; Christian 2003 (C); Dawson 1989; Liu 2012). There may be little to no difference between groups in congenital anomalies (41 versus 48 events; RR 0.88, 95% CI 0.58 to 1.33; low‐certainty evidence) (heterogeneity: Tau² = 0.00; Chi² = 1.00, df = 2 (P = 0.61); I² = 0%) (Analysis 1.48). There was little to no difference between subgroups for congenital anomalies (Analysis 1.49; Analysis 1.50; Analysis 1.51; Analysis 1.52).

1.48. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 48: Congenital anomalies (ALL)

1.49. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 49: Congenital anomalies: SUBGROUP ANALYSIS by gestational age at the start of supplementation)

1.50. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 50: Congenital anomalies: SUBGROUP ANALYSIS by anaemia status at the start of supplementation

1.51. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 51: Congenital anomalies: SUBGROUP ANALYSIS by dose of iron

1.52. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 52: Congenital anomalies: SUBGROUP ANALYSIS by malarial status of setting

Maternal secondary outcomes

Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more)

Data from 14 trials, with 2981 women, reported data for anaemia at or near term (Batu 1976; Chanarin 1971; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Fawzi 2010; Holly 1955; Makrides 2003; Milman 1991; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983). Iron supplementation may reduce maternal anaemia at term, compared to placebo or no iron supplementation (16.8% versus 40.0%; RR 0.31, 95% CI 0.22 to 0.46) (Analysis 1.53). However, due to the substantial heterogeneity in analyses, findings should be interpreted with caution (heterogeneity: Tau² = 0.24; Chi² = 57.09, df = 13 (P < 0.00001); I² = 77%).

1.53. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 53: Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)

Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more)

A total of eight trials, involving 2247 women, reported data for this outcome (Cogswell 2003; Eskeland 1997; Falahi 2010; Fawzi 2010; Makrides 2003; Milman 1991; Preziosi 1997; Tura 1989). Iron supplementation may reduce iron deficiency at or near term, compared to placebo or no iron supplementation (19.3% versus 34.3%; RR 0.44, 95% CI 0.30 to 0.65) (Analysis 1.54). Due to statistical heterogeneity in analyses for this outcome, the findings should be interpreted with caution (heterogeneity: Tau² = 0.22; Chi² = 42.55, df = 7 (P < 0.00001); I² = 84%).

1.54. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 54: Maternal iron deficiency at or near term (as defined by as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)

Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator of iron deficiency at 34 weeks' gestation or more)

In analyses of data from seven studies, involving 2042 women (Cogswell 2003; Eskeland 1997; Falahi 2010; Fawzi 2010; Makrides 2003; Milman 1991; Tura 1989), women who received iron supplementation during pregnancy may be less likely to have iron‐deficiency anaemia at or near term, compared to placebo or no iron supplementation (3.8% versus 11.0%; RR 0.35, 95% CI 0.22 to 0.58) (heterogeneity: Tau² = 0.12; Chi² = 7.59, df = 5 (P = 0.18); I² = 34%) (Analysis 1.55).

1.55. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 55: Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more) (ALL)

Maternal haemoglobin concentrations at or near term (at 34 weeks' gestation or more) and within six weeks postpartum period (g/L)

A total of 17 trials, involving 2665 women, reported data for this outcome (Batu 1976; Bloxam 1989; Buytaert 1983; Cantlie 1971; Chanarin 1965; Cogswell 2003; De Benaze 1989; Eskeland 1997; Falahi 2010; Fawzi 2010; Makrides 2003; Milman 1991; Puolakka 1980; Romslo 1983; Tura 1989; Van Eijk 1978; Wallenburg 1983). Women who received iron supplementation may have higher haemoglobin concentrations at term, compared to placebo or no iron supplementation, with an average difference of 9.5 g/L (MD 9.53 g/L, 95% CI 6.99 to 12.06). Based on the high statistical heterogeneity in analyses for this outcome, the findings should be interpreted with caution (heterogeneity: Tau² = 23.80; Chi² = 136.55, df = 17 (P < 0.00001); I² = 88%) (Analysis 1.56).

1.56. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 56: Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)

Maternal haemoglobin concentrations within six weeks postpartum (g/L)

Data from seven trials, with 818 women, contributed data to analyses for this outcome (Cantlie 1971; Christian 2003 (C); Lee 2005; Menendez 1994 (C); Milman 1991; Parisi 2017; Wills 1947). Women who received iron supplements during pregnancy had an average of 7.8 g/L higher haemoglobin concentrations within six weeks postpartum, compared to women who received placebo or no iron supplementation (MD 7.76 g/L, 95% CI 5.56 to 9.95) (heterogeneity: Tau² = 3.12; Chi² = 9.67, df = 6 (P = 0.14); I² = 38%) (Analysis 1.57).

1.57. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 57: Maternal Hb concentration within 6 weeks postpartum (in g/L) (ALL)

Maternal high haemoglobin concentrations (Hb greater than 130 g/L) at any time during second or third trimester

Eight studies, with 1461 women, assessed this outcome (Christian 2003 (C); Cogswell 2003; Eskeland 1997; Harvey 2007; Holly 1955; Makrides 2003; Milman 1991; Pritchard 1958), with estimable data reported in seven trials (Christian 2003 (C); Cogswell 2003; Eskeland 1997; Holly 1955; Makrides 2003; Milman 1991; Pritchard 1958). Women who received iron supplementation may be more likely to have high haemoglobin concentrations in the second or third trimester of pregnancy, compared to placebo or no iron supplementation (28.3% versus 12.9%; RR 2.00, 95% CI 1.22 to 3.30). There was high statistical heterogeneity for this outcome (heterogeneity: Tau² = 0.33; Chi² = 26.12 (P = 0.0002); I² = 77%) (Analysis 1.58).

1.58. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 58: Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)

Maternal high haemoglobin concentrations at or near term (Hb greater than 130 g/L) at 34 weeks' gestation or more

Seven trials with 1429 women contributed data for this outcome (Chisholm 1966; Cogswell 2003; Eskeland 1997; Holly 1955; Makrides 2003; Milman 1991; Pritchard 1958). Women who received iron supplements may be more likely to have high haemoglobin concentrations at term, compared to those who received placebo or no iron supplements (26.5% versus 8.1%; RR 3.96, 95% CI 1.80 to 8.74). Due to the high heterogeneity in analyses for this outcome, findings should be interpreted with caution (heterogeneity: Tau² = 0.62; Chi² = 19.91, df = 6 (P = 0.003); I² = 70%) (Analysis 1.59).

1.59. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 59: Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)

Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L)

Three trials, involving 766 women, reported on this outcome (Christian 2003 (C); Eskeland 1997; Makrides 2003), with estimable data from two trials (Christian 2003 (C); Makrides 2003). There may be little to no difference between groups for moderate anaemia during the postpartum period (2.6% versus 6.1%; RR 0.55, 95% CI 0.12 to 2.51) (heterogeneity: Tau² = 0.59; Chi² = 1.42, df = 1 (P = 0.23); I² = 29%) (Analysis 1.60).

1.60. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 60: Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)

Maternal severe anaemia at or near term (Hb less than 70 g/L) at 34 weeks' gestation or more

Seven trials, involving 1092 women, reported data for this outcome (Batu 1976; Cogswell 2003; Eskeland 1997; Holly 1955; Makrides 2003; Milman 1991; Romslo 1983). However, no cases of severe anaemia were reported in five of the trials. Two trials with 494 women reported cases of severe anaemia at or near term (Batu 1976; Makrides 2003); there may be little to no difference between groups who received iron supplementation compared to placebo or no iron supplementation (2 versus 8 events; RR 0.47, 95% CI 0.01 to 44.11). Heterogeneity was high for this outcome (heterogeneity: Tau² = 8.49; Chi² = 4.80, df = 1 (P = 0.03); I² = 79%) (Analysis 1.61).

1.61. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 61: Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)

Severe anaemia postpartum (Hb less than 80 g/L)

A total of seven trials, involving 1139 women, reported data for this outcome (Batu 1976; Christian 2003 (C); Eskeland 1997; Holly 1955; Makrides 2003; Milman 1991; Puolakka 1980), with estimable data from one trial (Christian 2003 (C)). There may be little to no difference in women who received iron supplementation compared to placebo or no iron supplementation (1.1% versus 0.0%; RR 0.08, 95% CI 0.00 to 1.33) (Analysis 1.62).

1.62. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 62: Severe anaemia postpartum (Hb less than 80 g/L) (ALL)

Puerperal infection (as defined by trialists)

Women who received iron supplementation may have a lower risk of puerperal infection, compared to placebo or no iron supplementation (3.5% versus 5.3%; RR 0.67, 95% CI 0.49 to 0.91) in three trials with 3647 women (heterogeneity: Tau² = 0.00; Chi² = 0.06, df = 2 (P = 0.97); I² = 0%) (Chan 2009; Christian 2003 (C); Willoughby 1967) (Analysis 1.63).

1.63. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 63: Puerperal infection (ALL)

Antepartum haemorrhage (as defined by trialists)

Data from one trial, involving 430 women, contributed data to this outcome (Makrides 2003); there may be little to no difference between groups who received iron supplementation compared to placebo or no iron supplementation (1 versus 0 events; RR 2.97, 95% CI 0.12 to 72.56) (Analysis 1.64).

1.64. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 64: Antepartum haemorrhage (ALL)

Postpartum haemorrhage (intrapartum and postnatal, as defined by trialists)

Two trials, involving 517 women, contributed data to this outcome (Eskeland 1997; Wills 1947); there may be little to no difference between groups who received iron supplementation compared to placebo or no iron supplementation (9.5% versus 11.6%; RR 0.81, 95% CI 0.49 to 1.34) (heterogeneity: Tau² = 0.00; Chi² = 0.01, df = 1 (P = 0.90); I² = 0%) (Analysis 1.65).

1.65. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 65: Postpartum haemorrhage (ALL)

Transfusion given (as defined by trialists)

One trial, involving 32 women, contributed data for this outcome (Puolakka 1980). There may be little to no difference between women who received iron supplementation compared to placebo or no iron supplementation (0 versus 1 event) (RR 0.33, 95% CI 0.01 to 7.62) (Analysis 1.66).

1.66. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 66: Transfusion provided (ALL)

Diarrhoea (as defined by trialists)

In data from two trials, with 361 women (Paintin 1966; Siega‐Riz 2001), individuals who received iron during pregnancy were less likely to report diarrhoea, compared to those who received placebo or no iron supplementation (8.2% versus 14.5%; RR 0.55, 95% CI 0.31 to 0.98) (heterogeneity: Tau² = 0.00; Chi² = 0.25, df = 1 (P = 0.62); I² = 0%) (Analysis 1.67).

1.67. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 67: Diarrhoea (ALL)

Other maternal secondary outcomes

There may be little to no difference between intervention groups for other maternal secondary outcomes, including:

• Constipation (as defined by trialists) (15.2% versus 13.8%; RR 0.91, 95% CI 0.49 to 1.69; 3 trials, 768 women) (heterogeneity: Tau² = 0.15; Chi² = 4.01, df = 2 (P = 0.13); I² = 50%) (Makrides 2003; Paintin 1966; Siega‐Riz 2001) (Analysis 1.68).

• Nausea (as defined by trialists) (18.1% versus 15.8%; RR 2.38, 95% CI 0.49 to 11.52; 3 trials, 650 women) (heterogeneity: Tau² = 1.06; Chi² = 3.94, df = 2 (P = 0.14); I² = 49%) (Hood 1960; Makrides 2003; Paintin 1966) (Analysis 1.69).

• Heartburn (as defined by trialists) (46.4% versus 44.3%; RR 1.16, 95% CI 0.79 to 1.70; 2 trials, 596 women) (heterogeneity: Tau² = 0.05; Chi² = 2.58, df = 1 (P = 0.11); I² = 61%) (Makrides 2003; Siega‐Riz 2001) (Analysis 1.70).

• Vomiting (as defined by trialists) (12.7% versus 12.8%; RR 0.92, 95% CI 0.61 to 1.40; 3 trials, 665 women) (heterogeneity: Tau² = 0.00; Chi² = 1.63, df = 2 (P = 0.44); I² = 0%) (Hood 1960; Makrides 2003; Siega‐Riz 2001) (Analysis 1.71).

• Maternal well‐being or satisfaction (as defined by trialists) (87.5% versus 96%; RR 0.91, 95% CI 0.77 to 1.08; 1 trial, 49 women) (Eskeland 1997) (Analysis 1.72).

• Placental abruption (as defined by trialists) (1 versus 0 events; RR 2.88, 95% CI 0.12 to 70.53; 1 trial, 1442 women) (Willoughby 1967) (Analysis 1.73).

• Pre‐eclampsia (as defined by trialists) (1 versus 2 events) (RR 0.64, 95% CI 0.08 to 5.07; 2 trials, 195 women) (heterogeneity: Tau² = 0.00; Chi² = 0.20, df = 1 (P = 0.66); I² = 0%) (Eskeland 1997; Falahi 2010) (Analysis 1.74).

1.68. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 68: Constipation (ALL)

1.69. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 69: Nausea (ALL)

1.70. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 70: Heartburn (ALL)

1.71. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 71: Vomiting (ALL)

1.72. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 72: Maternal wellbeing/satisfaction (ALL)

1.73. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 73: Placental abruption (ALL)

1.74. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 74: Pre‐eclampsia (ALL)

Several of these outcomes were reported in a small number of studies.

No trials reported data on premature rupture of membranes.

Infant secondary outcomes

Very premature birth (less than 34 weeks' gestation)

Five trials, with 4366 participants, reported data for this outcome (Cogswell 2003; Eskeland 1997; Fawzi 2010; Makrides 2003; Zeng 2008 (C)). Infants born to women who received iron supplementation during pregnancy may be less likely to be born very prematurely (less than 34 weeks' gestation), compared to placebo or no iron supplementation (1.7% versus 2.7%; RR 0.63, 95% CI 0.42 to 0.95) (heterogeneity: Tau² = 0.00; Chi² = 2.67, df = 4 (P = 0.62); I² = 0%) (Analysis 1.76).

1.76. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 76: Very premature birth (less than 34 weeks' gestation) (ALL)

Infant ferritin concentrations within the first six months (μg/L, counting the last reported measure after birth within this period)

One trial, with 197 participants, reported data for this outcome (Preziosi 1997). Infants born to women who received iron supplementation during pregnancy may have higher ferritin concentrations, compared to placebo or no iron supplementation, with a mean difference of 11.0 μg/L (MD 11.00 μg/L, 95% CI 4.37 to 17.63) (Analysis 1.78).

1.78. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 78: Infant serum ferritin concentration within first 6 months (in μg/L counting the last reported measure after birth within this period) (ALL)

Other infant secondary outcomes

A total of seven trials reported data for other infant outcomes. There was little to no difference between groups for outcomes including: infant very low birthweight (less than 1500 g) (8 versus 13 events; RR 0.65, 95% CI 0.24 to 1.78; 4 trials, 1960 infants) (heterogeneity: Tau² = 0.09; Chi² = 2.16, df = 2 (P = 0.34); I² = 7%) (Christian 2003 (C); Cogswell 2003; Eskeland 1997; Makrides 2003) (Analysis 1.75), infant haemoglobin concentrations within the first six months (MD ‐0.26, 95% CI ‐2.62 to 2.11; 3 trials, 12,077 infants) (Liu 2012; Makrides 2003; Preziosi 1997) (Analysis 1.77), or admission to a special care unit (0 events, 1 trial, 111 infants) (Meier 2003) (Analysis 1.79).

1.75. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 75: Very low birthweight (less than 1500 g) (ALL)

1.77. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 77: Infant Hb concentration within the first 6 months (in g/L counting the last reported measure after birth within this period) (ALL)

1.79. Analysis.

Comparison 1: Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), Outcome 79: Admission to special care unit (ALL)

No trials reported on the occurrence of other infant outcomes, including infant development or motor skills.

(2) Any supplements containing iron and folic acid versus the same supplements without iron or folic acid, or placebo or no treatment (eight trials)

Maternal primary outcomes

Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more)

Iron + folic acid supplementation during pregnancy probably reduces anaemia at term, compared to placebo or no iron + folic acid (12.1% versus 25.5%; RR 0.44, 95% CI 0.30 to 0.64; moderate‐certainty evidence) (heterogeneity: Tau² = 0.05; Chi² = 3.55, df = 2 (P = 0.17); I² = 44%), based on evidence from four trials amongst 1962 women (Barton 1994; Batu 1976; Chisholm 1966; Zhao 2014) (Analysis 2.1). We did not identify any evidence of differences between subgroups (Analysis 2.2; Analysis 2.3; Analysis 2.4; Analysis 2.5).

2.1. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 1: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)

2.2. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 2: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestation at the start of supplementation

2.3. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 3: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

2.4. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 4: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron

2.5. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 5: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting

Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more)

In one trial involving 131 women (Lee 2005), daily iron + folic acid supplements may reduce iron deficiency at term, compared to placebo or no iron + folic acid (3.6% versus 15%; RR 0.24, 95% CI 0.06 to 0.99; low‐certainty evidence) (Analysis 2.6).

2.6. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 6: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)

Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more)

In analyses of data from one trial with 131 women (Lee 2005), the evidence is very uncertain about the effect of daily iron + folic acid supplementation on iron‐deficiency anaemia at term, compared to placebo or no iron + folic acid (10.8% versus 25%; RR 0.43, 95% CI 0.17 to 1.09; very low‐certainty evidence) (Analysis 2.7).

2.7. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 7: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more) (ALL)

Maternal death (death while pregnant or within 42 days of termination of pregnancy)

Maternal mortality was evaluated in one trial including 131 women (Lee 2005), although no events were reported (very low‐certainty evidence;Analysis 2.8).

2.8. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 8: Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)

Adverse effects (any) reported throughout the intervention period

One trial, involving 456 women, evaluated adverse effects (Charoenlarp 1988). The evidence is uncertain about the effect of iron + folic acid supplementation on any adverse effects, compared to placebo or no iron + folic acid (21.0% versus 0.0%; RR 44.32, 95% CI 2.77 to 709.09; low‐certainty evidence) (Analysis 2.9). In this trial (Charoenlarp 1988), adverse effects reported included abdominal discomfort, nausea, vomiting, constipation, and diarrhoea.

2.9. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 9: Adverse effects (any reported throughout the intervention period) (ALL)

Severe anaemia at any time during second or third trimester (Hb less than 70 g/L)

Four trials, including 506 women, contributed data for this outcome (Barton 1994; Batu 1976; Christian 2003 (C); Lee 2005). The evidence is very uncertain about the effect of iron + folic acid supplementation on severe anaemia during second or third trimester, compared to placebo or no iron + folic acid (< 1% versus 5.6%; RR 0.12, 95% CI 0.02 to 0.63; very low‐certainty evidence) (heterogeneity: Tau² = 0.00; Chi² = 0.02, df = 1 (P = 0.88); I² = 0%) (Analysis 2.10).

2.10. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 10: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)

Clinical malaria

No studies reported data on this outcome.

Infection during pregnancy (including urinary tract infections)

One trial, with 48 women, reported data on infections during pregnancy (Taylor 1982). There may be little to no difference between groups for infection during pregnancy, comparing women taking iron + folic acid supplementation to placebo or folic acid alone (2 versus 2 events; RR 1.00, 95% CI 0.15 to 6.53; very low‐certainty evidence) (Analysis 2.15), but the evidence is very uncertain.

2.15. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 15: Infection during pregnancy (including urinary tract infections) (ALL)

Infant primary outcomes

Low birthweight (less than 2500 g)

Two trials, with 1311 participants, reported data for this outcome (Christian 2003 (C); Taylor 1982). There may be little to no difference between groups in infant low birthweight, comparing daily iron + folic acid supplementation to placebo or no iron + folic acid (33.4% versus 40.2%; RR 1.07, 95% CI 0.31 to 3.74; low‐certainty evidence) (heterogeneity: Tau² = 0.47; Chi² = 1.41, df = 1 (P = 0.24); I² = 29%) (Analysis 2.16).

2.16. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 16: Low birthweight (less than 2500 g) (ALL)

Birthweight (g)

Two trials, with 1311 participants, reported data for this outcome (Christian 2003 (C); Taylor 1982). Infants born to women who received iron + folic acid supplements during pregnancy probably have higher birthweight, compared to placebo or no iron + folic acid, with an average difference of 57.7 g (MD 57.73 g, 95% CI 7.66 to 107.79; moderate‐certainty evidence) (heterogeneity: Tau² = 116.92; Chi² = 1.03, df = 1 (P = 0.31); I² = 2%) (Analysis 2.17).

2.17. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 17: Birthweight (ALL)

Preterm birth (less than 37 weeks' gestation)

Three studies, with 1497 participants, reported data for this outcome (Christian 2003 (C); Lee 2005; Taylor 1982). There may be little to no difference between groups in preterm birth, comparing women who received daily iron + folic acid supplements to placebo or no iron + folic acid (19.4% versus 19.2%; RR 1.55, 95% CI 0.40 to 6.00; low‐certainty evidence) (heterogeneity: Tau² = 0.57; Chi² = 1.51, df = 1 (P = 0.22); I² = 34%) (Analysis 2.18). There was no evidence of differences between subgroups (Analysis 2.19; Analysis 2.20; Analysis 2.21; Analysis 2.22).

2.18. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 18: Preterm birth (less than 37 weeks of gestation) (ALL)

2.19. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 19: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestation at the start of supplementation

2.20. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 20: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

2.21. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 21: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron

2.22. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 22: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of settings

Neonatal death (within 28 days after delivery)

Three trials, amongst 1793 participants, reported data for neonatal death (Barton 1994; Christian 2003 (C); Taylor 1982), and two trials contributed estimable data to meta‐analyses (Barton 1994; Christian 2003 (C)). In one study (Barton 1994), authors reported 'perinatal death', but this outcome was not defined. There may be little to no difference between groups in neonatal death (3.4% versus 4.2%; RR 0.81, 95% CI 0.51 to 1.30; low‐certainty evidence) (heterogeneity: Tau² = 0.00; Chi² = 0.49, df = 1 (P = 0.48); I² = 0%) (Analysis 2.23), and there was no clear evidence of differences between subgroups (Analysis 2.24; Analysis 2.25; Analysis 2.26; Analysis 2.27).

2.23. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 23: Neonatal death (within 28 days after delivery) (ALL)

2.24. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 24: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestation at the start of supplementation

2.25. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 25: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

2.26. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 26: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron

2.27. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 27: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status at the start of supplementation

Congenital anomalies (including neural tube defects)

One study, with 1652 participants, reported data on congenital anomalies (Christian 2003 (C)). There may be little to no difference between the groups, comparing iron + folic acid supplementation to no placebo or iron + folic acid (1.7% versus 2.4%; RR 0.70, 95% CI 0.35 to 1.40; low‐certainty evidence) (Analysis 2.28).

2.28. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 28: Congenital anomalies (ALL)

Maternal secondary outcomes

Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more)

Three trials evaluated this outcome (Barton 1994; Batu 1976; Chisholm 1966), with estimable data from two trials (Batu 1976; Chisholm 1966). Women who received iron + folic acid supplements during pregnancy may be likely to have a reduced risk of anaemia at or near term, compared to women who received placebo or no iron + folic acid (15 versus 39 events; RR 0.34, 95% CI 0.21 to 0.54; 3 trials, 346 women) (heterogeneity: Tau² = 0.00; Chi² = 0.49, df = 1 (P = 0.48); I² = 0%) (Analysis 2.29).

2.29. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 29: Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)

Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more)

Women who received iron + folic acid supplements during pregnancy may have reduced iron deficiency at or near term, compared to women who received placebo or no iron + folic acid (4 versus 3 events; RR 0.24, 95% CI 0.06 to 0.99; 1 trial, 131 women) (Lee 2005) (Analysis 2.30).

2.30. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 30: Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)

Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more)

There may be little to no difference between intervention groups for iron‐deficiency anaemia (i.e. iron + folic acid supplementation compared to placebo or no iron + folic acid) (12 versus 5 events; RR 0.43, 95% CI 0.17 to 1.09; 1 trial, 131 women) (Lee 2005) (Analysis 2.31).

2.31. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 31: Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more) (ALL)

Maternal haemoglobin concentrations at or near term (g/L, at 34 weeks' gestation or more)

Three trials, including 140 women, reported data for this outcome (Barton 1994; Batu 1976; Taylor 1982). Women who received iron + folic acid supplementation during pregnancy may have higher haemoglobin concentrations at or near term, compared to placebo or no iron + folic acid, with a 16.1 g/L difference between groups (MD 16.13 g/L, 95% CI 12.74 to 19.52) (heterogeneity: Tau² = 0.00; Chi² = 0.44, df = 2 (P = 0.80); I² = 0%) (Analysis 2.32).

2.32. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 32: Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)

Maternal haemoglobin concentrations within six weeks postpartum (g/L)

Two studies, with 459 women, reported data for this outcome (Christian 2003 (C); Taylor 1982). Women who received daily iron + folic acid supplementation may have higher haemoglobin concentrations at one month postpartum, compared to placebo or no iron + folic acid, with a mean difference of 10.1 g/L (MD 10.07g/L, 95% CI 7.33 to 12.81) (heterogeneity: Tau² = 0.00; Chi² = 0.01, df = 1 (P = 0.91); I² = 0%) (Analysis 2.33).

2.33. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 33: Maternal Hb concentration within 6 weeks postpartum (in g/L) (ALL)

Maternal high haemoglobin concentrations at any time during second or third trimester (Hb greater than 130 g/L)

Two trials, including 446 women, reported data for this outcome (Christian 2003 (C); Lee 2005). There may be little to no difference between groups in the occurrence of high haemoglobin concentrations during the second or third trimester of pregnancy (18.6% versus 7.5%; RR 1.78, 95% CI 0.63 to 5.04) (heterogeneity: Tau² = 0.39; Chi² = 3.20, df = 1 (P = 0.07); I² = 69%) (Analysis 2.34).

2.34. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 34: Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)

Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more)

Two trials, with 314 women, contributed data for this outcome (Chisholm 1966; Lee 2005). There may be little to no difference between groups for high haemoglobin concentrations at term, between women who received daily iron + folic acid supplements and placebo or no iron + folic acid (6.4% versus 0.0%; RR 4.37, 95% CI 0.58 to 32.71) (heterogeneity: Tau² = 0.39; Chi² = 3.20, df = 1 (P = 0.07); I² = 69%) (Analysis 2.35).

2.35. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 35: Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)

Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more)

Three trials, involving 191 women, reported severe anaemia at or near term (Barton 1994; Batu 1976; Lee 2005). However, only one trial with three cases of severe anaemia contributed quantitative data for meta‐analyses (Batu 1976), with little to no difference between groups (0 versus 3 events; RR 0.14, 95% CI 0.01 to 2.63) (Analysis 2.37).

2.37. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 37: Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more ) (ALL)

Maternal severe or moderate anaemia at postpartum (Hb less than 80 g/L)

Three trials, with 491 women, assessed severe or moderate anaemia during the postpartum period (Batu 1976; Christian 2003 (C); Lee 2005), and two trials reported estimable data for inclusion in meta‐analyses (Batu 1976; Christian 2003 (C)). Iron + folic acid supplementation during pregnancy may reduce moderate anaemia postpartum (4.5% versus 14.0%; RR 0.33, 95% CI 0.17 to 0.65; 2 trials, 360 participants) (heterogeneity: Tau² = 0.00; Chi² = 0.03, df = 1 (P = 0.86); I² = 0%), compared to placebo or no iron + folic acid (Analysis 2.36). One trial reported estimable data for severe anaemia postpartum (Christian 2003 (C)); women who received iron + folic acid supplementation may be less likely to have severe anaemia postpartum, compared to placebo or no iron + folic acid (0 versus 14 events; RR 0.05, 95% CI 0.00 to 0.76; 1 trial, 236 participants) (Analysis 2.38).

2.36. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 36: Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)

2.38. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 38: Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)

Other maternal secondary outcomes

There may be little to no difference between groups for the following maternal secondary outcomes:

• Puerperal infection (5 versus 3 events; RR 0.55, 95% CI 0.13 to 2.28; 1 trial, 2863 women) (Willoughby 1967) (Analysis 2.39).

• Antepartum haemorrhage (3.9% versus 2.9%; RR 1.25, 95% CI 0.22 to 7.12; 1 trial, 145 women) (Barton 1994) (Analysis 2.40).

• Placental abruption (12 versus 0 events; RR 8.19, 95% CI 0.49 to 138.16; 1 trial, 2863 women) (Willoughby 1967) (Analysis 2.41).

• Pre‐eclampsia (1 versus 0 events; RR 3.00, 95% CI 0.13 to 70.16; 1 trial, 48 women) (Taylor 1982) (Analysis 2.42).

2.39. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 39: Puerperal infection (ALL)

2.40. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 40: Antepartum haemorrhage (ALL)

2.41. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 41: Placental abruption (ALL)

2.42. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 42: Pre‐eclampsia (ALL)

No trials reported data for other maternal secondary outcomes, including: postpartum haemorrhage (i.e. intrapartum and postnatal), transfusion received, premature rupture of membranes; diarrhoea, constipation, nausea, heartburn, or vomiting, and maternal well‐being or satisfaction.

Infant secondary outcomes

There may be little to no difference between groups for other infant secondary outcomes, including very low birthweight (less than 1500 g) (2 versus 0 events; RR 5.00, 95% CI 0.25 to 98.96; 1 trial, 48 infants) (Taylor 1982) (Analysis 2.43), very premature birth (less than 34 weeks' gestation) (2 versus 0 events; RR 5.00, 95% CI 0.25 to 98.96; 1 trial, 48 infants) (Taylor 1982) (Analysis 2.44), or admission to special care unit (0 events, 1 trial, 48 infants) (Taylor 1982) (Analysis 2.45).

2.43. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 43: Very low birthweight (less than 1500 g) (ALL)

2.44. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 44: Very premature birth (less than 34 weeks' gestation) (ALL)

2.45. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 45: Admission to special care unit (ALL)

No trials reported on the occurrence of other infant outcomes, including: haemoglobin (g/L) or ferritin (µg/L) concentrations in the first six months of life, and infant development or motor skills.

(3) Supplementation with iron alone versus placebo or no treatment (30 trials)

A total of 30 trials evaluated the effects of daily iron supplementation compared to placebo or no iron (Batu 1976; Buytaert 1983; Chan 2009; Chanarin 1971; Charoenlarp 1988; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Falahi 2010; Fawzi 2010; Harvey 2007; Holly 1955; Hood 1960; Kerr 1958; Makrides 2003; Meier 2003; Menendez 1994 (C); Milman 1991; Paintin 1966; Parisi 2017; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983; Tura 1989; Van Eijk 1978; Wallenburg 1983; Willoughby 1967; Wills 1947).

Maternal primary outcomes

Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more)

In 13 trials conducted amongst 1936 women (Batu 1976; Chanarin 1971; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Holly 1955; Makrides 2003; Milman 1991; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983), iron supplementation may reduce maternal anaemia at term, compared to placebo or no treatment (10.2% versus 33.4%; RR 0.25, 95% CI 0.15 to 0.42) (Analysis 3.1). However, due to the substantial heterogeneity in analyses, the findings should be interpreted with caution (heterogeneity: Tau² = 0.50; Chi² = 56.43, df = 12 (P < 0.00001); I² = 79%). Findings were similar when analyses were limited to trials that met a priori inclusion criteria for high quality (Cogswell 2003; Eskeland 1997; Makrides 2003; Preziosi 1997) (data not shown). There was little to no difference between subgroups for gestational age at enrolment, anaemia status at the start of supplementation, or dose of iron (Analysis 3.2; Analysis 3.3; Analysis 3.4). In analyses of data from two trials, the findings suggested that the effects of iron supplementation on maternal anaemia may be more pronounced in settings where malaria is not endemic, compared to malaria‐endemic settings (5.4% versus 42.9%), but the limited number of trials and statistical heterogeneity constrains the interpretation of findings (test for subgroup differences: Chi² = 11.75, df = 1 (P = 0.0006), I² = 91.5%) (Analysis 3.5).

3.1. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 1: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)

3.2. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 2: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation

3.3. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 3: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

3.4. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 4: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron

3.5. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 5: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting

Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more)

A total of seven trials, with 1256 women, contributed data to this outcome (Cogswell 2003; Eskeland 1997; Falahi 2010; Makrides 2003; Milman 1991; Preziosi 1997; Tura 1989). Iron supplementation during pregnancy may reduce maternal iron deficiency at term, compared to placebo or no supplementation (28.5% versus 51.3%; RR 0.43, 95% CI 0.27 to 0.66) (Analysis 3.6). Due to the substantial heterogeneity in analyses, the results should be interpreted with caution (heterogeneity: Tau² = 0.26; Chi² = 41.09, df = 6 (P < 0.00001); I² = 85%). Findings from subgroup analyses suggested that higher doses of iron (test for subgroup differences: I² = 90.9%, and Chi² = 19.52, df = 2 (P = 0.0001), I² = 89.8%) and mixed or unspecified anaemia status at the start of supplementation (test for subgroup differences: Chi² = 10.96, df = 1 (P = 0.0009)) were associated with more pronounced treatment effects (Analysis 3.8; Analysis 3.9).

3.6. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 6: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)

3.8. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 8: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

3.9. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 9: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron

Maternal iron‐deficiency anaemia at term (Hb below 110 g/L and at least one additional indicator of iron deficiency at 37 weeks' gestation or more)

In analyses of data from six trials with 1088 women (Cogswell 2003; Eskeland 1997; Falahi 2010; Makrides 2003; Milman 1991; Tura 1989), women who received daily iron supplements were less likely to have iron‐deficiency anaemia at term, compared to placebo or no supplementation (4.4% versus 13.2%; RR 0.33, 95% CI 0.16 to 0.69) (heterogeneity: Tau² = 0.30; Chi² = 7.77, df = 4 (P = 0.10); I² = 49%) (Analysis 3.11). There was little to no difference between subgroups (Analysis 3.12; Analysis 3.13; Analysis 3.14; Analysis 3.15).

3.11. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 11: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more) (ALL)

3.12. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 12: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation

3.13. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 13: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

3.14. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 14: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron

3.15. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 15: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting

Maternal death (death while pregnant or within 42 days of termination of pregnancy)

Two trials, including 1547 women, reported data for this outcome (Eskeland 1997; Fawzi 2010), and one trial provided estimable data for inclusion in meta‐analyses (Fawzi 2010). There was little to no difference between groups in maternal death (2 versus 3 events; RR 0.67, 95% CI 0.11 to 3.98) (Analysis 3.16).

3.16. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 16: Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)

Adverse effects (any reported throughout intervention period)

Nine trials, including 1677 women, reported data on adverse effects (Charoenlarp 1988; Cogswell 2003; De Benaze 1989; Eskeland 1997; Harvey 2007; Hood 1960; Kerr 1958; Makrides 2003; Paintin 1966). The findings suggested that the occurrence of adverse effects did not vary by intervention group (29% versus 21%; RR 1.59, 95% CI 1.00 to 2.52) (Analysis 3.17), and there was substantial heterogeneity between studies in treatment effects (heterogeneity: Tau² = 0.23; Chi² = 28.09, df = 7 (P = 0.0002); I² = 75%). Results were similar when restricted to trials that met a priori criteria for high quality (Cogswell 2003; Eskeland 1997; Harvey 2007; Makrides 2003) (data not shown). In subgroup analyses, findings suggested that the differences between groups may be more pronounced in malaria‐endemic settings, although only one trial in this analysis was conducted in a malaria‐endemic setting (Charoenlarp 1988) (test for subgroup differences: Chi² = 7.09, df = 1 (P = 0.008), I² = 85.9%) (Analysis 3.21). No other clear differences were identified between subgroups (Analysis 3.18; Analysis 3.19; Analysis 3.20).

3.17. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 17: Adverse effects (any reported throughout the intervention period) (ALL)

3.21. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 21: Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by malarial status of setting

3.18. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 18: Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by gestational age at the start of supplementation

3.19. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 19: Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

3.20. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 20: Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by dose of iron

Maternal severe anaemia at any time during the second or third trimester (Hb below 70 g/L)

Seven trials, involving 1078 women, evaluated severe anaemia during the second or third trimester (Batu 1976; Cogswell 2003; Eskeland 1997; Harvey 2007; Holly 1955; Makrides 2003; Milman 1991), although only two trials with 466 women provided estimable data for inclusion in quantitative analyses (Batu 1976; Makrides 2003). There may be little to no difference between groups for severe anaemia during the second or third trimester, comparing iron supplementation to placebo or no treatment (2 versus 3 events; RR 0.75, 95% CI 0.02 to 29.10) (heterogeneity: Tau² = 4.65; Chi² = 3.02, df = 1 (P = 0.08); I² = 67%) (Analysis 3.22). However, the limited number of trials and events reported constrains interpretation of the findings; in many cases, women who became anaemic during studies were treated and excluded from the analyses. There were no significant differences between subgroups (Analysis 3.23; Analysis 3.24; Analysis 3.25; Analysis 3.26).

3.22. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 22: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)

3.23. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 23: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestational age at the start of supplementation

3.24. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 24: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status age at the start of supplementation

3.25. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 25: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron

3.26. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 26: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting

Maternal clinical malaria (as defined by trialists)

No studies reported maternal clinical malaria as an outcome. However, one trial including 1003 women, reported data on placental malaria cases, defined based on placental histopathology (Fawzi 2010), with little to no difference between intervention groups (33 versus 33 events; RR 1.03, 95% CI 0.65 to 1.65) (Analysis 3.27).

3.27. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 27: Maternal clinical malaria

Other maternal primary outcomes

No studies reported data for other maternal outcomes, including infection during pregnancy.

Infant primary outcomes

Low birthweight (less than 2500 g)

In seven trials with 2499 participants (Cogswell 2003; Eskeland 1997; Falahi 2010; Fawzi 2010; Makrides 2003; Meier 2003; Menendez 1994 (C)), there may be little to no difference in infant low birthweight (less than 2500 g) (Analysis 3.28), between women who received daily iron supplementation during pregnancy and placebo or no treatment (5.6% versus 7.1%; RR 0.72, 95% CI 0.43 to 1.20) (heterogeneity: Tau² = 0.15; Chi² = 8.37, df = 5 (P = 0.14); I² = 40%) (Analysis 3.28). Findings were similar when analyses were limited to five trials that met pre‐specified criteria for high quality (Cogswell 2003; Eskeland 1997; Fawzi 2010; Makrides 2003; Menendez 1994 (C)) (data not shown). There were no clear differences between subgroups (Analysis 3.29; Analysis 3.30; Analysis 3.31; Analysis 3.32).

3.28. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 28: Low birthweight (less than 2500 g) (ALL)

3.29. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 29: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation

3.30. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 30: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

3.31. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 31: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron

3.32. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 32: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting

Birthweight (g)

In analyses of data from 10 trials with 1741 participants (Cogswell 2003; Eskeland 1997; Falahi 2010; Fawzi 2010; Harvey 2007; Makrides 2003; Milman 1991; Paintin 1966; Preziosi 1997; Puolakka 1980), there may be little to no difference between groups in infant birthweight (MD 14.7 g, 95% CI ‐35.60 to 65.01) (heterogeneity: Tau² = 1396.04; Chi² = 11.66, df = 9 (P = 0.23); I² = 23%) (Analysis 3.33). Results were similar when analyses were limited to trials that met a priori criteria for high quality (Cogswell 2003; Eskeland 1997; Fawzi 2010; Harvey 2007; Makrides 2003; Preziosi 1997) (data not shown), and there was little to no difference between subgroups (Analysis 3.34; Analysis 3.35; Analysis 3.36; Analysis 3.37).

3.33. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 33: Birthweight (g) (ALL)

3.34. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 34: Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation

3.35. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 35: Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

3.36. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 36: Birthweight (g): SUBGROUP ANALYSIS by dose of iron

3.37. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 37: Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting

Preterm birth (less than 37 weeks' gestation)

Seven trials, involving 3063 participants, provided data on preterm birth (less than 37 weeks' gestation) (Chan 2009; Cogswell 2003; Eskeland 1997; Falahi 2010; Fawzi 2010; Harvey 2007; Makrides 2003). There may be little to no difference between groups in preterm birth (10.3% versus 11.8%; RR 0.88, 95% CI 0.72 to 1.07) (heterogeneity: Tau² = 1396.04; Chi² = 11.66, df = 9 (P = 0.23); I² = 23%) (Analysis 3.38). Findings were similar when analyses were conducted with trials that met pre‐specified criteria for high quality (Cogswell 2003; Eskeland 1997; Fawzi 2010; Harvey 2007; Makrides 2003) (data not shown). There was no evidence of differences between subgroups (Analysis 3.39; Analysis 3.40; Analysis 3.41; Analysis 3.42).

3.38. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 38: Preterm birth (less than 37 weeks of gestation) (ALL)

3.39. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 39: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation

3.40. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 40: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

3.41. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 41: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron

3.42. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 42: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting

Neonatal death (within 28 days after delivery)

One trial, with 1367 participants, reported data for this outcome (Fawzi 2010). In this study, there was little to no difference in neonatal death between groups (3.0% versus 2.3%; RR 1.28, 95% CI 0.67 to 2.45) (Analysis 3.43).

3.43. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 43: Neonatal death (within 28 days after delivery) (ALL)

Congenital anomalies (including neural tube defects)

Two studies, with 2402 participants, reported data for congenital anomalies, including neural tube defects (Chan 2009; Christian 2003 (C)). There may be little to no difference in the risk of congenital anomalies between groups (2.9% versus 3.4%; RR 0.86, 95% CI 0.55 to 1.35) (heterogeneity: Tau² = 0.00; Chi² = 0.93, df = 1 (P = 0.33); I² = 0%) (Analysis 3.44).

3.44. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 44: Congenital anomalies (ALL)

Maternal secondary outcomes

Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more)

A total of 14 trials, involving 2678 women, contributed data for this outcome (Batu 1976; Chanarin 1971; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Fawzi 2010; Holly 1955; Makrides 2003; Milman 1991; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983). Iron supplementation may reduce maternal anaemia at or near term, compared to placebo or no supplements (17.5% versus 38.4%; RR 0.37, 95% CI 0.26 to 0.52) (Analysis 3.45). The substantial heterogeneity in analyses for this outcome, however, constrains interpretation of findings (heterogeneity: Tau² = 0.17; Chi² = 39.95, df = 13 (P = 0.0001); I² = 67%). Results were similar when analyses were restricted to trials that met a priori criteria for high quality (Cogswell 2003; Eskeland 1997; Fawzi 2010; Makrides 2003; Preziosi 1997) (data not shown).

3.45. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 45: Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)

Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more)

Eight trials, with 2248 women, reported data for maternal iron deficiency at or near term (Cogswell 2003; Eskeland 1997; Falahi 2010; Fawzi 2010; Makrides 2003; Milman 1991; Preziosi 1997; Tura 1989). Iron supplementation during pregnancy may reduce maternal iron deficiency at or near term, compared to placebo or no supplementation (19.3% versus 34.4%; RR 0.44, 95% CI 0.30 to 0.64) (Analysis 3.46). Due to high heterogeneity in analyses for this outcome, the results should be interpreted with caution (heterogeneity: Tau² = 0.22; Chi² = 42.78, df = 7 (P < 0.00001); I² = 84%). Findings were similar when analyses were restricted to trials meeting pre‐determined criteria for high quality (Cogswell 2003; Eskeland 1997; Makrides 2003; Preziosi 1997; Tura 1989) (data not shown).

3.46. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 46: Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)

Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional indicator of iron deficiency at 34 weeks' gestation or more)

A total of seven trials, involving 2043 women, contributed data for this outcome (Cogswell 2003; Eskeland 1997; Falahi 2010; Fawzi 2010; Makrides 2003; Milman 1991; Tura 1989). Iron supplementation may reduce maternal iron‐deficiency anaemia at or near term, compared to no treatment or placebo (3.8% versus 11.0%; RR 0.35, 95% CI 0.22 to 0.58) (heterogeneity: Tau² = 0.12; Chi² = 7.63, df = 5 (P = 0.18); I² = 34%) (Analysis 3.47). Findings were similar in analyses that were restricted to trials meeting apriori criteria for high quality (Cogswell 2003; Eskeland 1997; Fawzi 2010; Makrides 2003; Tura 1989) (data not shown).

3.47. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 47: Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more) (ALL)

Maternal haemoglobin concentrations at or near term (g/L, at 34 weeks' gestation or more)

A total of 16 trials, with 2599 women, reported data for this outcome (Batu 1976; Buytaert 1983; Cantlie 1971; Chanarin 1971; Cogswell 2003; De Benaze 1989; Eskeland 1997; Falahi 2010; Fawzi 2010; Makrides 2003; Milman 1991; Puolakka 1980; Romslo 1983; Tura 1989; Van Eijk 1978; Wallenburg 1983). Women who received iron supplements may have higher haemoglobin concentrations at term, compared to placebo or no treatment, with a mean difference of 8.8 g/L (MD 8.79 g/L, 95% CI 6.21 to 11.37) (Analysis 3.48). However, due to substantial heterogeneity in analyses, the findings should be interpreted with caution (heterogeneity: Tau² = 21.59; Chi² = 107.35, df = 15 (P < 0.00001); I² = 86%). In analyses limited to trials that met a priori criteria for high quality, the findings were similar (Cogswell 2003; Eskeland 1997; Fawzi 2010; Makrides 2003; Tura 1989; Wallenburg 1983) (data not shown).

3.48. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 48: Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)

Maternal haemoglobin concentrations within six weeks postpartum (in g/L)

Five trials, involving 521 women, reported data for haemoglobin concentrations during the postpartum period (Cantlie 1971; Lee 2005; Menendez 1994 (C); Milman 1991; Wills 1947). Iron supplementation during pregnancy may increase haemoglobin concentrations in the first six weeks postpartum, compared to placebo or no supplementation, with a mean difference of 7.4 g/L (MD 7.38 g/L, 95% CI 4.72 to 10.04) (heterogeneity: Tau² = 4.43; Chi² = 8.81, df = 5 (P = 0.12); I² = 43%) (Analysis 3.49).

3.49. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 49: Maternal Hb concentration within 6 weeks postpartum (in g/L) (ALL)

Maternal high haemoglobin concentrations at any time during second or third trimester (Hb greater than 130 g/L)

Seven trials, with 1146 women, evaluated the effects of iron supplementation on high haemoglobin concentrations during the second or third trimester of pregnancy, compared to placebo or no supplementation (Cogswell 2003; Eskeland 1997; Harvey 2007; Holly 1955; Makrides 2003; Milman 1991; Pritchard 1958). Women who received iron supplements during gestation may be more likely to have high haemoglobin concentrations during the second or third trimester of pregnancy, compared to placebo or no supplementation (30.6% versus 15.2%; RR 1.90, 95% CI 1.07 to 3.35) (Analysis 3.50). Due to substantial heterogeneity in analyses, the findings should be interpreted with caution (heterogeneity: Tau² = 0.38; Chi² = 24.50, df = 5 (P = 0.0002); I² = 80%). The results were similar when analyses were restricted to studies that met apriori criteria for high quality (Cogswell 2003; Eskeland 1997; Harvey 2007; Makrides 2003) (data not shown).

3.50. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 50: Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)

Maternal high haemoglobin concentrations at or near term (Hb greater than 130 g/L, at 34 weeks' gestation or more)

In analyses of data from seven trials involving 1189 women (Chisholm 1966; Cogswell 2003; Eskeland 1997; Holly 1955; Makrides 2003; Milman 1991; Pritchard 1958), women who received iron supplementation during pregnancy may be more likely to have high haemoglobin concentrations at or near term, compared to placebo or no treatment (30.1% versus 9.9%; RR 3.80, 95% CI 1.74 to 8.28) (heterogeneity: Tau² = 0.59; Chi² = 19.24, df = 6 (P = 0.004); I² = 69%) (Analysis 3.51). However, based on substantial heterogeneity in analyses, the results should be interpreted with caution. The findings were similar when analyses were limited to trials that met apriori criteria for high quality (Cogswell 2003; Eskeland 1997; Makrides 2003) (data not shown).

3.51. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 51: Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)

Other maternal secondary outcomes

There may be little to no difference between groups for other maternal secondary outcomes, including:

• Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (1 versus 3 events; RR 0.46, 95% CI 0.02 to 13.91; 3 trials, 453 women) (Batu 1976; Eskeland 1997; Makrides 2003) (heterogeneity: Tau² = 3.60; Chi² = 2.49, df = 1 (P = 0.11); I² = 60%) (Analysis 3.52).

• Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (2 versus 3 events; RR 0.74, 95% CI 0.02 to 27.81; 2 trials, 448 women) (Batu 1976; Makrides 2003) (heterogeneity: Tau² = 4.53; Chi² = 2.97, df = 1 (P = 0.08); I² = 66%) (Analysis 3.53).

• Severe anaemia postpartum (Hb less than 80 g/L) (0 events; 6 trials, 753 women) (Batu 1976; Eskeland 1997; Holly 1955; Makrides 2003; Milman 1991; Puolakka 1980) (Analysis 3.54).

• Puerperal infection (2.4% versus 3.9%; RR 0.65, 95% CI 0.41 to 1.03; 2 trials, 2292 women) (Chan 2009; Willoughby 1967) (heterogeneity: Tau² = 0.00; Chi² = 0.03, df = 1 (P = 0.86); I² = 0%) (Analysis 3.55).

• Antepartum haemorrhage (1 versus 0 events; RR 2.97, 95% CI 0.12 to 72.56; 1 trial, 430 women) (Makrides 2003) (Analysis 3.56).

• Postpartum haemorrhage (i.e. intrapartum and postnatal) (9.5% versus 11.6%; RR 0.81, 95% CI 0.49 to 1.34; 2 trials, 517 women) (Eskeland 1997; Wills 1947) (heterogeneity: Tau² = 0.00; Chi² = 0.01, df = 1 (P = 0.90); I² = 0%) (Analysis 3.57).

• Transfusion given (0 versus 1 event; RR 0.33, 95% CI 0.01 to 7.62; 1 trial, 32 women) (Puolakka 1980) (Analysis 3.58).

• Diarrhoea (2 versus 1 event; RR 0.98, 95% CI 0.09 to 10.61; 1 trial, 173 women) (Paintin 1966) (Analysis 3.59).

• Constipation (5.9% versus 5.4%; RR 0.88, 95% CI 0.18 to 4.40; 2 trials, 580 women) (Makrides 2003; Paintin 1966) (heterogeneity: Tau² = 0.83; Chi² = 2.03, df = 1 (P = 0.15); I² = 51%) (Analysis 3.60).

• Nausea (18.1% versus 15.8%; RR 2.38, 95% CI 0.49 to 11.52; 3 trials, 650 women) (Hood 1960; Makrides 2003; Paintin 1966) (heterogeneity: Tau² = 1.06; Chi² = 3.94, df = 2 (P = 0.14); I² = 49%) (Analysis 3.61).

• Heartburn (200 versus 200 events; RR 1.00, 95% CI 0.82 to 1.22; 1 trial, 408 women) (Makrides 2003) (Analysis 3.62).

• Vomiting (9.6% versus 11.8%; RR 0.88, 95% CI 0.38 to 2.07; 2 trials, 477 women) (Hood 1960; Makrides 2003) (heterogeneity: Tau² = 0.13; Chi² = 1.11, df = 1 (P = 0.29); I² = 10%) (Analysis 3.63).

• Maternal well‐being or satisfaction (87.5% versus 96%; RR 0.91, 95% CI 0.77 to 1.08; 1 trial, 49 women) (Eskeland 1997) (Analysis 3.64).

• Placental abruption (1 versus 0 events; RR 2.88, 95% CI 0.12 to 70.53; 1 trial, 1442 women) (Willoughby 1967) (Analysis 3.65).

• Pre‐eclampsia (1 versus 1 event; RR 0.96, 95% CI 0.06 to 14.43; 1 trial, 47 women) (Eskeland 1997) (Analysis 3.66).

3.52. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 52: Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)

3.53. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 53: Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)

3.54. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 54: Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)

3.55. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 55: Puerperal infection (ALL)

3.56. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 56: Antepartum haemorrhage (ALL)

3.57. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 57: Postpartum haemorrhage (ALL)

3.58. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 58: Transfusion provided (ALL)

3.59. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 59: Diarrhoea (ALL)

3.60. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 60: Constipation (ALL)

3.61. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 61: Nausea (ALL)

3.62. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 62: Heartburn (ALL)

3.63. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 63: Vomiting (ALL)

3.64. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 64: Maternal wellbeing/satisfaction (ALL)

3.65. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 65: Placental abruption (ALL)

3.66. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 66: Pre‐eclampsia (ALL)

None of the included trials reported data for other maternal secondary outcomes, including premature rupture of membranes.

Infant secondary outcomes

Infant ferritin concentrations in the first six months (μg/L, counting the last reported measure after birth within this period)

One trial, involving 197 participants, reported data for this outcome (Preziosi 1997). Infants born to women who received iron supplementation during pregnancy may have higher ferritin concentrations in the first six months of life, compared to placebo or no supplementation, with a mean difference of 11.0 μg/L (MD 11.00 μg/L, 95% CI 4.37 to 17.63 μg/L) (Analysis 3.70).

3.70. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 70: Infant serum ferritin concentration in the first 6 months (in μg/L, counting the last reported measure after birth within this period) (ALL)

Other infant secondary outcomes

There may be little to no difference between treatment groups for other infant secondary outcomes, including:

• Very low birthweight (less than 1500 g) (Cogswell 2003; Eskeland 1997; Makrides 2003) (2 versus 3 events; RR 0.55, 95% CI 0.03 to 9.07; 3 trials, 697 infants) (heterogeneity: Tau² = 2.24; Chi² = 2.19, df = 1 (P = 0.14); I² = 54%) (Analysis 3.67).

• Very premature birth (less than 34 weeks' gestation) (Cogswell 2003; Eskeland 1997; Fawzi 2010; Makrides 2003) (2.3% versus 3.6%; RR 0.68, 95% CI 0.41 to 1.14; 4 trials, 2040 infants) (heterogeneity: Tau² = 0.00; Chi² = 2.42, df = 3 (P = 0.49); I² = 0%) (Analysis 3.68).

• Infant haemoglobin concentrations in the first six months of life (g/L, counting the last reported measure after birth within this period) (MD ‐1.25 g/L, 95% CI ‐8.10 to 5.59; 2 trials, 533 infants) (heterogeneity: Tau² = 21.82; Chi² = 9.13, df = 1 (P = 0.003); I² = 89%) (Makrides 2003; Preziosi 1997) (Analysis 3.69).

• Admission to special care unit (0 events, 1 trial, 111 infants) (Meier 2003) (Analysis 3.71).

3.67. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 67: Very low birthweight (less than 1500 g) (ALL)

3.68. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 68: Very premature birth (less than 34 weeks' gestation) (ALL)

3.69. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 69: Infant Hb concentration in the first 6 months (in g/L, counting the last reported measure after birth within this period) (ALL)

3.71. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 71: Admission to special care unit (ALL)

No trials reported on other secondary infant outcomes, including infant development or motor skills.

(4) Supplementation with iron + folic acid versus placebo or no treatment (eight trials)

A total of eight trials contributed data comparing the effects of daily iron + folic acid supplementation to placebo or no treatment (Barton 1994; Batu 1976; Charoenlarp 1988; Chisholm 1966; Christian 2003 (C); Lee 2005; Taylor 1982; Willoughby 1967).

Maternal primary outcomes

Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more)

Three trials, including 346 women, contributed data for this outcome (Barton 1994; Batu 1976; Chisholm 1966). Iron + folic acid supplementation during pregnancy may reduce maternal anaemia (Hb < 110 g/L) at term, compared to placebo or no treatment (7.2% versus 28.2%; RR 0.34, 95% CI 0.21 to 0.54) (heterogeneity: Tau² = 0.00; Chi² = 0.49, df = 1 (P = 0.48); I² = 0%) (Analysis 4.1). There was no evidence of subgroup differences (Analysis 4.2; Analysis 4.3; Analysis 4.4; Analysis 4.5).

4.1. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 1: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)

4.2. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 2: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation

4.3. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 3: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

4.4. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 4: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron

4.5. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 5: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting

Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more)

In one trial, involving 131 women (Lee 2005), women who received iron + folic acid supplementation may be less likely to have iron deficiency at term, compared to placebo or no treatment (3.6% versus 15.0%; RR 0.24, 95% CI 0.06 to 0.99) (Analysis 4.6).

4.6. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 6: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)

Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more)

Data from one trial, involving 131 women (Lee 2005), suggests that women who received daily oral supplementation with iron + folic acid may be less likely to have iron‐deficiency anaemia at term, compared to women taking placebo or no treatment (10.8% versus 25.0%; RR 0.43, 95% CI 0.17 to 1.09) (Analysis 4.7).

4.7. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 7: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more) (ALL)

Maternal death

One study, including 131 women (Lee 2005), evaluated this outcome but did not report any estimable data for inclusion in quantitative analyses.

Adverse effects (any reported throughout the intervention period)

One trial, including 456 women, reported data on adverse effects (Charoenlarp 1988). In this study, women who received iron + folic acid supplementation may be more likely to report any adverse effects, compared to placebo or no supplementation (21.0% versus 0.0%; RR 44.32, 95% CI 2.77 to 709.09). However, this trial did not meet the pre‐determined criteria for high methodological quality (Analysis 4.9).

4.9. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 9: Adverse effects (any reported throughout the intervention period) (ALL)

Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L)

Two trials reported estimable data for this outcome (Batu 1976; Christian 2003 (C)). Findings from meta‐analyses suggest that women who received iron + folic acid supplementation may be less likely to have severe anaemia during the second or third trimester, compared to placebo or no supplementation (1 versus 15 events; RR 0.12, 95% CI 0.02 to 0.63) (heterogeneity: Tau² = 0.00; Chi² = 0.02, df = 1 (P = 0.88); I² = 0%) (Analysis 4.10).

4.10. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 10: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)

Maternal clinical malaria (as defined by trialists)

No studies reported data on this outcome.

Infection during pregnancy (including urinary tract infections)

One trial, with 48 women, reported data on infection in pregnancy (Taylor 1982), with two events in each group (Analysis 4.11).

4.11. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 11: Infection during pregnancy (including urinary tract infections) (ALL)

Infant primary outcomes

Low birthweight (less than 2500 g)

Two trials, with 1311 participants, reported data on this outcome (Christian 2003 (C); Taylor 1982). There may be little to no difference between groups for infant low birthweight, comparing iron + folic acid supplementation to placebo or no treatment (33.4% versus 40.2%; RR 1.07, 95% CI 0.31 to 3.74) (heterogeneity: Tau² = 0.47; Chi² = 1.41, df = 1 (P = 0.24); I² = 29%) (Analysis 4.12).

4.12. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 12: Low birthweight (less than 2500 g) (ALL)

Birthweight (g)

In analyses of data from two trials with 1365 participants (Christian 2003 (C); Taylor 1982), infants born to women who received iron + folic acid supplementation during pregnancy were 57.7 g heavier, compared to women who received placebo or no treatment (MD 57.73 g, 95% CI 7.66 to 107.79) (heterogeneity: Tau² = 116.92; Chi² = 1.03, df = 1 (P = 0.31); I² = 2%) (Analysis 4.13). One of these trials met apriori criteria for high quality (Christian 2003 (C)).

4.13. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 13: Birthweight (ALL)

Preterm birth (less than 37 weeks' gestation)

Three studies, with 1497 participants, reported data for this outcome (Christian 2003 (C); Lee 2005; Taylor 1982); two of these trials contributed estimable data for inclusion in quantitative analyses. There may be little to no difference between intervention groups for preterm birth (19.4% versus 19.2%; RR 1.55, 95% CI 0.40 to 6.00) (heterogeneity: Tau² = 0.57; Chi² = 1.51, df = 1 (P = 0.22); I² = 34%) (Analysis 4.14). One of these trials met pre‐determined criteria for high quality (Christian 2003 (C)). There was no evidence of differences in subgroup analyses (Analysis 4.15; Analysis 4.16; Analysis 4.17; Analysis 4.18).

4.14. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 14: Preterm birth (less than 37 weeks of gestation) (ALL)

4.15. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 15: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation

4.16. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 16: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

4.17. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 17: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron

4.18. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 18: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting

Neonatal death (within 28 days after delivery)

Three studies, with 1793 participants, reported data for this outcome (Barton 1994; Christian 2003 (C); Taylor 1982). There may be little to no difference in neonatal death between intervention groups (3.4% versus 4.2%; RR 0.81, 95% CI 0.51 to 1.30) (heterogeneity: Tau² = 0.00; Chi² = 0.49, df = 1 (P = 0.48); I² = 0%) (Analysis 4.19).

4.19. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 19: Neonatal death (within 28 days after delivery) (ALL)

Congenital anomalies, including neural tube defects

One trial, with 1652 participants, reported data on this outcome (Christian 2003 (C)); in this study, there may be little to no difference between groups for congenital anomalies (1.7% versus 2.4%; RR 0.70, 95% CI 0.35 to 1.40) (Analysis 4.24).

4.24. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 24: Congenital anomalies (ALL)

Maternal secondary outcomes

Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more)

In analyses of data from three trials including 346 women (Barton 1994; Batu 1976; Chisholm 1966), iron + folic acid supplementation may reduce anaemia at term (Hb < 110 g/L), compared to placebo or no supplementation (7.2% versus 28.2%; RR 0.34, 95% CI 0.21 to 0.54) (heterogeneity: Tau² = 0.00; Chi² = 0.49, df = 1 (P = 0.48); I² = 0%) (Analysis 4.25).

4.25. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 25: Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)

Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more)

One trial, involving 131 women, reported data for this outcome (Lee 2005). In this study, women who routinely received daily oral supplementation with iron + folic acid may be less likely to have iron deficiency at term, compared to placebo or no supplementation (3.6% versus 15%; RR 0.24; 95% CI 0.06 to 0.99) (Analysis 4.26).

4.26. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 26: Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)

Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more)

One trial, with 131 women, contributed data for this outcome (Lee 2005). There may be little to no difference between groups for iron‐deficiency anaemia at or near term (10.8% versus 25.0%; RR 0.43, 95% CI 0.17 to 1.09); this study did not meet the prespecified criteria for high quality (Analysis 4.27).

4.27. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 27: Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more) (ALL)

Maternal haemoglobin concentrations at or near term (g/L, at 34 weeks' gestation or more)

In analyses of data from three trials including 140 women (Barton 1994; Batu 1976; Taylor 1982), women who routinely received daily iron + folic acid supplementation may be more likely to have higher haemoglobin concentrations at or near term, compared to placebo or no supplements, with a mean difference of 16.1 g/L (MD 16.13 g/L, 95% CI 12.74 to 19.52) (heterogeneity: Tau² = 0.00; Chi² = 0.44, df = 2 (P = 0.80); I² = 0%) (Analysis 4.28). One trial met apriori criteria for high quality; in this study, iron + folic acid supplementation during pregnancy was associated with higher haemoglobin concentrations, compared to placebo or no supplementation (MD 17.10 g/L, 95% CI 8.44 to 25.76) (Barton 1994).

4.28. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 28: Maternal Hb concentration at term or near term (in g/L, at 34 weeks' gestation or more) (ALL)

Maternal haemoglobin concentrations within six weeks postpartum (g/L)

Two studies, involving 459 women, reported data on this outcome (Christian 2003 (C); Taylor 1982). Women who received daily iron + folic acid supplementation during pregnancy may be more likely to have higher haemoglobin concentrations during the first six weeks postpartum, compared to women who received placebo or no supplementation, with an average difference of 10.1 g/L (MD 10.07 g/L, 95% CI 7.33 to 12.81) (Tau² = 0.00; Chi² = 0.01, df = 1 (P = 0.91); I² = 0%) (Analysis 4.29).

4.29. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 29: Maternal Hb concentration within 6 weeks postpartum (g/L) (ALL)

Maternal high haemoglobin concentrations at any time during the second or third trimester of pregnancy (Hb greater than 130 g/L)

In analyses of data from two trials involving 446 women (Christian 2003 (C); Lee 2005), there may be little to no difference between groups for high haemoglobin concentrations, comparing women who received daily iron + folic acid supplements to placebo or no treatment (18.6% versus 7.5%; RR 1.78, 95% CI 0.63 to 5.04) (heterogeneity: Tau² = 0.39; Chi² = 3.20, df = 1 (P = 0.07); I² = 69%) (Analysis 4.30).

4.30. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 30: Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)

Maternal high haemoglobin concentrations at term (Hb greater than 130 g/L at 37 weeks' gestation or more)

There may be little to no difference between groups for high haemoglobin concentrations at term, in analyses of two trials with 344 women (Chisholm 1966; Lee 2005) (6.4% versus 0.0%; RR 4.37, 95% CI 0.58 to 32.71) (heterogeneity: Tau² = 0.00; Chi² = 0.00, df = 1 (P = 0.99); I² = 0%) (Analysis 4.31).

4.31. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 31: Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)

Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more)

Three trials, including 191 women, evaluated severe anaemia at term (Barton 1994; Batu 1976; Lee 2005); however, one trial reported cases of severe anaemia during the study period (Batu 1976) (0 versus 3 events; RR 0.14, 95% CI 0.01 to 2.63) (Analysis 4.33).

4.33. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 33: Maternal severe anaemia at term or near (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)

Maternal severe or moderate anaemia at postpartum (Hb less than 80 g/L)

One trial contributed estimable data to meta‐analyses for moderate anaemia (458 women) (Christian 2003 (C)) (Analysis 4.32) or severe anaemia (491 women) (Analysis 4.34) during the postpartum period.

4.32. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 32: Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)

4.34. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 34: Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)

Other maternal secondary outcomes

There may be little to no difference between groups for other maternal secondary outcomes, including the following.

• Puerperal infection (5 versus 3 events; RR 0.55, 95% CI 0.13 to 2.28; 1 trial, 2863 women) (Willoughby 1967) (Analysis 4.35).

• Antepartum haemorrhage (3 versus 2 events; RR 1.25, 95% CI 0.22 to 7.12; 2 trials, 145 women) (Barton 1994; Taylor 1982) (Analysis 4.36).

• Placental abruption (12 versus 0 events; RR 8.19, 95% CI 0.49 to 138.16; 1 trial, 2863 women) (Willoughby 1967) (Analysis 4.37).

• Pre‐eclampsia (1 versus 0 events; RR 3.00, 95% CI 0.13 to 70.16; 1 trial, 48 women) (Taylor 1982) (Analysis 4.38).

4.35. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 35: Puerperal infection (ALL)

4.36. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 36: Antepartum haemorrhage (ALL)

4.37. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 37: Placental abruption (ALL)

4.38. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 38: Pre‐eclampsia (ALL)

No trials reported on the remaining maternal secondary outcomes, including: postpartum haemorrhage (intrapartum and postnatal), transfusion given, diarrhoea, constipation, nausea, heartburn, vomiting, maternal well‐being or satisfaction, placental abruption, premature rupture of membranes, or pre‐eclampsia.

Infant secondary outcomes

There may be little to no difference between groups for the following infant secondary outcomes:

• Very low birthweight (less than 1500 g) (2 versus 0 events; RR 5.00, 95% CI 0.25 to 98.96; 1 trial, 48 infants) (Taylor 1982) (Analysis 4.39).

• Very premature birth (less than 34 weeks' gestation) (2 versus 0 events; RR 5.00, 95% CI 0.25 to 98.96; 2 trials, 92 infants) (Lee 2005; Taylor 1982) (Analysis 4.40).

• Admission to special care unit (0 events reported; 1 trial, 48 infants) (Taylor 1982) (Analysis 4.41).

4.39. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 39: Very low birthweight (less than 1500 g) (ALL)

4.40. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 40: Very premature birth (less than 34 weeks' gestation) (ALL)

4.41. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 41: Admission to special care unit (ALL)

There were no data reported for other infant secondary outcomes, including: infant haemoglobin concentrations in the first six months of life (g/L), ferritin concentrations in the first six months (μg/L), and infant development or motor skills.

(5) Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation (six trials)

Six trials were included in this comparison (Christian 2003 (C); Liu 2012 ; Zeng 2008 (C); Batu 1976; Chisholm 1966; Zhao 2014). In the study by Zeng 2008 (C), the reported sample size and event rate have been adjusted to account for the design effect of the cluster‐randomised trial. In the results below, we reported the effective sample size rather than the total number of women included in the trial.

Maternal primary outcomes

Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more)

Four studies, with 13,463 women, reported data on this outcome (Batu 1976; Chisholm 1966; Liu 2012; Zhao 2014). Iron + folic acid supplementation may reduce anaemia at term, compared to folic acid alone (4.2% versus 6.1%; RR 0.53, 95% CI 0.33 to 0.85) (Analysis 5.1). However, the substantial heterogeneity in these analyses constrained the interpretation of findings (heterogeneity: Tau² = 0.18; Chi² = 22.68, df = 3 (P < 0.0001); I² = 87%). Findings were similar when limited to trials that met apriori criteria for high quality (data not shown). Interpretation of results from subgroup analyses were constrained by imbalance between subgroups (Analysis 5.2; Analysis 5.3; Analysis 5.4; Analysis 5.5).

5.1. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 1: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)

5.2. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 2: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation

5.3. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 3: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

5.4. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 4: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more ): SUBGROUP ANALYSIS by dose of iron

5.5. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 5: Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting

Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more)

One trial, including 1617 women, reported data on this outcome (Zhao 2014). In this study, women who received iron + folic acid supplementation during pregnancy may be less likely to have iron deficiency at term, compared to folic acid alone (56.7% versus 77.1%; RR 0.74, 95% CI 0.69 to 0.79) (Analysis 5.6).

5.6. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 6: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)

Maternal iron‐deficiency anaemia at term (haemoglobin less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more)

One study, including 1616 women, reported data on maternal iron‐deficiency anaemia at term (Zhao 2014). In this study, women receiving iron + folic acid supplementation may be less likely to have iron‐deficiency anaemia at term, compared to folic acid without iron (10.6% versus 21.7%; RR 0.49, 95% CI 0.38 to 0.62) (Analysis 5.7).

5.7. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 7: Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more) (ALL)

Maternal death (death while pregnant or within 42 days of termination of pregnancy)

No studies reported this outcome.

Adverse effects (any reported throughout the intervention period)

One of the included trials reported on the occurrence of adverse effects (Zhao 2014). In this study, more than two‐thirds of women in both intervention groups (68.4% versus 68.2%; 1617 women) reported adverse effects, including nausea, vomiting, diarrhoea, or constipation. However, estimable data were not reported for inclusion in meta‐analyses.

Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L)

Two studies, with 320 women, evaluated severe anaemia during the second or third trimester of pregnancy (Batu 1976; Christian 2003 (C)), although one trial reported estimable data for inclusion in quantitative analyses (Christian 2003 (C)). In this study, women who received iron + folic acid during gestation may be less likely to have severe anaemia during the second or third trimester of pregnancy, compared to folic acid alone (1 versus 16 events; RR 0.06, 95% CI 0.01 to 0.47) (Analysis 5.8).

5.8. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 8: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)

Maternal clinical malaria (as defined by trialists)

No trials reported data on this outcome.

Infection during pregnancy (including urinary tract infections)

No studies reported this outcome.

Infant primary outcomes

Low birthweight (less than 2500 g)

Three trials contributed data to this outcome (Christian 2003 (C); Liu 2012 ; Zeng 2008 (C)). There may be little to no difference between intervention groups on infant low birthweight, comparing iron + folic acid supplementation to folic acid alone (5.2% versus 5.8%; RR 0.88, 95% CI 0.76 to 1.01; 3 trials, effective sample size: 15,416 infants) (heterogeneity: Tau² = 0.00; Chi² = 2.52, df = 2 (P = 0.28); I² = 21%) (Analysis 5.9). All of these trials met apriori criteria for high quality. Subgroup analyses were constrained due to the limited number of trials (Analysis 5.10; Analysis 5.11; Analysis 5.12; Analysis 5.13).

5.9. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 9: Low birthweight (less than 2500 g) (ALL)

5.10. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 10: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation

5.11. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 11: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

5.12. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 12: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron

5.13. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 13: Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting

Birthweight (g)

In analyses of data from three trials (Christian 2003 (C); Liu 2012; Zeng 2008 (C)), there may be little to no difference between groups for infant birthweight (MD 22.78 g, 95% CI ‐10.07 to 55.63; 3 trials, effective sample size: 15,416 infants) (heterogeneity: Tau² = 575.91; Chi² = 6.66, df = 2 (P = 0.04); I² = 70%) (Analysis 5.14). All of these studies met pre‐determined criteria for high quality. Subgroup analyses were limited by the number of trials (Analysis 5.15; Analysis 5.16; Analysis 5.17; Analysis 5.18).

5.14. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 14: Birthweight (g) (ALL)

5.15. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 15: Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation

5.16. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 16: Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

5.17. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 17: Birthweight (g): SUBGROUP ANALYSIS by dose of iron

5.18. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 18: Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting

Preterm birth (less than 37 weeks' gestation)

Three trials contributed data to this outcome (Christian 2003 (C); Liu 2012 ; Zeng 2008 (C)). Iron + folic acid supplementation likely did not reduce preterm birth, compared to folic acid alone (7.0% versus 7.4%; RR 0.96, 95% CI 0.86 to 1.08; 3 trials, effective sample size: 15,416 infants) (heterogeneity: Tau² = 0.00; Chi² = 2.08, df = 2 (P = 0.35); I² = 4%) (Analysis 5.19). All of these trials met a priori criteria for high quality. Subgroup analyses were constrained by the limited number of trials (Analysis 5.20; Analysis 5.21; Analysis 5.22; Analysis 5.23).

5.19. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 19: Preterm birth (less than 37 weeks of gestation) (ALL)

5.20. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 20: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation

5.21. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 21: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

5.22. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 22: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron

5.23. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 23: Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting

Neonatal death (within 28 days after delivery)

Three studies reported data for this outcome (Christian 2003 (C); Liu 2012; Zeng 2008 (C)). There may be little to no difference between groups for neonatal death (1.3% versus 1.5%; RR 0.93, 95% CI 0.72 to 1.21; 3 trials, effective sample size: 15,416 infants) (heterogeneity: Tau² = 0.00; Chi² = 0.99, df = 2 (P = 0.61); I² = 0%) (Analysis 5.24). Subgroup analyses were limited by the number of events in the included trials (Analysis 5.25; Analysis 5.26; Analysis 5.27; Analysis 5.28).

5.24. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 24: Neonatal death (within 28 days after delivery) (ALL)

5.25. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 25: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at the start of supplementation

5.26. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 26: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

5.27. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 27: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron

5.28. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 28: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting

Congenital anomalies, including neural tube defects

Two studies, with 13,586 participants, reported data for this outcome (Christian 2003 (C); Liu 2012). There may be little to no difference between groups in the occurrence of congenital anomalies (20 versus 28 events; RR 0.78, 95% CI 0.44 to 1.39) (heterogeneity: Tau² = 0.00; Chi² = 0.30, df = 1 (P = 0.58); I² = 0%) (Analysis 5.29).

5.29. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 29: Congenital anomalies (ALL)

Maternal secondary outcomes

Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more)

Two studies, with 303 women, reported maternal anaemia at or near term (Batu 1976; Chisholm 1966). Iron + folic acid supplements during pregnancy may reduce maternal anaemia at term, compared to folic acid alone (9.7% versus 30.4%; RR 0.34, 95% CI 0.21 to 0.55) (heterogeneity: Tau² = 0.00; Chi² = 0.85, df = 1 (P = 0.36); I² = 0%) (Analysis 5.30). Findings were similar when limited to trials that met a priori criteria for high quality (data not shown).

5.30. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 30: Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)

Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more)

No trials included reported data for this outcome.

Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional indicator of iron deficiency at 34 weeks' gestation or more)

No study reported this outcome.

Maternal haemoglobin concentrations at or near term (g/L, at 34 weeks' gestation or more)

One trial, with 44 women, contributed data to this outcome (Batu 1976). In this study, women who received iron + folic acid supplementation during pregnancy may be more likely to have higher mean haemoglobin concentrations at term, compared to folic acid alone (MD 19.00 g/L, 95% CI 11.02 to 26.98) (Analysis 5.31).

5.31. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 31: Maternal Hb concentration at or near term (in g/L at 34 weeks' gestation or more) (ALL)

Maternal haemoglobin concentration within six weeks postpartum (g/L)

One trial, with 297 women, contributed data for this outcome (Christian 2003 (C)). In this study, women who received iron + folic acid during pregnancy may be more likely to have higher mean haemoglobin concentrations during the first six weeks postpartum, compared to women who received folic acid alone (MD 9.20 g/L, 95% CI 5.78 to 12.62) (Analysis 5.32).

5.32. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 32: Maternal Hb concentration within 6 weeks postpartum (in g/L) (ALL)

Maternal high haemoglobin concentrations at any time during second or third trimesters (Hb greater than 130 g/L)

One study, with 315 women, reported data on this outcome (Christian 2003 (C)). In this trial, women who received iron + folic acid may be more likely to have high haemoglobin concentrations during the second or third trimester of pregnancy, compared to folic acid alone (17.6% versus 6.1%; RR 2.87, 95% CI 1.46 to 5.66) (Analysis 5.33).

5.33. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 33: Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)

Maternal high haemoglobin concentrations at or near term (at 37 weeks' gestation or more)

One study, with 240 women, reported data on this outcome (Chisholm 1966). In this trial, there may be little to no difference between groups for high haemoglobin concentrations at or near term (4 versus 0 events; RR 8.56, 95% CI 0.47 to 157.35) (Analysis 5.34).

5.34. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 34: Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)

Moderate anaemia postpartum (Hb between 80 and 109 g/L)

In one trial, with 353 women (Christian 2003 (C)), women who received iron + folic acid may be less likely to have moderate anaemia postpartum, compared to folic acid alone (5.1% versus 13.1%; RR 0.38, 95% CI 0.18 to 0.81) (Analysis 5.35).

5.35. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 35: Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)

Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more)

One trial amongst 46 women assessed this outcome (Batu 1976); no cases of severe anaemia were reported in either intervention group (Analysis 5.36).

5.36. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 36: Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)

Severe anaemia postpartum (Hb less than 80 g/L)

Two studies evaluated severe anaemia during the postpartum period (Batu 1976; Christian 2003 (C)), although one trial contributed estimable data to quantitative analyses (Christian 2003 (C)). There may be little to no difference between groups for severe anaemia postpartum (0 versus 6 events; RR 0.08, 95% CI 0.00 to 1.33) (Analysis 5.37).

5.37. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 37: Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)

Other maternal secondary outcomes

Other maternal secondary outcomes were not reported, including: puerperal infection, antepartum haemorrhage, postpartum haemorrhage (i.e. intrapartum and postnatal), transfusion provided, vomiting, diarrhoea, heartburn, nausea, constipation, placental abruption, premature rupture of membranes, pre‐eclampsia, and maternal well‐being or satisfaction.

Infant secondary outcomes

The following infant outcomes were reported in one trial each, and there may be little to no difference between intervention groups: very low birthweight (less than 1500 g) (6 versus 9 events; RR 0.66, 95% CI 0.24 to 1.84) (Christian 2003 (C)) (Analysis 5.38), very premature birth (less than 34 weeks' gestation) (1.1% versus 1.9%; RR 0.55, 95% CI 0.27 to 1.10) (Zeng 2008 (C)) (Analysis 5.39), or infant haemoglobin concentrations in the first six months (g/L) (MD 0.00 g/L, 95% CI ‐0.32 to 0.32) (Liu 2012) (Analysis 5.40).

5.38. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 38: Very low birthweight (less than 1500 g) (ALL)

5.39. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 39: Very premature birth (less than 34 weeks' gestation) (ALL)

5.40. Analysis.

Comparison 5: Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation, Outcome 40: Infant Hb concentration in the first 6 months (in g/L, counting the last reported measure after birth within this period) (ALL)

The following infant secondary outcomes were not reported: infant serum ferritin concentrations in the first six months of life (μg/L) or admission to a special care unit.

(6) Supplementation with iron + other vitamins and minerals supplementation versus the same other vitamins and minerals (without iron) supplementation (four trials)

Four trials contributed data to this comparison (Bloxam 1989; Cantlie 1971; Dawson 1989; Siega‐Riz 2001).

Maternal primary outcomes

Adverse effects (any reported throughout the intervention period)

One study, including 188 women, reported data on adverse effects (Siega‐Riz 2001); there was little to no difference in adverse effects between groups (38.3% versus 50%; RR 0.77, 95% CI 0.55 to 1.07) (Analysis 6.1).

6.1. Analysis.

Comparison 6: Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation, Outcome 1: Adverse effects (any reported throughout the intervention period) (ALL)

No trials reported the following maternal primary outcomes: maternal anaemia at term, iron deficiency at term, iron‐deficiency anaemia at term, maternal death, severe anaemia at any time during second and third trimester, clinical malaria, and infection during pregnancy.

Infant primary outcomes

Low birthweight (less than 2500 g)

Two trials, including 375 participants, provided data for this outcome (Dawson 1989; Siega‐Riz 2001). There may be little to no difference between groups for infant low birthweight (4.3% versus 9.0%; RR 0.49, 95% CI 0.22 to 1.09) (heterogeneity: Tau² = 0.00; Chi² = 0.05, df = 1 (P = 0.82); I² = 0%) (Analysis 6.2).

6.2. Analysis.

Comparison 6: Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation, Outcome 2: Low birthweight (less than 2500 g) (ALL)

Birthweight (g)

Three of the included trials, with 397 participants, reported data for this outcome (Bloxam 1989; Dawson 1989; Siega‐Riz 2001). There may be little to no difference in mean infant birthweight between intervention groups (MD 100.3 g, 95% CI ‐320.17 to 520.77) (heterogeneity: Tau² = 134154.64; Chi² = 105.97, df = 2 (P < 0.00001); I² = 98%) (Analysis 6.3).

6.3. Analysis.

Comparison 6: Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation, Outcome 3: Birthweight (g) (ALL)

Preterm birth (less than 37 weeks of gestation)

One study, involving 345 participants, reported data on this outcome (Siega‐Riz 2001). In this study, there may be little to no difference between groups for preterm birth (7.5% versus 14.0%; RR 0.54, 95% CI 0.28 to 1.02) (Analysis 6.4).

6.4. Analysis.

Comparison 6: Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation, Outcome 4: Preterm birth (less than 37 weeks of gestation) (ALL)

Neonatal death (within 28 days after delivery)

No trials reported data on neonatal death.

Congenital anomalies, including neural tube defects

One trial, with 41 participants, assessed congenital anomalies (Dawson 1989); no cases were reported in either group (Analysis 6.5).

6.5. Analysis.

Comparison 6: Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation, Outcome 5: Congenital anomalies (ALL)

Maternal secondary outcomes

Maternal haemoglobin concentrations at or near term (g/L, at 34 weeks' gestation or more)

Two studies, involving 49 women, reported data for this outcome (Bloxam 1989; Cantlie 1971). Women who received iron + other vitamins and minerals may be more likely to have higher haemoglobin concentrations at or near term, compared to the same supplements without iron, with a mean difference of 13.13 g/L (MD 13.13 g/L, 95% CI 10.97 to 15.30) (heterogeneity: Tau² = 0.00; Chi² = 0.09, df = 1 (P = 0.76); I² = 0%) (Analysis 6.6).

6.6. Analysis.

Comparison 6: Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation, Outcome 6: Maternal Hb concentration at or near term (in g/L at 34 weeks' gestation or more) (ALL)

Maternal haemoglobin concentrations within six weeks postpartum (g/L)

One study, involving 27 women, reported data for this outcome (Cantlie 1971). In this study, women who received iron + other vitamins and minerals may be more likely to have higher haemoglobin concentrations postpartum, compared to the same supplements without iron (MD 14.00, 95% CI 3.56 to 24.44 g/L) (Analysis 6.7).

6.7. Analysis.

Comparison 6: Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation, Outcome 7: Maternal Hb concentration within 6 weeks postpartum (in g/L) (ALL)

Other maternal secondary outcomes

One trial, with 188 women, reported data on adverse effects (Siega‐Riz 2001). There may be little to no difference between groups on the following adverse effects.

• Diarrhoea (14.0% versus 26.7%; RR 0.53, 95% CI 0.29 to 0.96) (Analysis 6.11).

• Constipation (38.3% versus 50%; RR 0.77, 95% CI 0.55 to 1.07) (Analysis 6.8).

• Heartburn (42.2% versus 28.3%; RR 1.49, 95% CI 0.95 to 2.34) (Analysis 6.9).

• Vomiting (18.8% versus 16.7%; RR 1.13, 95% CI 0.58 to 2.20) (Analysis 6.10).

6.11. Analysis.

Comparison 6: Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation, Outcome 11: Diarrhoea (ALL)

6.8. Analysis.

Comparison 6: Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation, Outcome 8: Constipation (ALL)

6.9. Analysis.

Comparison 6: Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation, Outcome 9: Heartburn (ALL)

6.10. Analysis.

Comparison 6: Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation, Outcome 10: Vomiting (ALL)

No trials reported other maternal secondary outcomes, including: puerperal infection (i.e. intrapartum and postnatal), antepartum haemorrhage, postpartum haemorrhage, transfusion provided, nausea, placental abruption, premature rupture of the membranes, or pre‐eclampsia.

Infant secondary outcomes

No studies reported data on infant secondary outcomes.

(7) Daily oral iron + folic acid + other vitamins and minerals supplementation versus folic acid + the same other vitamins and minerals (without iron) (0 trials)

None of the included trials evaluated the effects of daily oral supplementation with iron + folic acid + other vitamins and minerals, compared to folic acid + the same vitamins and minerals (without iron).

(8) Daily oral iron + folic acid + other vitamins and minerals supplementation versus the same other vitamins and minerals (without iron or folic acid) (0 trials)

No studies evaluated the effects of daily oral supplementation with iron + folic acid + other vitamins and minerals, compared to the same vitamins and minerals (without iron or folic acid).

Discussion

Summary of main results

This review included 57 randomised trials. A total of 41 trials contributed quantitative data to analyses: 40 trials evaluated the effects of iron supplementation compared to placebo or no iron, and eight trials evaluated the effects of iron + folic acid supplementation compared to placebo or no iron + folic acid. The summary of the main findings from this review and assessment of the certainty of the evidence are reported in the summary tables (Table 1; Table 2; Table 3; Table 4).

Iron supplementation compared to placebo or no iron (40 trials)

Maternal outcomes. Iron supplementation during pregnancy may reduce maternal anaemia at term (low‐certainty evidence), and maternal iron deficiency at term (low‐certainty evidence), and probably reduces maternal iron‐deficiency anaemia at term (moderate‐certainty evidence), compared to placebo or no iron (Table 1). However, there is probably little to no difference in maternal death (moderate‐certainty evidence), compared to placebo or no iron supplementation. There may be little to no difference between groups for other maternal primary outcomes, including adverse effects (very low‐certainty evidence) or severe anaemia (Hb < 70 g/L) in the second or third trimester (very low‐certainty evidence), but the evidence is very uncertain (Table 1). No trials reported maternal clinical malaria or infection during pregnancy. For some outcomes, there was substantial heterogeneity in analyses (i.e. the size of the treatment effect in individual studies varied considerably), and results should be interpreted with caution.

Infant outcomes. Iron supplementation during pregnancy probably reduced low birthweight (moderate‐certainty evidence), compared to placebo or no iron supplementation. The evidence is very uncertain for infant birthweight (very low‐certainty evidence); there is probably little to no difference between intervention groups for preterm birth (moderate‐certainty evidence), and there may be little to no difference in neonatal death (low‐certainty evidence), or congenital anomalies including neural tube defects (low‐certainty evidence) (Table 2).

Iron + folic acid supplementation compared to placebo or no iron + folic acid (8 trials)

Maternal outcomes. Iron + folic acid supplementation during pregnancy probably reduces maternal anaemia at term (moderate‐certainty evidence), and may reduce maternal iron deficiency at term (low‐certainty evidence); however, the evidence is very uncertain for iron‐deficiency anaemia (very low‐certainty evidence), or maternal death (very low‐certainty evidence), compared to placebo or no iron + folic acid supplementation. The evidence is uncertain about any adverse effects (low‐certainty evidence). The evidence is very uncertain for severe anaemia in the second or third trimester (very low‐certainty evidence), compared to placebo or no iron + folic acid (Table 3). Maternal death was included as an outcome in one trial, and no events were reported in either intervention group; few studies reported on the occurrence of adverse effects, and no studies reported data on maternal clinical malaria.

Infant outcomes. There may be little to no difference between intervention groups for infant outcomes, including infant low birthweight (low‐certainty evidence), and there is probably higher birthweight (moderate‐certainty evidence), compared to placebo or no iron + folic acid. There may be little to no difference between groups in other infant outcomes including preterm birth (low‐certainty evidence), neonatal death (low‐certainty evidence), or congenital anomalies including neural tube defects (low‐certainty evidence), comparing iron + folic acid supplementation to placebo or no iron + folic acid supplementation (Table 4).

Overall completeness and applicability of evidence

A total of 57 randomised trials were included in this review, conducted in 27 countries and beginning in 1947. Most of the trials included in this review were conducted during the last three decades. These trials were conducted amongst diverse populations and settings in 27 countries, and had a range of anaemia and iron status at enrolment and timing of initiation of iron supplementation in pregnancy.

This review was conducted to examine the effects of daily supplementation with iron during pregnancy, either provided alone, with folic acid, or in combination with other vitamins and minerals. In this review, two main comparisons were defined to evaluate the effects of daily supplementation with 1) iron compared to placebo or no iron supplementation and 2) iron + folic acid compared to placebo or no iron + folic acid supplementation. These comparisons were designed to evaluate the independent effects of iron, compared to the same supplements without iron (and iron + folic acid supplementation, compared to no iron + folic acid). Provided the composition of the supplement formulation and co‐interventions administered to intervention groups were the same, these comparisons enable evaluation of the effects of iron (or iron + folic acid) supplementation, independent of the other co‐interventions administered to groups being compared.

Most of the included trials in this review reported maternal haematological outcomes, including maternal haemoglobin concentrations, anaemia, iron deficiency, and iron‐deficiency anaemia, after a certain duration of iron supplementation. Results from analyses consistently demonstrated that daily iron supplementation during pregnancy reduced maternal anaemia and iron deficiency at term. Findings from this review are consistent with current World Health Organization (WHO) recommendations of daily iron supplementation during pregnancy (30 mg to 60 mg) for prevention of anaemia (WHO 2012a; WHO 2017).

In subgroup analyses, women who consumed higher amounts of iron (60 mg of iron or more per day) during pregnancy tended to have higher haemoglobin concentrations at the end or near term of pregnancy. In some cases, maternal haemoglobin concentrations at term were above 130 g/L (at sea level). Although the clinical significance of high haemoglobin concentrations has not been established, recent evidence suggests that high haemoglobin concentrations during gestation may be associated with increased risk of some adverse pregnancy outcomes (Dewey 2017; Young 2023). For example, in observational studies, maternal haemoglobin levels > 130 g/L have been associated with increased risk of preterm birth (Dewey 2017; Young 2023), low birthweight (Carpenter 2022; Dewey 2017; Young 2023), and pre‐eclampsia (Dewey 2017; Young 2023), and higher maternal haemoglobin concentrations have been associated with risk of stillbirth (Hb ≥ 140 g/L) (Maghsoudlou 2016) and pregnancy‐induced hypertension and acute respiratory distress syndrome (Hb ≥ 165 g/L) (Ohuma 2023). Findings from this review are consistent with current WHO recommendations for daily iron supplementation (30 mg to 60 mg) during pregnancy (WHO 2012a; WHO 2017). The potential efficacy of lower dose iron supplements in populations with lower prevalence of anaemia and iron deficiency is being evaluated elsewhere (Angeletti 2023; Sundler 2020).

Adverse effects are an important consideration for the design of interventions, to support adherence and inclusion of interventions in standard antenatal care. The occurrence of gastrointestinal adverse effects with higher dose iron supplementation (≥ 45 mg elemental iron daily), including nausea and constipation, has been well‐established (IOM 2001). Findings from this review suggest that there were no differences in the occurrence of adverse effects between groups receiving iron supplements and those receiving placebo or no iron supplements, although one trial reported that adverse effects with iron + folic acid supplementation may be higher compared to placebo or no folic acid. Of note is the limited number of trials included in this review that reported data on adverse effects (n = 12 iron supplementation versus placebo/no iron; n = 1 iron + folic acid versus placebo/no iron + folic acid), heterogeneity of definitions used, and limited information reported on adherence, which constrain the interpretation of findings. The Institute of Medicine (now National Academy of Medicine) set 45 mg of elemental iron per day as the tolerable upper limit for iron, based on the likelihood of having adverse effects, including nausea and constipation (IOM 2001). The potential efficacy of lower‐dose iron supplements (Angeletti 2023; Sundler 2020) and iron supplementation with other compounds (Elshahawy 2019; Karakochuk 2023) is being evaluated elsewhere, including iron compounds with higher bioavailability (i.e. that could potentially be administered at lower doses with fewer adverse effects) (Elshahawy 2019; Karakochuk 2023). However, there is limited evidence from randomised controlled trials in pregnant women (Makrides 2003; Milman 2014; Parisi 2017).

This updated review includes six additional randomised controlled trials. Findings from this review demonstrate that iron supplementation may reduce maternal anaemia at term (low‐certainty evidence), maternal iron deficiency at term (low‐certainty evidence), and probably reduces maternal iron‐deficiency anaemia at term (moderate‐certainty evidence), compared to placebo or no iron supplementation. However, there is probably little to no difference or the evidence is very uncertain between intervention groups for other primary maternal outcomes, including severe anaemia in the second or third trimester (very low‐certainty evidence), adverse effects (very low‐certainty evidence), or maternal death (moderate‐certainty evidence), compared to placebo or no supplementation. Findings on the effects of iron supplementation on maternal haematological outcomes are consistent with previous versions of this review (Peña‐Rosas 2012; Peña‐Rosas 2015). Similarly, iron supplementation during pregnancy probably reduces infant low birthweight (moderate‐certainty evidence), compared to placebo or no iron supplementation. However, the potential impact on other infant outcomes, including preterm birth (moderate‐certainty evidence), neonatal death (low‐certainty evidence), congenital anomalies including neural tube defects (low‐certainty evidence), or infant birthweight (very low‐certainty evidence) is less clear.

In the current update, iron + folic acid supplementation during pregnancy probably reduces maternal anaemia at term (moderate‐certainty evidence), may reduce maternal iron deficiency at term (low‐certainty evidence), but the evidence is very uncertain for severe anaemia in the second or third trimester (very low‐certainty evidence), compared to placebo or no iron + folic acid supplementation, which is consistent with the previous version of this review (Peña‐Rosas 2015). There may be little to no difference between intervention groups for other primary maternal outcomes, which is consistent with the previous review update. There may be little to no difference between intervention groups for infant outcomes, including infant low birthweight (low‐certainty evidence), preterm birth (low‐certainty evidence), neonatal death (low‐certainty evidence), or congenital anomalies (low‐certainty evidence), comparing iron + folic acid supplementation to placebo or no iron + folic acid supplementation, which is consistent with the previous review update. Infants born to women who received iron + folic acid supplements during pregnancy probably had higher birthweight (moderate‐certainty evidence), compared to placebo or no iron + folic acid, which is consistent with the previous version of this review.

Quality of the evidence

Risk of bias

The overall quality of the evidence in this review was heterogeneous: 53 of the included trials had unclear or high risk of bias and four of the trials were at low risk of bias (See Assessment of risk of bias in included studies, Figure 3; Figure 4). In nearly half of the included trials, the methods used to conceal the allocation of the intervention were not described, or were not adequately described. The methods for blinding of participants, care providers, and outcome assessors were not clearly described in five trials. Blinding was not attempted in two of the included trials, although in some included studies, technical staff conducting laboratory investigations were blinded to intervention group allocation. For some outcomes, such as laboratory outcomes (e.g. haemoglobin), the lack of blinding may have been unlikely to have impacted results; however, for other outcomes, such as maternal adverse effects reported to care providers, lack of blinding may represent a serious source of bias. Attrition was a concern in some of the included trials, and in some studies, it was not clear if loss to follow‐up was balanced across intervention groups.

Certainty of the evidence

Iron supplementation compared to placebo or no iron

Findings for this review update were consistent with previous versions of this review (Peña‐Rosas 2012; Peña‐Rosas 2015) (see Table 1; Table 2).

Maternal outcomes. The overall certainty of evidence in this review for maternal anaemia at term (low‐certainty evidence) and iron deficiency at term (low‐certainty evidence) was consistent with the previous versions of this review, and was downgraded due to study design limitations and inconsistency. In this review update, maternal iron‐deficiency anaemia was assessed as moderate‐certainty, with downgrading due to study design limitations. Similarly, the certainty of evidence for maternal severe anaemia during the second or third trimester (very low‐certainty evidence) and adverse effects (very low‐certainty evidence) were consistent with the previous review update, and were downgraded due to study design limitations, imprecision, and inconsistency. The certainty of evidence for maternal death was updated from very low to moderate‐certainty evidence, compared to the previous review update. This may be due to the inclusion of one study with minimal study design limitations (low risk of bias in all domains), and a larger sample size (14,060 versus 12,560), in the current review compared to the previous versions of this review.

Infant outcomes. The overall certainty of evidence for specific infant outcomes changed for infant low birthweight (low to moderate‐certainty evidence), neonatal death (low to moderate‐certainty evidence), and infant birthweight (moderate to very low‐certainty evidence), compared to the previous review update, mainly due to study design limitations of contributing studies. Specifically, inclusion of one trial with minimal study design limitations for infant low birthweight and neonatal death, and imprecision (wide confidence intervals) and inconsistency (considerable heterogeneity) for infant birthweight, in the current review compared to the previous review update, may have accounted for changes in certainty of evidence.

Iron + folic acid supplementation compared to placebo or no iron + folic acid

Findings for this review update were consistent with previous versions of this review (Peña‐Rosas 2012; Peña‐Rosas 2015) (see Table 3; Table 4).

Maternal outcomes. The overall certainty of evidence in this review for maternal anaemia at term (moderate‐certainty evidence) and iron deficiency at term (low‐certainty evidence) was consistent with the previous review update. Evidence in this review provided data for iron‐deficiency anaemia (very low‐certainty evidence), which was downgraded due to study design limitations. Similarly, the certainty of evidence for maternal severe anaemia during the second and third trimester (very low‐certainty evidence), adverse effects (very low‐certainty evidence), and maternal anaemia during the second or third trimester (very low‐certainty evidence) were consistent with the previous review update, and were downgraded due to study design limitations, imprecision, and inconsistency. The certainty of evidence for maternal death was updated from low to very low‐certainty evidence for maternal death, and moderate to low‐certainty for adverse effects, compared to the previous review update. For maternal death and adverse effects, the certainty of evidence was downgraded due to imprecision (wide confidence intervals crossing the line of no effect), inconsistency, and study design limitations (i.e. only one study contributing data was non‐blinded with insufficient data on allocation concealment and selective reporting).

Infant outcomes. The overall certainty of evidence for specific infant outcomes was consistent for preterm birth (low‐certainty evidence), infant low birthweight (low‐certainty evidence), neonatal death (low‐certainty evidence), infant birthweight (low‐certainty evidence), and congenital anomalies including neural tube defects (low‐certainty evidence), compared to the previous review update, mainly due to study design limitations of contributing studies.

Trustworthiness screening

We used the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (CPC‐TST, Figure 2) to evaluate the trustworthiness of evidence of studies. Due to the dates of conduct or publication of some trials (publication dates ranged between 1936 and 2019), the CPC‐TST was modified to allow for historical changes in methodological or reporting requirements. The evaluation process for trustworthiness screening meant that some studies published since the previous update of this review that met inclusion criteria in other respects, were assigned to ‘Awaiting classification’ rather than being included in this review update. Similarly, some studies included in the previous versions of this review were moved to ‘Awaiting classification’. These studies were not classified as ‘excluded’, as we attempted to contact the authors, and these studies may be included in future updates of this review, if information is provided that fulfils the CPC‐TST domains.

A total of 76 trials were evaluated for trustworthiness using the CPC‐TST, including 61 studies from the previous review (Peña‐Rosas 2015) and 16 new trials that were identified in this review update. Of the 61 studies from the previous review, 51 trials met trustworthiness criteria for this review update (n = 10 were assigned to 'Awaiting classification'). Of the 16 new trials that were identified in this review update, six trials met trustworthiness criteria (n = 10 were assigned to 'Awaiting classification'), and were included in the current review update.

There were fewer included trials in the current review update because all the included trials from the previous update (Peña‐Rosas 2015) were evaluated using the CPC‐TST. It is noteworthy that the results in this review update are based solely on the data from trials that were evaluated independently by two review authors and determined to meet CPC‐TST criteria for trustworthiness.

The decision to exclude 10 trials that were included in previous versions of this review (Corrigan 1936; Han 2011; Hankin 1963; Korkmaz 2014; Liu 2000; Ma 2010; Ouladsahebmadarek 2011; Sun 2010; Ziaei 2007; Ziaei 2008) was based on pre‐specified criteria based on the CPC‐TST, for governance, feasibility, and baseline characteristics domains, and included: unclear randomisation and blinding methods, no information provided on ethics or consent, no trial dates reported, and lack of trial registration or lack of information provided regarding registration.

Of the 10 previous trials that were assigned to 'Awaiting classification', four of the studies met our inclusion criteria in other respects, but the authors did not respond to concerns regarding aspects of study conduct (Han 2011; Korkmaz 2014; Ma 2010; Sun 2010). In six of the trials, we were unable to contact authors due to the date that the studies were conducted (Corrigan 1936; Hankin 1963) or due to lack of contact information provided (Liu 2000; Ouladsahebmadarek 2011; Ziaei 2007; Ziaei 2008).

Potential biases in the review process

We are aware of the potential for introducing bias at every stage of the review process. In this review update, we attempted to minimise bias in several ways. Two review authors (AC, JW) examined each study record to independently evaluate eligibility for inclusion, and applied the CPC‐TST criteria to studies that met the inclusion criteria. Four review authors (AC, JW, SV, DYL) independently conducted data extraction, and assessed the risk of bias and certainty of evidence for included trials. Individual review authors worked independently, results were consolidated, and any discrepancies were discussed together with the review team and senior author to reach consensus. Although we strived to minimise potential biases throughout the review, the process of reviewing research studies is known to be affected by prior beliefs and attitudes. It is challenging to control this type of bias in the review process. Although we attempted to be as inclusive as possible in the search strategy, the research publications identified were predominantly written in English, and published in North American and European journals. Although we attempted to evaluate reporting bias, this assessment relied largely on information available in published trial reports, and thus reporting bias may not be apparent.

Assessing the certainty of the evidence for specific outcomes is a challenging process. We used a priori criteria and a transparent evaluation process to develop summary of findings tables. Four review authors (AC, JW, SV, DYL) evaluated the evidence for each outcome and domain independently, results were consolidated, and any discrepancies were discussed together with the review team in order to reach consensus. In this review update, after inclusion of new trials and application of the CPC‐TST, the certainty of evidence for maternal anaemia at term, maternal iron deficiency at term, and maternal severe anaemia at term, preterm birth and congenital anomalies was consistent with the previous versions of this review. The certainty of evidence for iron‐deficiency anaemia was added to this review update. However, the certainty of evidence for maternal death, adverse effects, infection during pregnancy, and infant low birthweight, birthweight, and neonatal death, was updated compared to the previous versions of this review.

Agreements and disagreements with other studies or reviews

Daily iron and folic acid supplementation is currently recommended by the World Health Organization as part of antenatal care, and has been a long‐standing public health intervention. The role of iron supplementation in pregnancy, with or without folic acid or other vitamins and micronutrients, in the development of various perinatal outcomes has been evaluated in several recent reviews (Abraha 2019; Fischer 2023; Mwangi 2021; Shand 2021). Previous meta‐analyses have predominantly focused on the effects of iron supplementation on maternal haematological outcomes, such as maternal anaemia (Sloan 2002; Yakoob 2011), while some recently published meta‐analyses also included infant outcomes (Abraha 2019; Hansen 2023). However, the inclusion of different iron interventions and comparison arms in some meta‐analyses (Abraha 2019; Hansen 2023) and inclusion of trials that did not meet CPC‐TST criteria in the current review (Alizadeh 2016; Liu 2000; Ziaei 2008) constrain direct comparability of findings.

Other systematic reviews and meta‐analyses: In a systematic review of six randomised controlled trials evaluating the effects of daily oral iron supplementation on maternal iron status, women who received iron supplementation had higher serum ferritin concentrations, compared to placebo or no supplementation (Daru 2016). Findings for infant outcomes varied by baseline haemoglobin concentrations of women: in analyses amongst women without anaemia at enrolment, maternal iron supplementation during pregnancy was associated with improved infant birthweight, compared to placebo or no iron supplementation. However, heterogeneity across studies in haematological status at enrolment and timing of outcome assessments, constrains comparability of findings to this review.

Two meta‐analyses were recently conducted to evaluate the effects of daily oral iron supplementation during pregnancy on maternal and infant outcomes (Abraha 2019; Hansen 2023). In meta‐analyses of 11 randomised trials (Abraha 2019), iron supplementation during pregnancy reduced maternal anaemia and iron‐deficiency anaemia at term, compared to placebo or no treatment; however, there was little to no difference between groups in adverse effects, or in infant outcomes, including preterm birth, low birthweight, or infant mortality. In a meta‐analysis of eight randomised trials conducted amongst pregnant women without anaemia or iron deficiency at enrolment, daily oral prenatal iron supplementation reduced maternal iron deficiency and iron‐deficiency anaemia at term, compared to placebo or no supplementation (Hansen 2023). Findings suggest that iron supplementation during pregnancy reduces infant low birthweight, and may reduce preterm birth or small for gestational age infants. Together, findings from these meta‐analyses are consistent with the current review, and demonstrated that iron supplementation during pregnancy improved maternal anaemia and iron status, but the effects on other maternal and infant outcomes were less clear. However, the focus of reviews on pregnant women who were not anaemic or iron deficient at enrolment (Hansen 2023), analysis of heterogeneous iron interventions and comparison groups (i.e. iron alone or iron + folic acid supplementation) (Abraha 2019; Hansen 2023), and inclusion of trials that did not meet CPC‐TST criteria in this review (Alizadeh 2016; Liu 2000; Ziaei 2008) constrain comparability of findings to the current review.

In a meta‐analysis of micronutrient supplementation during pregnancy (including daily oral iron supplementation (or iron + folic acid)), and maternal, fetal, and child health and development outcomes (Keats 2021; Oh 2020), daily supplementation with iron (or iron + folic acid) with iron during pregnancy reduced maternal anaemia at term and infant low birthweight, compared to placebo or no iron (or no iron + folic acid) supplementation, which is consistent with findings from this review.

This Cochrane review is the most comprehensive assessment of the effects of daily iron supplementation during pregnancy on maternal and infant outcomes. Based on the original review (Peña‐Rosas 2006) and previous review updates (Peña‐Rosas 2012; Peña‐Rosas 2015), there is consistent evidence that daily iron supplementation during pregnancy improves maternal anaemia and maternal iron deficiency at term.

Authors' conclusions

Implications for practice.

Results from analyses of 57 trials demonstrated that daily iron supplementation during pregnancy reduced maternal anaemia and iron deficiency at term. However, the impact of iron supplementation during pregnancy on other maternal and infant outcomes is less evident.

Available data from 40 trials indicate that daily iron supplements (compared to placebo or no iron) amongst women:

• may reduce maternal anaemia at term and maternal iron deficiency at term, and probably reduce iron‐deficiency anaemia at term;

• may reduce maternal severe anaemia during the second and third trimesters of pregnancy, but the evidence is very uncertain;

• probably result in little to no difference between groups, or the evidence is very uncertain for other primary maternal outcomes, including: adverse effects, maternal death, or placental malaria cases;

• probably lower the risk of delivering low birthweight babies;

• probably result in or may result in little to no difference between groups for other primary infant outcomes, including: preterm birth, infant birthweight, neonatal death, or congenital anomalies (including neural tube defects).

Data from eight trials indicate that daily iron + folic acid supplements (compared to placebo or no iron + folic acid) amongst women:

• probably reduce maternal anaemia at term;

• may reduce maternal iron deficiency at term;

• may reduce iron‐deficiency anaemia at term, but the evidence is very uncertain;

• may reduce severe anaemia during the second and third trimesters of pregnancy, maternal death, or adverse effects, but the evidence is uncertain or very uncertain;

• probably result in infants with higher birthweight;

• may result in little to no difference between groups for other primary infant outcomes, including: infant low birthweight, preterm birth, neonatal death, or congenital anomalies (including neural tube defects).

Iron supplementation during pregnancy may be considered as a preventive strategy to reduce maternal anaemia and iron deficiency at term. The magnitude of the effect may vary depending on the background risk of maternal and infant health outcomes. In order to improve the success of iron supplementation as a public health intervention, it is important to consider accessibility to supplementation and adherence.

Implications for research.

Findings from this review indicate that iron supplementation during pregnancy reduces maternal anaemia and iron deficiency at term. Further evidence is needed to investigate the effects of daily iron alone or iron + folic acid supplementation during pregnancy on other maternal and infant health outcomes. Future research could consider addressing the following recommendations on iron supplementation during pregnancy:

• assessment of other maternal and infant health outcomes in trials, including adherence, adverse effects, maternal infections during pregnancy, malaria‐related outcomes, maternal mortality, and other infant outcomes, including congenital anomalies (including neural tube defects) and infant iron status, growth, and development;

• consideration of optimal dose of iron supplementation during pregnancy for maternal, pregnancy, and infant outcomes;

• effects of providing other vitamins and minerals (in addition to iron + folic acid) on maternal and infant outcomes;

• assessment of effectiveness, safety, and affordability of other iron supplementation compounds for use in public health preventive supplementation programmes, including preconception and prenatal supplementation;

• mechanisms and functional consequences of high haemoglobin concentrations during various gestational ages.

Feedback

Hemminki, June 2008,

Summary

My trial, Hemminki 1989a, is excluded from this review and it is not clear why. The comment in Characteristics of excluded studies is "Only women who were anaemic received iron in the unsupplemented group thus making any comparisons among the groups biased for the purposes of this review."
What bias is being referred to? Hemminki 1989a was in the previous version of this review. It was a randomised trial, analysed by intention to treat, having outcome data for all women randomised, and a high compliance (about 80% of women in both groups received the treatment they were allocated to). The 20% of women who received iron in the non‐routine supplementation group was as expected.
There are two options for dealing with women whose haemoglobin falls below a pre‐specified cut‐off in the non‐routine supplemented group:
1. give them iron, as in my study where 20% of women in the non‐routine treatment group had iron; or
2. call those who take iron non‐compliant and do the analysis by intention to treat, as did some of the included studies.

What is the difference between these two strategies? They seem to me to be essentially the same.

The effect of routine iron therapy on substantive health outcomes remains unclear. It is a real pity that you have excluded Hemminki 1989a, based on criteria I consider inappropriate: it had a large number of women, several health outcomes including long term follow up, and was well conducted.

A minor issue is that it is misleading to call this trial Hemminki 1989a. Although the study design was published in 1989, the main results were not published until 1991. Hence a more appropriate study identifier would be ‘Hemminki 1991’.

(Summary of feedback from Elina Hemminki, June 2008)

Reply

We agree that your trial was well conducted, had a large number of women and looked at several health outcomes including long term follow up. We did review all publications on the work you have conducted on assessing the effects of routine versus selective iron supplementation during pregnancy. This systematic review aims to assess the effectiveness and safety of daily and intermittent use of iron supplements by pregnant women, either alone or in conjunction with folic acid given as a preventive universal measure. Your trial provided 100 mg of elemental iron daily with various choice of iron compounds and dosage as determined individually by the midwives to all women in the routine iron supplementation group. For women in the "selective iron supplementation group", treatment with iron supplements as slow release form for two months or until the hematocrit increased to 0.32 was provided only to those whose hematocrit was lower than 0.30 on two consecutive visits. Consequently, we have included your trial in the included studies and we thank you for the additional data you have provided us for this analysis. Your study compared the effects of routine versus selective iron supplementation, an issue that certainly deserves better understanding and that reflects current practices.

We have changed the study identifier to Hemminki 1991 as requested.

Contributors

Juan Pablo Peña‐Rosas, MD, PhD, MPH

What's new

Date	Event	Description
15 August 2024	New search has been performed	A total of 115 new records were assessed for eligibility from the updated search, and eight additional records were evaluated that were identified in the previous review (as awaiting classification or ongoing). In this review update, a total of 57 trials were included, and 194 trials (263 reports) were excluded. A total of six new trials were included in this review update, 20 trials are awaiting classification, and one trial is ongoing.
15 August 2024	New citation required but conclusions have not changed	Most of the primary maternal and infant outcomes results have not changed since the previous version.

History

Protocol first published: Issue 2, 2004
Review first published: Issue 3, 2006

Date	Event	Description
5 March 2015	New citation required but conclusions have not changed	For most of the primary outcomes, results have not changed since the previous version. Effects on low birthweight, formerly borderline significant, are no longer so.
5 March 2015	New search has been performed	The review has been updated and a new author has joined the review team. Two new studies have been included (Korkmaz 2014; Liu 2012) and one study that was previously included has now been excluded after discussions among the review authors (Hemminki 1991). The review now includes a total of 61 trials.
1 November 2012	New citation required and conclusions have changed	This review updates part of Peña‐Rosas 2009 to only evaluate the effects of oral daily iron supplementation regimens. The effects of intermittent iron supplementation regimens are evaluated in a separate review (Peña‐Rosas 2012a).
2 July 2012	New search has been performed	In this split review we updated the search and used the latest Cochrane methodological guidance. We included information on the health worker cadre and malaria setting. Specific changes to the previous version are described in the section Differences between protocol and review. Two new authors have contributed to this review.
16 June 2009	New citation required but conclusions have not changed	In this update, trials assessing the effect of iron or folic acid when given in combination with other micronutrients were included as long as both groups being compared in the daily regimens received the same other micronutrient interventions. This has resulted in four trials previously excluded now being included (Cantlie 1971; Christian 2003 (C); Hemminki 1991a; Siega‐Riz 2001).
16 June 2009	New search has been performed	Search updated. Ten new trials included (Cantlie 1971; Christian 2003 (C); Hemminki 1991a; Harvey 2007Lee 2005; Meier 2003; Mukhopadhyay 2004; Siega‐Riz 2001; Ziaei 2007; Ziaei 2008). Twenty‐seven new trials excluded.
20 October 2008	Feedback has been incorporated	Feedback from Elina Hemminki added with response from author.
15 April 2008	Amended	Converted to new review format.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Pregnancy] explode all trees

#2 MeSH descriptor: [Pregnancy Complications] explode all trees

#3 MeSH descriptor: [Infant, Newborn] explode all trees

#4 MeSH descriptor: [Fetus] explode all trees

#5 MeSH descriptor: [Fetal Development] explode all trees

#6 MeSH descriptor: [Prenatal Diagnosis] explode all trees

#7 MeSH descriptor: [Fetal Monitoring] explode all trees

#8 MeSH descriptor: [Fetal Therapies] explode all trees

#9 MeSH descriptor: [Heart Rate, Fetal] explode all trees

#10 MeSH descriptor: [Extraembryonic Membranes] explode all trees

#11 MeSH descriptor: [Placenta] explode all trees

#12 MeSH descriptor: [Placental Function Tests] explode all trees

#13 MeSH descriptor: [Uterine Monitoring] explode all trees

#14 MeSH descriptor: [Pelvimetry] explode all trees

#15 MeSH descriptor: [Oxytocics] explode all trees

#16 MeSH descriptor: [Tocolytic Agents] explode all trees

#17 MeSH descriptor: [Tocolysis] explode all trees

#18 MeSH descriptor: [Maternal Health Services] explode all trees

#19 MeSH descriptor: [Peripartum Period] explode all trees

#20 MeSH descriptor: [Parity] explode all trees

#21 MeSH descriptor: [Perinatal Care] explode all trees

#22 MeSH descriptor: [Postpartum Period] explode all trees

#23 MeSH descriptor: [Labor Pain] explode all trees

#24 MeSH descriptor: [Anesthesia, Obstetrical] explode all trees

#25 MeSH descriptor: [Obstetric Surgical Procedures] explode all trees

#26 MeSH descriptor: [Analgesia, Obstetrical] explode all trees

#27 MeSH descriptor: [Obstetric Nursing] explode all trees

#28 MeSH descriptor: [Maternal‐Child Nursing] explode all trees

#29 MeSH descriptor: [Midwifery] explode all trees

#30 MeSH descriptor: [Apgar Score] explode all trees

#31 MeSH descriptor: [Breast Feeding] explode all trees

#32 MeSH descriptor: [Bottle Feeding] explode all trees

#33 MeSH descriptor: [Milk, Human] explode all trees

#34 {OR #1‐#33}

#35 pregnan*

#36 fetus

#37 foetus

#38 fetal

#39 foetal

#40 newborn

#41 "new born"

#42 birth

#43 childbirth

#44 laboring

#45 labour*

#46 antepart*

#47 prenatal*

#48 antenatal*

#49 perinatal*

#50 postnatal*

#51 postpart*

#52 caesar*

#53 cesar*

#54 obstetric*

#55 tocoly*

#56 oxytoci*

#57 placent*

#58 parturi*

#59 preeclamp*

#60 eclamp*

#61 intrapart*

#62 puerper*

#63 episiotom*

#64 amnio*

#65 matern*

#66 gestation*

#67 lactati*

#68 breastfe*

#69 breast NEXT fe*

#70 preconcept*

#71 periconcept*

#72 interconcept*

#73 {OR #35‐#72}

#74 #34 OR #73

Appendix 2. MEDLINE search strategy

1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized.ab.
4. placebo.ab.
5. drug therapy.fs.
6. randomly.ab.
7. trial.ab.
8. groups.ab.
9. or/1‐8
10. exp Pregnancy/
11. exp Pregnancy Complications/
12. exp Maternal Health Services/
13. exp Fetus/
14. exp Fetal Therapies/
15. exp Fetal Monitoring/
16. exp Prenatal Diagnosis/
17. Perinatal Care/
18. Labor pain/
19. Analgesia, Obstetric/
20. exp Obstetric Surgical Procedures/
21. Infant, Newborn/
22. exp Postpartum Period/
23. Breastfeeding/
24. or/10‐23
25. 9 and 24
26. exp animals/ not humans.sh.
27. 25 not 26

Appendix 3. Embase search strategy

1. CROSSOVER PROCEDURE/

2. DOUBLE BLIND PROCEDURE/

3. SINGLE BLIND PROCEDURE/

4. RANDOMIZED CONTROLLED TRIAL/

5. crossover$.ti,ab

6. (cross ADJ over$).ti,ab

7. placebo$.ti,ab

8. (doubl$ ADJ blind$).ti,ab

9. allocat$.ti,ab

10. random$.ti,ab

11. trial$.ti

12. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11

13. exp PREGNANCY/

14. exp PREGNANCY DISORDER/

15. exp OBSTETRIC PROCEDURE/

16. exp BREAST FEEDING/ OR exp BREAST FEEDING EDUCATION/

17. exp CHILDBIRTH/ OR exp CHILDBIRTH EDUCATION/

18. exp LABOR PAIN/

19. (antenatal* OR prenatal* OR puerper* OR postnatal* OR post‐natal* OR post ADJ natal* OR postpartum OR post‐partum OR post ADJ partum).ti,ab

20. (prepregnancy OR pre‐pregnancy OR pre ADJ pregnancy OR preconcept* OR pre‐concept* OR pre ADJ concept* OR periconcept* OR peri‐concept* OR peri ADJ concept*).ti,ab

21. ((preterm OR premature) AND (labour OR labor)).ti,ab

22. (eclamp* OR preeclamp* OR pre ADJ eclamp*).ti,ab

23. amniocentes*.ti,ab

24. (chorion* ADJ vill*).ti,ab

25. (breastfe* OR breast‐fe* OR breast ADJ fe* OR lactation).ti,ab

26. (caesarean OR cesarean OR caesarian OR cesarian OR cesarien OR caesarien).ti,ab

27. (newborn OR new ADJ born).ti,ab

28. (pregnancy OR pregnant OR pregnancies).ti

29. episiotom*.ti,ab

30. 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29

31. 12 AND 30

Appendix 4. CINAHL search strategy

1. exp CLINICAL TRIALS/

2. (clinic* ADJ trial*).ti,ab

3. (trebl* ADJ mask*).ti,ab

4. (tripl* ADJ blind*).ti,ab

5. (tripl* ADJ mask*).ti,ab

6. (doubl* ADJ blind*).ti,ab

7. (doubl* ADJ mask*).ti,ab

8. (singl* ADJ blind*).ti,ab

9. (singl* ADJ mask*).ti,ab

10. (randomi* ADJ control* ADJ trial*).ti,ab

11. RANDOM ASSIGNMENT/

12. (random* ADJ allocat*).ti,ab

13. placebo*.ti,ab

14. PLACEBOS/

15. QUANTITATIVE STUDIES/

16. (allocat* ADJ random*).ti,ab

17. breastfeeding.ti,ab

18. breastfed.ti,ab

19. exp BREAST FEEDING/

20. breast‐fe*.ti,ab

21. exp PREGNANCY/

22. exp PREGNANCY COMPLICATIONS/

23. (prenatal OR antenatal OR antepartum OR postpartum OR postnatal).ti,ab

24. (pregnant OR pregnancy).ti

25. ((preterm OR premature) AND (labor OR labour)).ti,ab

26. (midwife OR midwifery).ti,ab

27. CHILDBIRTH EDUCATION/

28. exp PREGNANCY, MULTIPLE/ OR exp PREGNANCY TRIMESTERS/

29. exp MATERNAL‐CHILD CARE/

30. (prenatal* OR pre‐natal* OR perinatal* OR peripartum OR antenatal* OR postnatal* OR post‐natal* OR postpart* OR post‐part* OR puerper* OR prepregnancy OR pre‐pregnancy OR preconcept* OR pre‐concept* OR periconcept* OR peri‐concept*).ti,ab

31. OBSTETRIC EMERGENCIES/

32. OBSTETRIC NURSING/

33. exp SURGERY, OBSTETRICAL/

34. exp DIAGNOSIS, OBSTETRIC/

35. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16

36. 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30 OR 31 OR 32 OR 33 OR 34

Appendix 5. Search methods for ClinicalTrials.gov and ICTRP

Review authors searched the WHO International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov for any ongoing or planned trials on 18 January 2024 using the terms "iron supplementation and pregnancy"; "iron and pregnancy"; "daily iron and pregnancy"; "iron supplements and pregnancy"; "daily supplements and pregnancy" and "anaemia and pregnancy". Duplicates were removed.

Data and analyses

Comparison 1. Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)	14	13543	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.20, 0.47]
1.2 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation	14	13543	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.20, 0.47]
1.2.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)	7	12093	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.13, 0.72]
1.2.2 Late gestational age (supplementation started at 20 weeks of gestation or later)	5	1178	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.22, 0.61]
1.2.3 Unspecified or mixed gestational age	2	272	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.01, 0.59]
1.3 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	14	13543	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.20, 0.47]
1.3.1 Non‐anaemic at the start of supplementation	8	12639	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.15, 0.67]
1.3.2 Unspecified or mixed anaemia status	6	904	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.12, 0.49]
1.4 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron	14	13543	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.20, 0.47]
1.4.1 Low daily dose (30 mg or less of elemental iron)	4	12134	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.37, 1.14]
1.4.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)	1	69	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.06, 0.73]
1.4.3 Higher daily dose (60 mg elemental iron or more)	9	1340	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.10, 0.38]
1.5 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting	14	13543	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.20, 0.47]
1.5.1 Malarial setting	2	330	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.44, 0.66]
1.5.2 Non‐malarial setting	12	13213	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.10, 0.42]
1.6 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)	8	2873	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.38, 0.68]
1.7 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation	8	2873	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.38, 0.68]
1.7.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)	5	2270	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.43, 0.84]
1.7.2 Late gestational age (supplementation started at 20 weeks of gestation or later)	3	603	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.18, 0.72]
1.8 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	8	2873	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.38, 0.68]
1.8.1 Non‐anaemic at the start of supplementation	6	2709	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.50, 0.79]
1.8.2 Unspecified/mixed anaemia status	2	164	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.07, 0.29]
1.9 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron	8	2873	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.38, 0.68]
1.9.1 Low daily dose (30 mg or less of elemental iron)	3	703	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.34, 0.78]
1.9.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)	1	241	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.73, 1.17]
1.9.3 Higher daily dose (60 mg elemental iron or more)	4	1929	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.11, 0.78]
1.10 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting	8	2873	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.38, 0.68]
1.10.1 Malarial setting	2	192	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.15, 0.53]
1.10.2 Non‐malarial setting	6	2681	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.43, 0.77]
1.11 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more) (ALL)	7	2704	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.26, 0.63]
1.12 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation	7	2704	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.26, 0.63]
1.12.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)	5	2276	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.29, 0.74]
1.12.2 Late gestational age (supplementation started at 20 weeks of gestation or later)	2	428	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.11, 0.58]
1.13 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	7	2704	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.26, 0.63]
1.13.1 Non‐anaemic at the start of supplementation	6	2584	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.31, 0.63]
1.13.2 Unspecified or mixed anaemia status	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.04 [0.00, 0.72]
1.14 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron	7	2704	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.26, 0.63]
1.14.1 Low daily dose (30 mg or less of elemental iron)	3	579	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.13, 1.11]
1.14.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)	1	241	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.16, 0.70]
1.14.3 Higher daily dose (60 mg elemental iron or more)	3	1884	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.02, 2.12]
1.15 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting	7	2704	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.26, 0.63]
1.15.1 Malarial setting	1	148	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.15.2 Non‐malarial setting	6	2556	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.26, 0.63]
1.16 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)	3	14060	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.12, 2.69]
1.17 Adverse effects (any reported throughout the intervention period) (ALL)	11	2423	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.83, 2.02]
1.18 Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by gestational age at the start of supplementation	11	2423	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.92, 1.91]
1.18.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)	5	1186	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.68, 1.45]
1.18.2 Late gestational age (supplementation started at 20 weeks of gestation or later)	5	1032	Risk Ratio (M‐H, Random, 95% CI)	1.43 [0.89, 2.29]
1.18.3 Unspecified or mixed gestational age	1	205	Risk Ratio (M‐H, Random, 95% CI)	62.79 [3.89, 1013.31]
1.19 Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	11	2423	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.92, 1.91]
1.19.1 Non‐anaemic at the start of supplementation	7	1648	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.85, 1.20]
1.19.2 Unspecified or mixed anaemia status	4	775	Risk Ratio (M‐H, Random, 95% CI)	5.16 [0.78, 34.29]
1.20 Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by dose of iron	11	2423	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.93, 1.89]
1.20.1 Low daily dose (30 mg or less of elemental iron)	6	1533	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.86, 1.16]
1.20.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)	2	225	Risk Ratio (M‐H, Random, 95% CI)	2.00 [0.66, 6.02]
1.20.3 Higher daily dose (60 mg elemental iron or more)	5	665	Risk Ratio (M‐H, Random, 95% CI)	4.33 [0.61, 30.67]
1.21 Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by malarial status of setting	11	2423	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.92, 1.91]
1.21.1 Malarial setting	1	205	Risk Ratio (M‐H, Random, 95% CI)	62.79 [3.89, 1013.31]
1.21.2 Non‐malarial setting	10	2218	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.91, 1.63]
1.22 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)	8	1398	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.01, 3.20]
1.23 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestational age at the start of supplementation	8	1398	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.01, 3.20]
1.23.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)	4	690	Risk Ratio (M‐H, Random, 95% CI)	0.06 [0.01, 0.47]
1.23.2 Late gestational age (supplementation started at 20 weeks of gestation or later)	3	559	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.00, 46.15]
1.23.3 Unspecified or mixed gestational age	1	149	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.24 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	8	1398	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.01, 3.20]
1.24.1 Non‐anaemic at the start of supplementation	4	667	Risk Ratio (M‐H, Random, 95% CI)	4.98 [0.24, 103.01]
1.24.2 Unspecified or mixed anaemia status	4	731	Risk Ratio (M‐H, Random, 95% CI)	0.06 [0.01, 0.30]
1.25 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron	8	1398	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.01, 3.20]
1.25.1 Low daily dose (30 mg or less of elemental iron)	3	654	Risk Ratio (M‐H, Random, 95% CI)	4.98 [0.24, 103.01]
1.25.2 Higher daily dose (60 mg elemental iron or more)	5	744	Risk Ratio (M‐H, Random, 95% CI)	0.06 [0.01, 0.30]
1.26 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting	8	1398	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.01, 3.20]
1.26.1 Malarial setting	2	375	Risk Ratio (M‐H, Random, 95% CI)	0.06 [0.01, 0.30]
1.26.2 Non‐malarial setting	6	1023	Risk Ratio (M‐H, Random, 95% CI)	4.98 [0.24, 103.01]
1.27 Maternal clinical malaria	1	1003	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.65, 1.65]
1.28 Low birthweight (less than 2500 g) (ALL)	12	18290	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.72, 0.99]
1.29 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation	12	18290	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.72, 0.99]
1.29.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)	6	13826	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.55, 1.01]
1.29.2 Late gestational age (supplementation started at 20 weeks of gestation or later)	3	665	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.50, 2.19]
1.29.3 Unspecified or mixed gestational age at the start of supplementation	3	3799	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.68, 1.15]
1.30 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	12	18290	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.72, 0.99]
1.30.1 Non‐anaemic at the start of supplementation	8	13157	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.43, 1.16]
1.30.2 Unspecified or mixed anaemia status	4	5133	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.73, 0.94]
1.31 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron	12	18290	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.72, 0.99]
1.31.1 Low daily dose of iron (30 mg or less of elemental iron)	6	12899	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.38, 1.25]
1.31.2 Higher daily dose of iron (60 mg elemental iron or more)	6	5391	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.73, 0.94]
1.32 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting	12	18290	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.72, 0.99]
1.32.1 Malarial setting	5	5281	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.73, 0.94]
1.32.2 Non‐malarial setting	7	13009	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.42, 1.27]
1.33 Birthweight (g) (ALL)	16	18554	Mean Difference (IV, Random, 95% CI)	24.90 [‐125.81, 175.60]
1.34 Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation	16	18554	Mean Difference (IV, Random, 95% CI)	24.90 [‐125.81, 175.60]
1.34.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)	11	14184	Mean Difference (IV, Random, 95% CI)	26.19 [‐168.55, 220.93]
1.34.2 Late gestational age (supplementation started at 20 weeks of gestation or later)	3	681	Mean Difference (IV, Random, 95% CI)	‐0.19 [‐77.46, 77.08]
1.34.3 Unspecified or mixed gestational age at the start of supplementation	2	3689	Mean Difference (IV, Random, 95% CI)	19.58 [‐10.38, 49.54]
1.35 Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	16	18554	Mean Difference (IV, Random, 95% CI)	24.90 [‐125.81, 175.60]
1.35.1 Non‐anaemic at the start of supplementation	10	13113	Mean Difference (IV, Random, 95% CI)	28.75 [‐183.71, 241.20]
1.35.2 Unspecified or mixed anaemia status	6	5441	Mean Difference (IV, Random, 95% CI)	29.17 [5.06, 53.29]
1.36 Birthweight (g): SUBGROUP ANALYSIS by dose of iron	16	18554	Mean Difference (IV, Random, 95% CI)	21.72 [‐124.69, 168.13]
1.36.1 Low daily dose (30 mg or less of elemental iron)	7	12988	Mean Difference (IV, Random, 95% CI)	6.33 [‐76.66, 89.32]
1.36.2 Higher daily dose (60 mg elemental iron or more)	10	5566	Mean Difference (IV, Random, 95% CI)	34.12 [‐161.55, 229.79]
1.37 Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting	16	18554	Mean Difference (IV, Random, 95% CI)	24.90 [‐125.81, 175.60]
1.37.1 Malarial setting	5	5297	Mean Difference (IV, Random, 95% CI)	32.52 [8.01, 57.03]
1.37.2 Non‐malarial setting	11	13257	Mean Difference (IV, Random, 95% CI)	18.24 [‐183.43, 219.92]
1.38 Preterm birth (less than 37 weeks of gestation) (ALL)	11	18827	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.84, 1.02]
1.39 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation	11	18827	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.84, 1.02]
1.39.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)	7	14674	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.86, 1.08]
1.39.2 Late gestational age (supplementation started at 20 weeks of gestation or later)	2	477	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.29, 1.13]
1.39.3 Unspecified or mixed gestational age at the start of supplementation	2	3676	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.71, 1.05]
1.40 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	11	18827	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.84, 1.02]
1.40.1 Non‐anaemic at the start of supplementation	7	13028	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.65, 1.06]
1.40.2 Unspecified/mixed anaemia status	4	5799	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.83, 1.08]
1.41 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron	11	18827	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.84, 1.02]
1.41.1 Low daily dose (30 mg or less of elemental iron)	5	12867	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.65, 1.09]
1.41.2 Higher daily dose (60 mg elemental iron or more)	6	5960	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.08]
1.42 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting	11	18827	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.84, 1.02]
1.42.1 Malarial setting	5	5947	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.08]
1.42.2 Non‐malarial setting	6	12880	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.65, 1.09]
1.43 Neonatal death (within 28 days after delivery) (ALL)	4	17243	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.77, 1.24]
1.44 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at the start of supplementation	4	17243	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.77, 1.24]
1.44.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)	2	13381	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.74, 1.51]
1.44.2 Unspecified or mixed gestational age at the start of supplementation	2	3862	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.62, 1.43]
1.45 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	4	17243	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.77, 1.24]
1.45.1 Non‐anaemic at the start of supplementation	1	11832	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.67, 1.82]
1.45.2 Unspecified or mixed anaemia status	3	5411	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.71, 1.24]
1.46 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron	4	17243	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.77, 1.24]
1.46.1 Low daily dose (30 mg or less of elemental iron)	1	11832	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.67, 1.82]
1.46.2 Higher daily dose (60 mg elemental iron or more)	3	5411	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.71, 1.24]
1.47 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting	4	17243	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.77, 1.24]
1.47.1 Malarial setting	3	5411	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.71, 1.24]
1.47.2 Non‐malarial setting	1	11832	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.67, 1.82]
1.48 Congenital anomalies (ALL)	4	14377	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.58, 1.33]
1.49 Congenital anomalies: SUBGROUP ANALYSIS by gestational age at the start of supplementation)	4	14377	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.58, 1.33]
1.49.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)	4	14377	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.58, 1.33]
1.50 Congenital anomalies: SUBGROUP ANALYSIS by anaemia status at the start of supplementation	4	14377	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.58, 1.33]
1.50.1 Non‐anaemic at the start of supplementation	2	11975	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.35, 2.84]
1.50.2 Unspecified or mixed anaemia status	2	2402	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.55, 1.35]
1.51 Congenital anomalies: SUBGROUP ANALYSIS by dose of iron	4	14377	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.58, 1.33]
1.51.1 Low daily dose (30 mg or less of elemental iron)	2	11975	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.35, 2.84]
1.51.2 Higher daily dose (60 mg elemental iron or more)	2	2402	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.55, 1.35]
1.52 Congenital anomalies: SUBGROUP ANALYSIS by malarial status of setting	4	14374	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.62, 1.26]
1.52.1 Malarial setting	2	2399	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.60, 1.26]
1.52.2 Non‐malarial setting	2	11975	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.35, 2.84]
1.53 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)	14	2981	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.22, 0.46]
1.54 Maternal iron deficiency at or near term (as defined by as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)	8	2247	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.30, 0.65]
1.55 Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more) (ALL)	7	2042	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.22, 0.58]
1.56 Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)	17	2665	Mean Difference (IV, Random, 95% CI)	9.53 [6.99, 12.06]
1.57 Maternal Hb concentration within 6 weeks postpartum (in g/L) (ALL)	7	818	Mean Difference (IV, Random, 95% CI)	7.76 [5.56, 9.95]
1.58 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)	8	1461	Risk Ratio (M‐H, Random, 95% CI)	2.00 [1.22, 3.30]
1.59 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)	7	1429	Risk Ratio (M‐H, Random, 95% CI)	3.96 [1.80, 8.74]
1.60 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)	3	766	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.12, 2.51]
1.61 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)	7	1092	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.01, 44.11]
1.62 Severe anaemia postpartum (Hb less than 80 g/L) (ALL)	7	1139	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.00, 1.33]
1.63 Puerperal infection (ALL)	3	3647	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.49, 0.91]
1.64 Antepartum haemorrhage (ALL)	1	430	Risk Ratio (M‐H, Random, 95% CI)	2.97 [0.12, 72.56]
1.65 Postpartum haemorrhage (ALL)	2	517	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.49, 1.34]
1.66 Transfusion provided (ALL)	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.62]
1.67 Diarrhoea (ALL)	2	361	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.31, 0.98]
1.68 Constipation (ALL)	3	768	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.49, 1.69]
1.69 Nausea (ALL)	3	650	Risk Ratio (M‐H, Random, 95% CI)	2.38 [0.49, 11.52]
1.70 Heartburn (ALL)	2	596	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.79, 1.70]
1.71 Vomiting (ALL)	3	665	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.61, 1.40]
1.72 Maternal wellbeing/satisfaction (ALL)	1	49	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.77, 1.08]
1.73 Placental abruption (ALL)	1	1442	Risk Ratio (M‐H, Random, 95% CI)	2.88 [0.12, 70.53]
1.74 Pre‐eclampsia (ALL)	2	195	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.08, 5.07]
1.75 Very low birthweight (less than 1500 g) (ALL)	4	1960	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.24, 1.78]
1.76 Very premature birth (less than 34 weeks' gestation) (ALL)	5	4366	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.42, 0.95]
1.77 Infant Hb concentration within the first 6 months (in g/L counting the last reported measure after birth within this period) (ALL)	3	12077	Mean Difference (IV, Random, 95% CI)	‐0.26 [‐2.62, 2.11]
1.78 Infant serum ferritin concentration within first 6 months (in μg/L counting the last reported measure after birth within this period) (ALL)	1	197	Mean Difference (IV, Random, 95% CI)	11.00 [4.37, 17.63]
1.79 Admission to special care unit (ALL)	1	111	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

Comparison 2. Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)	4	1962	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.30, 0.64]
2.2 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestation at the start of supplementation	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
2.2.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	1	97	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.2.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	1	66	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.22, 0.62]
2.2.3 Unspecified or mixed gestational age at start of supplementation	1	183	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.09, 0.68]
2.3 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
2.3.1 Non‐anaemic at start of supplementation	2	280	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.09, 0.68]
2.3.2 Unspecified or mixed anaemic status at start of supplementation	1	66	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.22, 0.62]
2.4 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
2.4.1 Higher daily dose (60 mg elemental iron and above)	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
2.5 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
2.5.1 Malarial setting	1	66	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.22, 0.62]
2.5.2 Non‐malarial setting	2	280	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.09, 0.68]
2.6 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)	1	131	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.06, 0.99]
2.7 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more) (ALL)	1	131	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.17, 1.09]
2.8 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)	1	131	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.9 Adverse effects (any reported throughout the intervention period) (ALL)	1	456	Risk Ratio (M‐H, Random, 95% CI)	44.32 [2.77, 709.09]
2.10 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)	4	506	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.02, 0.63]
2.11 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestation at the start of supplementation	4	506	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.02, 0.63]
2.11.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	3	456	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 0.83]
2.11.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.63]
2.12 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	4	506	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.02, 0.63]
2.12.1 Non‐anaemic at start of supplementation	1	97	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.12.2 Unspecified or mixed anaemic status at start of supplementation	3	409	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.02, 0.63]
2.13 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron	4	506	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.02, 0.63]
2.13.1 Low daily dose (30 mg elemental iron or less)	1	44	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.13.2 Higher daily dose (60 mg elemental iron and above)	3	462	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.02, 0.63]
2.14 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting	4	506	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.02, 0.63]
2.14.1 Malarial setting	3	409	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.02, 0.63]
2.14.2 Non‐malarial setting	1	97	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.15 Infection during pregnancy (including urinary tract infections) (ALL)	1	48	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.15, 6.53]
2.16 Low birthweight (less than 2500 g) (ALL)	2	1311	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.31, 3.74]
2.17 Birthweight (ALL)	2	1365	Mean Difference (IV, Random, 95% CI)	57.73 [7.66, 107.79]
2.18 Preterm birth (less than 37 weeks of gestation) (ALL)	3	1497	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
2.19 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestation at the start of supplementation	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.19.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	2	1366	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
2.19.2 Unspecified or mixed gestational age at start of supplementation	1	44	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.20 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.20.1 Unspecified or mixed anaemic status at start of supplementation	3	1497	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
2.21 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron	3	1497	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
2.21.1 Low daily dose (30 mg elemental iron or less)	1	131	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.21.2 Higher daily dose (60 mg elemental iron and above)	2	1366	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
2.22 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of settings	3	1497	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
2.22.1 Malarial setting	2	1449	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.92, 1.39]
2.22.2 Non‐malarial setting	1	48	Risk Ratio (M‐H, Random, 95% CI)	7.00 [0.38, 128.61]
2.23 Neonatal death (within 28 days after delivery) (ALL)	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
2.24 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestation at the start of supplementation	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
2.24.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
2.25 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
2.25.1 Non‐anaemic at start of supplementation	1	97	Risk Ratio (M‐H, Random, 95% CI)	2.50 [0.10, 59.88]
2.25.2 Unspecified or mixed anaemic status at start of supplementation	2	1696	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.49, 1.27]
2.26 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
2.26.1 Higher daily dose (60 mg elemental iron and above)	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
2.27 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status at the start of supplementation	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
2.27.1 Malarial setting	1	1648	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.49, 1.27]
2.27.2 Non‐malarial setting	2	145	Risk Ratio (M‐H, Random, 95% CI)	2.50 [0.10, 59.88]
2.28 Congenital anomalies (ALL)	1	1652	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.35, 1.40]
2.29 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
2.30 Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)	1	131	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.06, 0.99]
2.31 Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more) (ALL)	1	131	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.17, 1.09]
2.32 Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)	3	140	Mean Difference (IV, Random, 95% CI)	16.13 [12.74, 19.52]
2.33 Maternal Hb concentration within 6 weeks postpartum (in g/L) (ALL)	2	459	Mean Difference (IV, Random, 95% CI)	10.07 [7.33, 12.81]
2.34 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)	2	446	Risk Ratio (M‐H, Random, 95% CI)	1.78 [0.63, 5.04]
2.35 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)	2	314	Risk Ratio (M‐H, Random, 95% CI)	4.37 [0.58, 32.71]
2.36 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)	3	491	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.17, 0.65]
2.37 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more ) (ALL)	3	191	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.63]
2.38 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)	3	491	Risk Ratio (M‐H, Random, 95% CI)	0.05 [0.00, 0.76]
2.39 Puerperal infection (ALL)	1	2863	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.13, 2.28]
2.40 Antepartum haemorrhage (ALL)	2	145	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.22, 7.12]
2.41 Placental abruption (ALL)	1	2863	Risk Ratio (M‐H, Random, 95% CI)	8.19 [0.49, 138.16]
2.42 Pre‐eclampsia (ALL)	1	48	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 70.16]
2.43 Very low birthweight (less than 1500 g) (ALL)	1	48	Risk Ratio (M‐H, Random, 95% CI)	5.00 [0.25, 98.96]
2.44 Very premature birth (less than 34 weeks' gestation) (ALL)	2	92	Risk Ratio (M‐H, Random, 95% CI)	5.00 [0.25, 98.96]
2.45 Admission to special care unit (ALL)	1	48	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

2.11. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 11: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestation at the start of supplementation

2.12. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 12: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status at the start of supplementation

2.13. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 13: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron

2.14. Analysis.

Comparison 2: Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron or folic acid or placebo), Outcome 14: Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting

Comparison 3. Supplementation with iron alone versus no treatment/placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)	13	1936	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.15, 0.42]
3.2 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation	13	1999	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.16, 0.41]
3.2.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	6	549	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.06, 0.57]
3.2.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	6	1301	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.20, 0.53]
3.2.3 Unspecified or mixed gestational age at start of supplementation	1	149	Risk Ratio (M‐H, Random, 95% CI)	0.03 [0.00, 0.18]
3.3 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	13	1936	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.15, 0.42]
3.3.1 Non‐anaemic at start of supplementation	8	1244	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.10, 0.44]
3.3.2 Unspecified or mixed anaemic status at start of supplementation	5	692	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.18, 0.64]
3.4 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron	13	1999	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.16, 0.41]
3.4.1 Low daily dose (30 mg elemental iron or less)	3	590	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.24, 1.03]
3.4.2 Medium daily dose (31 mg to 59 mg elemental iron)	1	69	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.06, 0.73]
3.4.3 Higher daily dose (60 mg elemental iron and above)	9	1340	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.10, 0.38]
3.5 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting	13	1936	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.15, 0.42]
3.5.1 Malarial setting	2	267	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.46, 0.72]
3.5.2 Non‐malarial setting	11	1669	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.10, 0.34]
3.6 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)	7	1256	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.27, 0.66]
3.7 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation	7	1256	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.27, 0.66]
3.7.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	4	653	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.22, 0.93]
3.7.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	3	603	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.18, 0.72]
3.8 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	7	1256	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.27, 0.66]
3.8.1 Non‐anaemic at start of supplementation	5	1092	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.39, 0.82]
3.8.2 Unspecified or mixed anaemic status at start of supplementation	2	164	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.07, 0.29]
3.9 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron	7	1256	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.27, 0.66]
3.9.1 Low daily dose (30 mg elemental iron or less)	3	703	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.34, 0.78]
3.9.2 Medium daily dose (31 mg to 59 mg elemental iron)	1	241	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.73, 1.17]
3.9.3 Higher daily dose (60 mg elemental iron and above)	3	312	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.10, 0.41]
3.10 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting	7	1256	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.27, 0.66]
3.10.1 Malarial setting	2	192	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.15, 0.53]
3.10.2 Non‐malarial setting	5	1064	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.30, 0.78]
3.11 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more) (ALL)	6	1088	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.16, 0.69]
3.12 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation	6	1088	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.16, 0.69]
3.12.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	4	660	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.13, 1.11]
3.12.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	2	428	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.11, 0.58]
3.13 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	6	1088	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.16, 0.69]
3.13.1 Non‐anaemic at start of supplementation	5	968	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.20, 0.74]
3.13.2 Unspecified or mixed anaemic status at start of supplementation	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.04 [0.00, 0.72]
3.14 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron	6	1088	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.16, 0.69]
3.14.1 Daily low dose (60 mg elemental iron or less)	3	579	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.13, 1.11]
3.14.2 Medium dose (31 mg to 59 mg elemental iron)	1	241	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.16, 0.70]
3.14.3 High dose (60 mg elemental iron and above)	2	268	Risk Ratio (M‐H, Random, 95% CI)	0.04 [0.00, 0.72]
3.15 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting	6	1088	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.16, 0.69]
3.15.1 Malarial setting	1	148	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
3.15.2 Non‐malarial setting	5	940	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.16, 0.69]
3.16 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)	2	1547	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.11, 3.98]
3.17 Adverse effects (any reported throughout the intervention period) (ALL)	9	1677	Risk Ratio (M‐H, Random, 95% CI)	1.59 [1.00, 2.52]
3.18 Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by gestational age at the start of supplementation	9	1677	Risk Ratio (M‐H, Random, 95% CI)	1.59 [1.00, 2.52]
3.18.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	3	438	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.87, 2.19]
3.18.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	5	1034	Risk Ratio (M‐H, Random, 95% CI)	1.42 [0.89, 2.28]
3.18.3 Unspecified or mixed gestational age at start of supplementation	1	205	Risk Ratio (M‐H, Random, 95% CI)	62.79 [3.89, 1013.31]
3.19 Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	9	1677	Risk Ratio (M‐H, Random, 95% CI)	1.59 [1.00, 2.52]
3.19.1 Non‐anaemic at start of supplementation	5	900	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.91, 1.28]
3.19.2 Unspecified or mixed anaemic status at start of supplementation	4	777	Risk Ratio (M‐H, Random, 95% CI)	5.11 [0.78, 33.60]
3.20 Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by dose of iron	9	1677	Risk Ratio (M‐H, Random, 95% CI)	1.58 [1.02, 2.43]
3.20.1 Low daily dose (30 mg elemental iron or less)	4	785	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.90, 1.26]
3.20.2 Medium daily dose (31 mg to 59 mg elemental iron)	2	225	Risk Ratio (M‐H, Random, 95% CI)	2.00 [0.66, 6.02]
3.20.3 Higher daily dose (60 mg elemental iron and above)	5	667	Risk Ratio (M‐H, Random, 95% CI)	5.53 [0.81, 37.89]
3.21 Adverse effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by malarial status of setting	9	1677	Risk Ratio (M‐H, Random, 95% CI)	1.59 [1.00, 2.52]
3.21.1 Malarial setting	1	205	Risk Ratio (M‐H, Random, 95% CI)	62.79 [3.89, 1013.31]
3.21.2 Non‐malarial setting	8	1472	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.99, 1.97]
3.22 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)	7	1078	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.02, 29.10]
3.23 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestational age at the start of supplementation	7	1078	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.02, 29.10]
3.23.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	3	416	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
3.23.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	3	513	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.02, 29.10]
3.23.3 Unspecified or mixed gestational age at start of supplementation	1	149	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
3.24 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status age at the start of supplementation	7	1078	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.02, 29.10]
3.24.1 Non‐anaemic at start of supplementation	5	816	Risk Ratio (M‐H, Random, 95% CI)	4.98 [0.24, 103.01]
3.24.2 Unspecified or mixed anaemic status at start of supplementation	2	262	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.01, 2.21]
3.25 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron	7	1078	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.02, 29.10]
3.25.1 Low daily dose (30 mg elemental iron or less)	3	654	Risk Ratio (M‐H, Random, 95% CI)	4.98 [0.24, 103.01]
3.25.2 Higher daily dose (60 mg elemental iron and above)	4	424	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.01, 2.21]
3.26 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting	7	1078	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.02, 29.10]
3.26.1 Malarial setting	1	55	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.01, 2.21]
3.26.2 Non‐malarial setting	6	1023	Risk Ratio (M‐H, Random, 95% CI)	4.98 [0.24, 103.01]
3.27 Maternal clinical malaria	1	1003	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.65, 1.65]
3.28 Low birthweight (less than 2500 g) (ALL)	7	2499	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.43, 1.20]
3.29 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation	7	2499	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.43, 1.20]
3.29.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	2	361	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.15, 0.70]
3.29.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	3	665	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.50, 2.19]
3.29.3 Unspecified or mixed gestational age at the start of supplementation	2	1473	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.63, 1.35]
3.30 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	7	2499	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.43, 1.20]
3.30.1 Non‐anaemic at start of supplementation	5	955	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.25, 1.66]
3.30.2 Unspecified or mixed anaemic status at start of supplementation	2	1544	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.60, 1.27]
3.31 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron	7	2499	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.43, 1.20]
3.31.1 Low daily dose (30 mg elemental iron or less)	3	697	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.12, 2.96]
3.31.2 Higher daily dose (60 mg elemental iron and above)	4	1802	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.60, 1.22]
3.32 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting	7	2499	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.43, 1.20]
3.32.1 Malarial setting	3	1692	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.59, 1.20]
3.32.2 Non‐malarial setting	4	807	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.20, 2.70]
3.33 Birthweight (g) (ALL)	10	2741	Mean Difference (IV, Random, 95% CI)	14.71 [‐35.60, 65.01]
3.34 Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation	10	2741	Mean Difference (IV, Random, 95% CI)	14.71 [‐35.60, 65.01]
3.34.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	5	524	Mean Difference (IV, Random, 95% CI)	16.83 [‐130.09, 163.74]
3.34.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	4	854	Mean Difference (IV, Random, 95% CI)	‐8.70 [‐74.71, 57.31]
3.34.3 Unspecified or mixed gestational age at the start of supplementation	1	1363	Mean Difference (IV, Random, 95% CI)	18.00 [‐38.53, 74.53]
3.35 Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	10	2741	Mean Difference (IV, Random, 95% CI)	14.71 [‐35.60, 65.01]
3.35.1 Non‐anaemic at start of supplementation	6	889	Mean Difference (IV, Random, 95% CI)	19.19 [‐101.86, 140.25]
3.35.2 Unspecified or mixed anaemic status at start of supplementation	4	1852	Mean Difference (IV, Random, 95% CI)	11.30 [‐34.41, 57.02]
3.36 Birthweight (g): SUBGROUP ANALYSIS by dose of iron	10	2741	Mean Difference (IV, Random, 95% CI)	14.39 [‐32.12, 60.90]
3.36.1 Low daily dose (30 mg elemental iron or less)	4	786	Mean Difference (IV, Random, 95% CI)	46.63 [‐76.47, 169.72]
3.36.2 Higher daily dose (60 mg elemental iron and above)	7	1955	Mean Difference (IV, Random, 95% CI)	9.44 [‐35.39, 54.27]
3.37 Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting	10	2741	Mean Difference (IV, Random, 95% CI)	14.71 [‐35.60, 65.01]
3.37.1 Malarial setting	3	1708	Mean Difference (IV, Random, 95% CI)	22.12 [‐26.44, 70.69]
3.37.2 Non‐malarial setting	7	1033	Mean Difference (IV, Random, 95% CI)	2.52 [‐94.14, 99.19]
3.38 Preterm birth (less than 37 weeks of gestation) (ALL)	7	3063	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.72, 1.07]
3.39 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation	7	3063	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.72, 1.07]
3.39.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	4	1236	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.62, 1.35]
3.39.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	2	477	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.29, 1.13]
3.39.3 Unspecified or mixed gestational age at start of supplementation	1	1350	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.71, 1.17]
3.40 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	7	3063	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.72, 1.07]
3.40.1 Non‐anaemic at start of supplementation	5	851	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.45, 1.13]
3.40.2 Unspecified or mixed anaemic status at start of supplementation	2	2212	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.74, 1.15]
3.41 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron	7	3063	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.72, 1.07]
3.41.1 Low daily dose (30 mg elemental iron or less)	3	690	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.47, 1.24]
3.41.2 Higher daily dose (60 mg elemental iron and above)	4	2373	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.73, 1.12]
3.42 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting	7	3063	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.72, 1.07]
3.42.1 Malarial setting	3	2360	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.73, 1.12]
3.42.2 Non‐malarial setting	4	703	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.47, 1.24]
3.43 Neonatal death (within 28 days after delivery) (ALL)	1	1367	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.67, 2.45]
3.44 Congenital anomalies (ALL)	2	2402	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.55, 1.35]
3.45 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)	14	2678	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.26, 0.52]
3.46 Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)	8	2248	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.30, 0.64]
3.47 Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more) (ALL)	7	2043	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.22, 0.58]
3.48 Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)	16	2599	Mean Difference (IV, Random, 95% CI)	8.79 [6.21, 11.37]
3.49 Maternal Hb concentration within 6 weeks postpartum (in g/L) (ALL)	6	521	Mean Difference (IV, Random, 95% CI)	7.38 [4.72, 10.04]
3.50 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)	7	1146	Risk Ratio (M‐H, Random, 95% CI)	1.90 [1.07, 3.35]
3.51 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)	7	1189	Risk Ratio (M‐H, Random, 95% CI)	3.80 [1.74, 8.28]
3.52 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)	3	453	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.02, 13.91]
3.53 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)	7	1046	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.02, 27.81]
3.54 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)	6	753	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
3.55 Puerperal infection (ALL)	2	2292	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.41, 1.03]
3.56 Antepartum haemorrhage (ALL)	1	430	Risk Ratio (M‐H, Random, 95% CI)	2.97 [0.12, 72.56]
3.57 Postpartum haemorrhage (ALL)	2	517	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.49, 1.34]
3.58 Transfusion provided (ALL)	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.62]
3.59 Diarrhoea (ALL)	1	173	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.09, 10.61]
3.60 Constipation (ALL)	2	580	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.18, 4.40]
3.61 Nausea (ALL)	3	650	Risk Ratio (M‐H, Random, 95% CI)	2.38 [0.49, 11.52]
3.62 Heartburn (ALL)	1	408	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.82, 1.22]
3.63 Vomiting (ALL)	2	477	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.38, 2.07]
3.64 Maternal wellbeing/satisfaction (ALL)	1	49	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.77, 1.08]
3.65 Placental abruption (ALL)	1	1442	Risk Ratio (M‐H, Random, 95% CI)	2.88 [0.12, 70.53]
3.66 Pre‐eclampsia (ALL)	1	47	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.06, 14.43]
3.67 Very low birthweight (less than 1500 g) (ALL)	3	697	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.03, 9.07]
3.68 Very premature birth (less than 34 weeks' gestation) (ALL)	4	2040	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.41, 1.14]
3.69 Infant Hb concentration in the first 6 months (in g/L, counting the last reported measure after birth within this period) (ALL)	2	533	Mean Difference (IV, Random, 95% CI)	‐1.25 [‐8.10, 5.59]
3.70 Infant serum ferritin concentration in the first 6 months (in μg/L, counting the last reported measure after birth within this period) (ALL)	1	197	Mean Difference (IV, Random, 95% CI)	11.00 [4.37, 17.63]
3.71 Admission to special care unit (ALL)	1	111	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

3.7. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 7: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation

3.10. Analysis.

Comparison 3: Supplementation with iron alone versus no treatment/placebo, Outcome 10: Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting

Comparison 4. Supplementation with iron + folic acid versus no treatment/placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
4.2 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
4.2.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	1	97	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
4.2.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	2	249	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
4.3 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
4.3.1 Non‐anaemic at start of supplementation	2	280	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.09, 0.68]
4.3.2 Unspecified or mixed anaemic status at start of supplementation	1	66	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.22, 0.62]
4.4 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
4.4.1 Higher daily dose (60 mg elemental iron and above)	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
4.5 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
4.5.1 Malarial setting	1	66	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.22, 0.62]
4.5.2 Non‐malarial setting	2	280	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.09, 0.68]
4.6 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)	1	131	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.06, 0.99]
4.7 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more) (ALL)	1	131	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.17, 1.09]
4.8 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)	1	131	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
4.9 Adverse effects (any reported throughout the intervention period) (ALL)	1	456	Risk Ratio (M‐H, Random, 95% CI)	44.32 [2.77, 709.09]
4.10 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)	4	506	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.02, 0.63]
4.11 Infection during pregnancy (including urinary tract infections) (ALL)	1	48	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.15, 6.53]
4.12 Low birthweight (less than 2500 g) (ALL)	2	1311	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.31, 3.74]
4.13 Birthweight (ALL)	2	1365	Mean Difference (IV, Random, 95% CI)	57.73 [7.66, 107.79]
4.14 Preterm birth (less than 37 weeks of gestation) (ALL)	3	1497	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
4.15 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation	3	1410	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
4.15.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	2	1366	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
4.15.2 Unspecified or mixed gestational age at start of supplementation	1	44	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
4.16 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	3	1497	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
4.16.1 Unspecified or mixed anaemic status at start of supplementation	3	1497	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
4.17 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron	3	1497	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
4.17.1 Low daily dose (30 mg elemental iron or less)	1	131	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
4.17.2 Higher daily dose (60 mg elemental iron and above)	2	1366	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
4.18 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting	3	1497	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.40, 6.00]
4.18.1 Malarial setting	2	1449	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.92, 1.39]
4.18.2 Non‐malarial setting	1	48	Risk Ratio (M‐H, Random, 95% CI)	7.00 [0.38, 128.61]
4.19 Neonatal death (within 28 days after delivery) (ALL)	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
4.20 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at start of supplementation	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
4.20.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
4.21 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at start of supplementation	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
4.21.1 Non‐anaemic at start of supplementation	1	97	Risk Ratio (M‐H, Random, 95% CI)	2.50 [0.10, 59.88]
4.21.2 Unspecified or mixed anaemic status at start of supplementation	2	1696	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.49, 1.27]
4.22 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
4.22.1 Higher daily dose (60 mg elemental iron and above)	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
4.23 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting	3	1793	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.51, 1.30]
4.23.1 Malarial setting	1	1648	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.49, 1.27]
4.23.2 Non‐malarial setting	2	145	Risk Ratio (M‐H, Random, 95% CI)	2.50 [0.10, 59.88]
4.24 Congenital anomalies (ALL)	1	1652	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.35, 1.40]
4.25 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)	3	346	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.54]
4.26 Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)	1	131	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.06, 0.99]
4.27 Maternal iron‐deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more) (ALL)	1	131	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.17, 1.09]
4.28 Maternal Hb concentration at term or near term (in g/L, at 34 weeks' gestation or more) (ALL)	3	140	Mean Difference (IV, Random, 95% CI)	16.13 [12.74, 19.52]
4.29 Maternal Hb concentration within 6 weeks postpartum (g/L) (ALL)	2	459	Mean Difference (IV, Random, 95% CI)	10.07 [7.33, 12.81]
4.30 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)	2	446	Risk Ratio (M‐H, Random, 95% CI)	1.78 [0.63, 5.04]
4.31 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)	2	314	Risk Ratio (M‐H, Random, 95% CI)	4.37 [0.58, 32.71]
4.32 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)	2	458	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.17, 0.69]
4.33 Maternal severe anaemia at term or near (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)	3	191	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.63]
4.34 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)	3	491	Risk Ratio (M‐H, Random, 95% CI)	0.05 [0.00, 0.76]
4.35 Puerperal infection (ALL)	1	2863	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.13, 2.28]
4.36 Antepartum haemorrhage (ALL)	2	145	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.22, 7.12]
4.37 Placental abruption (ALL)	1	2863	Risk Ratio (M‐H, Random, 95% CI)	8.19 [0.49, 138.16]
4.38 Pre‐eclampsia (ALL)	1	48	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 70.16]
4.39 Very low birthweight (less than 1500 g) (ALL)	1	48	Risk Ratio (M‐H, Random, 95% CI)	5.00 [0.25, 98.96]
4.40 Very premature birth (less than 34 weeks' gestation) (ALL)	2	92	Risk Ratio (M‐H, Random, 95% CI)	5.00 [0.25, 98.96]
4.41 Admission to special care unit (ALL)	1	48	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

4.8. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 8: Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)

4.20. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 20: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at start of supplementation

4.21. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 21: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at start of supplementation

4.22. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 22: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron

4.23. Analysis.

Comparison 4: Supplementation with iron + folic acid versus no treatment/placebo, Outcome 23: Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting

Comparison 5. Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)	4	13463	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.33, 0.85]
5.2 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation	4	13463	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.33, 0.85]
5.2.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	2	13160	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.41, 1.24]
5.2.2 Late gestational age (20 weeks or more of gestation) at start of supplementation	2	303	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.55]
5.3 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	3	11847	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.21, 1.11]
5.3.1 Non‐anaemic at start of supplementation	2	11784	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.13, 1.97]
5.3.2 Unspecified or mixed anaemic status at start of supplementation	1	63	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.23, 0.67]
5.4 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more ): SUBGROUP ANALYSIS by dose of iron	4	13463	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.33, 0.85]
5.4.1 Low daily dose (30 mg elemental iron or less)	1	11544	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.76, 1.17]
5.4.2 Higher daily dose (60 mg elemental iron and above)	3	1919	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.30, 0.64]
5.5 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting	4	13463	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.33, 0.85]
5.5.1 Malarial setting	1	63	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.23, 0.67]
5.5.2 Non‐malarial setting	3	13400	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.33, 1.00]
5.6 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)	1	1617	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.69, 0.79]
5.7 Maternal iron‐deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more) (ALL)	1	1616	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.38, 0.62]
5.8 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)	2	320	Risk Ratio (M‐H, Random, 95% CI)	0.06 [0.01, 0.47]
5.9 Low birthweight (less than 2500 g) (ALL)	3	15416	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.76, 1.01]
5.10 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation	3	15416	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.76, 1.01]
5.10.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	2	13090	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.72, 1.12]
5.10.2 Unspecified or mixed gestational age at the start of supplementation	1	2326	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.59, 1.22]
5.11 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	3	15416	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.76, 1.01]
5.11.1 Non‐anaemic at start of supplementation	1	11827	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.81, 1.31]
5.11.2 Unspecified or mixed anaemia status	2	3589	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.72, 0.94]
5.12 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron	3	15416	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.76, 1.01]
5.12.1 Low daily dose (30 mg elemental iron or less)	1	11827	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.81, 1.31]
5.12.2 Higher daily dose (60 mg elemental iron and above)	2	3589	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.72, 0.94]
5.13 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting	3	15416	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.76, 1.01]
5.13.1 Malarial setting	2	3589	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.72, 0.94]
5.13.2 Non‐malarial setting	1	11827	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.81, 1.31]
5.14 Birthweight (g) (ALL)	3	15416	Mean Difference (IV, Random, 95% CI)	22.78 [‐10.07, 55.63]
5.15 Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation	3	15416	Mean Difference (IV, Random, 95% CI)	22.78 [‐10.07, 55.63]
5.15.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	2	13090	Mean Difference (IV, Random, 95% CI)	29.16 [‐32.10, 90.43]
5.15.2 Unspecified or mixed gestational age at the start of supplementation	1	2326	Mean Difference (IV, Random, 95% CI)	20.20 [‐15.13, 55.53]
5.16 Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	3	15416	Mean Difference (IV, Random, 95% CI)	22.78 [‐10.07, 55.63]
5.16.1 Non‐anaemic at start of supplementation	1	11827	Mean Difference (IV, Random, 95% CI)	1.90 [‐12.17, 15.97]
5.16.2 Unspecified or mixed anaemic status at start of supplementation	2	3589	Mean Difference (IV, Random, 95% CI)	39.61 [‐3.90, 83.13]
5.17 Birthweight (g): SUBGROUP ANALYSIS by dose of iron	3	15416	Mean Difference (IV, Random, 95% CI)	22.78 [‐10.07, 55.63]
5.17.1 Low daily dose (30 mg elemental iron or less)	1	11827	Mean Difference (IV, Random, 95% CI)	1.90 [‐12.17, 15.97]
5.17.2 Higher daily dose (60 mg elemental iron and above)	2	3589	Mean Difference (IV, Random, 95% CI)	39.61 [‐3.90, 83.13]
5.18 Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting	3	15416	Mean Difference (IV, Random, 95% CI)	22.78 [‐10.07, 55.63]
5.18.1 Malarial setting	2	3589	Mean Difference (IV, Random, 95% CI)	39.61 [‐3.90, 83.13]
5.18.2 Non‐malarial setting	1	11827	Mean Difference (IV, Random, 95% CI)	1.90 [‐12.17, 15.97]
5.19 Preterm birth (less than 37 weeks of gestation) (ALL)	3	15419	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.86, 1.08]
5.20 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation	3	15419	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.86, 1.08]
5.20.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	2	13093	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.88, 1.11]
5.20.2 Unspecified or mixed gestational age at the start of supplementation	1	2326	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.57, 1.09]
5.21 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	3	15419	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.86, 1.08]
5.21.1 Non‐anaemic at start of supplementation	1	11832	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.83, 1.11]
5.21.2 Unspecified or mixed anaemic status at start of supplementation	2	3587	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.71, 1.22]
5.22 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron	3	15419	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.86, 1.08]
5.22.1 Low daily dose (30 mg elemental iron or less)	1	11832	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.83, 1.11]
5.22.2 Higher daily dose (60 mg elemental iron and above)	2	3587	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.71, 1.22]
5.23 Preterm birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting	3	15419	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.86, 1.08]
5.23.1 Malarial setting	2	3587	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.71, 1.22]
5.23.2 Non‐malarial setting	1	11832	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.83, 1.11]
5.24 Neonatal death (within 28 days after delivery) (ALL)	3	15876	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.72, 1.21]
5.25 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at the start of supplementation	3	15876	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.72, 1.21]
5.25.1 Early gestational age (less than 20 weeks of gestation or pre‐pregnancy) at start of supplementation	2	13381	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.74, 1.51]
5.25.2 Unspecified or mixed gestational age at the start of supplementation	1	2495	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.56, 1.19]
5.26 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at the start of supplementation	3	15876	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.72, 1.21]
5.26.1 Non‐anaemic at start of supplementation	1	11832	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.67, 1.82]
5.26.2 Unspecified or mixed anaemic status at start of supplementation	2	4044	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.65, 1.19]
5.27 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron	3	15876	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.72, 1.21]
5.27.1 Low daily dose (30 mg elemental iron or less)	1	11832	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.67, 1.82]
5.27.2 Higher daily dose (60 mg elemental iron and above)	2	4044	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.65, 1.19]
5.28 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting	3	15876	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.72, 1.21]
5.28.1 Malarial setting	2	4044	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.65, 1.19]
5.28.2 Non‐malarial setting	1	11832	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.67, 1.82]
5.29 Congenital anomalies (ALL)	2	13586	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.44, 1.39]
5.30 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)	2	303	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.21, 0.55]
5.31 Maternal Hb concentration at or near term (in g/L at 34 weeks' gestation or more) (ALL)	1	44	Mean Difference (IV, Random, 95% CI)	19.00 [11.02, 26.98]
5.32 Maternal Hb concentration within 6 weeks postpartum (in g/L) (ALL)	1	297	Mean Difference (IV, Random, 95% CI)	9.20 [5.78, 12.62]
5.33 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)	1	315	Risk Ratio (M‐H, Random, 95% CI)	2.87 [1.46, 5.66]
5.34 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)	1	240	Risk Ratio (M‐H, Random, 95% CI)	8.56 [0.47, 157.35]
5.35 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)	1	353	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.18, 0.81]
5.36 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)	1	46	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
5.37 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)	2	386	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.00, 1.33]
5.38 Very low birthweight (less than 1500 g) (ALL)	1	1263	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.24, 1.84]
5.39 Very premature birth (less than 34 weeks' gestation) (ALL)	1	2326	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.27, 1.10]
5.40 Infant Hb concentration in the first 6 months (in g/L, counting the last reported measure after birth within this period) (ALL)	1	11544	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.32, 0.32]

Comparison 6. Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Adverse effects (any reported throughout the intervention period) (ALL)	1	188	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.55, 1.07]
6.2 Low birthweight (less than 2500 g) (ALL)	2	375	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.22, 1.09]
6.3 Birthweight (g) (ALL)	3	397	Mean Difference (IV, Random, 95% CI)	100.30 [‐320.17, 520.77]
6.4 Preterm birth (less than 37 weeks of gestation) (ALL)	1	345	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.28, 1.02]
6.5 Congenital anomalies (ALL)	1	41	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
6.6 Maternal Hb concentration at or near term (in g/L at 34 weeks' gestation or more) (ALL)	2	49	Mean Difference (IV, Random, 95% CI)	13.13 [10.97, 15.30]
6.7 Maternal Hb concentration within 6 weeks postpartum (in g/L) (ALL)	1	27	Mean Difference (IV, Random, 95% CI)	14.00 [3.56, 24.44]
6.8 Constipation (ALL)	1	188	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.55, 1.07]
6.9 Heartburn (ALL)	1	188	Risk Ratio (M‐H, Random, 95% CI)	1.49 [0.95, 2.34]
6.10 Vomiting (ALL)	1	188	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.58, 2.20]
6.11 Diarrhoea (ALL)	1	188	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.29, 0.96]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Barton 1994.

Study characteristics
Methods	RCT, 2‐arm trial with individual randomisation
Participants	97 healthy women attending prenatal care at National Maternity Hospital, Dublin, Ireland with singleton pregnancy, during their first trimester of pregnancy, and with Hb equal or higher than 140 g/L were assigned to the groups. Women were excluded if they had a recent blood transfusion, chronic respiratory disease, chronic hypertension, renal disease, diabetes mellitus, history of haematologic disorder, and alcohol dependence.
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1: received 60 mg elemental iron and 500 μg (0.5 mg) of folic acid to be taken by mouth twice daily Group 2: placebo tablets also to be taken by mouth twice daily Supplementation started at 12 weeks until delivery. No postpartum supplementation. Setting and health worker cadre: the intervention was performed by physicians at the National Maternity Hospital in Dublin, Ireland.
Outcomes	Maternal: Hb, HCT, serum erythropoietin concentrations at baseline and at 24, 28, 32, 36, and 40 weeks; serum ferritin at baseline and at 36 weeks; number of hypertensive disorders, antepartum haemorrhage, caesarean delivery Infant: perinatal death, birthweight below 10th percentile, Apgar score, need for neonatal resuscitation and admission to neonatal intensive care unit data recorded but not reported in paper. Cord blood values of Hb, HCT, serum ferritin, and erythropoietin concentrations.
Notes	Unsupervised No participants were withdrawn because of anaemia. Compliance not reported Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks of gestation) (12 weeks until delivery) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher daily dose (60 mg elemental iron or more) (120 mg elemental iron) Iron release formulation: normal release/not specified Iron compound: not specified Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random numbers.
Allocation concealment (selection bias)	Unclear risk	Insufficient information reported on the method used to conceal the allocation sequence.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Reported as double‐blind. The placebo tablets were identical in size, colour and shape to the iron and folic acid supplements and contained the same excipients.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It was not clear whether those assessing outcomes were aware of allocation, but it is unlikely that this possible lack of blinding affected the laboratory outcomes reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 5% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Low risk	No baseline imbalance apparent.

Batu 1976.

Study characteristics
Methods	RCT, 4‐arm trial with individual randomisation
Participants	133 women referred to investigators from a population of women attending an antenatal clinic for the first time in Yangoon (also known as Rangoon), Myanmar (Burma). Women with severe anaemia were excluded from the trial during the intervention for treatment.
Interventions	Participants were randomly assigned to 1 of 4 groups starting at 22 to 25 weeks: Group 1: received 60 mg of elemental iron (as ferrous sulphate) and 1 placebo tablet twice daily. Group 2: received 1 tablet containing 60 mg of elemental iron (as ferrous sulphate) and 1 tablet containing 500 μg (0.5 mg) of folic acid twice daily. Group 3: received 2 placebo tablets twice daily. Group 4: received 1 placebo tablet and 1 tablet containing 500 μg (0.5 mg) of folic acid twice daily. Administration of the treatments was carefully supervised. Supplementation started at 22 to 25 weeks until term. Setting and health worker cadre: the intervention was performed by physicians at an antenatal clinic in Rangoon, Burma.
Outcomes	Maternal: Hb concentrations at baseline, at term (38th to 40th week) and 4 to 7 weeks postpartum, serum iron, serum and red cell folate activity and hypersegmented polymorph count at baseline, at 38th to 40th week and postpartum
Notes	Supervised 32 women who had taken other supplements or whose Hb level at full term was not available were excluded from the analysis. 3 women from group 3 and 2 from group 4 developed severe anaemia and were also withdrawn from analysis. Gestational age at start of supplementation: late gestational age (more than 20 weeks at the start of supplementation) (22 to 25 weeks' gestation) Anaemic status at start of supplementation: unspecified/mixed anaemia status at the start of supplementation (women with severe anaemia excluded) Daily iron dose: higher daily dose (60 mg elemental iron or more) (120 mg of elemental iron) Iron release formulation: normal release iron supplement/not specified Iron compound: ferrous sulphate Malaria setting: yes. As of 2011: Malaria risk due predominantly to P. falciparum exists throughout the year at altitudes below 1000 m, excluding the main urban areas of Mandalayand Yangon. Risk is highest in remote rural, hilly, and forested areas. P. falciparum resistant to chloroquine and sulphadoxine‐pyrimethamine reported. Mefloquine resistance reported in Kayin state and the eastern part of Shan state. P. vivax resistance to chloroquine reported. Human P. knowlesi infection reported. Dates of study: not reported Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not stated; "randomly placed in one of four treatment regimens"
Allocation concealment (selection bias)	Unclear risk	Insufficient information reported on the method used to conceal the allocation sequence.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo‐controlled trial, so it is likely that staff and women were blind to allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It was not clear whether those assessing outcomes were aware of allocation, but it is unlikely that this possible lack of blinding affected the laboratory outcomes reported.
Incomplete outcome data (attrition bias) All outcomes	High risk	37 women (28%) were excluded for analysis. 133 women randomised, "32 women who had taken other hematinics or whose Hb level at full term was not available were excluded". 5 women developed anaemia and were given treatment. Loss was not balanced across groups.
Selective reporting (reporting bias)	High risk	32 women who had taken other supplements or whose Hb level at full term was not available were excluded from the analysis. 3 women from group 3 and 2 from group 4 developed severe anaemia and were also withdrawn from analysis.
Other bias	Low risk	No baseline imbalance apparent.

Bloxam 1989.

Study characteristics
Methods	2‐arm randomised controlled trial
Participants	Pregnant women (n = 40) attending an antenatal clinic at 16 weeks gestation Exclusion criteria: "Taking medication, was a vegetarian, or had a previous malformed baby"
Interventions	Intervention (n = 20): multivitamins with iron (2 capsules per day, each containing 0.5 mg folic acid, 2 mg thiamine mononitrate, 2 mg riboflavin, 1 mg pyridoxine hydrochloride, 10 mg nicotinamide, 2.17 mg calcium pantothenate, 50 mg ascorbic acid, 47 mg elemental iron as ferrous sulphate). Taken at any time of day. Control (n = 20): matched placebo with same multivitamins but without iron
Outcomes	No protocol Birthweight (kg) Hb concentration at 34 and 38 weeks
Notes	Gestational age: early, supplementation started before 20 weeks' gestation Anaemic status at start of intervention: non‐anaemic if Hb 110 g/L or above during first and third trimesters Dose of iron: higher daily dose of iron > 60 mg elemental iron Type of formulation: not specified Iron compound bioavailability in comparison to ferrous sulphate: equivalent or lower relative bioavailability: ferrous sulphate Malaria risk setting: malaria risk‐free countries Study dates: not provided (N/A as pre‐1990) Study funding sources: The Wellcome Trust, SmithKline and French Laboratories Limited and the SmithKline (1982) Foundation Study authors’ declarations of interest: not provided (N/A as pre‐1990) Ethical approval obtained? "each subject gave her written informed consent, and the study had the approval of the Hospital Ethical Committee". Study prospectively registered? N/A (pre‐1990)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Groups matched with respect to parity, weight, smoking and maternal age by the minimisation method of Taves adapted for use with a computer. Taking account of these matching factors, each participant was assigned by the computer a coded randomised treatment number.
Allocation concealment (selection bias)	Low risk	Neither recruiter nor participant knew whether the pack contained iron or placebo; study was not decoded until after measurements were made.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Neither recruiter nor participant knew whether the pack contained iron or placebo; study was not decoded until after measurements were made.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Neither recruiter nor participant knew whether the pack contained iron or placebo; study was not decoded until after measurements were made.
Incomplete outcome data (attrition bias) All outcomes	High risk	Three from each group removed because of serious medical issues or Hb dropping to < 10.4g/dl. 45% dropout rate in total: 6/20 lost to follow‐up in the intervention group, 12/20 lost to follow‐up in the control group.
Selective reporting (reporting bias)	Unclear risk	Not known (no prospective registration)
Other bias	Low risk	No other bias noted. Passed TST.

Butler 1967.

Study characteristics
Methods	RCT, 3‐arm trial with individual randomisation
Participants	200 women before 20th week of gestation and Hb above 100 g/L attending an antenatal clinic at the Maternity Hospital in Glossop Terrace, Cardiff, United Kingdom were studied. Exclusion criteria included urinary infection and threatened miscarriage, confusion over therapy, intercurrent illness and difficult veins, intolerant to the iron form, premature labour.
Interventions	Participants were randomly allocated to 1 of 3 groups: Group 1: received 122 mg of elemental iron (as ferrous sulphate) daily. Group 2: received 122 mg of elemental iron (as ferrous sulphate) + 3400 μg (3.4 mg) of folic acid daily. Group 3: received no intervention. A group 4 was formed as some participants (n = 38) from group 3 received iron supplements for treatment of anaemia in the course of the intervention. They are excluded from the analysis. Women were supplemented from week 20 to 40 of gestation. Setting and health worker cadre: the intervention was performed by obstetricians and haematologists at the antenatal clinic, Cardiff Maternity Hospital in Cardiff, United Kingdom.
Outcomes	Maternal: Hb concentrations, blood and plasma volume, HCT (not reported), MCV, albumin and globulin fractions at weeks 20, 28, 36, and 40 of gestation and at the first postanal visit, oedema, intrapartum haemorrhage
Notes	Unsupervised 154 women were followed through to the postnatal visit. Only 16 women (30%) in the no‐treatment group remained untreated. Compliance not reported. Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: mixed anaemia status (Hb above 100 g/L) Daily iron dose: higher daily dose (60 mg of elemental iron or more) (122 mg elemental iron) Iron release formulation: normal release iron supplement/not specified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: This work was done while holding a Research Fellowship supported by the Research Committee of the Cardiff United Hospitals. The tablets were a gift from Lederle Laboratories. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised list stratified by age, parity and initial Hb level.
Allocation concealment (selection bias)	Low risk	The code was not opened for the iron and iron + folic acid group until the end of the investigation, thus clinical staff could not anticipate the randomisation sequence. There was no treatment for 1 group.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participant and provider were blinded to treatment for groups 1 and 2. The control group received no treatment and did not get a placebo.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It was not clear whether those assessing outcomes were aware of allocation, but it is unlikely that this possible lack of blinding affected the laboratory outcomes reported.
Incomplete outcome data (attrition bias) All outcomes	High risk	More than 20% were lost to follow‐up at the postnatal visit. 154 women were randomised and for many outcomes there were missing data. 70% of the 54 women initially allocated to the no treatment group received iron supplements for anaemia (as there was no placebo, staff would be aware that women were not receiving supplements). Results for those women treated or not treated in the control group were reported separately. Results are therefore difficult to interpret.
Selective reporting (reporting bias)	Low risk	Authors provided the full database for this review.
Other bias	Low risk	No baseline imbalance apparent.

Buytaert 1983.

Study characteristics
Methods	RCT, 2‐arm trial with individual randomisation
Participants	45 non‐anaemic women with singleton pregnancy and no major illnesses attending the University Hospital Obstetric and Gynaecologic Clinic in Antwerp, Belgium
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1: received 105 mg of elemental iron (as ferrous sulphate sustained release preparation) daily. Group 2: received no iron supplement. Supplementation started at 14th to 16th week of gestation and continued until delivery. Setting and health worker cadre: the intervention was performed by obstetricians at the University Hospital Obstetrical Clinic of the Erasmus University at Rotterdam, The Netherlands or the University Hospital Obstetric and Gynecologic Clinic in Antwerp, Belgium.
Outcomes	Maternal: Hb, serum iron, serum transferrin and serum ferritin concentrations at 16, 28, 36 weeks, delivery, and 6 weeks postpartum
Notes	Unsupervised. The randomisation was made for each clinic in Antwerp, and the results are presented separately by clinic. Compliance not reported. We treated this study carried out collaboratively in 2 different sites as 2 different trials, 1 conducted in Rotterdam (Wallenburg 1983) and 1 conducted in Antwerp (Buytaert 1983). Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) (14th to 16th week) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher dose of iron (60 mg of elemental iron or more) (105 mg elemental iron) Iron release formulation: sustained release preparation Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random table numbers.
Allocation concealment (selection bias)	Low risk	By means of sealed envelopes.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Neither participant nor provider blinded. No placebo used.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Management was altered depending on outcomes (women in the no treatment group who developed anaemia were treated).
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Cantlie 1971.

Study characteristics
Methods	RCT, 2‐arm trial with individual randomisation
Participants	27 apparently healthy non‐anaemic pregnant women 17 to 35 years of age from 4 participating obstetricians' private practice clinics from Montreal, Canada in their 1st to 5th month of pregnancy with Hb 120 g/L or higher in first trimester and 110 g/L or higher in second trimester. Women with a history of pathological blood loss or gross dietary imbalance were excluded.
Interventions	Participants were randomly assigned to 2 groups: Group 1 received 39 mg elemental iron (Mol‐Iron®, ferrous iron) to be taken twice daily with meals (total daily 78 mg elemental iron). Group 2 received no iron tablets. As a co‐intervention, both groups received 1 tablet of multiple micronutrient supplement daily containing: 2 mg copper citrate, 6 mg magnesium stearate, 0.3 mg manganese carbonate, 1000 IU vitamin A, 500 IU vitamin D, bone flour 130 mg, 1 mg vitamin B1, 1 mg vitamin B2, 50 mg brewer yeast concentrate, 5 mg niacinamide, 25 mg vitamin C, 0.2 mg sodium iodide, and 0.049 μg folate (naturally occurring). Duration of supplementation unclear. Setting and health worker cadre: the intervention was performed by obstetricians and haematologists at the McGill University Medical Clinic, Royal Victoria Hospital in Montreal, Canada. Participants, of higher SES, were recruited from private obstetrical practices.
Outcomes	Maternal: Hb concentration, PCV, reticulocyte count, sedimentation rate, total white blood cell and differential counts, serum iron, unsaturated and total iron binding capacity, serum B12, serum and RBC folate at baseline and at 32, 36, 39th weeks and 7 days postpartum.
Notes	Supervision unclear. Compliance not reported. Gestational age at start of supplementation: mixed gestational age (1st to 5th month of pregnancy) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher daily dose (60 mg elemental iron or more) (78 mg elemental iron) Iron release formulation: normal release iron supplement/not specified Iron compound: Mol‐Iron®, ferrous iron Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: "Supported by the Medical Research Council of Canada, grant MBT‐1664. We wish to thank Charles E Frosst Company of Montreal for their generous supply of the vitamin and mineral preparations, and White Laboratories, Kenilworth, New Jersey, for the Mol‐Iron tablets which were provided to the patients." Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not stated; "divided randomly".
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Women and staff were not blind to treatment allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It was not clear whether those assessing outcomes were aware of allocation, but it is unlikely that this possible lack of blinding affected the laboratory outcomes reported.
Incomplete outcome data (attrition bias) All outcomes	High risk	27 women were randomised; 26 mentioned in the discussion; denominators were not provided for the results.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	Women in the intervention group had higher median serum folate levels at baseline (not significant).

Chan 2009.

Study characteristics
Methods	RCT (placebo‐controlled), 2‐arm trial, individual randomisation
Participants	1164 pregnant women with singleton pregnancies with a gestational age of 16 weeks or less able to understand English or Chinese attending their first antenatal care visit at Queen Mary Hospital, Hong Kong between April 2005 and March 2007 Exclusion criteria: women with existing diabetes, haemoglobinopathies, Hb levels < 80 g/L or > 140 g/L, women with possible thalassaemia (MCV < 80), women diagnosed with gestational diabetes at booking
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1: (n = 565 women) received 60 mg of elemental iron orally (as 300 mg ferrous sulphate) daily. Group 2: (n = 599 women) received daily placebo indistinguishable in appearance from the active supplements. Women in both groups were provided with a supply for 16 weeks. At 28 to 30 weeks further supplements were provided (up to 36 weeks) as long as women had not developed gestational diabetes mellitus or Hb level was > 140 g/L. If women in the placebo group developed anaemia (Hb < 80 g/L), they were given iron supplements as clinically indicated. Baseline investigations included a full blood count including Hb and HCT, MCV, white cells and platelets, along with serum ferritin concentration. An OGIT was carried out at baseline for women with risk factors for gestational diabetes (e.g. advanced maternal age, family history of diabetes). Otherwise, women in both groups received standard antenatal care. Setting and health worker cadre: the intervention was performed by physicians at a regional university teaching hospital in Hong Kong.
Outcomes	Follow‐up at 28 weeks and 36 weeks' gestation and delivery and 3 days postpartum Main outcome: development of gestational diabetes at 28 or 36 weeks. (According to WHO criteria for impaired glucose tolerance test (OGTT 2‐hour value > or = 7.8 < 11.1 mmol/L) or diabetes (OGTT 2‐hour value > or = 11.1 mmol), both were considered as gestational diabetes mellitus). Other maternal outcomes: Hb (g/L), serum transferrin (g/L), serum ferritin (pmol/L), compliance, glucose level, mode of delivery. Neonatal outcomes: gestational age at delivery, preterm delivery, birthweight, Apgar score at 1 and 5 minutes, arterial blood pH, Hb of cord blood (g/L), ferritin of cord blood (pmol/L), jaundice, birth trauma, infection, congenital abnormality, or metabolic disorder
Notes	Very high attrition (> 50% for outcomes at 36 weeks). 45.6% of controls and 43.1% of women in the study group were taking additional vitamin supplements. As the results reported in the paper were not completely clear to us, we preferred not to use the reported SDs and removed the information from this trial for continuous variables, while awaiting clarification from the authors. Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks) (16 weeks or less) Anaemic status at start of supplementation: mixed anaemia status (Hb levels > 80 and < 140 g/L) Daily iron dose: higher dose (60 mg elemental iron) Iron release formulation: normal release iron supplement/not specified Iron compound: ferrous sulphate Malaria setting: Yes. As of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine‐pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas. No. As of 2021: According to World Malaria Report 2022, of the 93 countries that were malaria endemic in 2015, 4 countries along with China have been certified malaria‐free since 2015. Dates of study: April 2005 to March 2007 Funding sources: This project is funded by a grant from the Research Grant Council, Hong Kong. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was carried out by a research nurse who was not involved in patient recruitment. Block randomisation with computer generation of sequence. The block size was 100.
Allocation concealment (selection bias)	Low risk	Sealed, opaque envelopes. The envelopes were sequentially numbered and sealed (by nurse A who did the block randomisation) and all the envelopes were accounted for. The research assistant who recruited the patients (nurse B) would sequentially open the numbered envelopes after the patient had consented to participate in the study.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Participants blinded; placebo‐controlled. After randomisation, “The participants but not the research assistants were blinded to group assignment”. Staff and research nurses were aware of the group allocation.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Outcomes were assessed by the principal investigator (the outcomes are mainly objective outcomes such as OGTT results, blood counts, birthweight, etc). Women who developed anaemia were treated and those developing gestational diabetes withdrawn. Compliance, side effects, and other outcomes reported as well as laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	High risk	1164 women were randomised. It was stated that an ITT analysis was performed, but data tables suggest there were missing data for most outcomes at 28 and 36 weeks and at delivery; e.g. at 28 weeks, 90.3% attended for follow‐up. Neonatal outcome data were available for 74% of those randomised. There were very high levels (> 50%) of missing data for laboratory values at 36 weeks.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Low risk	No baseline imbalance between groups apparent.

Chanarin 1965.

Study characteristics
Methods	Randomised controlled trial with 3 arms
Participants	190 pregnant women before 16 weeks of gestational age attending antenatal clinic for the first time in St Mary's Hospital in London, England, United Kingdom were invited to participate in the study and 189 accepted.
Interventions	Participants were randomly assigned to 1 of 3 groups: Group 1 received 3 tablets containing 100 mg of ferrous fumarate to be taken daily (total 300 mg ferrous fumarate daily). Group 2 received 3 tablets containing 100 mg of ferrous fumarate with 10 μg (0.01 mg) folic acid (total 300 mg ferrous fumarate and 30 μg (0.03 mg) folic acid daily. Group 3 received placebo (containing lactose). Setting and health worker cadre: the intervention was performed by obstetricians and pathologists at the antenatal clinic of St. Mary's Hospital in London, United Kingdom.
Outcomes	The outcomes measured include full blood count at 20th, 30th, 35th, and 39th week of gestation and 6th day after delivery.
Notes	The paper does not report SDs in the variables measured, and no data can be extracted. The trial is included but does not contribute data for the analysis. Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: unspecified or mixed anaemia status Daily iron dose: higher daily dose (60 mg of elemental iron or more) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous fumarate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: "We wish to express our indebtedness to Glaxo Research Ltd. for supplying the tablets used in the trial." Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Methods not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Partial blinding. This was a placebo‐controlled trial; bottles containing medication were colour‐coded, but it was stated that staff were not aware of the colour coding during the trial.
Blinding of outcome assessment (detection bias) All outcomes	High risk	It was stated that some women in the placebo group with anaemia were treated and withdrawn from the analysis for haematological outcomes; it was not clear whether staff were aware of allocation at the point of withdrawing these women. Excluding this section of the sample makes findings for the placebo group biased for these outcomes.
Incomplete outcome data (attrition bias) All outcomes	High risk	189 women were randomised and only 154 completed the study, but not all samples could be obtained from every participant. 35 women were further withdrawn from the trial. 9 participants in the placebo group and 1 in the iron + folic acid group required parenteral iron nutrition and were withdrawn from the analysis.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Chanarin 1971.

Study characteristics
Methods	Quasi‐RCT, 5‐arm trial with individual randomisation
Participants	251 women attending antenatal clinic at St Mary's Hospital, London, United Kingdom before 20th week of gestation
Interventions	Participants were allocated by sequence to 1 of 5 groups: Group 1: received an oral dose of 30 mg of elemental iron (as ferrous fumarate) daily. Group 2: received an oral dose of 60 mg of elemental iron (as ferrous fumarate) daily. Group 3: received an oral dose of 120 mg of elemental iron (as ferrous fumarate) daily. Group 4: received placebo. Group 5: received 1 g of iron (Imferon, 4 x 250 mg) intravenously before week 20, and thereafter oral 60 mg of elemental iron (as ferrous fumarate) daily (not included in this review). Supplementation started at the 20th week until the 37th week. Only the data related to comparisons of group 1: oral dose of 30 mg of elemental iron daily with group 4: placebo are used in this review, given that no data for the other groups could be desegregated. Setting and health worker cadre: the intervention was performed by obstetricians and pathologists at the antenatal clinic of St. Mary's Hospital in London, United Kingdom.
Outcomes	Maternal: full blood count, serum iron at 20, 25, 30, and 37th week. Sternal marrow aspiration at 37 weeks; antepartum haemorrhage, threatened abortion, urinary tract infection, fetal abnormalities, pregnancy hypertension, premature delivery, and puerperal infection measured but not reported by groups Infant: birthweight (not reported by groups)
Notes	Compliance not reported Gestational age at start of supplementation: late gestational age (supplementation started at 20 weeks' gestation) Anaemic status at start of supplementation: unspecified/mixed anaemia status Daily iron dose: different doses in different arms of trial (group 1 lower daily dose: 30 mg; group 2 and 3 higher daily dose 60 mg or more) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous fumarate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: "We are grateful for support from Glaxo Laboratories." Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quasi‐randomised study, assignment by sequence.
Allocation concealment (selection bias)	High risk	Women were "allocated in sequence to one of five groups"; allocation order could therefore be anticipated.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	1 of 5 groups was given an IV medication (not included in this review). The other 4 were given iron or placebo tablets and for the oral medication, it was stated that women and staff were not aware of which treatment women were receiving.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Women who developed anaemia were withdrawn from the study. It was not clear at what point investigators were aware of treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	It was not clear exactly how many women were randomised; there were approximately 50 in each of 5 groups. 11 women (9 from the placebo group) were withdrawn and given treatment for anaemia "after allowance had been made for the subjects dropping out of the study... there were just under 50 subjects in each group".
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Charoenlarp 1988.

Study characteristics
Methods	RCT, series of treatment conditions
Participants	325 pregnant women with Hb (AA) and 232 pregnant women with Hb (AE) attending midwife centres in 80 villages from the Varin Chamrab district of Ubon Province, Thailand. Chronic illness, complicated pregnancy, severe anaemia (Hb < 80 g/L), haemoglobinopathies Hb (EE) and (EF), and unwillingness to co‐operate were reasons for exclusion. Individuals with Hb (AA) have normal Hb genes. Individuals with Hb (AE) have a heterozygous Hb E trait with normal Hb gene (A‐adults) and an abnormal Hb gene (E). This is usually a clinically insignificant condition.
Interventions	Participants were divided into 2 groups according to Hb (AA) and Hb (AE) and studied separately. Women from each group were randomly assigned to 1 of the following 11 interventions: Group 1: received placebo, supervised. Group 2: received 120 mg of elemental iron (as ferrous sulphate) and 5000 μg (5 mg) folic acid daily supervised. Group 3: received 240 mg of elemental iron (as ferrous sulphate) daily supervised. Group 4: received 240 mg of elemental iron (as ferrous sulphate) daily supervised. Group 5: received 120 mg elemental iron (as ferrous sulphate) and 5000 μg (5 mg) of folic acid, motivated but unsupervised. Group 6: received 240 mg of elemental iron (as ferrous sulphate) and 5000 μg (5 mg) of folic acid daily, motivated but unsupervised. For the Hb (AE) group, women were randomly assigned to 1 of the following groups: Group 7: placebo, supervised Group 8: 240 mg elemental iron (as ferrous sulphate) and 5000 μg (5 mg) of folic acid daily, supervised Group 9: 240 mg of elemental iron (as ferrous sulphate) daily, supervised Group 10: 120 mg of elemental iron (as ferrous sulphate) and 5000 μg (5 mg) of folic acid daily, motivated but unsupervised Group 11: 240 mg of elemental iron and 5000 μg (5 mg) of folic acid daily, motivated but unsupervised Starting and ending time of supplementation not stated Setting and health worker cadre: the intervention was performed by community health workers under the supervision of a midwife and was delivered to the home of participants living in villages near Ubon, Thailand. Intervention was co‐ordinated from village midwife centres.
Outcomes	Maternal: Hb, serum ferritin after 10 and 15 weeks of supplementation, and side effects
Notes	Groups 1, 2, 3, 4, 7, 8, 9 supervised. Groups 5, 6, 10 and 11 motivated but unsupervised. For purposes of analysis, the groups were merged by iron alone or iron‐folic acid, and included as daily higher doses in both cases. Compliance not reported Gestational age at start of supplementation: gestational age not specified Anaemic status at start of supplementation: unspecified/mixed anaemia status Daily iron dose: higher daily dose (60 mg or more of elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: yes. As of 2011: Malaria: Malaria risk exists throughout the year in rural, especially forested and hilly, areas of the whole country, mainly towards the international borders, including the southernmost provinces. There is no risk in cities (e.g. Bangkok, Chiang Mai city, Pattaya), Samui island and the main tourist resorts of Phuket island. However, there is a risk in some other areas and islands. P. falciparum resistant to chloroquine and sulphadoxine‐pyrimethamine reported. Resistance to mefloquine and to quinine reported from areas near the borders with Cambodia and Myanmar. P. vivax resistance to chloroquine reported. Human P. knowlesi infection reported. Dates of study: not reported Funding sources: Supported by the World Health Organization, the Belgian Administration of Cooperation to Development (AGCD), the Danish International Development Authority (Danida), and the Swedish International Development Authority (SIDA). Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Set of random tables.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Placebo‐controlled study but 2 of the groups had tablets under supervision (not blinded) and some of the tablets had an odd taste, so this may have affected compliance and reporting of side effects.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Outcome assessment was only partially blinded and it is not clear what the impact of lack of blinding would be on some outcomes, although laboratory outcomes would be likely to be at low risk of bias.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Ranged from 10% to 15%.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Chisholm 1966.

Study characteristics
Methods	RCT, 6 arms
Participants	360 non‐anaemic women attending antenatal clinic at Radcliffe Infirmary, Oxford, United Kingdom before 28th week of gestation, who had not taken iron supplements in the preceding 8 weeks and with Hb ≥ 102 g/L or a normal serum iron reading. Exclusion criteria: Hb < 110 g/L and serum iron less than 60 μg/L.
Interventions	Participants were randomly assigned to 1 of various combinations of elemental iron as ferrous gluconate and folic acid, as follows: Group 1: received 900 mg elemental iron alone daily. Group 2: received 900 mg elemental iron and 500 μg (0.5 mg) folic acid daily. Group 3: received 900 mg elemental iron and 5000 μg (5 mg) folic acid daily. Group 4: received placebo. Group 5: received 500 μg (0.5 mg) folic acid daily. Group 6: received 5000 μg (5 mg) of folic acid daily. Iron and folic acid placebos were used. Supplementation started at the 28th week until the 40th week. Setting and health worker cadre: the intervention was performed by physicians at the antenatal clinic of The Radcliffe Infirmary, Oxford, United Kingdom.
Outcomes	Maternal: Hb, HCT, serum iron, serum folic acid activity, serum vitamin B12 estimation at 28 weeks of gestation and before delivery
Notes	Unsupervised For purposes of this review, the placebo group was the group who received neither iron nor folic acid. Groups 2 and 3 were merged for iron‐folic acid comparisons. Compliance not reported Gestational age at start of supplementation: late gestational age (from 28 weeks' gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher daily dose (60 mg or more of elemental iron) Iron release formulation: normal release preparation/not specified Iron compound: ferrous gluconate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: This study was financed by a grant from the Nuffield Committee for Advancement in Medicine. The folic acid was supplied without charge by Lederle Laboratories and the placebo iron tablets were made up by the Bayer Products Company and Sandoz Ltd. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	External randomisation.
Allocation concealment (selection bias)	Low risk	Bottles containing the tablets had been numbered by random selection at source and the code was unknown during the trial.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind trial. Placebo‐controlled and placebo and active treatment described as indistinguishable. Bottles containing tablets were numbered and treatment allocation was not revealed until after the trial.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Women with anaemia were treated (irrespective of allocation).
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow‐up apparent.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Christian 2003 (C).

Study characteristics
Methods	Cluster‐randomised trial with 5 treatment arms
Participants	4998 married pregnant women (with positive pregnancy test) living in the south‐eastern plains district of Sarlahi, Nepal. Widows were excluded.
Interventions	Participants were randomly assigned to 1 of 5 groups: Group 1 received 1000 μg retinol equivalent vitamin A (control) daily. Group 2 received 1000 μg retinol equivalent vitamin A and 400 μg (0.4 mg) folic acid daily. Group 3 received 1000 μg retinol equivalent vitamin A, 400 μg (0.4 mg) folic acid, and 60 mg elemental iron (as ferrous fumarate) daily. Group 4 received 1000 μg retinol equivalent vitamin A, 400 μg (0.4 mg) folic acid, 60 mg of elemental iron (as ferrous fumarate) and 30 mg of zinc sulphate daily. Group 5 received 1000 μg retinol equivalents vitamin A, 400 μg (0.4 mg) folic acid, 60 mg elemental iron (as ferrous fumarate), 30 mg of zinc, 10 μg vitamin D, 10 mg vitamin E, 1.6 mg thiamine, 1.8 mg riboflavin, 20 mg niacin, 2.2 mg vitamin B6, 2.6 μg vitamin B12, 100 mg vitamin C, 65 μg vitamin K, 2 mg cooper, and 100 mg magnesium daily. Only groups 1, 2, and 3 are considered in this review. Supplementation started at recruitment and continued until 3 months postpartum in the case of live births of 5 weeks or more after a miscarriage or stillbirth. All participating women were offered deworming treatment (albendazole 400 mg single dose) in the second and third trimester. Supplementation lasted 257.5 days in group 1 (control) and 251.7 days in the group 3 receiving vitamin A, iron and folic acid. Comparisons: group 3 vs group 1: effect of iron supplementation with folic acid; group 3 vs group 2: effect of iron supplementation alone. Setting and health worker cadre: the intervention was performed by community health workers in the home of the participants in remote villages in Sarlahi, Nepal. In Nepal, 8% of women received assistance from an auxiliary nurse midwife or doctor. Dosing and supplement replenishment was done by 426 local female workers, 1 per sector, or about 40 households.
Outcomes	Maternal: premature delivery, Hb and iron status at baseline in the third trimester (scheduled at 32 weeks of gestation) and Hb at 6 weeks postpartum, prevalence of anaemia in third trimester and at 6‐week postpartum, severe anaemia postpartum, moderate anaemia during third trimester, moderate anaemia postpartum, moderate high Hb concentrations during third trimester Infant: birthweight, prevalence of low birthweight, perinatal mortality, neonatal mortality, infant deaths, small‐for‐gestational age
Notes	Supplementation with 1000 μg retinol equivalent vitamin A (control) daily and deworming treatment (albendazole 400 mg single dose) in the second and third trimester were co‐interventions for purposes of the analysis. Unsupervised but trial personnel visited women twice each week to monitor supplement intake. Compliance during pregnancy measured by pill count was high (median 88%) and did not vary by groups. 98% of the women accepted the albendazole treatment at both times (second and third trimesters). Approximately 50% of women started supplementation before 9 weeks of gestational age. Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: unspecified/mixed anaemia status Daily iron dose: higher daily dose (60 mg or more elemental iron) Iron release formulation: normal release preparation/not specified Iron compound: ferrous fumarate Malaria setting: yes. As of 2011: Malaria risk due predominantly to P. vivax exists throughout the year in rural areas of the 20 Terai districts bordering India, with occasional outbreaks of P. falciparum from July to October inclusive. Seasonal transmission of P. vivax takes place in 45 districts of the inner Terai and mid hills. P. falciparum resistant to chloroquine and sulphadoxine‐pyrimethamine reported. Dates of study: enrolment of pregnant women took place from January 1999 through February 2000. Funding sources: Supported by the US Agency for International Development (USAID), the UNICEF Country Office, Kathmandu, Nepal, and the Bill and Melinda Gates Foundation. The study was carried out under Cooperative Agreement HRN‐A‐00‐97‐00015‐00 between the Office of Nutrition, USAID, Washington, DC, and the Center for Human Nutrition (CHN), Department of International Health, and the Sight and Life Research Institute, Johns Hopkins University, Bloomberg School of Public Health, Baltimore. The study was a joint undertaking between the CHN and the National Society for the Prevention of Blindness, Kathmandu, Nepal. Supplements were provided by Roche, Brazil, and were manufactured by NutriCorp International, CE Jamieson & Company Ltd, Windsor, Canada. Declarations of interest: none of the authors had any conflicts of interest. Included in 2024 update because although a trustworthiness red flag was discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023), this concern was dealt with in correspondence with the trial authors. Trustworthiness red flag: abstract only We reached out to the corresponding author, who sent us the full article.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Cluster‐randomisation. No evidence of recruitment bias. Participants did not know beforehand which cluster they were in.
Allocation concealment (selection bias)	Low risk	Coded.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	This was described as a double‐blind trial. It was reported that the study supplements were identical in appearance and women, staff, investigators, and statisticians were not aware of supplement codes until the end of the study.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Field staff and investigators were blinded.
Incomplete outcome data (attrition bias) All outcomes	High risk	More than 20% loss to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Low risk	This was a cluster‐randomised trial; baseline characteristics did not differ by treatment group in age at baseline, SES, parity, gestational age at enrolment, previous miscarriage. The level of compliance did not differ by group. Analysis was adjusted for the cluster‐design effect.

Cogswell 2003.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	275 legally competent, non‐imprisoned, non‐anaemic, low‐income pregnant women at < 20 weeks of gestation with ferritin levels above 20 μg/L enrolled at the Cuyahoga County, MetroHealth Center, Supplemental Nutrition Program for Women, Infants and Children in Cleveland, Ohio, USA
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1 received 1 gelatin capsule containing 30 mg of elemental iron (as ferrous sulphate) daily. Group 2 received 1 placebo soft gelatin capsule daily for 119 days. Supplementation started at an average of 11 weeks of gestation until delivery.
Outcomes	Maternal: prevalence of anaemia at 28 and 38 weeks, side effects, compliance to treatment, maternal weight gain, iron status (MCV, Hb concentration, serum ferritin, erythrocyte protoporphyrin concentrations at 28 and 38 weeks) Infant: birthweight, birth length, proportion of low birthweight, low birthweight and premature, small‐for‐gestational age Setting and health worker cadre: the intervention was performed by a dietician at the Cuyahoga County, MetroHealth Medical Center, Supplemental Nutrition Program for Women, Infants and Children in Cleveland, Ohio, United States of America.
Notes	Unsupervised. Women were re‐evaluated at 28 weeks of gestation, and according to Hb concentrations at that time were prescribed treatment following the Institute of Medicine guidelines for iron supplementation during pregnancy. Compliance was 63.4% and 65.2% in groups 1 and 2 respectively. Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: lower daily dose (30 mg of elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: between June 1995 and September 1998, 513 low‐income pregnant women in Cleveland were enrolled in the study before 20 weeks of gestation. Funding sources: Supported by the US Department of Health and Human Services, Centers for Disease Control and Prevention (Cooperative Agreement no. U50/CCU 50855) and the National Institutes of Health (grant no. RO1 HL52447). Declarations of interest: none of the authors had any conflicts of interest. Included in 2024 update because although a trustworthiness red flag was discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023), this concern was dealt with in correspondence with the trial authors. Trustworthiness red flag: abstract only We reached out to the corresponding author, who sent us links to the final reports.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	By computerised random numbers.
Allocation concealment (selection bias)	Low risk	Placebo‐controlled trial. Randomisation by study data manager. The placebo and active treatment were indistinguishable and all staff were blind to group allocation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo‐controlled trial, with placebo indistinguishable from the active treatment. Bottles were coded and treatment group was only known to a data manager. It was stated that women and staff were not aware of treatment.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It was stated that laboratory analysts and staff collecting information on side effects were blind to treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	High risk	More than 20% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Dawson 1989.

Study characteristics
Methods	Parallel, randomised, 2‐arm trial
Participants	Inclusion criteria: pregnant women between the ages of 16 and 20 years averaging 13 weeks (range 8 to 17 weeks) gestational age, who had not received prenatal multivitamin‐mineral supplementation during the preceding 30 days. Attending antenatal care at the University of Texas Medical Branch at Galveston. Exclusion criteria: hypertension, diabetes or other medical problems as well as for haemoglobin concentrations < 110 g/L or haematocrit concentrations below 0.33, which are the clinical criteria for iron deficiency anaemia during pregnancy
Interventions	Intervention: (n = 20) 60‐day supply of multivitamin with 18 mg Fe (One‐A‐Day, manufactured by Miles Laboratories, Inc, Elkhard, IN) with first supply at 13 weeks, then weeks 20, 32, 38, at delivery, and 4 and 12 weeks postpartum. Control/comparison: (n = 21) 60‐day supply of multivitamin without 18 mg Fe (One‐A‐Day, manufactured by Miles Laboratories, Inc, Elkhard, IN) with first supply at 13 weeks, then weeks 20, 32, 38, at delivery, and 4 and 12 weeks postpartum
Outcomes	Gestational age at delivery, CS, birthweight, low‐birthweight babies, 5‐min Apgar score, pregnancy‐induced hypertension, intrauterine growth retardation, congenital malformation
Notes	Gestational age: early, supplementation started before 20 weeks' gestation Anaemic status at start of intervention: non‐anaemic Hb 110 g/L or above during first and third trimesters Dose of iron: low daily dose of iron if 30 mg or less of elemental iron Type of formulation: not specified Iron compound bioavailability in comparison to ferrous sulphate: not specified Malaria risk setting: study carried out in malaria risk‐free countries Compliance not validated. Baseline Fe was 16 ± 2 μmol/L for control group, and 13 ± 2 μmol/L for intervention group – mean 23% higher for control group Study dates: not given (n/a because of trial age) Study funding sources: not given (n/a because of trial age) Study authors’ declarations of interest: not given (n/a because of trial age) Ethical approval obtained? "Subjects informed of study protocol in compliance with our institutional review board’s requirements, and written consent obtained from each participant". Study prospectively registered? No registration (n/a because of trial age) Dates of study: not reported Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Only states "each subject was randomly provided" with supplement. No further detail given.
Allocation concealment (selection bias)	Unclear risk	Process not described in trial report.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No details given.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details given.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete outcome data.
Selective reporting (reporting bias)	Unclear risk	No prospective protocol.
Other bias	Unclear risk	Compliance to intervention not validated. Passed TST.

De Benaze 1989.

Study characteristics
Methods	RCT, 2‐arm trial with individual randomisation
Participants	191 non‐anaemic pregnant women with 12 to 18 weeks of gestation attending antenatal care clinic at the Maternity Ward at Poissy Hospital, Paris, France. Exclusion criteria included women who had taken iron or folate supplements in the prior 6 months and those with language barriers for proper communication. Supplementation started at 12 to 18 weeks until delivery.
Interventions	Participants were randomly allocated to 1 of 2 groups: Group 1: received a daily intake of 45 mg of elemental iron (as ferrous betainate hydrochloride) (15 mg elemental iron per tablet). Group 2: received placebo tablets. Setting and health worker cadre: the intervention was performed by physicians at the Maternity Ward of Poissy Hospital, Poissy, France.
Outcomes	Maternal: Hb, MCV, serum iron, total iron binding capacity, transferrin saturation, serum ferritin at baseline, at 5 months, at 7 months, at delivery and 2 months postpartum.
Notes	Unsupervised Serum ferritin values presented as arithmetic and geometric means. No SD in transformed ferritin values is presented. Women in the placebo group were prescribed treatment after delivery thus not allowing comparisons at 2 months postpartum among the groups. Compliance reported as good Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: medium daily dose (45 mg elemental iron) Iron release formulation: normal release preparation/not specified Iron compound: ferrous betainate hydrochloride Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised but method used unclear.
Allocation concealment (selection bias)	Low risk	Placebo‐controlled trial. Active and placebo tablets were in identical packaging and packages were provided randomly.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	(Assessment from translated notes). Placebo‐controlled trial with active and placebo supplements in identical packaging and tablets were identical in appearance.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Placebo‐controlled trial and laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% loss to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Dommisse 1983.

Study characteristics
Methods	RCT, 2‐arm trial with individual randomisation
Participants	146 pregnant women with less than 20 weeks of gestation who had not received iron therapy recently, attending the Peninsula Maternity Service, Department of Obstetrics and Gynecology, University of Cape Town, Groote Schuur Hospital, South Africa
Interventions	Participants were randomly allocated to receive either a multivitamin tablet twice a day or a multivitamin tablet in conjunction with a standard ferrous sulphate tablet twice a day, providing a total of 120 mg of elemental iron daily. Setting and health worker cadre: the intervention was performed by obstetricians and professional staff at the Peninsula Maternity Service of the Department of Obstetrics and Gynecology of the University of Cape Town and Groote Schuur Hospital in Cape Town, South Africa.
Outcomes	Hb, PCV, MCV, MCHC, serum iron, transferrin, red cell folate, ferritin, iron storage depletion at baseline and at 36 weeks' gestation, compliance
Notes	Mean Hb and other outcomes at term were reported, but no SDs were provided. We have therefore not been able to include data from this trial in the review. Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: mixed/not specified Daily iron dose: higher daily dose (60 mg or more elemental iron) Iron release formulation: normal release preparation/not specified Iron compound: ferrous sulphate Malaria setting: yes. As of 2011: Malaria risk due predominantly to P. falciparum exists throughout the year in the low altitude areas of Mpumalanga Province (including the Kruger National Park), Northern Province and north‐eastern KwaZulu‐Natal as far south as the Tugela River. Risk is highest from October to May inclusive. Resistance to chloroquine and sulphadoxine‐pyrimethamine reported. Dates of study: not reported Funding sources: This project was sponsored by Fisons Ltd Pharmaceutical Division. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Patients were randomly allocated."
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding mentioned.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No blinding, but all outcomes were laboratory measures. The large number of women excluded after randomisation is likely to have affected results and compliance (assessed by unblinded staff) may have been systematically different in the 2 arms of the trial.
Incomplete outcome data (attrition bias) All outcomes	High risk	146 were randomised but when compliance was assessed as poor or doubtful, the participant was excluded from the trial. 21 patients were excluded for poor or doubtful compliance and 20 patients delivered before 36th weeks' gestation. Only 105 completed the trial.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Eskeland 1997.

Study characteristics
Methods	RCT, 3‐arm trial with individual randomisation
Participants	90 healthy non‐anaemic pregnant women with singleton pregnancy of less than 13 weeks, attending an inner city maternity centre in Bergen, Norway and willing to participate. Exclusion criteria: uncertain gestational age according to menstrual history, Hb concentration < 110 g/L, chronic disease or pregnancy complications (hypertension, diabetes, bleeding), multiple pregnancy, liver enzymes out of normal range and logistic difficulties foreseen at baseline (moving out of area).
Interventions	Participants were randomly allocated to 1 of the following: Group 1: received 3 tablets containing 1.2 mg heme iron from porcine blood and 9 mg of elemental iron (as ferrous fumarate) (Hemofer®) and 1 placebo tablet (total 27 mg elemental iron a day). Group 2: received 1 tablet containing 27 mg elemental iron (as iron fumarate) with 100 mg vitamin C (Collet®) and 3 placebo tablets. Group 3: received 4 placebo tablets. Supplementation started at the 20th week until the 38th to 40th week. Setting and health worker cadre: the intervention was performed by midwives and physicians at an inner city maternity centre in Bergen, Norway.
Outcomes	Maternal: Hb, RBC count, HCT, MCV, MCH, MCHC, reticulocytes, serum iron, total iron binding capacity, serum transferrin, erythrocyte protoporphyrin at baseline and at 20, 28, 38 weeks, 8 weeks postpartum, and 6 months postpartum; pregnancy complications: hypertension, pre‐eclampsia, forceps, postpartum haemorrhage, maternal well‐being and breastfeeding duration. Infant: birthweight and length.
Notes	Unsupervised Only groups 1 and 3 (placebo) were included in this review. Compliance was 81% and 82% in groups 1 and 3 respectively. Gestational age at start of supplementation: late gestational age (supplementation started at or after 20 weeks' gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: lower daily dose (less than 30 mg elemental iron daily) Iron release formulation: normal release preparation/not specified Iron compound: iron fumarate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: February 1992 to April 1993 Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated.
Allocation concealment (selection bias)	Low risk	This was a placebo‐controlled trial.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Described as a double‐blind trial (placebo‐controlled). It was stated that staff providing care were not aware of treatment allocation and were only given information about Hb.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind trial and laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	High risk	23% and 21% in groups included.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Falahi 2010.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	148 non‐anaemic pregnant women, 20 to 35 years of age with gestational age less than 20 weeks, primigravidae, BMI less than 25 and less than 30 and Hb concentrations lower than 110 g/L and serum ferritin higher than 20 μg/L who visited the gynaecology centre in Khorramabad city, Lorestan Province, Western Iran. Participants who had diabetes mellitus, renal disease, coronary heart disease, or reported having used multivitamins and minerals, drugs or being on a special diet were excluded.
Interventions	Participants were randomly allocated to 1 of 2 groups: Group 1 (n = 70) received tablets containing 60 mg elemental iron (as ferrous sulphate). Group 2 (n = 78) received placebo tablets until delivery. Women who were anaemic or iron deficient were referred for medical evaluation and treated. Setting and health worker cadre: the intervention was performed by physicians at a gynaecology centre in Khorramabad city, Lorestan Province, Western Iran.
Outcomes	Hb concentration, serum ferritin at baseline, week 28 and at delivery; birthweight, birth length, pregnancy duration
Notes	Gestational age at start of supplementation: early gestational age (supplementation started less than 20 weeks' gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: high daily dose (60 mg elemental iron daily) Iron release formulation: normal release preparation/not specified Iron compound: ferrous sulphate Malaria setting: yes. As of 2011: Malaria risk due to P. vivax and P. falciparum exists from March to November inclusive in rural areas of the provinces of Hormozgan and Kerman (tropical part) and the southern part of Sistan‐Baluchestan. P. falciparum resistant to chloroquine and sulphadoxine‐pyrimethamine reported. Dates of study: October 2009 to July 2010 Funding sources: not reported Declarations of interest: not reported Included in 2024 update because although trustworthiness red flags were discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023), this concern was dealt with in correspondence with the trial authors. Trustworthiness red flags: no dropouts mentioned; no trial dates given in the paper (the trial register states September to December 2008, with 148 participants in 3 months) We reached out to the corresponding author, who replied: "Thank you for your attention to our paper. Regards to your questions: The start and end dates of the recruitment of samples were October 2009 to July 2010. The number of samples was initially 80 for each group. During the study, 2 people from the placebo group and 10 people from the intervention group withdrew from the study for various reasons. Finally, data analysis was performed for 78 people in the placebo group and 70 people in the intervention group."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Low risk	This was a placebo‐controlled trial.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Described as a triple‐blind trial, placebo‐controlled. Placebos described as indistinguishable from active supplements. It was stated that participants and staff were not aware of treatment allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It was stated that staff and analysts were not aware of treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	148 women were randomised. It was not clear whether any women were lost to follow‐up or if there were any missing data.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	Groups appeared comparable at baseline.

Fawzi 2010.

Study characteristics
Methods	Randomised clinical trial
Participants	Inclusion criteria: at or before 19 weeks of gestation, primigravida or secundigravidae, not‐anaemic (defined as Hb < 85 g/L), not iron deficient (defined as serum ferritin < 12 µg/L), HIV‐uninfected, intend to stay in Dar es Salaam until delivery and for at least 6 weeks thereafter Exclusion criteria: after 19 weeks' gestation, not primigravida or secundigravidae, anaemic, iron deficient, HIV‐infected, high iron stores at baseline (i.e. serum ferritin > 200 µg/L), do not intend to stay in Dar es Salaam until delivery and for at least 6 weeks thereafter
Interventions	Intervention: daily oral dose of 60 mg elemental iron (as ferrous sulfate) from the time of enrolment until delivery. Total number randomised: n = 750 (loss to follow‐up = 257. Total at endline = 493). Control/comparison: placebo. The active and placebo tablets and packaging were indistinguishable from one another Total number randomised: n = 750 (loss to follow‐up = 240. Total at endline = 510). "Participants attended a clinic monthly until delivery and were provided with standard prenatal care, including 5 mg/d of folic acid and intermittent preventive treatment of malaria during pregnancy using 1500 mg of sulfadoxine and 75 mg of pyrimethamine in the second and third trimesters."
Outcomes	Primary: incidence of placental malaria (time frame: delivery); infant birthweight (time frame: delivery); maternal Hb (time frame: 20 weeks' gestation); maternal Hb (time frame: 30 weeks' gestation); maternal Hb (time frame: 6 weeks postpartum); maternal Hb (time frame: delivery); placental malaria parasite density (time frame: delivery) Secondary: low birthweight (time frame: delivery); maternal anaemia (time frame: 20 weeks' gestation); maternal anaemia (time frame: 30 weeks' gestation); maternal anaemia (time frame: 6 weeks postpartum); maternal anaemia (time frame: delivery); maternal malaria infection (time frame: 20 weeks' gestation); maternal malaria infection (time frame: 30 weeks' gestation); maternal malaria infection (time frame: 6 weeks postpartum); maternal malaria infection (time frame: delivery)
Notes	Gestational age: mixed gestational ages at start of supplementation (at or before 27 weeks, mean 18.2 weeks) Anaemic status at start of intervention: not severely anaemic (haemoglobin > 8.5 g/dL), not iron deficient (serum ferritin > 12 μg/L) Dose of iron: higher daily dose (60 mg elemental iron) Type of formulation: not specified Iron compound bioavailability in comparison to ferrous sulphate: equivalent or lower relative bioavailability: ferrous sulphate Malaria risk setting: “The trial was carried out in Dar es Salaam, Tanzania. Though malaria remains endemic in Tanzania, infection prevalence in Dar es Salaam is currently in a low risk category (PfPR2‐10 ≤ 5%). Recent estimates of malaria incidence and mortality show steady declines since a peak in 2003, where the decrease in Tanzania is among the highest in SSA at 7 – 8%. Nevertheless, in the absence of malaria interventions, risk for at least one placental infection during pregnancy in the Dar es Salaam area is 40–50% in primi‐ and secundigravida.” Study dates: September 2010 to October 2012 Study funding sources: This study was supported by a grant from the National Institute of Child Health and Human Development (NICHD U01 HD061232). CD was supported in part by 1K24HD058795. The NIH did not have any role in the design of the study, data collection, data analysis, data interpretation, or writing of this report. Study authors’ declarations of interest: Competing interest. None of the authors have any conflict of interest. Ethical approval obtained? The Harvard School of Public Health Human Subjects Committee, the MUHAS Senate Research and Publications Committee, and Tanzania’s National Institute for Medical Research granted institutional review board approval. Study prospectively registered? Yes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation sequence using blocks of size 20 created by a scientist not involved in data collection.
Allocation concealment (selection bias)	Low risk	Study clinics were issued pre‐labelled regimen bottles according to this sequence. At enrolment, each participant was assigned to the next numbered bottle of regimen at that site. At each subsequent visit, study supplements were dispensed in identical bottles labelled with the participant’s study identification number prepared by study pharmacists who had no contact with the participants.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The active and placebo tablets and packaging were indistinguishable from one another.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Unclear when allocation concealment was broken, but the majority of outcomes are unlikely to be influenced by blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 10% dropout for birth outcomes. Large dropout rate for placenta samples, but dropouts are balanced across groups and reasons given for each withdrawal.
Selective reporting (reporting bias)	Low risk	All outcomes reported from protocol.
Other bias	Low risk	Balanced baseline data. Passed TST.

Fenton 1977.

Study characteristics
Methods	Quasi‐randomised trial, 2 arms with individual randomisation
Participants	154 pregnant women with less than 14 weeks of gestation, and who had not received or were receiving treatment for a blood disorder at a clinic in Cardiff, United Kingdom
Interventions	Participants were divided into 2 groups according to the day on which they attended the clinic in Cardiff: group 1 received 60 mg of elemental iron (as ferrous sulphate) daily and group 2 received no iron supplement. Setting and health worker cadre: the intervention was performed by physicians at the Antenatal Clinic of the Welsh National School of Medicine at the University Hospital of Wales, Cardiff, United Kingdom.
Outcomes	Hb concentration, MCV, serum ferritin, serum iron and total iron binding capacity were measured at 10 to 14 weeks and at term
Notes	The data in the paper are presented with no SD values. No data can be extracted from the publication for this review. Gestational age at start of supplementation: early gestational age Anaemic status at start of supplementation: mixed/unspecified anaemia status Daily iron dose: higher daily dose (60 mg elemental iron) Iron release formulation: normal release preparation/not specified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: "We should like to acknowledge support given by the Blood Research Fund". Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	By day of clinic attendance.
Allocation concealment (selection bias)	High risk	By day of clinic attendance.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Laboratory outcomes but women were treated for anaemia and this may have affected results for this outcome.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All women appear to be accounted for in the analyses; separate figures are provided for women in the control arm who received supplements.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Fleming 1974.

Study characteristics
Methods	RCT with randomisation by blocks of 50 consecutive participants into 5 arms
Participants	146 consecutive pregnant women attending a public antenatal clinic in Western Australia before the 20th week of gestation who had not received iron supplements and were willing to participate. Women with Hb < 100.0 g/L were excluded.
Interventions	Participants were randomly assigned in sequences of 50 to 1 of the 5 intervention groups: Group 1 received placebo. Group 2 received 60 mg of elemental iron (as ferrous sulphate). Group 3 received 500 μg (0.5 mg) of folic acid. Group 4 received 60 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid. Group 5 received 60 mg of elemental iron (as ferrous sulphate) and 5000 μg (5 mg) of folic acid. Supplementation with iron was from 20th week of gestation until delivery. All women had received 50 mg of ascorbic acid daily from the first visit until the 20th week Setting and health worker cadre: the intervention was performed by obstetricians at a public antenatal clinic in western Australia. Patients were of a low SES.
Outcomes	Hb, serum and red cell folate, serum vitamin B12 at first attendance, and at 20, 28, 35 weeks and at delivery, and 6 weeks postpartum; pregnancy complications, anaemia defined as Hb lower than 100 g/L, premature delivery, abortion, compliance; birthweight, placental weight, Apgar score at delivery (full outcome data were not reported for group 5, which received a higher dose of folic acid).
Notes	More than 20% of the women were lost to follow‐up. We decided not to include outcome data for mean Hb at term, as the SDs provided in the paper represent a single SD for all groups and this assumes that distributions were similar in each treatment group. Gestational age at start of supplementation: late gestational age (supplementation started at or after 20 weeks' gestation) Anaemic status at start of supplementation: mixed/unspecified anaemia status Daily iron dose: higher daily dose (60 mg elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: This work was supported by the Arnold Yeldham and Mary Raine Medical Research foundation, Smith, Kline and French (Australia) Ltd, and The National Health and Medical Research Council of Australia. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"they were allotted according to randomised sequences of 50."
Allocation concealment (selection bias)	Unclear risk	Not clear, women were provided with colour‐coded packages which identified the regimens.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	It was stated that the contents of the treatment packages were not known to women or investigators until after the completion of the trial.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Laboratory outcomes; women with anaemia excluded post‐randomisation, although loss appeared balanced across groups.
Incomplete outcome data (attrition bias) All outcomes	High risk	146 women randomised, 89 women completed the trial and women were removed from the trial for reasons that may have related to outcomes (e.g. women developed anaemia).
Selective reporting (reporting bias)	Unclear risk	There was high attrition in this trial and data were not reported for all treatment groups.
Other bias	Unclear risk	No other bias apparent.

Fleming 1985.

Study characteristics
Methods	RCT, 5 arms with individual randomisation
Participants	200 apparently healthy primigravidae Hausa women living in Zaria, Nigeria and planning to deliver in Zaria, with less than 24 weeks of gestation, who had not taken any antimalarial treatment or iron supplements in current pregnancy
Interventions	Participants were randomly assigned to 1 of 5 groups: Group 1: received no active treatment. Group 2: received chloroquine 600 mg base once, followed by proguanil 100 mg per day. Group 3 received in addition to chloroquine and proguanil, 60 mg elemental iron daily. Group 4 received in addition to chloroquine and proguanil, 1000 μg (1 mg) of folic acid daily. Group 5: in addition to chloroquine and proguanil, received 60 mg of elemental iron and 1000 μg (1 mg) of folic acid daily. Setting and health worker cadre: the intervention was performed by an obstetrician working with a Hausa‐speaking social worker in Zaria
Outcomes	Full blood count, malarial parasites, serum and red cell folate, at first attendance, 28 weeks and 36 weeks gestational age, at delivery, and at 6 weeks postpartum, serum vitamin B12 at first attendance and at 36 weeks gestational age, Hb electrophoresis and fetal microscopy once, and bone marrow at delivery, clinical malaria
Notes	Relevant groups are: Group 3 vs group 2 for comparison 2: daily oral supplementation with iron alone vs no treatment/placebo Group 4 vs group 5 for comparison 4: daily oral iron + folic acid supplementation vs daily oral folic acid alone (without iron) supplementation Results were not reported separately for each randomised group, and we have been unable to include data from this trial in the review. Gestational age at start of supplementation: mixed gestational age (up to 24 weeks' gestation) Anaemic status at start of supplementation: mixed/unspecified anaemia status Daily iron dose: higher daily dose (60 mg elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: not clear Malaria setting: yes. Described as a malaria endemic area: 28% of P falciparum in the sample and 40% of those anaemic. As of 2011: Malaria risk due predominantly to P falciparum exists throughout the year in the whole country. Resistance to chloroquine and sulphadoxine‐pyrimethamine reported. Dates of study: 1 January 1977 to 31 December 1984 Funding sources: This work was supported by the World Health Organization and Ahmadu Bello University. Smith Kline and French Laboratories Limited (United Kingdom) and Imperial Chemical Industries (ICI) provided all tablets and capsules. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers table.
Allocation concealment (selection bias)	Low risk	Treatment allocation code; "Neither the researchers nor the patients were aware of the treatment allocated until after the completion of the study".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and researchers blinded. Placebos were provided which were packaged so that they "could not be distinguished by sight".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	High risk	Women who were excluded because they developed anaemia or "defaulted"; were replaced. Further loss to follow‐up occurred during the trial; it was not clear how many women were followed up at each data collection point. 89 out of 200 women randomised delivered in the hospital and no complete, clear data could be extracted for the outcomes of interest in this review.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Foulkes 1982.

Study characteristics
Methods	Quasi‐randomised trial, 2 arms with individual randomisation
Participants	568 apparently healthy pregnant women with less than 20 weeks of pregnancy and no prior iron supplementation
Interventions	Participants were allocated alternatively to receive 100 mg of elemental iron and 350 μg (0.35 mg) folic acid daily or no treatment.
Outcomes	Ferritin and Hb concentrations were measured at baseline and at 28 and 36 weeks of gestation and 2 days postpartum. MCV and MCH were measured at 2 days postpartum. Number of women developing anaemia in the 2nd and 3rd trimester was reported (Hb < 105 g/L). Setting and health worker cadre: the intervention was performed by obstetricians at Southmead Hospital in Bristol, United Kingdom.
Notes	Only means and median are presented for continuous outcomes. No SDs are reported and for ferritin concentrations no ln‐transformed data are presented. Limited data were extractable from the paper and subsequent communication with the author. The paper reported the number of women developing Hb < 105 g/L from the start of supplementation to delivery. No data were extracted from this trial. Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: mixed/unspecified anaemia status Daily iron dose: higher daily dose (60 mg or more elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: not clear Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Alternation.
Allocation concealment (selection bias)	High risk	Alternate allocation.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding. No placebo.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Women who did not comply or who became anaemic were treated. Outcomes reported unlikely to be affected by lack of blinding.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	537 women randomised, then 67 excluded post‐randomisation for reasons that may have related to outcomes (non‐compliance). Subsequent loss to follow‐up was not clear as denominators were not reported in the text or figures.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Freire 1989.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	412 non‐black pregnant women with 26 ± 2 weeks of gestation, who had not received iron supplements in the previous 6 months, from low SES using the prenatal unit of public obstetric hospital in Quito, Ecuador
Interventions	Participants were randomly assigned to receive 2 tablets containing 78 mg of elemental iron (as ferrous sulphate) daily or placebo during a period of 2 months. Setting and health worker cadre: the intervention was performed by physicians in the Prenatal Unit of Quito's public obstetric hospital in Quito, Ecuador.
Outcomes	Hb, PCV, red cell indices, serum ferritin, total iron binding capacity, serum folate, serum vitamin B12 at baseline and after 2 months. Prevalence of iron deficiency was estimated by response to therapy.
Notes	Apart from mean Hb levels at term, no other prespecified outcomes from this review are presented in the paper. No data can be extracted from this trial. Gestational age at start of supplementation: late gestational age (supplementation started after 20 weeks' gestation) Anaemic status at start of supplementation: mixed/unspecified anaemia status Daily iron dose: high daily dose (60 mg or more elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. The study was conducted in Quito, where there is no risk of malaria. As of 2011: Malaria risk – P. vivax (87%), P. falciparum (13%) – exists throughout the year below 1500 m, with moderate transmission risk in coastal provinces. There is no risk in Guayaquil, Quito and other cities of the inter‐Andean region. P. falciparum resistance to chloroquine and sulphadoxine‐pyrimethamine reported. Dates of study: January 1984 to January 1986 Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described ("randomly assigned").
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Described as "double‐blind", placebo tablets provided.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	High risk	412 women were recruited and 240 followed up. Loss to follow‐up was 41.7% and there were missing data for some outcomes.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Groner 1986.

Study characteristics
Methods	RCT, 2 arms, individual randomisation
Participants	40 pregnant women attending antenatal care at the Adolescent Pregnancy Clinic and Obstetrics Clinics at the Johns Hopkins and Sinai Hospital in Baltimore, Maryland, USA at or before 16 weeks of pregnancy with HCT equal or above 31%. 2 women objected to the randomisation and 13 dropped out of the study. Both groups received multiple micronutrients. Supplementation lasted a month.
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1 (n = 16) received 60 mg of elemental iron (as ferrous fumarate) and prenatal vitamins daily. Group 2 (n = 9) received only the prenatal vitamins with no iron. Setting and health worker cadre: the intervention was performed by physicians at the Adolescent Pregnancy Clinic and Obstetrics Clinic of Johns Hopkins and Sinai Hospitals in Baltimore, Maryland, United States of America.
Outcomes	Psychometric tests (arithmetic, total digit span, digit symbol, vocabulary and others) were performed, and haematologic status was measured at baseline and after a month.
Notes	Haematologic outcomes cannot be extracted from the paper. None of the other outcomes were sought. Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: mixed/unspecified anaemia status Daily iron dose: higher daily dose (60 mg or more elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous fumarate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: November 1981 to August 1982 Funding sources: The Robert Wood Johnson Foundation provided most of the funding for this project through the General Pediatrics Academic Development Program; additional support was provided by the Clinical Research Center, Johns Hopkins Hospital. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Each subject was handed an unlabeled bottle of capsules... The test administrator was also unaware of the content of the capsules distributed."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It was stated that the test administrator was not aware of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	15 of the 40 women randomised were not followed up. Group size at follow‐up was not balanced (16 vs 9).
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Harvey 2007.

Study characteristics
Methods	RCT, 2 arms, individual randomisation
Participants	13 apparently healthy non‐anaemic non‐smokers pregnant women aged 18 to 40 years and < 14 weeks of gestation with singleton pregnancy recruited through local medical practitioners and the Maternity Department of the Norfolk and Norwich University Hospital, England, United Kingdom
Interventions	Participants were randomly assigned to 1 of 2 groups: group 1 received 100 mg elemental iron (as ferrous gluconate) daily after food and group 2 received a placebo. Supplementation started at 16th week of gestation until delivery. Setting and health worker cadre: the intervention was performed by midwives and obstetricians at the Maternity Department of the Norfolk and Norwich University Hospital in Norwich, United Kingdom.
Outcomes	Maternal: Hb, serum ferritin, transferrin receptor, plasma zinc, exchangeable zinc pool, zinc excretion and zinc absorption at 16, 24, and 34 weeks of gestation Infant: birthweight (not reported)
Notes	Unsupervised Compliance not reported Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher daily dose (60 mg or more elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous gluconate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: Supported by the European Commission (FeMMES Project contract no. QLK1‐1999‐00337) and the Biotechnology and Biological Sciences Research Council. Declarations of interest: None of the authors had a personal or financial conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Coded bottles were provided by manufacturer.
Allocation concealment (selection bias)	Low risk	Supplied in coded opaque bottles.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Described as a single‐blind, placebo‐controlled trial. Placebo and active tablets were described as identical. Women blinded; not clear that staff were.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Investigators not blinded. Laboratory outcomes likely to be at low risk of bias from blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Hoa 2005 (C).

Study characteristics
Methods	Randomisation may have been by cluster (communes) rather than individual women. Block randomised trial with 4 arms.
Participants	202 apparently healthy pregnant women 20 to 32 years of age attending health clinics from 12 communes in Dong Hung District, Thai Binh Province, Vietnam with 14 to 18 weeks of gestation who agreed to participate in the study were selected to participate.
Interventions	Participants were assigned through block randomisation to 1 of 4 interventions: Group 1 (n = 44) received 400 mL fortified milk with iron (ferrous fumarate), 17.5 mg vitamin C, and 200 μg (0.2 mg) folic acid daily. Group 2 (n = 41) received 400 mL of fortified milk containing 17.5 mg vitamin C and 200 μg (0.2 mg) folic acid but no iron daily. Group 3 (n = 40) received 1 tablet containing 60 mg of elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) folic acid daily. Group 4 (n = 43) received 1 placebo tablet daily. Setting and health worker cadre: the intervention was performed by community health workers working from a commune health centre operated by the National Ministry of Health in the rural delta area of the Red River in northern Vietnam (Dong Hung District, Thai Binh Province).
Outcomes	Hb at baseline, 5, 10, 16 weeks after start of the study, total iron‐binding capacity, serum transferrin saturation, anaemia, iron deficiency, weight, presence of hookworms
Notes	For purposes of this review, groups 3 vs group 4 comparing iron and folic acid supplements are relevant. However, no data on outcomes of interest could be extracted from the published report. It was reported in the paper that the "decrease in haemoglobin concentration in the supplemented groups was significantly less"; and that, "the transferrin saturation level increased slightly in the supplement group". Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: unspecified/mixed anaemia status Daily iron dose: higher dose (60 mg of elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: yes. As of 2011: Malaria risk due predominantly to P. falciparum exists in the whole country, excluding urban centres, the Red River delta, the Mekong delta, and the coastal plain areas of central Vietnam. High‐risk areas are the highland areas below 1500 m south of 18˚N, notably in the 4 central highlands provinces Dak Lak, Dak Nong, Gia Lai and Kon Tum, Binh Phuoc province, and the western parts of the coastal provinces Khanh Hoa, Ninh Thuan, Quang Nam and Quang Tri. Resistance to chloroquine, sulphadoxine‐pyrimethamine and mefloquine reported. Dates of study: 1996‐7 Funding sources: This research was supported by Friesland Dairy Foods, Leeuwarden, The Netherlands. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	It was not clear whether individual women or communes were randomised; "For practical reasons it was possible to implement only 1 type of intervention per commune (block randomly adjusted)". It was not clear whether staff were aware of allocation before randomisation.
Allocation concealment (selection bias)	Unclear risk	Little information about study methods was provided.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Partial blinding. Placebo preparations were provided. Described as single‐blind. Staff aware of allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Likely to be low risk for laboratory outcomes reported.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Loss to follow‐up not described. Not clear if any clusters were lost.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Low risk	Groups appeared comparable at baseline. Data from this study were not included in the review.

Holly 1955.

Study characteristics
Methods	RCT, 3 arms with individual randomisation
Participants	207 pregnant women with less than 26 weeks of gestation and Hb > 100 g/L attending antenatal care clinic in Nebraska, USA
Interventions	Participants were randomly assigned to 1 of 3 groups: Group 1 received 1 g of an iron salt daily. Group 2 received 0.8 g to 1.2 g of ferrous sulphate and 60 mg to 90 mg of cobalt chloride daily. Group 3 received no treatment. Supplementation started at various times before the 26th week of gestation for each of the participants until delivery. Setting and health worker cadre: the intervention was performed by obstetricians at the Department of Obstetrics and Gynecology of the University of Nebraska, College of Medicine in Omaha, Nebraska, United States of America.
Outcomes	Maternal: Hb, HCT, serum iron, erythrocyte protoporphyrin at 3 to 6 months and pre‐delivery
Notes	Unsupervised 3 iron compounds (n = 94) were used: ferrous gluconate (n = 40), ferrous sulphate (n = 32) and Mol‐Iron® (n = 22). The iron‐treated groups with different iron salts were merged together by the author as an iron‐treated group since the results were comparable. The iron and cobalt treatment group is not included in this review. Compliance not reported Gestational age at start of supplementation: mixed gestational age at the start of supplementation (before 26 weeks) Anaemic status at start of supplementation: mixed anaemia status (Hb > 100 g/L) Daily iron dose: higher daily dose (60 mg or more elemental iron) Iron release formulation: normal release preparation/not specified Iron compound: mixed (groups merged in analysis) Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: These studies were aided in part by a grant from Eli Lilly and Company, Indianapolis, Indiana, and Lloyd Brothers, Inc., Cincinnati, Ohio. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Neither participants nor provider blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Laboratory outcomes reported.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Loss to follow‐up not described.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Hood 1960.

Study characteristics
Methods	RCT, 3 arms, individual randomisation
Participants	75 consecutive, apparently healthy pregnant women with 32 to 34 weeks of gestation attending the maternity clinic at St Anthony's Hospital, Oklahoma City, Oklahoma, USA
Interventions	Participants were randomly divided into 3 groups: Group 1 served as control and received no treatment. Group 2 received 220 mg elemental iron (as ferrous sulphate) daily. Group 3 received 55 mg elemental iron (as sustained release ferrous sulphate) daily. Supplementation started at 32 to 34 weeks of gestation until delivery. Setting and health worker cadre: the intervention was performed by obstetricians at the Department of Obstetrics and Gynecology of St. Anthony's Hospital in Oklahoma City, Oklahoma, United States of America.
Outcomes	Maternal: Hb, HCT, incidence and severity of side effects on a weekly basis until delivery
Notes	Unsupervised For any iron vs no treatment, comparison groups were merged. Compliance not reported Gestational age at start of supplementation: late gestational age (supplementation started after 20 weeks' gestation) Anaemic status at start of supplementation: unspecified/mixed anaemia Daily iron dose: medium dose (55 mg elemental iron) and higher dose (220 mg elemental iron) Iron release formulation: sustained release preparation and normal release preparation/not specified Iron compound: ferrous sulphate and sustained release ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Neither participant nor provider blinded.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Outcome assessor unclear. Low risk for laboratory outcomes but uncertain risk of bias for reported side effects.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% loss to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Kerr 1958.

Study characteristics
Methods	RCT, 4 arms with individual randomisation
Participants	430 apparently healthy women with 24 to 25 weeks of singleton pregnancy and Hb equal or above 104 g/L attending antenatal clinic at Simpson Memorial Maternity Pavillion, Edinburgh, United Kingdom
Interventions	Participants were randomly allocated to 1 of 4 groups: Group 1 received 35 mg of elemental iron (as ferrous sulphate) 3 times a day. Group 2 received 35 mg of elemental iron (as ferrous gluconate) 3 times a day. Group 3 received 35 mg of elemental iron (as ferrous gluconate) with 25 mg of ascorbic acid, 3 times a day. Group 4 received placebo. Supplementation started at 24th to 25th week of gestation until term. Setting and health worker cadre: the intervention was performed by physicians at the Simpson Memorial Maternity Pavilion in Edinburgh, United Kingdom.
Outcomes	Maternal: Hb, red cell count, HCT at baseline and at 37th week
Notes	Unsupervised Groups 1 and 2 were merged for analysis. Group 3 was not used in this review. Compliance not measured Gestational age at start of supplementation: late gestational age (supplementation started after 20 weeks' gestation) Anaemic status at start of supplementation: unspecified/mixed anaemia status (no severe anaemia, all had Hb equal or above 104 g/L) Daily iron dose: higher iron dose (all treatment groups received more than 60 mg of elemental iron daily (105 mg)) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous gluconate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: February‐March and August‐September of 1955 and 1956 Funding sources: "We are indebted to Messrs. John Wyeth and Brother Limited for the iron preparations tested and for financial assistance." Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	By cards shuffle.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Partial blinding. Placebo and all supplements described as identical. Women were blinded, but medical staff were aware of which was the control group.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Low risk for laboratory outcomes. Possible risk of bias for dietary survey and reporting of side effects.
Incomplete outcome data (attrition bias) All outcomes	High risk	23% of participants were lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Kuizon 1979.

Study characteristics
Methods	RCT, 4 groups (with supplementation depending on Hb levels at baseline), individual randomisation
Participants	385 pregnant women attending antenatal care at government health centres in the Greater Manila area, Philippines. Mean gestation at recruitment was approximately 21 weeks until delivery. Women were assessed at baseline and women with anaemia (Hb < 120 g/L in 1st and < 110 g/L in 2nd trimester) received a higher dose of supplements.
Interventions	Participants were randomly assigned to 1 of 4 groups: Group 1 received placebo (anaemic and non‐anaemic women received 1 placebo capsule). Group 2 received 65 mg of elemental iron (as 325 mg ferrous sulphate); women received either 1 or 3 oral tablets daily. Group 3 received 100 mg ascorbic acid (either 1 or 3 oral tablets daily). Group 4 received 65 mg elemental oral iron (as ferrous sulphate) plus 100 mg ascorbic acid ‐ women received either 1 or 3 tablets. Supplementation started from recruitment in first and second trimester until delivery. Setting and health worker cadre: the intervention was performed by health centre staff at government health centres and maternity clinics in the greater Manila area, Manila, Philippines.
Outcomes	Mean Hb concentration at 32 and 39 weeks (for women anaemic and not anaemic at baseline), HCT at 32 and 39 weeks, serum iron at 32 and 39 weeks, transferring saturation levels at 32 and 39 weeks
Notes	Attrition in this study was very high (half of the women were lost to follow‐up by 32 weeks' gestation and more than 75% by term). For this reason, we have not included data from this study in our data and analyses tables. Gestational age at start of supplementation: mixed gestational age at the start of supplementation (mean gestation at start of supplementation was 21 weeks) Anaemic status at start of supplementation: mixed anaemia status (dose depended on Hb level at baseline) Daily iron dose: higher daily dose (greater than 60 mg of elemental iron daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: yes. As of 2011: Malaria risk exists throughout the year in areas below 600 m, except in the 22 provinces of Aklan, Albay, Benguet, Biliran, Bohol, Camiguin, Capiz, Catanduanes, Cavite, Cebu, Guimaras, Iloilo, Northern Leyte, Southern Leyte, Marinduque, Masbate, Eastern Samar, Northern Samar, Western Samar, Siquijor, Sorsogon, Surigao Del Norte and metropolitan Manila. No risk is considered to exist in urban areas or in the plains. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported. Human P. knowlesi infection reported in the province of Palawan. Dates of study: not reported Funding sources: "The authors wish to express their thanks and appreciation to the National Science Development Board for financial assistance to the project; (and) to Smith Kline and French Overseas Co. through Dr Horacia Estrada for donations of placebo capsules, ferrous sulfate and ascorbic acid tablets used in the study." Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	"randomly assigned."
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Placebo was provided, but women received different doses (and number of tablets). It was not clear if staff were aware of allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It was not clear if outcome assessment was blind. Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	High risk	Very high attrition. 679 women recruited. In non‐anaemic women, 189/385 followed up (49%). In anaemic group, 146/294 (50%) followed up at 32 weeks; by 39 weeks, only 94/385 non‐anaemic women followed up (24%) and 60 in anaemic group (20%).
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	High risk	The reasons for the very high levels of attrition were not explained (except that some women delivered before term). The very high loss to follow‐up means that results are very difficult to interpret.

Lee 2005.

Study characteristics
Methods	RCT, 5 arms with individual randomisation
Participants	154 apparently healthy pregnant women seeking prenatal care in Gwangju, South Korea during the first trimester of pregnancy who did not receive other supplements or medications throughout pregnancy and who were willing to participate
Interventions	Participants were randomly allocated to 1 of 5 groups: Group 1 received 30 mg elemental iron (as ferrous sulphate) and 175 μg (0.17 mg) folic acid daily from first trimester until delivery. Group 2 received 60 mg of elemental iron (as ferrous sulphate) with 350 μg (0.35 mg) of folic acid from first trimester until delivery. Group 3 received 30 mg elemental iron (as ferrous sulphate) and 175 μg (0.17 mg) of folic acid from the 20th week of gestation until delivery. Group 4 received 60 mg elemental iron (as ferrous sulphate) and 350 μg (0.35 mg) of folic acid from 20th week of gestation until delivery. Control group: received no supplement. Setting and health worker cadre: the intervention was performed by physicians at a hospital and health centre in Gwangju, Korea.
Outcomes	Maternal: Hb, HCT, serum ferritin, serum soluble transferrin receptor concentrations at baseline and during first, second, third trimester of pregnancy and at delivery
Notes	Unsupervised Compliance not reported Included in comparison 3: daily iron + folic acid vs no treatment/placebo and only different groups included in the subgroup analysis by gestational age at start of supplementation (early (group 1 + group 2); late (group 3 + group 4); and by iron dose: low (group 1 + group 3); higher (group 2 + group 4)). Gestational age at start of supplementation: mixed gestational ages (different arms started supplementation before or after 20 weeks' gestation) Anaemic status at start of supplementation: mixed/unspecified anaemia status Daily iron dose: mixed (with different arms receiving lower (30 mg) and higher (60 mg) of elemental iron daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: yes. As of 2011: limited malaria risk due exclusively to P. vivax exists mainly in the northern areas of Gangwon‐do and Gyeonggi‐do Provinces and Incheon City (towards the Demilitarized Zone or DMZ). Dates of study: April 2000 to January 2002 Funding sources: Supported by a grant of the Korea Health 21 R and D Project, Ministry of Health and Welfare, Republic of Korea (HMP‐00‐B‐22000‐0158). Declarations of interest: none of the authors had any conflicts of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Described as "truly random" but the method was not stated.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding (and some women requested a change in assigned group).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Li 2020.

Study characteristics
Methods	RCT, 5‐arm with cluster‐randomisation
Participants	760 pregnant women, 15 to 49 years, at less than 20 weeks gestation were recruited from Xunyi, Bin, and Changwu counties located in rural Northwest China Inclusion criteria: women of reproductive age (15 to 49 years) who reside in the study areas; women who are prepared for pregnancy in 1 to 3 months or have already been pregnant for less than 20 months; women who have provided written informed consent Exclusion criteria: women who have already taken supplements containing vitamin B complex, iron, or folic acid for more than 2 weeks at enrolment; women who have given birth to children with congenital heart disease or other birth defects before; women with diabetes; women with severe heart, liver or kidney disease Setting and health worker cadre: health workers within counties where pregnant women resided
Interventions	Townships were randomly assigned to 1 of 3 groups: Iron (n = 275): ferrous sulfate 60 mg daily Vitamin B complex (n = 236): vitamin B1 2 mg, vitamin B2 2 mg, vitamin B6 2 mg, vitamin B12 2 µg, calcium pantothenate 5 mg, and nicotinamide 15 mg daily Control (n = 249): no intervention All women received folic acid 400 µg/day during pre‐pregnancy and early pregnancy. For the purposes of this review, we will compare iron + folic acid vs folic acid alone.
Outcomes	Primary outcome measures: neonatal pulse oximetry oxygen saturation measured by pulse oximetry (time frame: 6‐72 hours after delivery) Secondary outcome measures: Incidence of congenital heart disease and the subtypes (time frame: half a year after delivery) Birthweight measured by baby scale (time frame: within 1 hour of delivery) Incidence of low birthweight (time frame: within 1 hour of delivery) Gestational age at birth (time frame: at delivery) Incidence of preterm birth (time frame: at delivery) Incidence of perinatal mortality (time frame: between 28 weeks of gestational duration and 7 days after delivery) Incidence of stillbirth (time frame: at delivery) Incidence of neonatal mortality (time frame: first 28 days after birth) Incidence of early neonatal mortality (time frame: first 7 days after birth) Incidence of pregnancy complications: hypertension, preeclampsia, antepartum haemorrhage, and infections (time frame: After enrolment until at delivery)
Notes	Compliance: calculated by dividing the number of supplements consumed by days of enrolment to delivery. Compliance with supplementation ≥ 80%, ranges from 29.3% to 31.1% (iron + folic acid) vs 39.0% to 42.7% (folic acid alone). Gestational age at start of supplementation: mixed gestational age (1st to 5th month of pregnancy) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher daily dose (60 mg elemental iron or more) (60 mg elemental iron) Iron release formulation: not specified Iron compound: ferrous sulfate Malaria setting: non‐malarial setting. As of 2021: Malaria: China was certified malaria free in 2021. Dates of study: July 2015 to December 2019 Funding sources: This study was sponsored by the National Key Research and Development Program of China (grant number 2017YFC0907200, grant number 2017YFC0907201), the National Natural Science Foundation of China (grant number 81230016), the Project of birth defect control and prevention in Shaanxi (grant number Sxwsjswzfcght2016‐013), the China Postdoctoral Science Foundation (grant number 2015M582678) and Xi’an Jiaotong University (xjj2018146). Declarations of interest: no conflicts of interest reported Ethical approval: Ethics review committee of the Xi’an Jiaotong University Health Science Center (No. 2012008) Outcome data were reported as genetic polymorphisms by intervention groups; data were not presented in a form for inclusion in statistical meta‐analysis
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Before the enrollment, we applied a cluster randomization method to randomize the townships (the unit of randomization) of the study region to the intervention groups with a 1:1:1 ratio."
Allocation concealment (selection bias)	Unclear risk	Insufficient reporting on allocation concealment method to permit evaluation.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: (Trials registry) "None (Open Label)" Trial was open‐label with participants and trial personnel non‐blinded to treatment groups.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "The entire experiment was double‐blinded." Insufficient information on how blinding of outcome assessors was maintained throughout the trial to permit judgement.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcome data were available for ~80% of randomised participants (Intervention: iron group; and vitamin B complex + FA: 431 vs control, FA alone: 175/249). Attrition rate was ~20%.
Selective reporting (reporting bias)	Low risk	No apparent indication of outcome selection on the basis of results.
Other bias	Unclear risk	Some differences in compliance with the intervention (29.3% to 31.1%) compared to the control (39.0% to 42.7%) group. No additional concerns for baseline imbalance, attrition of clusters, or incorrect analysis.

Liu 2012.

Study characteristics
Methods	3‐arm, double‐blind randomised controlled trial, individually randomised. Randomisation was stratified by county, and random block sizes of 3, 6, and 9 were used to ensure geographical balance with an approximately equal distribution of treatments within and across study counties.
Participants	18,775 nulliparous pregnant women 20 years of age or older, with mild or no anaemia (Hb level greater than 100 g/L), with no more than 20 weeks of gestation attending prenatal care in 5 rural counties in Hebei Province, northern China, where basic health services were provided through 3‐tier (county, township, and village) healthcare networks of northern China, from May 2006 through April 2009. Additionally, eligible women had not consumed micronutrient supplements other than folic acid in the prior 6 months. Women were followed monthly from early pregnancy through delivery and at 4 to 8 weeks postpartum. Their infants were followed monthly from birth until 1 year of age.
Interventions	Participants were randomly assigned to 1 of 3 groups: Group 1 (n = 6261) received 400 µg (0.4 mg) folic acid daily (control). Group 2 (n = 6252) received 30 mg elemental iron (as ferrous fumarate) plus 400 µg (0.4 mg) folic acid daily. Group 3 (n = 6262) received 30 mg elemental iron (as ferrous fumarate) with 400 µg (0.4 mg) folic acid daily and 800 μg vitamin A, 10 mg vitamin E, 5 μg vitamin D, 70 mg vitamin C, 1.4 mg thiamine, 1.4 mg riboflavin, 1.9 mg vitamin B6, 2.6 μg vitamin B12, 18 mg niacin, 15 mg zinc, 2 mg copper, 150 μg iodine, and 65 μg selenium. The supplements were provided before 20 weeks of gestation to delivery. Each woman received 2 bottles of supplements at enrolment and 1 at monthly follow‐up visits. Each bottle contained 31 supplements, including the type of supplements per group according to lot number. Only groups 1 and 2 are considered in this review (folic acid vs iron + folic acid). Health worker cadre: trained county or township physicians completed relevant measurements and collected data based on a perinatal and child healthcare surveillance system. At enrolment, the physician assigned women the next lot number on the randomisation schedule and provided the supplements.
Outcomes	Perinatal mortality, neonatal deaths, infant deaths, maternal Hb concentration and anaemia at 24 to 28 weeks of gestation, birthweight, birth length, duration of gestation, preterm delivery, compliance
Notes	By gestational age: early, if supplementation started before 20 weeks' gestation Anaemic status at start of intervention: non‐anaemic Dose of iron: low daily dose of iron if 30 mg or less of elemental iron Type of formulation: normal release iron supplement/not specified Iron compound bioavailability in comparison to ferrous sulphate: equivalent bioavailability: ferrous fumarate Malaria risk setting: not reported. It is presumed to be malaria‐free. Dates of study: May 2006 to April 2009 Funding sources: Supported by a cooperative agreement between Peking University Health Science Center and the CDC. Declarations of interest: Z. Mei, M. K. Serdula, J.‐m. Liu, R. C. Flores‐Ayala, L. Wang, R. Ye, and L. M. Grummer‐Strawn, no conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A statistician external to the study randomly assigned ten 4‐digit lot numbers to each of the 3 supplement types (masked to the formulation and allocation) and generated the assignment list for each county proportional to the expected number of participants; within each county and block, lot numbers were randomly assigned using RANUNI in SAS statistics software (SAS Institute Inc)."
Allocation concealment (selection bias)	Low risk	Ten 4‐digit lot numbers to each of the 3 supplement types (masked to the formulation and allocation). At enrolment, the physician assigned women the next lot number on the randomisation schedule.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Aside from a pharmaceutical engineer who ensured allocation of lot numbers to the correct supplement formulations, all others (ie, participants, local physicians, study personnel, and investigators) were masked to the identity of the supplements. Treatment codes were broken after completion of the study and main analyses."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Aside from a pharmaceutical engineer who ensured allocation of lot numbers to the correct supplement formulations, all others (ie, participants, local physicians, study personnel, and investigators) were masked to the identity of the supplements. Treatment codes were broken after completion of the study and main analyses."
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were 299/6261 (4.77%) losses to follow‐up in group 1, 280/6252 (4.47%) in group 2, and 299/6262 (4.77%) in group 3 for various reasons: permanently moved, induced abortions, spontaneous abortions, dropped out or maternal death. The attrition was balanced among groups.
Selective reporting (reporting bias)	Low risk	There appears to be no selective reporting. Trial registration: clinicaltrials.gov identifier: NCT00133744.
Other bias	Low risk	No other bias apparent.

Makrides 2003.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	430 non‐anaemic pregnant women attending antenatal clinics at Women's and Children's Hospital in Adelaide, Australia with singleton or twin pregnancies and informed consent. Exclusion criteria: diagnosis of thalassaemia, history of drug or alcohol abuse and history of vitamin and mineral preparations containing iron prior to enrolment in study.
Interventions	Participants were randomly assigned to receive 1 tablet containing 20 mg of elemental iron daily between meals from week 20 until delivery or a placebo tablet. Setting and health worker cadre: the intervention was performed by Paediatricians and Obstetricians in a maternity hospital in Adelaide, Australia.
Outcomes	Maternal: Hb concentration at 28 weeks, at delivery, and at 6 months postpartum; ferritin concentration at delivery and at 6 months postpartum; maternal gastrointestinal side effects at 24 and 36 weeks of gestation; serum zinc at delivery and at 6 months postpartum; maternal wellbeing at 36 weeks of gestation, at 6 weeks and at 6 months postpartum; pregnancy outcomes: type of birth, blood loss at delivery, gestational age. At 4 years postpartum: general health of mothers using the SF‐36, a self‐administered questionnaire that assesses 8 concepts of health. Infant: birthweight, birth length, birth head circumference, Apgar scores, and level of nursery care. Follow‐up at 4 years: intelligence quotient (IQ) using Stanford‐Binet Intelligence Scale, child behaviour using Strength and Difficulties Questionnaire parent‐report form.
Notes	Unsupervised but monthly phone calls to encourage compliance If anaemia was detected in the routine 28‐week blood sample or if the clinician considered her Hb too low, the woman was advised to purchase and take a high‐dose iron supplement (containing > 80 mg elemental iron per tablet) until the end of pregnancy. Compliance was 86% and 85% in the iron and placebo groups respectively. Gestational age at start of supplementation: late gestational age (supplementation started at 20 weeks' gestation or later) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: lower daily dose (less than 30 mg iron daily) (20 mg) Iron release formulation: normal release preparation Iron compound: not clear Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: December 1997 to April 1999 Funding sources: Supported by the Channel 7 Children’s Medical Research Foundation, the Women’s & Children’s Hospital Perinatal Pathology Fund, the Gunn & Gunn Medical Research Foundation, and Soul Pattinson Manufacturing. MM was supported by a National Health & Medical Research Council Applied Health Sciences Fellowship and a National Health & Medical Research Council R Douglas Wright Fellowship. The iron and placebo tablets were manufactured and donated by Soul Pattinson Manufacturing, Kingsgrove, New South Wales, Australia. Declarations of interest: the authors had no known conflicts of interest. Included in 2024 update because although a trustworthiness red flag was discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023), this concern was dealt with in correspondence with the trial authors. Trustworthiness red flag: included abstract We reached out to the corresponding author, who sent an email confirming that the abstract agreed with the final data.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated sequence with balanced blocks and stratified for parity.
Allocation concealment (selection bias)	Low risk	Opaque bottles marked with sequential numerical code prepared by the Pharmacy Department of Women's & Children's Hospital.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	This was described as a double‐blind trial.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes. Side effects likely to be recorded by blinded staff.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Meier 2003.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	144 non‐iron deficient adolescents 15 to 18 years old in their first pregnancy and adult women 19 or older in their first or greater pregnancy attending prenatal care at Marshfield Clinic, Wisconsin, USA
Interventions	Participants were randomly assigned to receive once‐daily 60 mg of elemental iron (as ferrous sulphate) or a placebo. All women received 1000 μg (1 mg) of folic acid daily.
Outcomes	Maternal: prevalence of iron‐deficiency anaemia, compliance to treatment, side effects, vomiting, nausea, constipation, diarrhoea, caesarean section, serum ferritin and Hb concentrations at 24 to 28 weeks' gestation and at 36 to 40 weeks' gestation Infant: perinatal morbidity and mortality, birthweight, birth length, Apgar scores at 1 and 5 minutes, admission to neonatal unit, prevalence of birthweight Setting and health worker cadre: the intervention was performed at a multicentre clinic in central Wisconsin.
Notes	Unsupervised All adolescents and adult pregnant women who developed iron‐deficiency anaemia at 24 to 28 weeks' gestation were offered 60 mg elemental iron 3 times a day. Compliance was assessed through pill counts and ranged from 32% to 124% (median 95.5% in iron supplemented group and 87.4% in placebo group). Gestational age at start of supplementation: unspecified/mixed gestational age Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher daily dose (60 mg elemental iron daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: Research was supported by BRSG S07 RR05960‐01 awarded by the Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health and in part by a grant 128‐01‐06 from the Marshfield Medical Research Foundation, the Mead‐Johnson Nutritional Division, and Hybritech, Inc, San Diego, California. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Stratified by age group.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo‐controlled, double‐blind trial. The placebo was reported to be identical in appearance to the active treatment.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	High risk	More than 20% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Menendez 1994 (C).

Study characteristics
Methods	Cluster‐randomised trial, 2‐arm trial
Participants	550 multi‐gravidae pregnant women with less than 34 weeks of gestation attending antenatal care clinics in 18 villages near the town of Farafenni, in North Bank Division, Gambia, where malaria is endemic with high transmission during 4 to 5 months a year
Interventions	Participants were allocated randomly by compound of residence to receive 60 mg of elemental iron (as ferrous sulphate) or placebo. All pregnant women received a weekly tablet of 5000 μg (5 mg) of folic acid but no antimalarial chemoprophylaxis. Supplementation started at 23 to 24 weeks until delivery. Setting and health worker cadre: the intervention was performed by traditional birth attendants in villages in the North Bank Division of The Gambia within the national village‐based primary healthcare programme.
Outcomes	Maternal: Hb concentrations at baseline, 4 to 6 weeks before delivery and 1 week postpartum; plasma iron, total iron binding capacity, transferrin saturation, deposition of malaria pigment in placenta Infant: birthweight within 7 days of delivery
Notes	Unsupervised Malaria prophylaxis is provided to primigravidae in The Gambia. 30 women with PCV less than 25% after enrolment (17 in iron group and 13 in placebo) were treated and withdrawn from study and analysis. Additionally, 29 women (7 in iron and 22 in placebo group) had PCV below 25% at the second visit and were also withdrawn from study. No differences in the prevalence and severity of peripheral blood or placental malaria infection. No increase in the susceptibility to malaria infection in the 2 groups. Compliance: estimated tablet consumption was 81.1 and 81.7 tablets in the iron and placebo groups respectively. Gestational age at start of supplementation: late gestational age (more than 20 weeks' gestation at the start of supplementation) Anaemic status at start of supplementation: unspecified/mixed anaemia status Daily iron dose: higher daily dose (60 mg daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: high malaria risk area. As of 2011: Malaria risk due predominantly to P. falciparum exists throughout the year in the whole country. Resistance to chloroquine and sulphadoxine‐pyrimethamine reported. Dates of study: not reported Funding sources: "Hoffman La Roche kindly provided the iron and placebo tablets" Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised but method unclear.
Allocation concealment (selection bias)	High risk	Not described. Active treatment and placebo were different colours.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Partial blinding. This was a placebo‐controlled trial but the active and placebo supplements were different colours. Women were likely to be blind, but staff may have been aware of allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Laboratory outcomes unlikely to have been affected by partial blinding.
Incomplete outcome data (attrition bias) All outcomes	High risk	More than 20% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	This was a cluster‐randomised trial; there was no clear baseline imbalance. Data in the original analysis were not adjusted for the cluster design effect but have been adjusted in this review.

Milman 1991.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	248 healthy Caucasian Danish women attending a birth clinic in Copenhagen, Denmark within 9 to 18 weeks of gestation and normal pregnancy. Exclusion criteria: complicated delivery, excessive smoking (> 9 cigarettes/day).
Interventions	Participants were randomly assigned to receive 66 mg of elemental iron (as ferrous fumarate) daily (n = 121) or placebo (n = 127) until delivery. Supplementation started at 8th to 9th week until delivery. Setting and health worker cadre: the intervention was performed by obstetricians at the Birth Clinic of the Department of Obstetrics, Herning Hospital in Copenhagen, Denmark.
Outcomes	Maternal: Hb, HCT, erythrocyte indices, iron status, serum ferritin, serum transferrin saturation, serum erythropoietin at baseline and every 4th week until delivery, and 1 to 8 weeks after delivery in subsample; pregnancy complications Infant: birthweight, serum ferritin, transferrin saturation, and serum erythropoietin in umbilical cord
Notes	Unsupervised Of the 248 women, 20 placebo and 21 iron‐treated were excluded by the authors in some of the analysis for the following reasons: withdrawn consent, 10; uterine bleeding episodes, 5; placental insufficiency, placenta praevia and abruptio placenta, 7; pre‐eclampsia, 3; partus prematurus, 5; excessive smoking, 3. Sample size has been adjusted for ITT. Compliance: number of tablets consumed was 159 ± 38 and 93 ± 43 tablets in the iron‐treated and placebo groups respectively. Gestational age at start of supplementation: early gestational age (less than 20 weeks' gestation at the start of supplementation) Anaemic status at start of supplementation: mixed anaemia status at baseline Daily iron dose: higher daily dose (60 mg or more of elemental iron daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous fumarate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: 1985 Funding sources: The study was supported by Sundhedspuljen (grant no. 5910‐32‐1987 and 5910‐264‐1989) and Fonden for Lægevidenskabelig Forskning ved Sygehusene I Ringkøbing, Ribe og Sønderjyllands Amter. Declarations of interest: not reported Included in 2024 update because although trustworthiness red flags were discovered using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023), these concerns were dealt with in correspondence with the trial authors. Trustworthiness red flags: no mention of ethics or consent; unclear randomisation; no trial dates given We reached out to the corresponding author who stated: "The study was approved by the Regional Ethics Committee and oral as well as written informed consent was obtained from all participants. The study fulfilled the Declaration of Helsinki. The investigation was designed as a double‐blind, placebo‐controlled, block‐randomized study. The principal investigator Chief Physician Anders Ole Agger, MD, who was the head of the Obstetric Department at that time is unfortunately deceased. The inclusion of the women was performed in the one‐year period, from January 1st to December 31st, 1985, so the study was closed in August 1986. I am not able to provide the document approval from the Ethics Committee nor the written information to the participants, I assume these documents are no longer available due to the long timespan and the subsequent reorganizations of the Danish Health Care System since the study was performed in 1985‐1986. Randomization was performed as block‐randomization by a person who was not an active participant in the study. The participants were randomized and given a number code, the significance of which was not known to any of the authors. When the last participant had completed the study in August 1986, the code was broken. The placebo tablets were produced by the hospital pharmacy and had the same color and shape as the iron tablets, being produced by a pharmaceutical company."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Described as a double‐blind, placebo‐controlled trial. Not clear whether blinding was effective; there was a major disparity in the number of tablets consumed by women in the active treatment and placebo groups (means 159 vs 93).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	For laboratory outcomes the impact of blinding on outcomes was likely to be small.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Paintin 1966.

Study characteristics
Methods	RCT, 3 arms with individual randomisation
Participants	180 primigravidae women with less than 20 weeks' gestation and Hb > 100 g/L attending antenatal clinic in Aberdeen Maternity Hospital, United Kingdom
Interventions	Participants were randomly assigned to 1 of 3 groups: Group 1 received 3 tablets containing 4 mg elemental iron each (total 12 mg daily). Group 2 received 3 tablets containing 35 mg elemental iron (total 105 mg elemental iron daily). Group 3 received placebo. Intervention was from week 20 to week 36 of gestation. Setting and health worker cadre: the intervention was performed by clinic and laboratory staff of the Obstetric Medicine Research Unit of Aberdeen Maternity Hospital and Castle Terrace Antenatal Clinic in Aberdeen, United Kingdom.
Outcomes	Maternal: Hb, HCT at baseline, and at weeks 20, 30, 36 of gestation and 7 to 13 days postpartum; plasma volume at 30 weeks, total red cell volume, serum iron and total iron binding capacity at 30 weeks, subjective health and side effects at 30 weeks
Notes	Unsupervised Compliance estimated by measuring tablets returned. Authors report good compliance. Gestational age at start of supplementation: late gestational age (20 weeks' gestation at the start of supplementation) Anaemic status at start of supplementation: unspecified/mixed anaemia status at the start of supplementation Daily iron dose: mixed doses (lower‐dose group 12 mg daily; higher‐dose group 105 mg daily) Iron release formulation: normal release preparation/not specified Iron compound: not specified Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: September 1961 to June 1962 Funding sources: "We are grateful to Riker Laboratories who prepared and supplied the tablets containing iron amniotes." Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Low risk	Placebo‐controlled with sequentially numbered packages.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	It was stated that women and staff were blind to treatment allocation. Placebo described as identical.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It was stated that laboratory staff were blind to allocation until after the trial had been completed.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 5%.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Parisi 2017.

Study characteristics
Methods	4‐arm, parallel randomised controlled trial
Participants	Setting: public antenatal clinic of Obstetrics and Gynecology, Hospital LuigiSacco, Milan, Italy Inclusion criteria: all healthy Italian women, aged 18 to 45 years, with a normal singleton pregnancy, were eligible for participation. Exclusion criteria: any known maternal pathology, use of drugs, any micronutrient supplementation in the first trimester of pregnancy with the only exception of folic acid supplement use, extreme body mass index (BMI < 18 or > 30 kg/m2), Hb value < 10.5 g/d/L, and/or ferritin < 15 mg/L at enrolment, known fetal pathologies, complicated pregnancy. Also excluded women with specific dietary pattern adherences (i.e. vegetarian or vegan diet) or any dietary restriction (i.e. allergies or food intolerance), leading to the assumption of homogeneous iron intake in the study population, as previously reported in Italian adult women.
Interventions	Group 1: received F1 30 mg ferrous sulphate; total number randomised: n = 20. Group 2:received LI14 14 mg liposomal iron (higher bioavailability); total number randomised: n = 20. Group 3: received LI28 28 mg liposomal iron; total number randomised: n = 20. Control/comparison: received no treatment; total number randomised: n = 20. Groups 1 and control included in analysis. Authors contacted 16 May 2013 to confirm composition of supplements given to groups 2 and 3.
Outcomes	Data on birth outcomes (gestational age at delivery, birthweight, placental weight, umbilical pH, Apgar score, estimated blood losses, pregnancy complications) were collected at delivery. Side effects, discontinuation or inappropriate use of supplementation were recorded at 20 to 28 weeks of gestation, at delivery and at 6 weeks postpartum.
Notes	Gestational age: early, supplementation started before 20 weeks' gestation Anaemic status at start of intervention: non‐anaemic if Hb 110 g/L or above during first and third trimesters Dose of iron: low daily dose of iron if 30 mg or less of elemental iron Type of formulation: not specified Iron compound bioavailability in comparison to ferrous sulphate: higher bioavailability and not specified Malaria risk setting: malaria risk‐free countries Study dates: January 2010 to October 2013 Study funding sources: the authors thank Pharmanutra S.r.l. for donating the pharmacological formulations. Study authors’ declarations of interest: the authors report that they have no conflicts of interest. Ethical approval obtained? The study was approved by the Regional Ethics Committee (protocol no. 92/2010/71/09/AP) Study prospectively registered? "Since both LI and FI (30 mg) are considered as food supplements the trial was not registered at the European Drug Regulating Authorities Clinical Trials (EudraCT)"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not detailed in report.
Allocation concealment (selection bias)	Unclear risk	Randomised by using sequentially numbered sheets into 4 groups in relation to different kinds and dosages of commercially available iron supplementations. Not enough detail reported to establish process.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Non‐blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Non‐blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	There were a total of 23 dropouts. This high percentage (28.7%) may be explained also by the presence of a control group of non‐supplemented women with a high incidence of maternal IDA (30%). The dropout distribution in the 4 groups consists of 8 in the control group (6 for pre‐partum anaemia and 2 for withdrawn consent); 6 in the F1 group (3 for pre‐partum IDA, 2 for postpartum IDA and 1 for nausea and constipation); 5 in the LI14 group (2 for pre‐partum IDA, 2 for postpartum IDA, and 1 for withdrawn consent); 4 in the LI28 group (2 for postpartum IDA and 2 for gastrointestinal side effects).
Selective reporting (reporting bias)	High risk	“In order to reduce the effect of dropouts and missing data, we decided to exclude data from the post‐ partum period in the analysis of Hb and ferritin trend.” No denominators given in results. Side effects not clearly reported apart from listing dropouts (1 in ferrous sulphate, 2 in LI28)
Other bias	Unclear risk	Baseline characteristics narratively reported.

Preziosi 1997.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	197 healthy pregnant women 17 to 40 years of age, with 28 ± 3 weeks of gestation attending antenatal care clinic in a Mother‐Child Health Centre in Niamey, Niger
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1 received 100 mg of elemental iron (as ferrous betainate) daily. Group 2 received placebo. Supplementation was from 28 ± 3 weeks of gestation until delivery. Setting and health worker cadre: the intervention was performed by physicians at an isolated, urban maternal and child health centre serving low‐ or middle‐class villagers in Niger.
Outcomes	Maternal: Hb concentration, MCV, HCT, erythrocyte protoporphyrin, serum iron, transferrin, total iron binding capacity, serum ferritin concentrations, at baseline and at the first stage of labour and at 3 and 6 months postpartum, prevalence of iron deficiency and iron‐deficiency anaemia Infant: birthweight and length, Hb concentration, MCV, erythrocyte protoporphyrin, serum iron, transferrin saturation, serum ferritin concentrations at birth and at 3 and 6 months; Apgar scores
Notes	Supervised by physicians who recorded tablet consumption Compliance not reported Gestational age at start of supplementation: late gestational age (more than 20 weeks gestation) Anaemic status at start of supplementation: mixed anaemia status at baseline Daily iron dose: higher daily dose (more than 60 mg elemental iron daily) Iron release formulation: normal release preparation/not specified Iron compound: ferrous betainate Malaria setting: high‐risk malaria setting. As of 2011: Malaria risk due predominantly to P. falciparum exists throughout the year in the whole country. Chloroquine‐resistant P. falciparum reported. Dates of study: not reported Funding sources: supported by a grant from the Nestlé Foundation Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	By random numbers.
Allocation concealment (selection bias)	Low risk	Packages of tablets numbered by manufacturer.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind, placebo‐controlled trial. Placebo prepared by manufacturer. Women and staff blind.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Most outcomes reported were laboratory results; newborn outcomes were reported, but these were most likely recorded by clinic staff blind to allocation.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Loss to follow‐up not described.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Pritchard 1958.

Study characteristics
Methods	RCT, 3 arms with individual randomisation
Participants	172 pregnant women believed to be in the second trimester of pregnancy by date of last menstrual period attending antenatal care clinic in Parland Memorial Hospital, Dallas, Texas, USA
Interventions	Participants were randomly assigned to 1 of 3 interventions: Group 1 received 1000 mg of iron intramuscularly as iron‐dextran. Group 2 received 112 mg of elemental iron (as ferrous gluconate) daily in 3 tablets. Group 3 received placebo tablets. Supplementation started during 2nd trimester until delivery. Setting and health worker cadre: the intervention was performed by physicians at a prenatal clinic in the United States of America.
Outcomes	Maternal: Hb concentration at baseline and at delivery
Notes	Unsupervised Only groups 2 (oral iron) and 3 (placebo) were included in this review. Compliance not reported Gestational age at start of supplementation: mixed gestational age at the start of supplementation (2nd trimester) Anaemic status at start of supplementation: mixed anaemia status at baseline Daily iron dose: higher daily dose (more than 60 mg elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous gluconate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: Supported in part by a grant from the National Heart Institute, National Institutes of Health, Public Health Service (H‐2156 C). Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Partial blinding. Placebo and active treatment compared. It was not clear whether staff were aware of allocation. It was stated that women given active supplements were repeatedly urged to take the tablets. It was not clear whether or not the placebo group received the same instruction.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessor not blinded. Outcomes reported unlikely to be affected by any lack of blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up not described (no loss to follow‐up apparent).
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Low risk	No other bias apparent.

Puolakka 1980.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	32 healthy non‐anaemic pregnant women attending antenatal care at maternity centres of Oulu University Central Hospital, Finland with uncomplicated pregnancy of less than 16 weeks, and no earlier haematological problems
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1 received 200 mg of elemental iron (as ferrous sulphate) daily. Group 2 received no treatment. Supplementation started at 16th week of gestation until 1 month postpartum Setting and health worker cadre: the intervention was performed by obstetricians at maternity centres in Oulu, Finland.
Outcomes	Maternal: Hb, HCT, RBC count, leucocyte count, reticulocytes, MCV, MCH, serum iron, total iron binding capacity, transferrin, vitamin B12, whole folate, and serum ferritin concentration at baseline, and at weeks, 16, 20, 24, 28, 32, 36, 40 and 5 days, 1, 2, and 6 months postpartum. Bone marrow aspirates at 16th and 32nd week and at 2 months postpartum Infant: birthweight, Apgar scores at 5 minutes
Notes	Unsupervised Compliance not reported Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher daily dose (more than 60 mg elemental iron daily) Iron release formulation: normal release preparation/not specified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	"randomly divided into two groups."
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding mentioned.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% lost to follow‐up. It was stated that no women discontinued the study.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Romslo 1983.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	52 healthy pregnant women attending outpatient Women's Clinic at Haukeland Hospital, Bergen, Norway within first 10 weeks of a normal singleton pregnancy with uncomplicated delivery at 37 to 42 weeks
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1 received 200 mg of elemental iron (as ferrous sulphate) daily. Group 2 received placebo. Supplementation started at 10 weeks of gestation. Setting and health worker cadre: the intervention was performed by physicians at the outpatient clinic of the Women's Clinic, Haukeland Hospital in Bergen, Norway.
Outcomes	Maternal: Hb, HCT, PCV, erythrocyte count, leucocyte count, MCV, MCH, MCHC, serum iron, iron binding capacity, erythrocyte protoporphyrin, serum ferritin at baseline and every month during 2nd trimester and every 2 weeks until delivery Infant: birthweight and Apgar scores
Notes	Unsupervised Compliance measured by tablet count was 55% in the iron‐treated group Gestational age at start of supplementation: early gestational age (less than 20 weeks' gestation at the start of supplementation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher daily dose (more than 60 mg elemental iron daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: "We thank Hassle (Molndal, Sweden) for providing us with tablets". Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	"randomly divided into two groups."
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Placebo‐controlled trial – placebo was reported to look and taste the same as active treatment. Not clear if staff blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% (7/52 lost to follow‐up).
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Siega‐Riz 2001.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	429 non‐anaemic, iron replete women with less than 20 weeks of gestation attending who had not taken supplements containing iron in the last month, with a singleton pregnancy attending the prenatal clinic at the Wake County Human services in Raleigh, North Carolina, USA
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1 received multivitamin/mineral supplements containing 30 mg of iron (as ferrous sulphate) daily. Group 2 received multivitamin/mineral supplements containing 0 mg of iron (no iron) until 29 weeks of gestation. Supplementation started on average at 12 weeks. The multivitamin/mineral supplement contained the following: 4000 IU vitamin A; 400 IU vitamin D; 70 mg vitamin C; 500 μg (0.5 mg) folic acid; 1.5 mg thiamine; 1.6 mg riboflavin; 17 mg niacin; 2.6 mg vitamin B6; 2.5 μg vitamin B1; 200 mg calcium; 100 mg magnesium; 1.5 mg copper; 15 mg zinc. Folic acid supplements were prescribed for all women who had received a positive pregnancy test until the first prenatal visit. Setting and health worker cadre: the intervention was performed by physicians at a clinic serving patients of a low socioeconomic group in Raleigh, North Carolina, United States of America.
Outcomes	Maternal: prevalence of anaemia, iron repletion and iron‐deficiency anaemia at 26 to 29 weeks, side effects, compliance with treatment, iron status (Hb concentration, serum ferritin at 26 to 29 weeks), preterm delivery Infant: birthweight, proportion of low birthweight, small‐for‐gestational age
Notes	Unsupervised Compliance measured by pill counts and a questionnaire and was 66% in the iron group and 63% in the control group. Compliance was also measured by the Medication Event Monitoring System (MEMS) in a subsample of 100 women. Gestational age at start of supplementation: early gestational age (less than 20 weeks' gestation at the start of supplementation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: lower daily dose (30 mg or less elemental iron daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: August 1997 through December 1999 Funding sources: "Supported by a grant from the Association of Schools of Public Health and the Centers for Disease Control and Prevention (# S0454) and from a Center grant from National Institute of Child Health and Human Development to the Carolina Population Center (#HD05798). We thank Mead Johnson Pharmaceuticals for providing the supplements". Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	By using random number generator.
Allocation concealment (selection bias)	Low risk	Tretament provided in coded bottles by pharmacy.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Described as double‐blind, randomised trial.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	High risk	More than 20% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Simmons 1993.

Study characteristics
Methods	RCT, 3 arms with individual randomisation
Participants	376 pregnant women with ages between 16 and 35 years, with mild anaemia (Hb concentrations between 80 and110 g/L) attending 8 maternal and child health centres in Kingston, St. Andrews and Spanish Town, Jamaica, with gestational age between 14 and 22 weeks.
Interventions	Participants were randomly assigned to 1 of 3 groups: Group 1 received 1 placebo tablet daily. Group 2 received 100 mg of elemental iron (as ferrous sulphate) daily. Group 3 received 50 mg of elemental iron (in a gastric delivery system capsule) daily. All women received 400 μg (0.4 mg) of folic acid. Setting and health worker cadre: the intervention was performed by clinic nurses and field workers at maternal and child health centres in urban areas of Jamaica.
Outcomes	Hb, HCT, MCV, white cell count, serum iron, total iron binding capacity, serum ferritin, serum transferrin receptor, at baseline, at 6 weeks and at 12 weeks after start of supplementation, as well as side effects
Notes	Gestational ages differed in the participants, and we have not included outcome data from this trial in the review. Gestational age at start of supplementation: mixed gestational age (up to 22 weeks' gestation at recruitment) Anaemic status at start of supplementation: anaemic at the start of supplementation (mild anaemia Hb 80 to 110 g/L) Daily iron dose: mixed dose (medium‐dose group 50 mg elemental iron in gastric delivery system capsule; higher‐dose group 100 mg of elemental iron) Iron release formulation: gastric delivery system capsule (controlled release preparation) Iron compound: ferrous sulphate Malaria setting: no. As of 2011: no longer have indigenous malaria, and are in the prevention of reintroduction stage. P. falciparum malaria outbreaks that began in 2006 were under control by 2010 with zero locally‐acquired cases. It is considered to be well prepared for the prevention and management of possible future outbreaks. Dates of study: not reported Funding sources: "Supported by the International Center for Research on Women through AID Cooperative Agreement DAN‐1010‐A‐00‐7061‐00, and by AID Cooperative Agreement DAN‐5115‐A‐00‐7908‐00. The GDS capsules were kindly supplied by F Hoffmann‐La Roche Ltd, Basel, Switzerland". Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	By random number table.
Allocation concealment (selection bias)	Low risk	Sealed envelopes distributed to clinics (not clear if envelopes were opaque).
Blinding of participants and personnel (performance bias) All outcomes	High risk	Partial blinding. A placebo was provided, but this was a single tablet while women in treatment groups received either 2 tablets or a capsule. It was stated that women were not told which preparations contained iron, but staff would be aware of treatment.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	High risk	376 women were recruited. 275 women were followed up (73.1%) but laboratory results were available for 66% of the original sample.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Low risk	The 3 groups were reported to have similar characteristics at baseline.

Suharno 1993.

Study characteristics
Methods	RCT, 4 arms with individual randomisation
Participants	305 women randomised and follow‐up data were available for 251 pregnant women aged 17 to 35 years, parity 0 to 4 and Hb concentrations between 80 and 109 g/L from rural villages in Bogor, West Java, Indonesia. Women recruited at 16 to 24 weeks' gestation.
Interventions	Participants were randomly allocated to 1 of 4 groups: Group 1 received 2.4 mg of retinol and 1 placebo iron tablet daily. Group 2 received 60 mg of elemental iron (as ferrous sulphate) and a placebo vitamin A tablet daily. Group 3 received 2.4 mg of retinol and 60 mg of elemental iron (as ferrous sulphate). Group 4 received 2 placebos for 8 weeks. Setting and health worker cadre: the intervention was performed by village workers among middle and low socioeconomic groups in rural villages in Bogor, West Java, Indonesia.
Outcomes	Hb, HCT, serum ferritin, serum iron, total iron binding capacity, serum retinol, transferrin saturation, at baseline and after 8 weeks of supplementation (2nd and 3rd trimester)
Notes	Relevant comparison in this review: Group 3 (iron + vit A) vs group 1 (vit A but no iron) for comparison 5: daily oral iron + other vitamins and minerals supplementation vs daily oral same other vitamins and minerals (without iron) supplementation Group 2 (iron + placebo) vs group 4 (placebo) for comparison 2: daily oral supplementation with iron alone vs no treatment/placebo No prespecified outcome available for extraction. No data included. Gestational age at start of supplementation: mixed gestational age at the start of supplementation (16 to 24 weeks' gestation) Anaemic status at start of supplementation: anaemic at the start of supplementation (Hb < 110 g/L) Daily iron dose: higher daily dose (60 mg elemental iron) Iron release formulation: normal release preparation/not specified Iron compound: ferrous sulphate Malaria setting: high malaria risk area. As of 2011: Malaria risk exists throughout the year in all areas of the 5 eastern provinces of East Nusa Tenggara, Maluku, North Maluku, Papua and West Papua. In other parts of the country, there is malaria risk in some districts, except in Jakarta Municipality, in big cities. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported. P.vivax resistant to chloroquine reported. Human P.knowlesi infection reported in the province of Kalimantan. Dates of study: April to September 1992 Funding sources: "We thank Hoffmann‐La Roche, Basel, Switzerland who provided the vitamin and placebo preparations through their Sight and Life project. Funds for the Project were provided by a loan from the World Bank for the Second Nutrition and Community Health Project (IBRD 2636‐IND)". Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Carried out by independent researcher.
Allocation concealment (selection bias)	Low risk	"Subjects were allocated a sequential number from 1 to 305. An independent researcher randomly labelled the iron and placebo preparations", which were colour‐coded.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Described as a double‐masked study and placebo provided.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Allocation was not revealed until after the study was completed. Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	305 women were randomised and follow‐up data were available for 251 (83%). Reasons for loss to follow‐up were described and were similar across groups.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Low risk	Groups appeared similar at baseline.

Svanberg 1975.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	60 healthy primiparous women attending antenatal care clinic in Goteborg, Sweden with uncomplicated pregnancy and less than 14 weeks of gestation and with Hb concentrations above 120 g/L who had not received iron supplements in the previous 6 months or parenteral iron at any previous time. Women whose Hb concentration fell below 100 g/L during the study period were excluded and received immediate therapy.
Interventions	Participants were randomly allocated to receive 200 mg of elemental iron (as a sustained release preparation of ferrous sulphate) daily or placebo from 12 weeks of gestation until 9 weeks post delivery. Setting and health worker cadre: the intervention was performed by physicians at the University of Göthenburg in Sweden.
Outcomes	Maternal: iron absorption measurements; Hb concentration, HCT, bone marrow haemosiderin, MCHC, total iron binding capacity, transferrin saturation at baseline, and at weeks 16, 20, 24, 28, 32, and 35; and 8 to 10 weeks after delivery
Notes	Unsupervised Compliance measured by remaining pill count was 86 ± 3% Gestational age at start of supplementation: early gestational age (less than 20 weeks' gestation at the start of supplementation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher dose (more than 60 mg elemental iron daily) Iron release formulation: sustained release preparation of ferrous sulphate Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: This study was supported by a grant from the Medical Faculty, University of Goteborg. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, care provider, and outcome assessor blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants, care provider, and outcome assessor blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Taylor 1982.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	48 healthy pregnant women with no adverse medical or obstetric history attending antenatal care clinic in Newcastle, England, United Kingdom before 12 weeks of gestation
Interventions	Participants were randomly allocated to 1 of 2 groups: Group 1 received about 65 mg elemental iron (as 325 mg of ferrous sulphate) and 350 μg (0.35 mg) of folic acid daily from 12 weeks until delivery. Group 2 received no supplements. Setting and health worker cadre: the intervention was performed by physicians at the Princess Mary Maternity Hospital in Newcastle upon Tyne, United Kingdom.
Outcomes	Maternal: Hb concentration, serum ferritin, MCV at 12 weeks and every 4 weeks until delivery, and at 6 days, 6 weeks and 6 months after delivery; plasma volume at 12 and 36 weeks of gestation Infant: birthweight, infant death, admission to special care unit
Notes	Unsupervised Compliance not reported Gestational age at start of supplementation: early gestational age (less than 20 weeks gestation at the start of supplementation) Anaemic status at start of supplementation: mixed/unspecified anaemia status Daily iron dose: higher daily dose (more than 60 mg elemental iron daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: "The Gamma Dab Radioimmunoassay Kits were generously donated by Travenol Laboratories Inc. We also gratefully acknowledge financial support by the Scientific and Research Committee of the Newcastle upon Tyne Area Health Authority (Teaching)". Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	"Randomly assigned".
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Tholin 1993.

Study characteristics
Methods	RCT, 3‐arm trial with individual randomisation
Participants	83 healthy nulliparous non‐vegetarian, non‐anaemic pregnant women with serum ferritin concentrations above 10 μg/L
Interventions	Participants were randomly assigned to 1 of 3 groups: Group 1 received 100 mg of elemental iron (as ferrous sulphate) daily. Group 2 received placebo. Group 3 received dietary advice only. Setting and health worker cadre: the intervention was performed by physicians at the Maternal Health Unit of Ostersund Hospital in Ostersund, Sweden.
Outcomes	Blood Hb, serum ferritin and blood manganese were determined at baseline before 15th week of gestation, between 25 and 28 weeks, and between 35 and 40 weeks of gestation. Median and ranges are presented.
Notes	The aim of this study was to examine the relationship between iron and zinc levels during pregnancy. No outcomes were extractable from this report for this review. Median serum zinc levels were reported by randomisation group, "levels did not differ between groups". Median Hb levels were reported for women who had normal vs complicated deliveries (rather than by randomisation group). Results for mean Hb and serum ferritin levels were depicted in graphs. Gestational age at start of supplementation: early gestational age at the start of supplementation (supplementation started before 20 weeks gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher daily dose (more than 60 mg elemental iron daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: This work was supported by grants from Värmlands läns lasting, Karlstad, Sweden and Wasabröd AB, Filipstad, Sweden. Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as "randomly assigned".
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind for iron‐supplemented group. Placebo‐controlled trial with outcome assessment by an obstetrician blind to group assignment.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	There were some discrepancies in the figures reported in 2 study publications. (We have not included data from this trial in the review.)
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	High risk	Results were not simple to interpret and some results were not reported according to randomisation group.

Tura 1989.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	254 non‐anaemic non‐iron deficient healthy pregnant women from multiple centres in Italy between 12 and 16 weeks of gestation. Exclusion criteria: acquired or congenital anaemia, haemoglobinopathies, thalassaemia, medically or surgically treated cardiopathy, abortion, hypertension, gastric resection, metabolic or endocrine disorder, hepatic or renal disease, epilepsy or another neurological disease, previously treated for cancer, alcohol or substance dependence.
Interventions	Participants were randomly assigned to receive 40 mg of elemental iron (containing 250 g of ferritin in a micro‐granulated gastric‐resistant capsule) daily or no treatment from 12 to 16 weeks of gestation until the end of puerperium. Setting and health worker cadre: the intervention was performed by physicians in health centres in Italy.
Outcomes	Maternal: Hb concentration, RBC count, MCV, serum iron, total transferrin, transferrin saturation, serum ferritin at 12 to 16 weeks, 2 times during pregnancy, at 38 to 42 weeks, and at puerperium 48 to 52 weeks
Notes	Unsupervised The study included another sample of women who were iron deficient and received 2 forms of iron preparation. This sample is not used in this review. Compliance reported as higher than 98.5% Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: medium iron dose (more than 30 and less than 60 mg) Iron release formulation: micro‐granulated gastric‐resistant capsule Iron compound: not specified Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: 1987 to 1988 Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	By random number lists.
Allocation concealment (selection bias)	Low risk	Sealed envelopes, progressively numbered.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No mention of blinding. No placebo.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% loss to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Van Eijk 1978.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	30 pregnant women with uncomplicated pregnancies and deliveries attending antenatal care clinic at the University Hospital Obstetric Unit in Rotterdam, Netherlands
Interventions	Participants received 100 mg of elemental iron (as ferrous sulphate) daily or no treatment from the third month of gestation until delivery. Follow‐up was until 12 weeks after delivery. Setting and health worker cadre: the intervention was performed by physicians at the University Hospital Obstetrical Clinic in Rotterdam, the Netherlands.
Outcomes	Maternal: Hb concentration, serum iron, serum ferritin, transferrin concentration at baseline and every 3 to 4 weeks until delivery, and 3 months after delivery Infant: Hb concentration, transferrin, serum iron, serum ferritin in cord blood at term
Notes	Unsupervised Compliance not reported Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks gestation) Anaemic status at start of supplementation: mixed/unspecified anaemia status Daily iron dose: higher daily dose (more than 60 mg elemental iron daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	High risk	Not used.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% loss to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Wallenburg 1983.

Study characteristics
Methods	RCT, 2 arms with individual randomisation
Participants	44 non‐anaemic Caucasian women with singleton pregnancy and no major illnesses attending the University Hospital Obstetrical Clinic of the Erasmus University in Rotterdam who had not received iron supplementation during their first visit
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1: received 105 mg of elemental iron (as ferrous sulphate) daily in a sustained release preparation. Group 2: received no iron supplement. Supplementation started at 14th to 16th week of gestation until delivery. Setting and health worker cadre: the intervention was performed by physicians at the Antenatal Clinic of the University Hospital Dijkzigt in Rotterdam, the Netherlands.
Outcomes	Maternal: Hb, serum iron, serum transferrin and serum ferritin concentrations at 16, 28, 36 weeks, delivery, 6 and 12 weeks postpartum
Notes	Unsupervised Compliance not reported We treated this study, carried out collaboratively in 2 different sites, as 2 different trials: 1 conducted in Rotterdam (Wallenburg 1983) and 1 conducted in Antwerp (Buytaert 1983). Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: higher daily dose (more than 60 mg elemental iron daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	By random table numbers.
Allocation concealment (selection bias)	Low risk	By means of sealed envelopes.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Neither participant nor provider blinded. No placebo used.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% losses to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Willoughby 1967.

Study characteristics
Methods	RCT, 5‐arm trial
Participants	3599 pregnant women with Hb above 100 g/L at their antenatal care clinic visit at Queen's Mother's Hospital in Glasgow, Scotland, United Kingdom. Women who reported not taking the tablets regularly were excluded as well as those diagnosed with anaemia during the study.
Interventions	Participants were randomly allocated to 1 of 5 interventions: Group 1 received no prophylactic supplements. Group 2 received 105 mg of elemental iron daily (as chelated iron aminoates). Group 3 received 105 mg of elemental iron with 100 μg (0.1 mg) of folic acid. Group 4 received 105 mg of elemental iron daily with 300 μg (0.3 mg) of folic acid. Group 5 received 105 mg elemental iron daily with 450 μg (0.45 mg) of folic acid. Starting and ending time of supplementation variable Setting and health worker cadre: the intervention was performed by a team of nurses and physicians at the Antenatal Clinic of the Queen Mother's Hospital in Glasgow, United Kingdom.
Outcomes	Maternal: Hb concentration at baseline and at every visit, at early puerperium and during postnatal visit; incidence of obstetric complications, incidence of megaloblastic anaemia Infant: Hb and whole blood folate levels at 6 weeks of age, incidence of neonatal complications
Notes	Unsupervised Groups 3 to 5 were merged for the purposes of this review. Women were excluded from the trial and the analysis if they were diagnosed as anaemic. Compliance not reported Gestational age at start of supplementation: mixed gestational age at the start of supplementation Anaemic status at start of supplementation: mixed anaemia status (Hb > 100 g/L) Daily iron dose: higher daily dose (more than 60 mg elemental iron daily) Iron release formulation: not clear? Normal release preparation/unspecified Iron compound: chelated iron aminoates Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: "All the iron and folic acid supplements were kindly made to our specification and supplied by Riker Laboratories, Loughborough, who have given us every co‐operation throughout. The crystalline samples of pteroylglutamic acid were kindly supplied by Miss Buckland of Lederle Ltd." Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding. Women with anaemia or non‐compliant were withdrawn from the study.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Low risk for laboratory outcomes.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Less than 20% loss to follow‐up. However, women were excluded from the trial and the analysis if they were diagnosed as anaemic.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Wills 1947.

Study characteristics
Methods	Quasi‐randomised trial, 2 arms with individual randomisation
Participants	500 pregnant women attending antenatal care clinic at the Royal Free Hospital in London, England, United Kingdom during wartime, with ages between 18 and 43 years. Women with severe anaemic or rheumatoid arthritis were excluded.
Interventions	Participants were alternatively allocated to receive 580 mg of elemental iron (as ferrous gluconate) daily or placebo from their first visit. Supplementation starting variable and ending time unclear Setting and health worker cadre: the intervention was performed by nurses and physicians at the Antenatal Clinic of the Obstetrical Department at the Royal Free Hospital in London, United Kingdom.
Outcomes	Maternal: Hb concentration using the Haldane method at baseline and every 4 weeks until delivery, then day 1, 2 to 4 days, 5 to 16 days and 6 weeks postpartum; serum protein and pregnancy complications (not reported by group) Infant: birthweight (not reported)
Notes	Unsupervised The study was conducted during wartime and a bomb incident interrupted the work, allowing only a small portion of the original sample to be studied and reported. Women were receiving special food rations. Compliance not reported Gestational age at start of supplementation: mixed gestational age (variable) Anaemic status at start of supplementation: mixed anaemia status/unspecified Daily iron dose: higher daily dose (more than 60 mg elemental iron daily) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous gluconate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Dates of study: not reported Funding sources: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quasi‐randomised, alternate.
Allocation concealment (selection bias)	High risk	Alternate allocation.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Placebo provided but authors suggest blinding may not have been convincing to staff.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It was suggested that laboratory staff may have been aware of allocation, but this was unlikely to have affected outcomes.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	More than 20% lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	No other bias apparent.

Zeng 2008 (C).

Study characteristics
Methods	Cluster‐randomised trial (3 arms). Villages were assigned to interventions. Villages were stratified and there was block randomisation to ensure geographical balance in 2 participating counties.
Participants	5828 eligible pregnant women with less than 28 weeks and resident in 2 poor rural counties in Shaanxi Province of north west China participated in the study. Village doctors recruited women by active surveillance. In the study areas, there were no specific policies for the distribution of multiple micronutrients or iron‐folic acid supplements even in disadvantaged areas, although folic acid supplements were promoted to prevent NTDs. Their villages were randomly assigned for women to receive 1 of 3 groups.
Interventions	Their villages were randomly assigned for participants to receive 1 of 3 groups: Group 1: received daily antenatal multiple micronutrients containing 30 mg elemental iron, 400 µg (0.4 mg) folic acid and 15 mg zinc, 2 mg copper, 65 µg selenium, 150 µg iodine, 800 µg vitamin A, 1.4 mg vitamin B1 (thiamine), 1.4 mg vitamin B2 (riboflavin), 1.9 mg vitamin B6, 2.6 µg vitamin B12, 5 µg vitamin D, 70 mg vitamin C, 10 mg vitamin E, and 18 mg niacin. Group 2: received a tablet containing 60 mg elemental iron and 400 μg (0.4 mg) of folic acid. Group 3: a tablet containing 400 μg (0.4 mg) folic acid alone (control). Setting and health worker cadre: the intervention was performed by local maternal and child health workers in rural, antenatal clinics and local health facilities in Shaanxi Province, China.
Outcomes	Birthweight within 1 hour of delivery, low birthweight, birth length, gestational age at birth, preterm delivery, small‐for‐gestational age babies, maternal Hb concentration in the third trimester (gestation 28 to 32 weeks), anaemia in the third trimester, fetal losses during pregnancy, birth outcome, delivery information, neonatal and maternal deaths; neonatal survival at the 6 weeks, perinatal deaths, neonatal deaths, stillbirths. A follow‐up publication describes a follow‐up to 850 children born to women who participated in the study and focused on mental development outcomes using the Bayley scales of infant development at 3, 6, 12, and 24 months of age.
Notes	We have only included groups 2 (iron + folic acid) and 3 (folic acid alone) in the analyses. In the data tables we have adjusted the raw data presented in the paper to take account of the cluster‐design effect. We have calculated an effective sample size by dividing figures by the design effect calculated using the ICC for the trial’s primary outcome: birthweight ICC = 0.03. We have used the same sample adjustment for all outcomes. 65.9 of women in group 2 (iron + folic acid) and 65.2% of women in group 3 (folic acid) started supplementation before 16 weeks of gestational age. Gestational age at start of supplementation: mixed/unspecified gestational age Anaemic status at start of supplementation: mixed anaemia status Daily iron dose: higher‐dose group (60 mg elemental iron daily) in 1 group and 30 mg in another group (multiple micronutrients) Iron release formulation: normal release preparation/unspecified Iron compound: unspecified Malaria setting: Yes. As of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine‐pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas. No. As of 2021: According to World Malaria Report 2022, of the 93 countries that were malaria endemic in 2015, 4 countries along with China have been certified malaria‐free since 2015. Dates of study: August 2002 to January 2006 Funding sources: This work was supported by the United Nations Children’s Fund (grant No YH101‐H12/03) through a cooperative agreement between UNICEF and the Centers for Disease Control and Prevention, Atlanta, US, and the National Natural Science of Foundation of China (grant No 30271131), Beijing, China. Sight and Life and DSM Nutritional Products, China, provided the nutrient supplement, which was manufactured by Beijing Vita Nutritious Products, Beijing, China. Declarations of interest: MJD was consultant for UNICEF China UNICEF Pyongyang during the conduct of the trial. SC was nutrition consultant for UNICEF China from 2001 to 2002, and is now the liaison officer for UNICEF with the Ministry of Health.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“The randomisation schedule was generated off site with a pseudo‐random number generator.” Recruitment bias was unlikely.
Allocation concealment (selection bias)	Low risk	Off‐site randomisation.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Cluster trial; all women in village received the same intervention.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Low risk for laboratory outcomes but unclear for other outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Total clusters 531. Total women 5828 (in 3 groups, 2 groups included in the analyses, total randomised 3929). Overall, 133 women lost to follow‐up and 279 stopped taking supplements and were excluded (7% lost to follow‐up). 3270 women in groups 1 and 2 had live births (3306 babies). Approximately 6% further missing data for primary outcome (infant birthweight). Further missing data for other outcomes. Available case analysis for primary outcome (LBW).
Selective reporting (reporting bias)	Unclear risk	There is insufficient information to permit judgement.
Other bias	Unclear risk	The trial was stopped early because of funding constraints. The treatment groups appeared similar at baseline. Results were adjusted for the cluster design effect.

Zhao 2014.

Study characteristics
Methods	2‐arm, double‐blind controlled trial
Participants	2371 pregnant women 18 years and older attending prenatal care clinic in 3 hospitals (Sanhe Maternity and Child Health Care Center, Sanhe General County Hospital, and Sanhe Hospital of Traditional Chinese Medicine) in Beijjing, China enrolled from June 2009 through December 2011 with uncomplicated singleton pregnancies and first prenatal visits at 20 weeks or less of gestation Inclusion criteria: women were recruited at their first prenatal visit at Sanhe MCHC. Women were eligible if they had an uncomplicated singleton pregnancy, a first Sanhe MCHC visit at #20 wk gestation, and plans to give birth at a participating hospital. Exclusion criteria: < 18 years, not living in Sanhe, not mentally competent, having chronic health problem, haemoglobin < 100 g/L, or having taken medicinal iron for any duration
Interventions	Participants assigned to 1 of 2 groups: Intervention group: (n = 1185, 823 with iron status outcome data) capsules with iron (300 mg ferrous sulfate (60 mg elemental iron)) …and capsules with 0.40 mg folate. Participants were instructed to take one of each kind of supplement daily from enrolment to delivery and to return to the clinic for more supplements when they ran out. Women received 100 capsules of each supplement upon enrolment and after 3 mo, typically at 26 to 32 weeks gestation. Control/comparison group: (n = 1186, 809 with iron status data) placebo (starch, dextrin, sucrose, and magnesium stearate) and capsules with 0.40 mg folate.
Outcomes	Iron status, pregnancy outcomes, including pregnancy and delivery complications, preterm rate, perinatal death rate, and birth rate, weight changes during pregnancy, and rates of pregnancy diabetes, pregnancy high blood pressure, fetus growth restriction, low birthweight, and fetal macrosomia
Notes	Malaria setting: Yes. As of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine‐pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas. No. As of 2021: According to World Malaria Report 2022, of the 93 countries that were malaria endemic in 2015, 4 countries along with China have been certified malaria‐free since 2015. Dates of study: eligible pregnant women were enrolled from June 2009 through December 2011. Data collection ended on December 2011 (final data collection date for primary outcome measure). Funding sources: The pregnancy study was supported by a grant from Vifor Pharma Ltd. (GZ, Principal Investigator). The laboratory measures of iron status were supported by a grant from the NIH (R01 HD052069; BL, Principal Investigator), which included funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Office of Dietary Supplements. Declarations of interest: Author disclosures: G Zhao, G Xu, M Zhou, Y Jiang, B Richards, KM Clark, N Kaciroti, MK Georgieff, Z Zhang, T Tardif, M Li, and B Lozoff, no conflicts of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Taiyuan Satellite Pharmaceutical Co., Ltd. prepared equal quantities of iron or placebo capsules and folate capsules and assigned 4‐digit package numbers beginning with 0001 according to a random‐number chart prepared by a statistician who was not part of the study.
Allocation concealment (selection bias)	Low risk	Study participants, personnel, and investigators were unaware of supplement group. The code was not broken until the study and primary analyses were completed. Supplement packs differed in appearance only by number.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Code unbroken until study completed; identical placebo used.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Appears blinded, outcomes not subjective
Incomplete outcome data (attrition bias) All outcomes	High risk	Over 20% dropout rate, reasons described in report.
Selective reporting (reporting bias)	Unclear risk	Outcomes reported as described in protocol, but protocol was registered following trial completion
Other bias	Low risk	None noted.

BMI: body mass index
cRCT: cluster‐randomised controlled trial
FA: folic acid
Fe: iron
GGT: gamma‐glutamyl transferase
GSH‐Px: glutathione peroxidase
Hb: haemoglobin
HCT: haematocrit (same as PCV: packed cell volume)
ICC: intraclass correlation coefficient
IDA: iron deficiency anaemia
ITT: intention‐to‐treat
IV: intravenous
LBW: low birthweight
MCH: mean corpuscular (or cell) haemoglobin
MCHC: mean corpuscular (or cell) haemoglobin concentration
MCV: mean corpuscular (or cell) volume
MDA: malondialdehyde
n/a: not applicable
OGIT: oral glucose intolerance test
OGTT: oral glucose tolerance test
PCV: packed cell volume (same as HCT: haematocrit)
RBC: red blood cell
RCT: randomised controlled trial
SD: standard deviation
SES: socioeconomic status
SOD: superoxide dismutase
TST: Trustworthiness Screening Tool
vs: versus

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Aaseth 2001	67 non‐anaemic pregnant women attending prenatal care clinics in Kingsvinger Hospital, in Kingsvinger, Norway were allocated to a daily regimen of either 100 mg Fe or 15 mg Fe. Both groups received iron at different doses. No comparisons allowed within the scope of this review.
Abel 2000	Community‐based study in Vellore district, India using a pre‐post experimental design measuring the impact of an iron supplementation programme, helminthic treatment, and education intervention on the prevalence of anaemia in the different trimesters of pregnancy. The same pregnant women were not followed. The type of study (not a prospective, parallel RCT) is not eligible for inclusion in this review.
Adaji 2019	This study was conducted at the Department of Obstetrics and Gynaecology and the Department of Haematology of University of Abuja Teaching Hospital, Abuja, involving 164 pregnant women who presented at the booking clinic during the study period. The population was a mixture of rural and urban dwellers. This was a randomised clinical trial to compare the effectiveness and safety of once daily versus twice daily ferrous sulphate supplementation in the prevention of anaemia in pregnancy. Each ferrous sulphate tablet (200 mg) contained 65 mg of elemental iron. Both groups were given iron supplementation in different types of regimen, so the trial was not eligible for this review.
Adhikari 2009	320 pregnant women attending the Tribhuvan University Teaching Hospital, Nepal for antenatal care were randomised to 1 of 4 groups: Group 1: received 60 mg elemental iron daily (as ferrous sulphate). Group 2: received 60 mg elemental iron daily (as ferrous sulphate) with a count of unused pills at antenatal appointments. Group 3: received 60 mg elemental iron daily (as ferrous sulphate) with education (direct counselling and colour brochure) on iron and anaemia. Group 4: received 60 mg elemental iron daily (as ferrous sulphate) with pill count and education (direct counselling and colour brochure) on iron and anaemia. In this randomised trial, the aim of the intervention was to increase compliance and all 4 intervention groups received daily iron supplements. This type of intervention (different types of administration) does not allow for comparisons within the scope of this review.
Afifi 1978	260 pregnant women from Cairo, Egypt (formerly part of United Arab Republic) were randomly allocated to 1 of 2 groups: Group 1: received 130 mg elemental iron daily (a slow release ferrous sulphate preparation, Plexafer‐F®) and 360 μg (0.36 mg) folic acid. Group 2: received iron (as ferrous sulphate, no dose reported) in addition to 5000 μg (5 mg) folic acid. Both groups received daily iron supplementation in different preparations. The type of intervention does not allow for comparisons within the scope of this review.
Agrawal 2011	75 pregnant women aged 19 to 40 years attending the department of Obstetrics and Gynaecology, Kasturba Hospital, Manipal India, with normal Hb levels between 13 and 16 weeks' gestation will be randomly assigned to 2 supplementation groups: Group 1: received ferrous fumarate with 98.6 mg of elemental iron (Continuous group) 1 capsule daily (all days a week). Group 2: received ferrous fumarate with 98.6 mg of elemental iron (Intermittent group) 1 capsule daily 4 days a week (i.e. from Monday to Thursday). The supplementation period will start at 13 to 16 weeks and continue up to delivery and in the postnatal period. The study was excluded because there are 2 groups receiving iron, 1 group daily and the other intermittently. This type of comparison (different types of regimen) is outside the scope of this review.
Ahamed 2018	This was a community‐based, open‐labelled, parallel, block‐randomised controlled trial including 400 pregnant women in a rural setting of north India carried out from January to December 2014. In the intervention group, the first dose of iron‐folic acid (IFA) supplementation every week was supervised and women were instructed to take the remaining tablets during the week as per the prescription. In the control group, IFA tablets were supplied without any direct supervision. This trial was excluded as both groups received iron supplementation with different types of administration.
Ahn 2006	209 pregnant women between 18 and 45 years of age, attending outpatient obstetric clinics at North York General Hospital and the Hospital for Sick Children in Toronto, Canada were randomly assigned to receive multiple micronutrient supplements containing 60 mg of elemental iron (as ferrous fumarate) (Materna®) or another supplement (PregVit®) to be taken twice daily with the morning dose containing 35 mg of elemental iron (as ferrous fumarate) and the evening dose containing 300 mg calcium, and other vitamins and minerals. Both groups received daily iron in different doses as well as other vitamins and minerals. The type of intervention does not allow for comparisons within the scope of this review.
Alaoddolehei 2012	145 healthy pregnant women 20 to 40 years of age with Hb 110g/L or higher at 20 weeks' gestation attending the Gynecology and Obstetrics Clinic, Babol, Iran, from October 2002 to September 2005 were assigned (on the basis of the number given them at first visit) to 1 of 2 groups: Group 1 (even numbers, n = 73) received daily iron supplement at 50 mg/day. Group 2 (odd numbers, n = 72) received an intermittent dose of 3 times per week (50 mg/each time) from 20th week gestation until delivery. Women with β minor thalassaemia, Hb less than 11 g/dL, more than 1 delivery and diagnosed with internal and infectious diseases were excluded. Blood samples were assessed for complete blood count (Hb, HCT, RBC), iron, ferritin, and zinc at baseline in the first trimester in all participants. Both groups received iron supplements in different regimens. The type of intervention is outside the scope of this review.
Ali 2016	This was a randomised controlled trial (NCT02858505) conducted at the Woman's Health Hospital, Assiut, Egypt, between August 2015 and June 2016. It included 120 non‐anaemic pregnant women with twin gestations in the first trimester. Women were randomly assigned to either group I (27 mg elemental iron) or group II (54 mg elemental iron) daily starting from 12 weeks of pregnancy till 36 weeks. This study was excluded because both groups received iron supplementation in different doses.
Angeles‐Agdeppa 2003	744 apparently healthy pregnant (with less than 20 weeks) and non‐pregnant women of reproductive age (15 to 49 years) from the municipalities of Calasiao, Binmaley and Santa Barbara, Philippines who were pregnant or most likely to become pregnant within the 12‐month duration of the study, and who volunteered to participate in the study were provided 2 preparations of iron‐folic acid supplements. Women with severe anaemia or history of malaria were excluded. Non‐pregnant women were prescribed 4 capsules monthly each containing 60 mg of elemental iron and 3500 μg (3.5 mg) folic acid to be taken once weekly before bedtime (to be purchased by the women in local drug stores). Pregnant women received free of cost 4 capsules monthly each containing 120 mg of elemental iron and 3500 μg (3.5 mg) of folic acid to be taken once a week before bedtime until delivery and for 3 months thereafter. Pregnant women seen at the health centres with 20 weeks or more of gestation were advised to take their usual daily dose of iron‐folic acid tablets containing 60 mg of elemental iron and 500 μg (0.5 mg) of folic acid. Women were followed for 12 months. Hb, HCT, MCV, MCHC Hb concentration, serum ferritin, transferrin receptors, prevalence of iron deficiency and anaemia, compliance were assessed at baseline, 4.5, 9 and 12 months. There was not randomisation and the control group was not appropriate for comparisons. The types of comparisons are not relevant for the scope of this review.
Angulo‐Barroso 2016	This study was a randomised controlled trial (RCT) of infancy iron supplementation conducted in Hebei, China. A total of 1482 infants were randomly assigned to receive placebo (n = 730) or supplemental iron (n = 752) from 6 weeks to 9 months. This study was excluded because infants, not pregnant women, were randomised and received iron supplementation.
Antonia 2023	Placebo‐controlled randomised trial in Australia. Pregnant women, at least 18 years of age, with a gestational age of 26 to 32 weeks, who have mild to moderate iron deficiency anaemia (Hb 80 to 104 g/L and ferritin < 30 μg/ L) were included. Participants were randomised to receive either 1) oral elemental iron capsules 80 mg/day plus placebo intravenous saline solution, or 2) intravenous ferric carboxymaltose 1000 mg/day plus placebo oral capsules. We excluded this study as both study arms received iron, and the trial compared oral versus intravenous iron administration; hence it is beyond the scope of this review.
Arija 2014	878 non‐anaemic pregnant women older than 18 years of age with ≤ 12 weeks' gestation without anaemia (Hb > 110 g/L), capable of understanding the official State languages (Castilian or Catalan) at early gestation stage, and their subsequent newborns attending 10 Primary Care Centers from Catalunya (Spain) of the Catalunya Sexual and Reproductive Healthcare Service (Atención a la Salud Sexual y Reproductiva (ASSIR)) of the Catalan Institute of Health (Instituto Catalán de la Salud (ICS)) subdivided in 2 strata as a function of the Hb levels at the start of the pregnancy. Women with multiple pregnancy, taking > 10 mg iron during the months prior to week 12, hypersensitivity to egg protein (due to the iron prescription formula contains ovalbumin), previous serious illness (immunosuppressed status) or chronic illness that could affect the nutritional development (e.g. cancer, diabetes), malabsorption, and liver disease such as chronic hepatitis or cirrhosis. Participants are randomly assigned to 1 of 2 groups per stratum starting from around the 12th week of gestation and continuing up to partum: Group 1: women will receive 20 mg elemental iron (150 mg ferrimanitol ovoalbumin). Group 2: women will receive 80 mg per day of elemental iron (600 mg ferrimanitol ovoalbumin). The reference dose is the control group: women will receive 40 mg elemental iron (300 mg ferrimanitol ovoalbumin), similar to that routinely prescribed in clinical practice. The study was excluded because all women received iron supplements. The type of intervention is outside the scope of this review.
Babior 1985	15 healthy pregnant women 22 to 32 years old, in the first trimester of pregnancy from Boston, Massachusetts, USA were randomly assigned to 3 different multiple micronutrient preparations to assess absorption of iron. All women received iron in the multiple micronutrient supplements. The type of intervention is not relevant to the scope of this review.
Bah 2019	This was a 3‐arm, randomised, double‐blind, non‐inferiority trial in 19 rural communities in the Jarra West and Kiang East districts of The Gambia. Eligible participants were pregnant women aged 18 to 45 years at between 14 weeks and 22 weeks of gestation, randomly allocated to either WHO’s recommended regimen (i.e. a daily UN University, UNICEF, and WHO international multiple‐micronutrient preparation (UNIMMAP) containing 60 mg iron), a 60 mg screen‐and‐treat approach (i.e. daily UNIMMAP containing 60 mg iron for 7 days if weekly hepcidin was < 2.5 μg/L or UNIMMAP without iron if hepcidin was ≥ 2.5 μg/L), or a 30 mg screen‐and‐treat approach (i.e. daily UNIMMAP containing 30 mg iron for 7 days if weekly hepcidin was < 2.5 μg/L or UNIMMAP without iron if hepcidin was ≥ 2.5 μg/L). The trial used a block design stratified by amount of haemoglobin at enrolment (above and below the median amount of haemoglobin on every enrolment day) and stage of gestation (14 to 18 weeks vs 19 to 22 weeks). Participants and investigators were unaware of the random allocation. The primary outcome was the amount of haemoglobin at day 84 and was measured as the difference in haemoglobin in each screen‐and‐treat group compared with WHO’s recommended regimen; the non‐inferiority margin was set at ‐5.0 g/L. The primary outcome was assessed in the per‐protocol population, which comprised all women who completed the study. This trial was registered with the ISRCTN registry, number ISRCTN21955180. This trial was excluded because it examined different regimens of iron supplementation.
Balmelli 1974	42 pregnant women attending antenatal care clinic at the Hospital University of Berne, Switzerland were randomly assigned to 1 of 2 groups: Group 1 received 37 mg elemental iron (as ferrous sulphate) and succinic acid 3 times daily (total daily dose of 111 mg elemental iron and 555 mg succinic acid). Group 2 received 37 mg elemental iron (as ferrous sulphate) and succinic acid 3 times daily (total daily dose of 111 mg elemental iron and 555 mg succinic acid) and 1 tablet 3 times a day containing 100 μg (0.1 mg) folic acid and 100 μg vitamin B12. Both groups received iron supplements. The type of intervention is outside the scope of this review.
Bencaiova 2007	260 women with singleton pregnancy in Zurich, Switzerland, were randomised at 21 to 24 weeks of gestation to receive either intravenous iron (further divided into 2 doses of 200 mg iron saccharate or 3 doses of 200 mg iron) or 80 mg elemental iron (as ferrous sulphate) daily. Both groups received iron in different routes of administration. No comparisons allowed within the scope of this review.
Berger 2003	864 apparently healthy married pregnant and non‐pregnant nulliparous women of reproductive age planning to have a child soon from 19 rural communes of the Thanh Mien district in Hai Duong province, Vietnam were invited to participate and assigned to 1 of the following interventions according to their pregnancy status at baseline: women who were pregnant received free of charge UNICEF tablets containing 60 mg of elemental iron and 250 μg (0.25 mg) of folic acid to be taken daily and women who were non‐pregnant were prescribed pink packs of tablets containing 60 mg of elemental iron and 3500 μg (3.5 mg) of folic acid that they could buy at their village from the Women's Union, to be taken once weekly. If these women became pregnant, women received red packs of tablets containing 120 mg of elemental iron and 3500 μg (3.5 mg) of folic acid free of charge to be taken once weekly. After delivery, women were given tablets containing 60 mg of elemental iron and 0.5 mg of folic acid free of charge for 3 months to be taken weekly. Hb concentration, serum ferritin, and serum ferritin receptors, prevalence of anaemia and iron deficiency and compliance were measured at baseline, at 4.5, 9, and 12 months. This is not a randomised study and no comparisons can be made relevent to the aims of this review.
Bergsjo 1987	Planned study registered at the Oxford Database of Perinatal Trials. Author contacted and informed the project was not completed.
Bhatla 2009	109 pregnant non‐anaemic women between 14 and 18 weeks (49% vegetarian) with no prior intake of iron supplements in the Department of Obstetrics and Gynaecology of the All India Institute of Medical Sciences in New Delhi, India were randomly allocated into 1 of 3 different groups: Group 1 (n = 37) received the standard Government of India supply of Irofol® tablets containing 100 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid (Nestor Pharmaceuticals Ltd., Faridabad, Haryana, India) to be taken once daily. Group 2 (n = 36) received the standard Government of India supply of Irofol® tablets containing 100 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid and were instructed to take 2 tablets on any 1 day of the week; 1 before lunch and the other before dinner (total 200 mg elemental iron and 1000 μg (1 mg) folic acid per week) with no tablets taken during the rest of the week. Group 3 (n = 36) received Ferium® tablets iron (III)‐hydroxide poly maltose complex tablets daily containing iron (III) hydroxide polymaltose containing 100 mg elemental iron and 350 μg (0.35 mg) folic acid to be taken 1 tablet daily (Emcure Pharmaceuticals Ltd., Pune). All groups received health education regarding the importance of diet in pregnancy, iron‐rich foods, and appropriate dietary practices and were instructed to take the tablets 30 min before meals and not with tea, coffee or milk. All women were also advised to take calcium supplements after meals. All groups received iron with different regimens. The type of intervention is not within the scope of this review.
Bhatt 2020	This was a cross‑sectional study carried out in the Department of Obstetrics and Gynecology, Acharya Vinoba Bhave Rural Hospital (AVBRH), a tertiary care teaching hospital in the rural area of Wardha district, Maharashtra, India. 154 pregnant women with a haemoglobin value more than 10 g/dL were included in the study, and they were randomly divided into 2 groups. Tablet albendazole 400 mg was given at the beginning of the study to all. Group 1 received 3 doses of injection iron sucrose 200 mg in 100 mL normal saline as an infusion over 1 to 20 min at 20 to 24 weeks, 25 to 28 weeks, and 29 to 32 weeks of gestation, respectively, after IV iron sucrose‐sensitivity testing. Group 2 received oral ferrous sulfate 200 mg, containing elemental iron of 65 mg, daily. This study was excluded because both groups received different types of iron supplementation.
Blot 1980	203 pregnant women attending prenatal care clinics in Antonie Beclere Hospital, Paris, France during their 6th month visit were randomly allocated to either 105 mg of elemental iron with 500 mg of ascorbic acid or a placebo. The intervention group received iron with ascorbic acid in comparison to placebo. The type of intervention does not allow for comparisons within the scope of this review.
Bokhari 2011	33 healthy non‐smokers, Caucasian, primiparous, with singleton pregnancy (week 20 to week 30) pregnant women with pre‐pregnancy BMI between 19.8 and 26 not taking medicines known to influence iron status nor iron supplements and free from gastrointestinal disorders or allergies were randomised to eat 3 to 4 slices of iron‐rich or control bread daily for 6 weeks. Women with Hb concentrations not within the normal range (below 70 g/L or over 160 g/L) were excluded. Low versus high iron fortified breads were compared. Two 24‐hour‐prompted (multiple‐pass) dietary recalls were completed, and validated algorithms were used to determine the amount of ‘available iron’ from the diet. Findings from this study show that iron‐rich staple foods can help women reach dietary targets for iron. Further research using fortified staple foods containing higher levels of iron is now warranted to establish physiological benefits. The study was excluded because food fortification is out of the scope of this review. The intervention is outside the scope of this review.
Bokhari 2012	65 pregnant women 18 to 45 years between weeks 20 and 30 gestation were recruited from South Manchester University Hospital antenatal clinic, United Kingdom and 33 participants that attended their first appointment were randomised to 1 of 2 groups: Group 1 were provided 3 to 4 slices of functional bread containing flour (Eragrostis tef) that was naturally rich in iron (2.1 mg iron per 50 g slice) and added enzyme phytase or control bread daily for 6 weeks. Participants substituted the bread they would normally eat with the intervention provided. Two 24‐hour‐prompted (multiple‐pass) dietary recalls were completed, and validated algorithms were used to determine the amount of ‘available iron’ from the diet. Levels of total ‘available iron’ were similar in both groups and correlated positively with total dietary iron. This study assessed the effects of an iron rich bread with a control bread. The type of intervention is outside the scope of this review.
Breymann 2015	In this international, open‐label study, with 252 pregnant women, in their second or third trimester (gestational weeks 16 to 33), with IDA were randomised 1:1 to receive 1000 mg to 1500 mg iron as FCM intravenously or oral ferrous sulfate (FS) 200 mg iron/day for 12 weeks. This study was excluded because both groups received iron supplementation (IV vs oral).
Brown 1972	109 pregnant women attending prenatal care clinics in Manchester, England, United Kingdom were randomly allocated to 1 of 3 groups: Group 1 received 1 tablet daily given in 'reminder packs'. Group 2 received 1 tablet daily given in loose forms. Group 3 received 2 tablets daily given in loose form. Tablets contained 50 mg of elemental iron (as slow release ferrous sulphate) and 400 μg (0.4 mg) of folic acid. All groups received iron daily. The type of intervention does not allow for comparisons within the scope of this review.
Burslem 1968	472 pregnant women attending the booking clinic in Manchester, England, United Kingdom were alternatively allocated to 2 forms of iron: Group 1 received 105 mg elemental iron (as a slow release ferrous sulphate preparation) and a tablet containing 5000 μg (5 mg) folic acid daily. Group 2 received 3 tablets of combined conventional 60 mg elemental iron (as ferrous sulphate) and 1 tablet containing 5000 μg (5 mg) folic acid for a total of 180 mg elemental iron daily. Both groups received daily iron supplementation in different preparations. The type of intervention does not allow for comparisons within the scope of this review.
Buss 1981	18 pregnant women were randomly assigned to receive either a tablet containing 80 mg of elemental iron with a new mucous membrane vaccine (Tardyferon®) or a tablet containing 80 mg elemental iron with 350 μg (0.35 mg) folic acid (Tardyferon‐Fol®) for a period of 3 months. All women received daily iron. The type of intervention does not allow for comparisons within the scope of this review.
Callaghan‐Gillespie 2017	This study was a single‐blind randomised controlled clinical trial conducted in southern Malawi among 1828 pregnant women with moderate malnutrition, defined as a midupper arm circumference (MUAC) ≥ 20.6 and ≤ 23.0 cm. Women received 1 of 3 dietary treatment regimens. It compared maternal and offspring anthropometry between those receiving ready‐to‐use supplemental food (RUSF), a fortified corn‐soy blend (CSB+) with a daily multiple micronutrient antenatal supplement (United Nations International Multiple Micronutrient Preparation (UNIMMAP)), or the standard of care comprising CSB+ and iron and folic acid (IFA). This trial was excluded because it was a comparison of dietary interventions.
Carrasco 1962	2 liquid preparations were used in this study: 1 with D‐sorbitol and the other without. Both preparations contained vitamin B12, vitamin B6, ferric pyrophosphate and folic acid. The type of intervention does not allow for comparisons within the scope of this review.
Casanueva 2003a	120 singleton pregnant women attending the Instituto Nacional de Perinatologia in Mexico City, Mexico with Hb concentrations higher than 115 g/L at 20 weeks of gestation (equivalent to 105 g/L at sea level) were randomly assigned to 1 of 2 groups: Group 1: received 1 tablet containing 60 mg of elemental iron (as ferrous sulphate), 200 μg (0.2 mg) folic acid, and 1 μg vitamin B12 given daily. Group 2: received 2 tablets (total 120 mg of elemental iron (as ferrous sulphate), 400 μg (0.4 mg) folic acid, and 2 μg vitamin B12) to be taken once weekly. The groups received either daily supplementation or weekly supplementation at no cost. Supplement tablets were identical in content and were to be ingested from the 20th week of pregnancy until delivery. No comparisons allowed within the scope of this review.
Castren 1968	126 healthy pregnant women attending Maternity Centres of Turku, Finland were assigned to 1 of 2 groups: Group 1 (n = 63) received 3 tablets a day providing a total 120 mg elemental iron (as ferrous sulphate) daily. Group 2 (n = 63) received 3 tablets a day providing total 120 mg elemental iron (as ferrous sulphate) + 9000 μg (9 mg) folic acid daily from their first visit at 10th to 20th week of gestation until term. Both groups received iron. The type of intervention is outside the scope of this review.
Chanarin 1968	206 women attending the antenatal clinic at St. Mary's Hospital, London, United Kingdom who were less than 16 weeks pregnant at the first attendance. At the 20th week, they were allotted to 1 of 2 groups: Group 1 received tablets to be taken once daily containing 260 mg ferrous fumarate. Group 2 received tablets to be taken daily containing 260 mg ferrous fumarate and 100 μg (0.1 mg) of folic acid. Iron deficiency was largely eliminated by giving 1 g of intravenous iron dextran as 4 x 250 mg doses at weekly intervals to all participants in early pregnancy. Both groups received iron. The type of comparison is not within the scope of this review.
Chawla 1995	81 pregnant women with 20 ± weeks of gestation from Ludhiana City, India were divided to 1 of 3 groups: Group 1: received 60 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid daily. Group 2: received 60 mg of elemental iron (as ferrous sulphate) and 2,000,000 IU of vitamin A. Group 3: did not receive any supplements. Supplementation was for a period of 15 weeks. Outcomes measured included Hb, RBC count, total iron binding capacity, transferrin saturation, serum iron, serum vitamin A at baseline and at 36 ± 2 weeks of gestation. Poor methodological quality. Pregnant women who were willing to go to the hospital or centre once a week to collect the iron supplements were included in groups 1 and 2. The rest of the participants were included in the control group. This is not a randomised trial.
Chew 1996a	256 clinically healthy pregnant women with low SES attending 1 antenatal care clinic in Guatemala City, Guatemala and Hb > 80 g/L were recruited. City of Guatemala is at 1500 m above sea level, so values were adjusted by altitude subtracting 5 g/L in Hb. Participants were randomly assigned to 1 of 2 groups: Group 1: daily supervised intake of 60 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid. Group 2: weekly supervised intake of 180 mg of elemental iron (as ferrous sulphate) and 3500 μg (3.5 mg) of folic acid in 1 intake once a week. Supplementation started at different gestational age for each participant. Average gestational age at start was 20.5 weeks until 38th week. All groups received iron with different regimens. The type of intervention is not within the scope of this review.
Chew 1996b	120 clinically healthy pregnant women attending 1 antenatal care clinic in Guatemala City, Guatemala with Hb > 80 g/L were recruited. Women were of low SES. The city of Guatemala is 1500 m above sea level, so values were adjusted by altitude subtracting 5 g/L in Hb. Participants of low SES were randomly assigned to 1 of 2 groups: Group 3: daily unsupervised intake of 60 mg elemental iron (as ferrous sulphate) and 0.5 mg folic acid. Group 4: weekly unsupervised intake of 180 mg of elemental iron (as ferrous sulphate) and 3.5 mg of folic acid in 1 intake once a week. Supplementation started at an average of 20.5 weeks of gestation until 38th week. All groups received iron with different regimens. The type of intervention are not within the scope of this review.
ChiCTR1800017574 (first received 2018)	A total of 240 pregnant women at 11 to 13 weeks of gestation without iron‐deficiency anaemia (IDA) in South China were recruited to this single‐blind clinical trial (non‐IDA referred to both haemoglobin (Hb) ≥ 110g/L and serum ferritin (SF) ≥ 15 ng/mL), randomly assigned to 1) control, 2) IRFs containing 20 mg iron/d (IRF‐20), or 3) IRFs containing 40 mg iron/d (IRF‐40). The IRFs were consumed 3 days a week, including pork liver, chicken/duck blood, soybean, and agaric. The IRFs started at recruitment and ended in the predelivery room. Primary outcomes included anaemia (Hb < 110 g/L), iron deficiency (ID, definition 1: SF < 15 ng/mL; definition 2: SF < 12 ng/mL), and IDA (ID and Hb <110 g/L). Secondary outcomes were plasma Hb and iron indices, including SF, serum hepcidin, and iron. This trial was excluded because it was comparing dietary regimens.
Coelho 2000	100 pregnant women with 20 to 34 weeks of gestation attending the antenatal clinic at The Bandra Holy Family Hospital, Bandra, Mumbai, India were randomly assigned to 1 of 2 groups: Group 1 received 30 mg elemental iron + other essential vitamins and minerals daily. Group 2 received 116 mg elemental iron, folic acid, zinc, and vitamin C daily. Outcomes included Hb concentration, maternal weight gain, infant birthweight and maternal compliance and side effects. Both groups received daily iron supplementation. The type of intervention does not allow for comparisons within the scope of this review.
Compaore 2017	This study was of 39 taped in‐depth interviews with participants in a randomised, controlled, periconceptional iron supplementation trial for young nulliparous women living in a rural, malaria endemic region of Burkina Faso. Participants with good, medium or poor adherence were selected. Interviews were transcribed and analysed thematically. This study was excluded because the participants were not pregnant.
Cook 1990	200 women at Kansas University Medical Center, Kansas, USA were randomly assigned to receive 50 mg elemental iron daily given either as Gastric Delivery System (GDS) or conventional ferrous sulphate. Gastrointestinal side effects were evaluated. The participants were non‐pregnant women.
CTRI/2017/10/010057 (first received 2017)	This is a registration for a randomised controlled trial of 60 mg vs 100 mg elemental iron with fixed dose of 0.5 mg folic acid oral supplementation for iron deficiency anaemia prophylaxis in pregnant women at a secondary care hospital in Haryana, India. This trial was excluded because both groups received iron; it compared regimens.
CTRI/2019/08/020917 (first received 2019)	This is a registration for studying the effect of ayurvedic medicines in combination with conventional therapy for a healthy pregnancy and postpartum period. Interventions were various doses of these medicines with the control intervention of conventional iron supplementation antenatal care as per WHO guidelines. This was excluded as the scope of this review does not allow for comparing ayurvedic medicines with iron supplementation.
CTRI/2019/09/021372 (first received 2019)	In this trial registration, the trial intervention was to use iron‐fortified iodised salt for cooking the family meal; the pregnant women in this group were also to receive daily oral supplementation of two tablets of 60 mg of elemental iron, 500 µg of folic acid, and 2 tablets of 500 mg of elemental calcium and 250 IU of vitamin D. The control Intervention was to use iodised salt for cooking the family meal; the pregnant women in this group were to receive daily supplementation of 2 tablets of 60 mg of elemental iron and 500 µg of folic acid and 2 tablets of 500 mg of elemental calcium and 250 IU of vitamin D. This trial was excluded as both groups received iron.
CTRI/2020/09/028053 (first received 2020)	This trial registration was for a comparison of amalaki rasayana 5 g daily in 2 divided doses, with a control intervention of ferrochelate‐XT: folic acid 1.5 mg + elemental iron 100 mg single dose daily. This trial was excluded as the scope of this review does not allow for comparing supplementation of amalaki rasayana with iron supplementation.
CTRI/2021/03/032434 (first received 2021)	This trial registration was to study the role of Jeevantyadi Avaleha on fetal growth and maternal wellbeing in the second trimester of pregnancy compared with conventional supplementation. The intervention was to take Jeevantyadi Avaleha orally at a dose of 10 g twice daily before food with milk as anupana for 16 weeks (i.e. from 13th to 14th week to 28th to 29th week). The control intervention was routine supplementation in pregnancy: that is, 1 calcium carbonate tablet ‐ 500 mg orally with water at bedtime after food once daily and 1 ferrous sulphate tablet ‐ 200 mg orally with water in the morning after food once daily (for 16 weeks: i.e. from 13th to 14th week to 28th to 29th week). This trial was excluded as the scope of the review does not include this comparison.
CTRI/2021/09/036960 (first received 2021)	This registration is for a clinical trial to study the effect of garbhini paricharya in the 6th and 7th months of pregnancy. The intervention was gokshursiddha ghrita 5 mL twice a day before meal (Apankal) in the 6th month of pregnancy and prithakparnyadisiddha ghrita 5 mL twice a day before meal (Apankal) in the 7th month of pregnancy. The control intervention was ferrous sulphate 200 mg (containing 60 mg elemental iron) and calcium carbonate 500 mg in the 6th and 7th month of pregnancy. This trial was excluded as it does not fall within the scope of this review.
CTRI/2022/02/040426 (first received 2022)	This trial registration was for a study of an intergenerational nutritional supplementation approach for the establishment of a healthy microbiome in pregnant women and their newborns. The intervention was an oral intake of 100 mg iron with a 500 mL native banana curd shake daily. The control intervention was an oral intake of 100 mg iron. This trial was excluded as the trial assessed nutritional supplements.
Dawson 1962	2498 pregnant women attending an antenatal care clinic in Crumpsal Hospital, Manchester United Kingdom were grouped to receive folic acid or as controls. The assignment was not randomised. Participants whose Hb fell below 100 g/L after 28th week received oral iron if they had not previously received oral iron, had not reached the 36th week of gestation, and had a MCHC of less than 30%. If these participants had been receiving oral iron, iron was then provided parenterally. This study was excluded as it was not a randomised trial.
Dawson 1987	42 healthy women with less than 16 weeks of pregnancy entering prenatal care at the Department of Obstetrics and Gynecology, University of Texas, Texas, USA were randomly assigned to receive either a multiple micronutrient supplement containing 65 mg of elemental iron or 1 multiple micronutrient supplement with no iron, calcium, zinc and copper and pantothenic acid. Both groups received different multiple micronutrient supplement formulations. No comparisons allowed within the scope of this review.
Dewey 2019	This study in Bangladesh examined the effects of the Rang Din Nutrition Study (RDNS) interventions on children born to mothers < 20 years of age. The RDNS was a cluster‐randomised effectiveness trial with 4 arms: (1) women and children both received small‐quantity lipid‐based nutrient supplements (LNS‐LNS), (2) women received iron and folic acid (IFA) and children received LNS (IFA‐LNS), (3) women received IFA and children received micronutrient powder (MNP) (IFA‐MNP), and (4) women received IFA and children received no supplements (IFA‐Control). It enrolled 4011 women at < 20 weeks gestation; 1552 were adolescents. This trial was excluded as it compared lipid‐based supplements vs IFA interventions. This is outside the scope of this review.
Dijkhuizen 2004	170 pregnant women with less than 20 weeks' gestation from 13 adjacent villages in a rural area in Bogor District, West Java, Indonesia were randomly assigned to receive daily supplementation with B‐carotene (4.5 mg), zinc (30 mg), both, or placebo containing 30 mg elemental iron and 400 μg (0.4 mg) folic acid. Both groups received daily iron and folic acid. The type of intervention does not allow for comparisons within the scope of this review.
Edgar 1956	179 pregnant women with Hb levels below 105 g/L and more than 16 weeks of gestation volunteered for this study and were divided into 4 supplementation groups according to the stage of pregnancy at which iron was introduced: 16th week, 20th week, 24th week, and non‐supplemented controls. 37% of these women were lost to follow‐up and were excluded from the final analysis. This is not a randomised trial.
Eeesha 2022	This study was designed to compare the efficacy and conduct a cost‐effectiveness analysis of 3 commonly used oral iron preparations among anaemic women (n = 150) of gestation (12 to 24 weeks) in a tertiary hospital in Pune, India. A retrospective analysis was made of data collected from pregnant women in their second trimester (between 14 and 20 weeks) from the antenatal clinic. The patients were divided into 3 groups (n = 50) each and treated with iron polymaltose complex, ferrous fumarate, and ferrous ascorbate respectively. This trial was excluded as all groups received different types of iron.
Ekstrom 1996	176 pregnant women attending Ilula Lutheran Health Centre's antenatal service in Iringa region, Tanzania with 21 to 26 weeks of gestational age and Hb > 80 g/L were randomly assigned to receive 120 mg elemental iron (as ferrous sulphate in conventional form) daily or 50 mg elemental iron as gastric delivery system (GDS) daily. Both groups received different types of iron supplementation in different preparations. The type of intervention does not allow for comparisons within the scope of this review.
Ekstrom 2002	209 apparently healthy women attending antenatal care clinics in rural areas of Mymemsingh thana, Bangladesh, with fundal height of 14 to 22 cm (18 to 24 weeks of gestation), who had not used iron supplements prior to the study. Exclusion criteria: women with Hb concentrations < 80 g/L. Each clinic was randomly assigned to 1 of 2 interventions: 60 mg of elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) folic acid given in 1 tablet daily, or 120 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid once a week (given in 2 tablets 1 day of the week). Supplementation continued until 6 weeks postpartum. Supplementation started at baseline for 12 weeks. All groups received iron with different regimens. The type of intervention is not within the scope of this review.
EUCTR2012‐005480‐28‐ES (first received 2013)	This clinical trial registration was to study the effectiveness of adapting the dose of iron supplementation in pregnancy on maternal‐child health in pregnant women at less than 12 weeks' gestation, without anaemia (Hb < 110 g/dL). The 2 groups were to receive either 40 mg or 80 mg of a powder for oral solution (ferrimanitol ovalbumin). This study was excluded as both groups were to receive different doses of iron.
EUCTR2022‐001815‐25‐IE (first received 2022)	This is a clinical trial registration of a single‐blind randomised controlled trial in Ireland to evaluate whether alternate day oral iron is non‐inferior to daily oral iron for the treatment of iron deficiency anaemia after 4 weeks of therapy. Pregnant women, aged 18 to 64 years, with a gestational age of 14 to 34 weeks with iron deficiency anaemia (Hb < 10.5 g/dL but not = 7 g/dL and serum ferritin of < 30 μg/L) were to be enrolled. Participants were to be randomised to ferrous fumarate 305 mg/day, or ferrous fumarate 305 mg every second day. We excluded this study as both study arms were to receive iron, therefore there is no eligible comparison group and it is beyond the scope of this review.
Fletcher 1971	643 pregnant women attending an antenatal clinic in London, England, United Kingdom were randomly assigned to 1 of 2 groups: Group 1 received 200 mg of ferrous sulphate daily. Group 2 received 200 mg of ferrous sulphate with 5000 μg (5 mg) of folic acid daily. No comparisons allowed within the scope of this review.
Giles 1971	528 pregnant women in the first antenatal care visit at the Royal Women’s Hospital Melbourne, Australia were divided into 4 groups: Group 1: those attending the antenatal clinic for the first time before 10 weeks of gestation Group 2: those attending the antenatal clinic for the first time from 10 to 20 weeks of gestation Group 3: those attending the antenatal clinic for the first time from 20 to 30 weeks of gestation Group 4: those attending the antenatal clinic for the first time at or after 30 weeks of gestation They received a 200 mg ferrous sulphate and a 5 mg folic acid tablet a day, for the remainder of the pregnancy and 5 mg of folic acid was administered to 1 group (n = 265) and a placebo (n = 263) to the other. The study was excluded because both study groups received iron, and the difference was the supplementation or not with 5 mg of folic acid daily. This type of comparison is outside the scope of this review.
Glosz 2018	This trial measured micronutrient status and change in moderately malnourished pregnant Malawian women randomised to one of 3 nutritional interventions. Serum vitamin B12, 25‐hydroxyvitamin D, folate, retinol, ferritin, zinc, albumin and C‐reactive protein were measured in pregnant women with MUAC between 20.6 cm and 23.0 cm at enrolment (n = 343) and after 10 weeks (n = 229) of receiving: (1) ready‐to‐use supplementary food (RUSF); (2) fortified corn‐soy blend (CSB+) with multiple‐micronutrient supplement (CSB+UNIMMAP); or (3) CSB+ with iron and folic acid (CSB+IFA). This trial was excluded as the intervention (food supplementation and multiple micronutrients) did not satisfy the inclusion criteria.
Gomber 2002	40 apparently healthy women with singleton pregnancy in their second trimester (between 16 and 24 weeks of gestation), living in urban slums, from low SES attending Guru Teg Bahadur Hospital, Delhi, India were randomly assigned to receive 1 tablet containing 100 mg of elemental iron (as ferrous sulphate) with 500 μg (0.5 mg) folic acid daily or once a week. Weekly intake was supervised. Duration of supplementation was 100 days. Hb and HCT concentrations at baseline, at 4 weeks, 8 weeks and 14 weeks of supplementation, serum ferritin concentration, at baseline, at 14 weeks of supplementation and at delivery. Both groups received iron and folic acid in different regimens (daily versus weekly). The type of intervention does not allow for comparisons within the scope of this review.
Goonewardene 2001	92 pregnant women from 14 to 24 weeks of gestation attending the university antenatal clinic, in Galle, Sri Lanka were randomly assigned to 1 of 3 regimens: Group 1 (n = 26) received a tablet containing 100 mg of elemental iron (as ferrous fumarate), with additional micronutrients once a week. Group 2 (n = 35) received the same tablet but 3 times a week. Group 3 (n = 31) received the same supplement in a daily fashion. All groups were receiving iron and multiple micronutrients with different regimens (daily, weekly, 3 times a week). The type of intervention does not allow for comparisons within the scope of this review.
Gopalan 2004	900 pregnant women of poor SES attending government antenatal care clinics in New Delhi, India were grouped in 3 groups: Group 1 (n = 300) received routine antenatal care. Group 2 (n = 300) received 100 mg of elemental iron and 500 μg (0.5 mg) folic acid daily from the 20th week of gestation. Group 3 (n = 300) received 100 mg of elemental iron and 500 μg (0.5 mg) folic acid daily from the 20th week of gestation and additionally 900 mg of alpha‐linolenic acid from the 22nd week of gestation. Outcomes assessed included birthweight, low birthweight, premature delivery The study was excluded as it was not reported as randomised.
Goshtasebi 2012	370 pregnant women were randomly assigned to receive either daily or twice weekly iron supplementation during pregnancy. There were no significant differences in initial and delivery Hb and HCT levels between the 2 groups. Ferritin concentrations were significantly lower in the twice‐weekly group at delivery, but hypoferritinaemia (ferritin < 15 μg/L) was not observed in either group. The frequency of nausea, vomiting, and constipation was significantly lower in the twice‐weekly group. The type of intervention (different types of regimen) is not within the scope of this review.
Gringras 1982	40 pregnant women attending antenatal care clinic in Cheshire, England, United Kingdom were given a tablet containing 47 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid daily or a tablet containing 100 mg of elemental iron (as ferrous glycine sulphate) daily. Each group received different types of iron. No comparisons allowed within the scope of this review.
Grover 1998	200 pregnant women with gestation 16 to 24 weeks attending for care in a rural health centre in Gazipur village in East Delhi, India from January to December 1994 with Hb 70 g/L or more and no tuberculosis, chronic diseases, "toxaemia", bleeding piles were randomly assigned to 1 of 2 groups: Group 1: women received 100 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid on alternate days: (data available for 56 women). Group 2: women received 100 mg of elemental iron daily (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid (data available for 64 women). The type of intervention (different regimens) does not allow for comparisons within the scope of this review.
Guldholt 1991	192 pregnant women in Horsens Hospital, Denmark were consecutively randomised to receive 1 of 2 treatments: Group 1: received a daily vitamin‐mineral tablet containing 15 mg of elemental iron. Group 2: received a daily vitamin‐mineral tablet containing 100 mg of elemental iron. Both groups received iron in different doses. No comparisons allowed within the scope of this review.
Gunaratna 2015	A double‐blind, randomised controlled trial of 800 non‐pregnant women and adolescent girls was conducted in 2 rural wards in Rufiji District, Pwani Region, Tanzania. Participants were recruited between October 2010 and June 2011 and randomly assigned to receive daily oral supplements of folic acid alone, folic acid and iron, or folic acid, iron, and vitamins A, B‐complex, C, and E. This trial was excluded as the participants were not pregnant.
Hampel 1974	65 untreated and 54 treated pregnant women in West Berlin, Germany were assessed during pregnancy for Hb concentrations, iron and folate levels, total iron binding capacity, and RBC count. No data are presented for outcomes prespecified in the review. Women were of different gestational ages. No outcomes can be extracted from the paper.
Hanieh 2013	1258 pregnant women older than 16 years of age and with less than 16 week gestation living in 104 communes from Ha Nam province, a malaria‐free province in Vietnam were assigned at the cluster (commune) level to 1 of 3 groups: Group 1 received 60 mg elemental iron plus 400 μg (0.4 mg) folic acid daily. Group 2 received 60 mg elemental iron plus 1500 μg (1.5 mg) folic acid per capsule; administered as 2 capsules/week. Group 3 received 60 mg elemental iron plus 1500 μg (1.5 mg) plus a variation of the dose of micronutrients in the UNIMMAP daily supplement; administered as 2 capsules/week. Women were excluded if they had a high‐risk pregnancy ‐ multi‐fetal pregnancy (confirmed on palpation or ultrasound), a significant medical condition or if they had severe anaemia (Hb concentration lower than 80 g/L) at enrolment were referred to the commune health station for further management. A placebo control was not contemplated, as it was considered unethical to withhold iron supplementation during pregnancy. Primary outcome was birthweight. The type of intervention (all groups receiving iron in different doses and regimens) is outside the scope of this review.
Hartman‐Craven 2009	In this cross‐over study 2 types of multivitamin supplements were compared: 18 healthy pregnant women 24 to 32 weeks' gestation attending a Toronto hospital were recruited and received 2 different supplements in a random order and followed up over 8 hours. This trial was excluded as both preparations contained iron and folic acid. The aim of the study was to see whether absorption was improved with a powdered preparation.
Hawkins 1987	This trial was excluded as no report was available of the study results. N.B. For the 2024 update, the trustworthiness tool was not applied and so we did not reach out to the trial authors, as the study had already been excluded.
Hemminki 1991	2960 pregnant women were recruited by midwives in 27 maternity health centres in Tampere (15 centres) and in 5 neighbouring communities (12 centres) in Finland, and randomised into 2 groups: selective and routine iron supplementation. Routine group: Women received iron throughout pregnancy regardless of Hb level, starting at the latest in the 17th week of gestation. A dose of 100 mg elemental iron per day was recommended, but this could be tailored according to the midwife's judgement. Intervention group: any pregnant women after the 14th week of gestation showing HCT < 0.30 (Hb < 100 g/L) in 2 consecutive visits. If the Hb was still less than 100 g/L and/or MCV was less than 82 and a low ferritin was found, 50 mg iron twice a day as ferrous sulphate was recommended. The length of the treatment was to be 2 months or until the HCT was > 10.32 or higher (Hb 110 g/L) or higher). By request of the midwives, the treatment schedule was relaxed later during the trial: iron therapy was begun if the mother's HCT was 0.31 or below after the 33rd week. The study was excluded because there was no comparable control group because both groups received different types of iron. The routine group received 100 mg of iron as elemental iron and was composed of anaemic and non‐anaemic women. In group 2, anaemic women received 2 doses of 50 mg of iron as ferrous sulphate in slow release form, while for non‐anaemic women it was not clear if women received routine treatment. Group 2 was separated into anaemic and non‐anaemic women.
Hemminki 2016	This pragmatic randomised controlled clinical trial compared routine versus selective (i.e. screening and treatment for anaemia) prenatal iron prophylaxis in a malaria‐endemic and HIV‐prevalent setting, an extended analysis including previously missing data in 2 health centres in Maputo, Mozambique. Pregnant women (≥ 18 years old; non‐high‐risk pregnancy) were randomly allocated to routine iron (n = 2184) and selective iron (n = 2142) groups. In the routine group, women received 60 mg ferrous sulfate plus 400 μg folic acid daily. In the selective group, women received 1 mg of folic acid daily and haemoglobin (Hb) screening at each visit; with low Hb (cut‐off 9 g/dL) treatment (120 mg + 800 μg of folic acid daily) for a month. This trial was excluded as both groups received iron in different doses and regimens.
Hermsdorf 1986	120 unselected pregnant women were given 114 mg of elemental iron daily from week 15 until delivery, or no treatment. Only an abstract with insufficient data available. N.B. For the 2024 update, the trustworthiness tool was not applied and so we did not reach out to the trial authors, as the study had already been excluded.
Horgan 1966	42 apparently healthy pregnant women attending 2 antenatal care clinics in London, England were assigned to 1 of 3 interventions: Group 1 received 200 mg ferrous sulphate with 5000 μg (5 mg) folic acid 3 times a day. Group 2 received 350 mg of ferrous aminoate with 50 μg (0.05 mg) folic acid 3 times a day. Group 3 received 200 mg of ferrous sulphate with 500 μg (0.5 mg) folic acid once a day. Intervention period was 3 weeks. All groups received daily iron and folic acid. No comparisons allowed within the scope of this review.
Hosokawa 1989	84 anaemic women seeking antenatal care in the Department of Obstetrics and Gynaecology of the Fukui School of Medicine Hospital, Japan were randomly assigned to receive 100 mg of elemental iron (as ferrous sulphate) daily after the evening meal, or the same dose + vitamin C for 4 weeks. No comparisons allowed within the scope of this review.
Hossain 2014	200 pregnant women attending the outpatient obstetric clinic at the Civil Hospital Karachi in Karachi, Pakistan with 20 weeks or less of gestation, a singleton pregnancy, and normoglycaemic and normotensive at the time of antenatal booking were randomly allocated to 1 of 2 groups: Group 1 (n = 100) received routine antenatal care, which included ferrous sulphate 200 mg, twice daily, and 600 mg of calcium lactate daily. Group 2 (n = 100) received routine antenatal care regimen and an oral liquid formulation (400 IU/drop) of vitamin D3 at a daily dose of 4000 IU (10 drops daily) starting at completed 20 weeks of gestation. Both groups received iron with or without other supplements. This type of intervention is outside the scope of this review.
Huda 2018	This trial studied the effect of the early use of iron‐folic acid supplements on neonatal mortality using a community‐based, cluster‐randomised controlled trial in 5 districts in rural Bangladesh with 30,000 live births. In intervention clusters, trained BRAC village volunteers identified pregnant women and provided iron‐folic acid supplements. Groundwater iron levels were measured in all study households using a validated test kit. The analysis followed the intention‐to‐reat principle comparing neonatal mortality rates and their 95% confidence intervals adjusted for clustering between treatment groups in each groundwater iron‐level group. This trial was excluded as all groups received iron supplementation with varying levels of groundwater iron.
Iglesias‐Vazquez 2022	This study assessed whether prenatal iron supplementation adapted to the needs of each pregnant woman affected their child’s neurodevelopment. It was a community‐based RCT involving 503 mother‐child pairs. Non‐anaemic pregnant women recruited in Tarragona (Spain) early in pregnancy were prescribed a daily iron dose based on their initial haemoglobin levels: Stratum 1 (Hb = 110 to 130 g/L, 80 or 40 mg/d of iron) and Stratum 2 (Hb > 130 g/L, 40 or 20 mg/d of iron). Women receiving 40 mg/d were considered the control group in each Strata. The child’s neurodevelopment was assessed at 40 days of age using the Bayley Scales of Infant Development‐III (BSID‐III). Adjusted multiple regression models were used. This study was excluded as it was comparing iron regimens.
ISRCTN77724888 (first received 2017)	This trial registration is for 250 participants randomised to 1 of 2 groups: Arm 1 (daily group) participants will receive 1 tablet of ferrous sulphate (Fesulf by Therapeutic pharmaceuticals, Lagos) 200 mg BP, equivalent to 65 mg elemental iron once daily from 20 weeks of gestation until delivery. Arm 2 (weekly group) participants will receive 3 tablets of ferrous sulphate (Fesulf 200mg BP by Therapeutic pharmaceuticals, Lagos) at once on a particular day of the week from 18 weeks until delivery. This trial was excluded as it compared iron regimens.
Itam 2003	266 pregnant women from Calabar coastal southeastern Nigeria were randomly assigned to 1 of 3 groups: Group 1 received a supplement containing iron (as 300 mg ferrous fumarate), 5000 ug (5 mg) folic acid, 10 ug vitamin B12, 25 mg vitamin C, 0.3 mg zinc sulphate, and 0.3 mg magnesium sulphate. Group 2 received iron (as 200 mg ferrous sulphate) and 5000 ug (5 mg) folic acid once daily. Group 3 received iron (as 200 mg ferrous sulphate) 3 times daily and 5000 ug (5 mg) folic acid once daily. The intervention lasted from the 18th week of gestation till term. There were also 2 subgroups under each major group: anaemic and non‐anaemic groups. Blood samples were collected from each participant on admission into the study and every 2 weeks and analysed for packed cell volume (HCT), Hb, MCHC, reticulocytes, and ferritin levels. All participants received iron of different types, doses, and regimens. The type of intervention is outside the scope of this review.
Iyengar 1970	800 pregnant women with less than 24 weeks of gestation and Hb > 85 g/L in India were assigned by rotation to 1 of 4 groups: Group 1 received placebo tablets. Group 2 received 30 mg of elemental iron as ferrous fumarate in a single tablet daily. Group 3 received 30 mg of elemental iron (as ferrous fumarate) with 500 μg (0.5 mg) folic acid in a single tablet. Group 4 received in addition to iron and folic acid, 2 μg of vitamin B12 in a single tablet. Loss to follow‐up was 65%. This is not a randomised trial.
Jones 2021	This was a study of the association of 1) maternal and neonatal iron status with maternal and neonatal hepcidin concentrations, and 2) maternal prepregnancy weight status with maternal and neonatal hepcidin concentrations. It examined haematologic data from 405 pregnant women and their infants from the placebo treatment group of a pregnancy iron supplementation trial in rural China, measuring hepcidin, serum ferritin (SF), soluble transferrin receptor (sTfR), and high‐sensitivity C‐reactive protein in maternal blood samples at mid‐pregnancy and in cord blood at delivery. Regression analysis was used to examine the association of maternal prepregnancy overweight or obese status with maternal hepcidin concentration in mid‐pregnancy and cord hepcidin concentrations. Path analysis was used to examine mediation of the association of maternal prepregnancy overweight or obese status with maternal iron status by maternal hepcidin, as well as with neonatal hepcidin by neonatal iron status. This trial was excluded as the study was not an RCT.
Kaestel 2005	2100 pregnant women (22 ± 7 weeks' gestation at entry) attending antenatal clinics in Bissau, Guinea‐Bissau or who were identified by The Bandim Health project were randomly assigned to receive a daily multi micronutrient tablet containing 1 RDA of 15 micronutrients, or daily multi micronutrients containing 2 times the RDA except for iron that was maintained at 1 RDA or a conventional prenatal daily iron (60 mg elemental iron) and 400 μg (0.4 mg) folic acid supplement. In a follow‐up analysis (Andersen 2010), of the previous study a 2‐year follow‐up examined the effects of the interventions on fetal loss and under 2 mortality. 2169 women were recruited from 4 suburban districts followed by the Bandim Health project in collaboration with the Danish Epidemiology Science Centre in Guinea‐Bissau. Women with severe anaemia (Hb less than 70 g/L) received 60 mg elemental iron daily in addition to the intervention. All participants received an impregnated bed net at inclusion and were provided weekly anti‐malarial prophylaxis with chloroquine phosphate (300 mg base) throughout pregnancy. Also women with more than 10 parasite per 200 leucocytes were offered anti‐malarial treatment with chloroquine. All groups received different types of iron and folic acid with different supplements. No comparisons allowed within the scope of this review.
Kann 1988	36 healthy non‐anaemic pregnant women in second or third trimesters of gestation were randomly assigned to receive 1 of 4 groups: Group 1 received a tablet (Stuartnatal® 1 + 1) containing 65 mg elemental iron, 1000 μg (1 mg) folic acid and 12 additional micronutrients daily. Group 2 received a tablet (Stuart Prenatal®) containing 60 mg elemental iron, 800 μg (0.8 mg) folic acid and 11 additional micronutrients. Group 3 received a tablet (Materna®) containing 60 mg elemental iron, 1000 μg (1 mg) folic acid and 17 additional micronutrients daily. Group 4 received a tablet (Natalins Rx®) containing 60 mg elemental iron, 1000 μg (1 mg) folic acid and 14 additional micronutrients daily. All participants received iron and multiple micronutrients. No comparisons allowed within the scope of this review.
Khambalia 2009	In this randomised trial carried out in Bangladesh, childless, non‐pregnant married women under 40 were randomised to receive food supplements (sprinkles) containing either iron and folic acid or folic acid alone. 272 women were randomised and women were followed up for 9 months. If women became pregnant, they were withdrawn from the study and all pregnant women received both iron and folic acid. The study was excluded as it focused on a non‐pregnant population.
Khan 2017	This study evaluated the effect of breastfeeding counselling on the duration of exclusive breastfeeding, and whether the timing of prenatal food and different micronutrient supplements further prolonged this duration. Pregnant women in Matlab, Bangladesh, were randomised to receive daily food supplements of 600 kcal at nine weeks of gestation or at the standard 20 weeks. They were also allocated to either 30 mg of iron and 400 μg folic acid, or the standard programme 60 mg of iron and folic acid or multiple micronutrients. At 30 weeks of gestation, 3188 women were randomised to receive either 8 breastfeeding counselling sessions or the usual health messages. This study was excluded as the interventions were outside the scope of this review.
Khangura 2021	This study compared non‐anaemic pregnant females receiving daily oral iron versus weekly iron supplements in the third trimester of pregnancy in a Rawalpindi hospital (India) betweenNovember 2019 andMay 2020. 70 pregnant females of 15 to 45 years, with singleton pregnancies, at gestational amenorrhoea 14 to 22 weeks at the time of inclusion with haemoglobin level 11 g/dl and above were included. Group A (35) received daily oral iron and Group B (35) received weekly oral iron. This study was excluded as both groups received different regimens of iron.
Kinnunen 2016	Reanalysis of trial conducted between 1985 and 1986 comparing routine and intermittent iron supplementation. Data was re‐analysed from a randomised controlled trial of iron supplementation to see whether it supported the risk of gestational diabetes found in observational studies. The trial was conducted in primary health care settings in 5 municipalities in Finland in 1985‐1986. The participants were 2944 women (95% of pregnant women in the area) who were randomly allocated either to (1) the selective iron group (elemental iron 50 mg twice a day only if diagnosed as anaemic, continuing until their haemoglobin increased to 110 g L(‐1)) or (2) the routine iron group (elemental iron 100 mg day(‐1) throughout the pregnancy regardless of haemoglobin level). The trial was excluded as it was a reanalysis of a previous trial of different iron supplementation regimes.
Kone 2020	This study assessed the effectiveness of personal information (INFO) sessions and personal information sessions plus home deliveries (INFO+DELIV) to increase coverage of IFA supplementation and intermittent preventive treatment in pregnancy (IPTp), and their effectiveness on postpartum anaemia and malaria infection. It assessed 118 clusters randomised to a control (39), INFO (39), and INFO+DELIV (40) arm, in a trial conducted between 2020 and 2021 with pregnant women (age ≥ 15 years) in their first or second trimester of pregnancy in Taabo, Côte d’Ivoire. This study was excluded from the review as the interventions were outside its scope.
Kulkarni 2010	This study examined factors affecting compliance with antenatal micronutrient supplementation and women's perceptions of supplement use. Randomised controlled supplementation trial of 4 alternative combinations of micronutrients were given during pregnancy through to 3 months postpartum. Women were visited twice‐weekly to monitor compliance and to replenish tablets by female study workers. At 6 weeks postpartum women with live births (n 4096) were interviewed regarding their perceptions of the supplement. This study was excluded because it was a secondary analysis of the data from the Christian 2003 (C) study included in the review.
Kumar 2005	220 pregnant women with a singleton pregnancy and Hb between 80 and 110 g/L at 16 to 24 weeks' gestation from New Delhi, India were randomly allocated to receive daily oral iron therapy of 100 mg elemental iron (as ferrous sulphate) with 500 μg (0.5 mg) folic acid or 250 mg of iron sorbitol intramuscularly and repeated at an interval of 4 to 6 weeks. This trial compares the effects of daily oral iron with 2 injections of high‐dose parenteral iron.It was excluded because it compared different types of iron supplementation administration.
Lee 2022	This was a cluster‐randomised controlled trial following 4868 and 4821 pregnant women in the intervention and control arms, respectively, from March 2021 to July 2022 in Ethiopian health centres. The Enhancing Nutrition and Antenatal Infection Treatment (ENAT) intervention was implemented in Ethiopia to improve newborn birthweight by strengthening the contents and quality of antenatal care, especially point‐of‐care testing for maternal infections; this study examined the effect of the ENAT intervention on birthweight. This study was excluded because it was a comparison of a nutrition package and standard care. This is a comparison outside the scope of this review.
Lira 1989	199 pregnant women with less than 16 weeks' gestation attending antenatal care at the Hospital Clinica Universidad Catolica ein Santiago, Chile were randomly assigned to 1 of 2 groups: Group 1 (n = 78) received 105 mg elemental iron (as ferrous sulphate) and 500 mg ascorbic acid. Group 2 (n = 75) received 105 mg elemental iron (as ferrous sulphate), 500 mg ascorbic acid and 350 ug (0.35 mg) folic acid daily. There were 36 losses to follow‐up. Both groups received different types of iron. The type of intervention provided is outside the scope of this review.
Liu 1996	395 healthy, anaemic and non‐anaemic, pregnant women attending prenatal care at 2 outpatient clinics in Xianjiang, China. Women with Hb < 80 g/L were excluded. Maternal age was 25.15 ± 2.28 years. Women were randomly assigned to 1 of 3 groups: Group 1: received 60 mg elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) of folic acid daily. Group 2: received 120 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid daily. Group 3: received 120 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid once weekly. All women randomised to treatment received iron. A control group that received no iron was composed of women who did not want to participate in the study and did not receive any iron supplements. This study was excluded as it studied different regimens of iron.
Lozoff 2016	This study assessed the effects of iron supplementation in infancy and/or pregnancy on infant iron status, illnesses, and growth at 9 months. Enrolment occurred from December 2009 to June 2012 in Hebei, China. Infants born to women in a pregnancy iron supplementation trial were randomly assigned 1:1 to iron (∼1 mg Fe/(kg · d) as oral iron proteinsuccynilate) or placebo from 6 weeks to 9 months, excluding infants with cord ferritin < 35 μg/L. Study groups were pregnancy placebo/infancy placebo (placebo/placebo), pregnancy placebo/infancy iron (placebo/iron), pregnancy iron/infancy placebo (iron/placebo), and pregnancy iron/infancy iron (iron/iron). This study was excluded as the randomisation was of infants, not pregnant women.
Ma 2008	366 pregnant women between 20 and 35 years of age in rural China with 12 to 24 weeks' gestation; with Hb 105 g/L or lower, all receiving 60 mg elemental iron and 400 μg (0.4 mg) folic acid were randomly assigned to 1 of 4 groups: Group 1 (n = 93) received daily 60 mg elemental iron (as ferrous sulphate) and 400 μg (0.4 mg) folic acid. Group 2 (n = 91) received daily 60 mg elemental iron (as ferrous sulphate), 400 μg (0.4 mg) folic acid + 2000 μg retinol (as retinyl palmitate). Group 3 (n = 91) received daily 60 mg elemental iron (as ferrous sulphate), 400 μg (0.4 mg) folic acid + 1.0 mg riboflavin. Group 4 (n = 91) received daily 60 mg elemental iron (as ferrous sulphate), 400 μg (0.4 mg) folic acid, 2000 μg retinol (as retinyl palmitate) + 1.0 mg riboflavin. The intervention lasted 2 months. All groups received iron. The types of comparisons are outside the scope of this review.
Madan 1999	109 apparently healthy pregnant women with 16 to 24 weeks of gestation who had not received iron supplements were randomly assigned to 1 of 3 groups: Group 1 received 60 mg of elemental iron + 500 μg (0.5 mg) of folic acid once daily. Group 2 received 120 mg of elemental iron + 500 μg (0.5 mg) of folic acid once daily. Group 3 received 120 mg of elemental iron twice daily + 500 μg (0.5 mg) of folic acid. Duration of supplementation was 12 to 14 weeks. All participants received different doses and regimens of iron and folic acid daily. No comparisons are allowed within the scope of this review.
Marin 2012	360 pregnant women 16 years or older from La Plata, Buenos Aires province, Argentina or who lived in the region for over a year, and who voluntarily accepted to participate in the study (consent agreement) were randomly assigned to 1 of 2 groups: Group 1 (n = 174) received free medicines from the health centre near their homes consisting of 60 mg of elemental iron (as ferrous sulphate) once (prophylaxis) or twice (treatment) daily and 5000 ug (5 mg) folic acid daily. Group 2 (n = 186) were contacted monthly by a member of the health team in order to personalise free 60 mg of elemental iron (as ferrous sulphate) once (prophylaxis) or twice (treatment) daily and 5000 ug (5 mg) folic acid daily during all of the pregnancy period until 45 days after the delivery. This medicine was always dispensed by that same health professional either through the health centre, or in case that the patient did not attend her periodical consultation, drugs were dispensed at the participant's home. All women received iron and folic acid. The difference was in the access to the supplements or the personalised assistance and delivery of the intervention. These types of interventions ‐ different types of administration ‐ are outside the scope of this review.
Mbaye 2006	1035 pregnant women attending mother and child health clinics near the town of Farafenni, The Gambia were randomised to receive either folic acid (500 to 1500 μg/day) together with oral iron (47 mg of ferrous sulphate per tablet) or oral iron alone (60 mg of ferrous sulphate per tablet) daily for 14 days. All women received treatment with 3 tablets of SP (25 mg of pyrimethamine and 500 mg of sulphadoxine). Both groups received iron daily. No comparisons allowed within the scope of this review.
McKenna 2002	102 healthy pregnant women attending antenatal clinics at the Royal Jubilee Maternity Hospital in Belfast, Ireland with a singleton pregnancy and Hb > 104 g/L and known gestational age of less than 20 weeks who were non‐compliers with routine prescription of 200 mg of ferrous sulphate daily, were randomly assigned to receive 2 sachets of 24 mL each of Spatone® water containing 10 mg of elemental iron or placebo. Participants were instructed to take the 2 sachets daily half an hour before breakfast, diluting it in orange juice. Primary outcomes were compliance and side effects. Duration of intervention was from week 22 to week 28 of gestation. The intervention is not an iron supplement but an iron‐fortified water product.
Menon 1962	273 healthy pregnant women with 16 to 24 weeks of gestation and Hb concentrations at or above 105 g/L attending antenatal care clinics were divided in order in which they were registered in 3 groups: Group 1 was given 5 g of ferrous sulphate daily. Group 2 received 5000 μg (5 mg) of folic acid daily. Group 3 received 5 g of ferrous sulphate and 5000 μg (5 mg) of folic acid daily. All participants were given 3 multivitamin tablets daily containing vitamin A, vitamin B, C and D. The study was excluded because it was not randomised.
Metz 1965	355 Bantu and white pregnant women attending antenatal clinics at the Baragwanath and South Rand Hospitals, Johannesburg, South Africa were allocated by random numbers to 1 of 3 groups: Group 1 received 200 mg of iron by mouth. Group 2 received 5000 μg (5 mg) of folic acid daily by mouth in addition to the iron. Group 3 received 50 μg of vitamin B12 by mouth in addition to the folic acid and iron. With the white participants, supplementation was started after the 24th week, while the Bantu participants started after the 28th. Both groups received iron. The types of comparisons are outside the scope of this review.
Milman 2005	427 healthy Danish pregnant women living in the northeastern part of Copenhagen County, Denmark were randomly allocated to receive iron (as ferrous fumarate) in daily doses of 20 mg (n = 105), 40 mg (n = 108), 60 mg (n = 106), and 80 mg (n = 108) from 18 weeks of gestation. Hb, serum ferritin, and serum soluble transferrin receptor concentrations were measured at 18 weeks (inclusion), 32 weeks, and 39 weeks of gestation and 8 weeks postpartum. All women received iron daily. No comparisons (of dosages) allowed within the scope of this review.
Milman 2014	80 healthy ethnic Danish pregnant women, urban and rural residents attending the antenatal care clinic, were allocated in 2 groups to compare the effects of oral ferrous bisglycinate 25 mg iron/day vs ferrous sulphate 50 mg iron/day. Women were allocated to ferrous bisglycinate 25 mg elemental iron (Aminojern®) (n = 40) or ferrous sulphate 50 mg elemental iron (n = 40) from 15 to 19 weeks of gestation to delivery. Haematological status (Hb, red blood cell indices) and iron status (plasma iron, plasma transferrin, plasma transferrin saturation, and plasma ferritin) were measured at 15 to 19 weeks (baseline), 27 to 28 weeks, and 36 to 37 weeks of gestation. The study was excluded because both study groups received iron. This type of comparison is outside the scope of this review.
Mitra 2012	959 low‐income postpartum girls and women aged 13 years and older, between 2 and 6 weeks after delivery, and certified for WIC from 11 clinics selected the Mississippi Primary Health Care Association and the Mississippi Department of Health, in Mississippi, United States of America. The clinics were randomised to 1 of 3 groups: Group 1: (n = 364, 4 clinics) women received universal anaemia screening and treatment of anaemic women as iron supplement containing 65 mg of elemental Fe (as 325 mg ferrous sulphate). Group 2: (n = 348, 3 clinics) received universal iron supplements daily containing 65 mg of elemental Fe (as 325 mg ferrous sulphate) for 2 months to all low‐income women. Group 3: (n = 247, 4 clinics) only women at high risk and diagnosis of anaemia were treated with iron supplement containing 65 mg of elemental Fe (as 325 mg ferrous sulphate) (control). Supplements were provided free of charge to the women in the control group. All study participants within each clinic received the same treatment. Women were followed up at 6 months after delivery. Hb was measured at baseline and at follow‐up. The primary outcome variable was the proportion of women with anaemia after treatment. The participants were postpartum women. The type of participants is outside the scope of this review.
Morgan 1961	356 pregnant women attending 2 different antenatal care clinics at the King Edward Memorial Hospital for Women in Subiaco, Australia received, according to the clinic they visited, either no treatment or 100 mg of elemental iron (as ferrous gluconate) daily. This study was excluded as it was not a randomised trial; no systematic allocation was used in this open trial.
Morrison 1977	105 pregnant women attending the University Unit, Mater Misericordiae Mothers' Hospital, South Brisbane, Australia, with normal height, weight and nutrition for the Australian population and with no previous adverse medical, surgical or obstetrical history were allotted by random selection to 1 of 4 types of supplements: Group 1 received 50 mg of elemental iron (as dried ferrous sulphate) daily. Group 2 received 80 mg elemental iron (as dried ferrous sulphate) with 300 μg (0.3 mg) folic acid daily. Group 3 received 105 mg elemental iron (as ferrous sulphate). Group 4 received 105 mg of elemental iron (as ferrous sulphate) with 300 μg (0.3 mg) of folic acid. All groups received iron daily. No comparisons allowed within the scope of this review.
Mukhopadhyay 2004	111 apparently healthy pregnant women with less than 20 weeks of gestation and no prior intake of iron supplements during this pregnancy with Hb equal or higher than 100 g/L and singleton pregnancy in New Delhi, India were randomly assigned to 1 of 2 groups: Group 1 received 2 tablets of 100 mg elemental iron and 500 μg (0.5 mg) folic acid each (total 200 mg elemental iron and 1000 μg (1 mg) folic acid, to be taken only once a week, 1 tablet before lunch and another tablet before dinner. Group 2 received 1 tablet of 100 mg elemental iron and 500 μg (0.5 mg) folic acid daily. Women were advised to take the supplements 30 minutes before the meals and not with tea, coffee, or milk. Also, women were advised to take calcium supplements after meals (500 mg elemental calcium twice daily). Iron supplementation started between 14 and 20 weeks until delivery. Deworming, if required, was carried out with Mebendazole 100 mg twice a day for 3 days in the second trimester. Both groups received iron and folic acid in different regimens (daily versus weekly).
Mumtaz 2000	191 anaemic pregnant women between the ages of 17 and 35 years of age, and uneventful obstetric history attending the Maternity wing of the Federal Government Services Hospital in Islamabad and the Maternal & Child Health Clinic at the Christian Mission Hospital in Taxila, Pakistan were randomly assigned to 1 of 2 interventions: Group 1 received 40 mg elemental iron (as ferrous sulphate) with 1000 μg (1 mg) of folic acid once daily. Group 2 received 40 mg elemental iron (as ferrous sulphate) with 1000 μg (1 mg) of folic acid on 2 days of the week and placebo the rest of the days. Participants and care providers were blinded to the treatments. Outcomes measured included Hb concentration and serum ferritin at baseline and during the 3 following consecutive visits, as well as compliance and weight. Change in Hb Z‐scores after supplementation was the main outcome variable, in women from different gestational ages and duration of intervention. Both groups received iron and folic acid in different regimens (daily versus bi‐weekly).
Mwangi 2015	This study was a randomised, placebo‐controlled trial conducted from October 2011 through April 2013 in a malaria endemic area among 470 rural Kenyan women aged 15 to 45 years with singleton pregnancies, gestational age of 13 to 23 weeks, and haemoglobin concentration of 9 g/dL or greater. All women received 5.7 mg iron/day through flour fortification during intervention, and usual intermittent preventive treatment against malaria was given. Supervised daily supplementation with 60 mg of elemental iron (as ferrous fumarate, n = 237 women) or placebo (n = 233) was given from randomisation until 1 month postpartum. This study was excluded as both groups received different types of iron supplementation.
Nadimin 2019	This study was an Indonesian RCT using a sample of non‐anaemic pregnant women divided into 2 groups: an intervention group given moringa leaf extract and a control group given iron folic supplements. The nutritional status of pregnant women was assessed using a measure of upper arm circumference and weight gain during pregnancy. This trial was excluded because it compared the effect of iron and folic acid with moringa leaf extract. This is a comparison outside the scope of this review.
Nadimin 2020	This study was of pregnant women in Makassar, Indonesia. Group 1 received Moringa leaf extract; Group 2 received iron folate supplement (60 mg iron and 0.25 mg folate). The intervention was given for 12 weeks. The trial was excluded because it compared iron and folic acid with moringa leaf extract supplementation. This is a comparison outside the scope of this review.
NCT03836703 (first received 2019 Feb 11)	In this study, iron‐deficient women with twin gestations were randomised to receive a single or a double dose of daily iron from 16 weeks of gestation until 6 weeks postpartum. This study was excluded as its intervention was outside the scope of the review.
NCT04250428 (first received 2020 Jan 31)	This trial registration was for a study carried out in the Taabo health and demographic surveillance system (HDSS) in south‐central Côte d'Ivoire. It was a cluster‐randomised trial targeting 720 consenting pregnant women aged ≥ 15 years. The 118 clusters constituting the Taabo HDSS monitoring area were randomly allocated to one of the following 3 groups with equal probability: a control group, an information only group, and an information plus home delivery group, with an endline survey to assess the relative effectiveness of each strategy. This trial was excluded as it was of strategies to increase the coverage of iron and folic acid. This is a comparison outside the scope of this review.
NCT04363905 (first received 2020 Apr 27)	This was a study of the effects of iron deficiency on the physical performance of 68 Mexican non‐pregnant women, using a randomised, double‐blind design that assigned marginally iron‐depleted, physically active women between 18 and 45 years to 2 treatments. One half of the women were randomly assigned to a daily oral iron supplement (20 mg of elemental iron as slow release ferrous sulfate) while the remaining women received a placebo.
Nguyen 2008	167 pregnant women with less than 20 weeks of gestation who called either Motherisk General Information line or the Motherisk Nausea and Vomiting of Pregnancy (NVP) Helpline (Hospital for Sick Children, Toronto) and had not started taking or had discontinued any multivitamin due to adverse events were randomly assigned to 1 of 2 groups: Group 1 were provided with a small‐size supplement (PregVit®), containing 35 mg elemental iron (as ferrous fumarate) and multivitamins. Group 2 received high iron content, small‐size supplement (Orifer F®) containing 60 mg elemental iron (as ferrous sulphate) and multivitamins. Follow‐up interviews documented pill intake and adverse events. This study was excluded because participants from both groups received iron in different doses and compounds.
Nguyen 2012	This study evaluated whether providing additional pre‐pregnancy weekly iron‐folic acid (IFA) or multiple micronutrient (MM) supplements compared to only folic acid (FA) improves iron status and anaemia during pregnancy and early postpartum. It was a double‐blind randomised controlled trial in which 5011 Vietnamese women were provided with weekly supplements containing either only 2800 μg FA (control group), IFA (60 mg Fe and 2800 μg FA) or MM (15 micronutrients with similar amounts of IFA). All women who became pregnant (n = 1813) in each of the 3 groups received daily IFA (60 mg Fe and 400 μg FA) through delivery. This study was excluded because all groups received iron in different doses and regimens.
Nguyen 2012a	This study described adherence data collected prospectively from a double‐blind randomised controlled trial in rural Vietnam. 5011 of reproductive age were randomised to receive preconception supplements for weekly consumption containing either: folic acid, iron and folic acid (IFA), or multiple micronutrients. This study was excluded because it compared different regimens and doses of iron supplementation.
Nogueira 2002	74 low‐income pregnant adolescents ranging from 13 to 18 years of age attending antenatal care at the Evangelina Rosa Maternity Hospital in Teresina, Piaui State, Brazil were distributed into 5 groups: Group 1 received 120 mg elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) of folic acid daily. Group 2 received 80 mg elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) folic acid daily. Group 3 received 120 mg of elemental iron, with 5 mg of zinc sulphate and 250 μg (0.25 mg) of folic acid daily. Group 4 received 80 mg of elemental iron (as ferrous sulphate), with 5 mg of zinc sulphate and 250 μg (0.25 mg) of folic acid daily. Group 5 received 120 mg elemental iron (as ferrous sulphate, routine regime locally). All groups received iron and 2 groups received zinc in addition to iron and folic acid. No comparisons allowed within the scope of this review.
Nur 2020	This study analysed the effect of extract of moringa leaf on the incidence of anaemia in pregnant Indonesian women. A sample of 40 pregnant women were divided into 2 groups. The intervention group was given capsules of moringa leaf extract and iron capsules every day. The control group was only given iron capsules. This study was excluded as it was outside the scope of this review.
Nwaru 2015	This was a pragmatic randomised controlled trial comparing routine iron supplementation vs screening and treatment for anaemia during pregnancy. The setting was 2 health centres in Maputo, Mozambique. Pregnant women (≥ 12‐week gestation; ≥ 18 years old; and not with a high‐risk pregnancy, n = 4326) were recruited. The women were randomly assigned to 1 of 2 iron administration policies: a routine iron group (n = 2184) received 60 mg of ferrous sulphate plus 400 μg of folic acid daily, while a selective iron group (n = 2142) had screening and treatment for anaemia and a daily intake of 1 mg of folic acid. This study was excluded because one group received 60 mg of ferrous sulphate plus 400 mg of folic acid daily; the other had screening and treatment for anaemia and a daily intake of 1 mg of folic acid.
Ogunbode 1984	80 apparently healthy non‐anaemic pregnant women attending University College Hospital and Inalende Maternity Hospital in Ibadan, Nigeria during the first and second trimesters of pregnancy were randomly allocated to 1 of 2 groups: Group 1 (n = 39) received 1 tablet Ferrograd Folic 500 Plus® daily, a sustained‐released formulation containing ferrous sulphate and folic acid (composition is not available). Group 2 (n = 41) received a capsule containing 200 mg ferrous sulphate and 5000 μg (5 mg) of folic acid. All patients were also provided 25 mg weekly of pyrimethamine throughout pregnancy as an anti‐malarial agent. Patients who became anaemic during pregnancy were excluded from the study and analysis. Outcomes measured included reticulocyte count, HCT, anaemia, and side effects. Both groups received iron and folic acid supplements, thus making the comparisons not suitable for this review.
Ogunbode 1992	315 apparently healthy pregnant women attending 4 prenatal care clinics in 4 geographical areas of Nigeria with mild to moderate anaemia (as defined by HCT between 26% to 34%) and 18 to 28 weeks of gestation, single pregnancies, no complications, and who consented to participate in the study were randomly allocated to 1 of 2 groups: Group 1 (n = 159) received 1 daily capsule of a multiple micronutrient supplement Chemiron® containing 300 mg of ferrous fumarate, 5000 μg (5 mg) folic acid, 10 μg vitamin B12, 25 mg of vitamin C, 0.3 mg magnesium sulphate and 0.3 mg of zinc sulphate. Group 2 (n = 156) received a capsule containing 200 mg ferrous sulphate and 5000 μg (5 mg) of folic acid. All patients were also provided 600 mg of chloroquine to be taken under supervision and 25 mg weekly of pyrimethamine throughout pregnancy. Patients who became anaemic during pregnancy were excluded from the study and analysis. Outcomes measured included blood Hb, anaemia, HCT, serum ferritin levels, side effects. A second published study followed these same women and their infants. Both groups received iron and folic acid supplements, thus making the comparisons not suitable for this review.
Ortega‐Soler 1998	41 healthy pregnant women, attending prenatal care clinics at Hospital Diego Paroissien in La Matanza, Province of Buenos Aires, Argentina with serum ferritin below 50 mg/mL were assigned to 1 of 2 groups: Group 1 received 100 mg of elemental iron daily (as ferric maltosate). Group 2 received no treatment. Supplementation started at 21 ± 7 weeks of gestation until birth. Maternal outcomes measured included: Hb, erythrocyte protoporphyrin, serum ferritin at baseline and term, dietary intake. The iron intake was unsupervised and compliance was not reported. The trial is not randomised nor quasi‐randomised so it does not meet the inclusion criteria for this review.
Osifo 1970	52 pregnant women 18 to 40 years of age with 15 to 22 weeks of gestation attending routine prenatal care in the village of Osegere, Nigeria with no complications were divided into 3 groups based on the day of the week convenient to them to attend the weekly clinic: Group 1 received iron supplements (200 mg ferrous sulphate) 3 times a day. Group 2 received iron supplements (200 mg ferrous sulphate) 3 times a day plus a tablet containing 5000 μg (5 mg) folic acid daily. Group 3 received iron supplements (200 mg ferrous sulphate) 3 times a day plus a tablet containing 5000 μg (5 mg) folic acid daily and 800 mg of cholorique sulphate (Nivaquine; May & Baker Ltd, Dagenham, Essex) at first and 25 mg of pyrimethamine (Daraprim; Burroughs Wellcome, 10 Lancaster Onike Road, Yaba, Lagos, Nigeria) weekly. Blood samples were collected each week and assessed for Hb and HCT concentrations. The study was excluded because it was not randomised.
Osrin 2005	1200 healthy pregnant women with a singleton pregnancy and less than 20 weeks' gestation attending an antenatal clinic at Janakpur zonal hospital in Nepal, were randomly assigned to receive routine 60 mg elemental iron daily and 400 μg (0.4 mg) folic acid supplements or a multiple micronutrient supplement containing 15 vitamins and minerals including 30 mg elemental iron and 400 μg (0.4 mg) folic acid. Both groups received iron and folic acid. No comparisons allowed within the scope of this review.
Pandey 2015	This study evaluated the effect of vitamin D and iron supplementation compared to iron supplementation alone. 20 recruited pregnant women in India with 25 (OH) D < 2 0ng/mL and Hb 8 to 10 g/dL were randomised into groups: Group 1 received tablets containing fixed‐dose combination of vitamin D (1000 IU) + ferrous ascorbate (100 mg of elemental iron) + folic acid (1 mg) + vit B12 (7.5 μg) (1 tab/day) for 12 weeks. Group 2 received tablets containing fixed‐dose combination of ferrous ascorbate (100 mg of elemental iron) + folic acid (1.1 mg) (1 tablet/day) for 12 weeks. This study was excluded because both groups received iron.
Parkkali 2013	4326 non‐high risk pregnant women 18 years of age or older attending prenatal care consultation at the 2 health centres (1° de Maio and Machava) in Maputo, Mozambique, a setting of endemic malaria and high prevalence of HIV. In this pragmatic randomised controlled trial to compare 2 iron administration policies were evaluated. Participants randomly allocated to 1 of 2 groups: Group 1 (n = 2184) received routine iron 60 mg (as ferrous sulphate) and 400 μg (0.4 mg) of folic acid daily throughout pregnancy. Group 2 (n = 2142) were assigned to the selective intervention (i.e. regular screening for Hb level and treatment for anaemia only after diagnosis) where they were screened and treated for anaemia and daily intake of 1000 µg (1 mg) of folic acid. In group 2 (selective iron group), women’s Hb levels were measured at each visit by the study nurses using a rapid Hb measure, HemoCue Hb 201+ (Hemocue AB, Ängelholm, Sweden). If the Hb was 90 g/L or more, they received 30 tablets of 1000 µg (1 mg) of folic acid per day. If their Hb was below the cut‐off of < 90 g/L Hb, they received a monthly double dose of iron (60 mg + 60 mg) for the treatment of anaemia. The usual care recommendations at the time of the trial included daily 60 mg elemental iron + 400 μg folic acid) throughout pregnancy; 1 dose of mebendazol 500 mg for intestinal parasite; 3 doses of sulphadoxine pyrimethamine for malaria prophylaxis (started around 20 weeks' gestation, or when quickening occurs or when the fetal heart is heard); Hb measurement (Lovibond is routinely used) and syphilis screening at the first prenatal visit and 3 doses of tetanus vaccine (at the fifth and seventh months and at delivery). The study was excluded because the women received different doses of iron and folic acid. The comparisons in this study are outside the scope of this review.
Payne 1968	200 pregnant women attending antenatal clinics in Glasgow, Scotland with less than 20 weeks' gestation, whose antenatal care was undertaken wholly by the hospital antenatal clinic and who subsequently had a normal delivery, were randomly allocated to receive 200 mg of ferrous sulphate daily or 200 mg of ferrous sulphate with 1700 μg (1.7 mg) of folic acid daily throughout pregnancy. Both groups received iron. No comparisons allowed within the scope of this review.
Peña‐Rosas 2003	116 pregnant women of 10 to 30 weeks of gestational age attending antenatal care clinics in Trujillo, Venezuela were randomly allocated to receive a 120 mg oral dose of iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid weekly (n = 52) or 60 mg elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) folic acid and a placebo twice‐weekly (n = 44). Hb, HCT, serum ferritin and transferrin saturation were estimated at baseline and at 36 to 39 weeks of gestation. All groups received iron and folic acid in 2 intermittent regimens with no control group. No comparisons allowed within the scope of this review.
Picha 1975	In a randomised, double‐blind study, the new effervescent iron tablet Loesferron® was tested in 57 postpartum women. The study was excluded because the participants were not pregnant women.
Pita Martin 1999	203 healthy pregnant women with normal blood pressure at first visit, attending an antenatal care clinic at Diego Paroissien Hospitalin the Province of Buenos Aires, Argentina were included in the study. Participants were assigned to 1 of 3 groups: Group 1 received 60 mg of elemental iron (as ferrous fumarate) daily. Group 2 received 60 mg elemental iron (as ferrous fumarate) every 3 days. Group 3 received no treatment. Supplementation started at 8 to 28 weeks until 34 to 37 weeks of gestation. Outcomes: maternal: Hb, HCT, erythroporphyrin, serum ferritin concentration at baseline and at 34 to 37 weeks' gestation, premature delivery, birthweight. Unsupervised. Compliance not reported. Women from control group (group 3) were not assigned randomly. These women were recruited but due to delays in the acquisition of the iron tablets and the progression of their pregnancies without supplementation, they were left as controls in the study. This study was excluded because it was a comparison of different types of regimen.
Powers 1985	81 pregnant 14 to 36 weeks of gestation or lactating (1 to 20 months postpartum) women with Hb less than 140 g/L living in a village in The Gambia were allocated to 1 of 4 groups: Group 1 received daily placebo. Group 2 received 5 mg riboflavin. Group 3 received 30 mg ferrous sulphate. Group 4 received 30 mg ferrous sulphate + 5 mg riboflavin. At the beginning of the study and at 3 and 6 weeks thereafter, women were examined clinically and blood samples collected for haematological and biochemical measurements. This is not a randomised trial.
Priliani 2019	The aim of this study was to assess the impact of MMN supplementation on maternal mitochondrial DNA copy number (mtDNA‐CN) using data from SUMMIT, a cluster‐randomised, double‐blind, controlled trial in which midwives were randomly assigned to distribute maternal micronutrients (MMN) or iron and folic acid (IFA) to pregnant women. This study was of 108 sets of paired baseline and postsupplementation samples (MMN = 54 and IFA = 54). Maternal mtDNA‐CN was determined by real‐time quantitative polymerase chain reaction in baseline and postsupplementation specimens. This trial was excluded because it assessed nutritional supplements.
Quintero 2004	107 healthy pregnant women with 6 to 20 weeks of gestation, who had not received iron supplements during the current pregnancy attending 19 health units in the State of Morelos, Mexico, were randomly assigned by block pairs to receive either 120 mg of elemental iron (as ferrous sulphate) in a single dose daily or once weekly. Hb concentration, prevalence of anaemia, and nutrient consumption at baseline and after 10 weeks of supplementation were measured. This study was excluded because both groups received iron in different regimens (daily versus weekly).
Rabindrakumar 2021	This study evaluated the effectiveness of iron supplementation in relation to baseline iron and inflammatory status of pregnant women and their offspring in Sri Lanka. Apparently healthy women aged 18 to 36 years at < 12 weeks of gestation prior to receiving any supplementation were randomly recruited at the antenatal clinics. They received 60 mg of elemental iron in combined iron‐folic acid pills from 12 weeks of gestation until delivery via the National Maternal Supplementation Programme. The women were grouped as iron sufficient‐inflammation (+), iron sufficient‐inflammation (‐), iron deficient‐inflammation (+) and iron deficient‐inflammation (‐) based on their baseline iron stores and low‐grade inflammation (hs‐CRP > 5 < 10 mg/L) at baseline and late pregnancy. This trial was excluded as it was not a randomised controlled trial.
Rae 1970	In this quasi‐randomised trial, pregnant women attending an antenatal clinic at the Department of Obstetrics and Department of Haematology, Walton Hospital, Liverpool, United Kingdom were assigned to 1 of 2 groups: Group 1 received 200 mg ferrous gluconate 3 times a day throughout pregnancy. Group 2 received 200 mg ferrous gluconate + 5000 μg (5 mg) 3 times a day. Both groups received iron daily. The type of comparison is outside the scope of this review.
Ramakrishnan 2003	873 pregnant women living near Cuernavaca, Morelos, Mexico with less than 13 weeks of gestation who did not use micronutrient supplements were randomly assigned to receive a daily multiple micronutrient supplement or a daily iron‐only supplement. Both supplements contained 60 mg of elemental iron (as ferrous sulphate). Supplement intake was supervised by trained workers from registration until delivery by home visits 6 days a week. This study was excluded because both groups received iron with or without other supplements.
Ramakrishnan 2016	This study evaluated whether preconception supplementation with weekly iron and folic acid (IFA) or multiple micronutrients (MMs) improves birth outcomes compared with FA alone. 5011 women of reproductive age participated in a double‐blind, randomised controlled trial in Vietnam, provided with weekly supplements containing either 2800 mg FA, 60 mg Fe and 2800 mg FA (IFA), or the same amount of FA and iron plus other MMs until they conceived (n = 1813). All pregnant women received daily IFA through delivery. The trial was excluded because the trial recruited and randomised the participants before they conceived.
Rayado 1997	394 healthy, non‐anaemic adult pregnant women with 24 to 32 weeks of gestation and singleton pregnancy from Fuentalabra, Spain were randomly assigned to 1 of 2 groups: Group 1 received 40 mg of elemental iron (as iron mannitol albumin) daily. Group 2 received 40 mg elemental iron (as iron protein succinylate) daily. Both groups received different types of iron daily. No comparisons allowed within the scope of this review.
Reddaiah 1989	110 pregnant women attending the antenatal clinic at Comprehensive Rura Health Services Project Hospital, Ballabgarh, India, with 16 to 24 weeks of gestation were randomly assigned to 1 of 3 groups: Group 1 received 60 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid daily. Group 2 received 120 mg elemental iron (as ferrous sulphate) with 500 μg (0.5 mg) of folic acid daily. Group 3 received 240 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid daily. All groups received different doses of iron daily. No comparisons allowed within the scope of this review.
Reddy 2016	Pregnant women (n = 150) were enrolled from a semi government hospital of urban Vadodara, Gujarat, India at (< 12 weeks) and followed up until the end of gestation. Group 1 were double fortified salt supplemented and the control group used iodised salt. The impact on iron and iodine status was assessed by Hb concentration and UIE respectively. The trial was excluded because it compared iodised salt versus double fortified salt. This comparison was outside the scope of this review.
Ridwan 1996	176 pregnant women with 8 to 24 weeks of gestation attending antenatal care at 6 health centres in West Java, Indonesia. Health centres were randomised to 1 of 2 interventions: weekly regimen, where women received 120 mg of elemental iron (as ferrous sulphate) with 500 μg (0.5 mg) of folic acid; or daily regimen where women received 60 mg of elemental iron (as ferrous sulphate) with 250 μg (0.25 mg) of folic acid daily until week 28 to 32 of gestation. Supplementation started at 8 to 24 weeks until 28 to 32 weeks of gestation. This study was excluded because both groups received iron in different regimens.
Robinson 1998	680 pregnant women served by 11 health centres from 5 sub‐districts on or near the western end of the island of Seram in the Province of Maluku, Indonesia were assigned to 1 of 2 interventions: Group 1 received 60 mg of elemental iron (as ferrous sulphate) with 250 μg (0.25 mg) of folic acid daily from a traditional birth attendant. Group 2 received 120 mg of elemental iron (as ferrous sulphate) with 500 μg (0.5 mg) of folic acid once a week from the traditional home visiting birth attendants. A control group was formed by participants receiving traditional iron supplements (60 mg elemental iron) with folic acid from health centres, self‐administered without incentive. This study was excluded because groups 1 and 2 both received iron in different regimens.
Rolschau 1979	36 pregnant women were selected consecutively, paired 2 and 2, and allotted to 2 groups, 1 of which was supplied daily with 5000 μg (5 mg) folic acid, and the second with tablets without folic acid, from the 23rd week of pregnancy. This study was excluded because this type of comparison is outside the scope of this review.
Roth 1980	23 pregnant women were assigned to 1 of 2 groups during August 1976 and September 1977: Group 1 (n = 11) received a supplement daily "Tardyferon‐Fol®" containing 80 mg ferrous sulphate and 350 μg (0.35 mg) folic acid. Group 2 (n = 12) received a supplement daily "Tardyferon®" containing 80 mg ferrous sulphate. The study was excluded because both groups received iron. This type of intervention is outside the scope of this review.
Roztocil 1994	84 non‐anaemic pregnant women at Mazarik University Brno in the Czech Republic were treated from 20 to 24 weeks with 1 capsule of Actiferrin Compositum®, and from 36 weeks to delivery with 2 capsules. The group was compared with 57 non‐anaemic pregnant women who received no supplements. The supplement contained 34.5 mg of elemental iron (as ferrous sulphate), 500 μg (0.5 mg) of folic acid, and 0.3 mg of cyanocobalamin. This study was excluded because it was not a randomised trial. No comparisons allowed within the scope of this review.
Rukhsana 2006	90 pregnant women attending the Department of Obstetrics and Gynaecology Jinnah Postgraduate Medical Centre Karachi, with clinical signs of anaemia (Hb < 110 g/L) were randomly assigned to 1 of 3 supplementation groups (30 women in each group): Group 1 received 60 mg iron/daily. Group 2 received 60 mg iron/once a week. Group 3 received 120 mg iron/once a week for 12 weeks. Hb, RBC count, red cell indices and reticulocyte count were measured and results compared to baseline to 12 weeks and between groups. The study was excluded because there were 3 groups receiving iron, 1 group daily and the other 2 intermittently. This type of comparison is outside the scope of this review.
Rybo 1971	117 pregnant women between 20 and 29 weeks of gestation were alternatively assigned during 3 consecutive 2‐week periods to receive daily tablets containing 200 mg of elemental iron (as ferrous sulphate), 200 mg of elemental iron (as a sustained released iron), or placebo. After each 2‐week treatment period, women were questioned about possible side effects. This study was excluded because women received different types of iron.
Sachdeva 1993	In this study carried out in rural India, 66 pregnant women from low‐ and middle‐income groups received nutritional supplements. Women in both groups received both iron and folic acid supplements. In addition, women in the experimental group received a calcium supplement, individual and group counselling, and a booklet about nutrition in pregnancy. All women received iron and folic acid supplements (the dose and regimen were not clear) and it was not clear that allocation to groups was random. This trial was excluded because both groups received iron and one group received an additional intervention.
Saha 2007	100 pregnant women aged 20 to 40 years at 14 to 27 weeks' gestation, with Hb < 90 g/L, and serum ferritin < 12 μg/L, attending the Department of Pharmacology and the Department of Obstetrics and Gynaecology at the Postgraduate Institute of Medical Education and Research, Chandigarh, India were randomly assigned to 1 of 2 groups: Group 1 received 100 mg elemental iron (as iron polymaltose complex) and 500 μg (0.5 mg) folic acid daily. Group 2 received 120 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid daily for 8 weeks. Both groups received iron and folic acid. No comparisons can be made within the scope of this review.
Salma 2021	This study assessed the effect of giving red seaweed (Kappaphycus alvarezii) biscuits to pregnant women in the first trimester attending a community health centre in Indonesia from April to June 2021. A total of 45 pregnant women were selected purposely and assigned to 3 different groups. The first group was given two pieces of red seaweed biscuit per day. The second group was given two pieces of red seaweed biscuit plus Fe tablets (60 mg/day), and the last group was given Fe tablets only (60 mg/day). This trial was excluded because it compared seaweed versus iron plus seaweed supplementation. This comparison is outside the scope of this review.
Sandstad 2003	233 pregnant women attending their second antenatal care visit at the University Health Services of Oslo, Norway with serum ferritin concentration < 60 μg/L were randomised to 2 different iron preparations: Group 1 received 1 tablet containing 60 mg of elemental iron (as ferrous sulphate) daily. Group 2 received 3 tablets each containing 1.2 mg of heme iron from porcine blood plus 8 mg of elemental iron (as ferrous fumarate) per tablet (total 3.6 heme iron and 24 mg elemental iron) daily. A third group (n = 93) of pregnant women who had been given advice to take or not the iron supplements according to the centre recommendations were enrolled in the trial at 6 weeks postpartum and served as control. The study was excluded because the groups were not randomised.
Schoorl 2012	25 pregnant women in the third trimester of pregnancy with suspected IDE during pregnancy (Hb ≤ 110g/L, Ret‐He < 29.6 pg, zinc protoporphyrin > 75 mol/mol hem) participated in the study, receiving ferrous fumarate (200 mg 2 times a day, approx. 200 mg iron a day) according to local practice during 4 weeks. From the first trimester of pregnancy, 400 ug of folic acid was given as a supplement in a multivitamin tablet (Centrum® Materna). Blood samples were drawn to establish haemocytometric parameters to evaluate RBC and reticulocyte Hb content. The study was excluded because there was a single group of women receiving iron during the third trimester of pregnancy without control, placebo or other intervention groups. There was not randomisation. This type of intervention is outside the scope of this review.
Seck 2008	221 apparently healthy pregnant women, who had not used iron supplements prior to enrolment, who were at 12 to 16 weeks of gestation, were recruited from 6 health centres in Dakar, Senegal during their first prenatal visit, and randomly assigned to receive either a prescription to purchase iron/folic acid tablets to be taken daily, according to official policy, or to receive free tablets. Compliance was assessed 20 weeks after enrolment through interviews and pill count. This study was excluded because it examined comparisons outside the scope of this review.
Shaheen 2020	This study investigated the risk of asthma in offspring of mothers who took part in a randomised trial comparing 2 regimens of iron supplementation in pregnancy. Pregnant women recruited to a trial of iron supplementation in Finland in 1985‐6 were randomised to receive either 100 mg elemental iron/day throughout pregnancy (routine iron (RI) group, n = 1336) or 50 mg twice a day if they were found to be anaemic, continuing until their haemoglobin improved (selective iron (SI) group, n = 1358). Using national register linkage, offspring asthma was ascertained based on receipt of reimbursement for purchase of asthma medications between 10 and 32 years of age. This trial was excluded because it compared different regimens of iron supplementation.
Shankar 2016	This study investigated the iron dynamics in anaemic and healthy pregnant women supplemented with daily and weekly IFA supplementation and its relation with clinical outcomes in Denmark. The subjects were non‐anaemic primigravida (NAP) (haemoglobin (Hb) > 11 g/ dl, N = 60) and anaemic primigravida (AP) (8.0 < Hb < 11 g/dL, N = 60) randomly allocated to a daily dose comprising 100 mg iron and 500 μg folic acid tablets or a weekly dose containing 2 IFA tablets/ week till 6 weeks postpartum. This trial was excluded because it compared daily versus weekly iron supplementation.
Shatrugna 1999	115 healthy pregnant women with 20 to 28 weeks of gestation attending the antenatal clinic of the National Institute of Nutrition, Government Maternity Hospital, India were randomly assigned to 1 of 11 different formulations and doses of iron and then to undergo iron tolerance tests. They received ferrous sulphate tablets containing 60 mg, 12 mg, and 180 mg of elemental iron; formulations contained 60 mg of elemental iron as pure ferrous sulphate salt, ferrous fumarate tablets, ferrous fumarate syrup, excipients added to pure ferrous sulphate salts; powdered ferrous sulphate tablets, iron tablets distributed by the National Nutritional Anaemia Prophylaxis Programme and pure ferrous salt in gelatin capsules. This study was excluded because all groups received different types of iron.
Sinha 2011	50 pregnant women between 16 and 20 weeks of gestation with Hb equal or greater than 100 g/L in Allahabad, in the north Indian state of Uttar Pradesh, India were randomly assigned to 1 of 2 groups: Group 1 (n = 22): women received 2 doses of 400 mg iron sucrose infusion, 1 at 16 to 20 weeks' gestation and a second infusion at 28 to 32 weeks' gestation. Group 2 (n = 28): women received 100 mg oral ferrous ascorbate daily starting at 16 to 20 weeks' gestation. This study was excluded because it compared different types of administration of iron supplementation.
Sjostedt 1977	300 pregnant women attending the Maternity Welfare Center, in Oulu, Finland before the 5th month of pregnancy were randomly assigned to 1 of 3 groups: Group 1 received 100 mg of elemental iron (as sustained‐release tablets) daily. Group 2 received 200 mg of elemental iron daily (as sustained‐release tablets). Group 3 received 200 mg of elemental iron daily (as rapidly disintegrating ferrous sulphate tablets). All groups received iron in different doses and formulations.
Sood 1979	151 healthy pregnant women with Hb > 50 g/L who had not received iron supplements during the last 6 months from Delhi and Vellore, India were divided into 1 of 3 strata according to Hb concentration (50 to 79 g/L; 80 to 109 g/L;110 g/L and above) and within each strata were allocated randomly to 1 of 5 interventions: Group 1 received 120 mg of elemental iron (as ferrous sulphate) 6 days a week. Group 2 received 100 mg of elemental iron (as iron dextran complex) intramuscular twice per week. Group 3 received iron as group 1 + pteroylmonoglutamic acid 5 mg/d 6 days a week + cyanocobalamin 100 μg intramuscular once per 14 days. Group 4 received 100 mg of elemental iron intramuscular + pteroylmonoglutamic acid + cyanocobalamin 100 μg intramuscular. Group 5 received iron dextran complex intramuscular in a single total dose infusion + 5 mg/d pteroylmonoglutamic acid + 100 μg intramuscular cyanocobalamin once per 14 days. This study was excluded because it compared different types of administration of iron supplementation.
Srisupandit 1983	567 pregnant women 16 to 30 years of age with 18 to 26 weeks' gestation attending an antenatal care clinic, in the department of Obstetrics and Gynecology of the Siriraj Hospital, Thailand were randomly assigned to 1 of 3 groups: Group 1 received 60 mg elemental iron daily. Group 2 received 180 mg elemental iron daily. Group 3 received 180 mg elemental iron and 5000 ug (5 mg) folic acid daily. The intervention lasted 3 months. There were 101 losses to follow‐up. This study was excluded as all participants received elemental iron in different doses with or without folic acid. This type of intervention is outside the scope of this review.
Steer 1992	Trial abandoned. No data available.
Stone 1975	248 healthy pregnant women attending hospital antenatal clinic in London, England, were allocated randomly to receive 105 mg of elemental iron (as ferrous sulphate slow release dose) and 350 μg (0.35 mg) of folic acid daily or 80 mg of elemental iron (as ferrous fumarate) and 400 μg (0.4 mg) of folic acid daily in a standard preparation. This study was excluded because both groups received iron in different doses and preparations.
Suhartatik 2020	This study compared the effect of moringa oleifera flour supplementation with the effect of iron tablet supplementation on 40 pregnant and breastfeeding mothers in Indonesia. This study was excluded because it compared iron supplementation with moringa flour supplementation. This comparison is outside the scope of this review.
Swain 2011	100 women with uncomplicated pregnancy were assigned to received either injectable iron sucrose (400 mg diluted in 400 mL of normal saline) over 2 to 3 hours or to receive an oral dose of 100 mg elemental iron daily. This study was excluded because it examined different types of administration of iron supplementation.
Tampakoudis 1996	82 pregnant women with Hb concentrations 140 g/L or above attending a clinic in Thessaloniki, Greece were randomised to receive 80 mg iron protein succinylate daily or a placebo. Serial Hb, HCT, and serum erythropoietin were measured from maternal blood and cord blood on delivery; serum ferritin was measured at frequent intervals. Abstract only available. This trial was excluded because there was insufficient information to assess the characteristics of the trial. N.B. For the 2024 update, the trustworthiness tool was not applied and so we did not reach out to the trial authors, as the study had already been excluded.
Tan 1995	285 healthy middle‐class pregnant women with Hb concentration above 100 g/L attending an antenatal clinic at the University Hospital at Kuala Lumpur, Malaysia were assigned to receive daily iron supplements or no treatment. This study was excluded because only an abstract was available. No additional information was available, including doses, regimens, or any other characteristics of the trial. N.B. For the 2024 update, the trustworthiness tool was not applied and so we did not reach out to the trial authors, as the study had already been excluded.
Tange 1993	128 anaemic and non‐anaemic pregnant females aged 10 to 19 years old, with an average gestation of 16 weeks, were grouped for 3 levels of iron supplementation: Group 1 (n = 42 non‐anaemic participants) received placebo (no iron). Group 2 (n = 41 anaemic and non‐anaemic participants) received 22 mg of elemental iron daily. Group 3 (n = 45 anaemic and non‐anaemic participants) received 55 mg elemental iron daily. Women were supplemented from 16 weeks until delivery. Outcomes assessed included Hb, HCT, RBC count, MCV, serum iron, serum transferrin, and serum ferritin measured every 4 weeks. The study was not reported as randomised, so was excluded.
Thane‐Toe 1982	135 healthy pregnant women between 22 and 28 weeks of gestation attending an antenatal clinic in Burma, were randomly assigned to receive a daily dose of 60 mg, 120 mg, or 240 mg of elemental iron (as ferrous sulphate). A control group was composed of 47 apparently healthy adults (17 males and 30 single women). This study was excluded because it examined different doses of iron supplementation.
Thomsen 1993	52 healthy non‐anaemic nulliparous women with normal singleton pregnancy and serum ferritin levels above 15 mg/L at 16th week in Herlev, Denmark were randomly assigned to receive either a daily tablet containing 18 mg elemental iron or a daily tablet containing 100 mg of elemental iron from 16 weeks until delivery. All women received 300 μg (0.3 mg) of folic acid daily. This study was excluded because all women received iron in different doses.
Tofail 2008	This study compared the efficacy and effectiveness of 3 different micronutrient supplements on maternal micronutrient status when combined with food supplementation in the MINIMat (Maternal and Infant Nutrition Intervention, Matlab) trial in Bangladesh. 4436 pregnant women were randomly assigned to daily intake of 3 types of micronutrient capsules: 30 mg Fe and 400 μg folic acid (Fe30F), 60 mg Fe and 400 μg folic acid (Fe60F), or multiple micronutrient supplements (MMNs) combined with early (week 9 of pregnancy) or usual (week 20 of pregnancy) food supplementation in a 2 by 3 factorial design. The trial was excluded because it compared 2 different regimens of iron supplementation.
Trigg 1976	158 pregnant women seeking antenatal care with general practitioners in the former South‐east England Faculty of the Royal College of General Practitioners, in South England, United Kingdom were assigned to 1 of 2 groups: Group 1 (n = 76) received 50 mg ferrous sulphate daily and was compared with giving ferrous sulphate 50 mg daily + 500 μg (0.5 mg) folic acid. After the first test, patients were randomly allocated to 1 of the 2 treatments, which was either a minimum of 50 mg of ferrous sulphate daily or a minimum of 50 mg of ferrous sulphate plus 500 μg (0.5 mg) of folic acid daily, and afterwards allocation was in sequence. This study was excluded because both groups received iron.
Vazquez 2019	This study evaluated the effectiveness of different doses of iron supplementation adjusted for the initial levels of haemoglobin (Hb) on maternal iron status and described some associated prenatal determinants. 791 women were randomised into 2 groups: Stratum 1 (Hb = 110 to 130 g/L, received 40 mg or 80 mg iron daily) and Stratum 2 (Hb > 130 g/L, received 20 mg or 40 mg iron daily). The trial was excluded because it compared different regimens of iron supplementation.
Vogel 1963	191 consecutive pregnant women, when attending antenatal care clinics and at 32 weeks of gestation, were divided into 2 groups by alternate allocation by clinic: Group 1 received 140 mg of elemental iron daily (as ferrous gluconate) in 4 tablets. Group 2 received 150 mg elemental iron daily (as ferrous glutamate) in 3 tablets. This study was excluded because all participants received iron at different doses.
Wali 2002	60 iron‐deficient anaemic pregnant women with a gestational age of 12 to 34 weeks were randomly assigned to 1 of 3 groups: Group 1 (n = 15) received intravenous 500 mg of iron sucrose for storage. Group 2 (n = 20) received intravenous iron sucrose according to deficit, calculated as per formula, with 200 mg of iron given for storage. Group 3 received intramuscular iron sorbitol at the dose used as practice. This study was excluded because it compared different administrations of iron supplementation.
Wasim 2023	This study will assess the treatment of non‐anaemic iron deficiency (NAID) with iron to improve the outcome of the mother and the offspring. It will be a multicentre randomised controlled trial conducted in multiple clinical academic obstetrics units in Lahore. Pregnant women at gestational age < 20 weeks with haemoglobin 11 to 13 g/L and ferritin below the threshold (< 30 ng/mL) will be invited to take part in the study. One group (usual care or oral group) will be offered a routine care prophylactic dose of oral iron (30 to 45 mg/day) and the other group (intervention arm or IV group) will be offered a therapeutic dose of IV iron (dose calculated by Ganzoni formula) in addition to usual care. This trial has been excluded because it compares different administrations of iron supplementation.
Weil 1977	29 women attending a clinic at University of Basel, Switzerland between May and November 1976 with 20 weeks' gestation were randomly assigned in 1 of 2 groups: Group 1 (n = 15) received 80 mg elemental iron slow release as ferrous sulphate (Tardyferon®). Group 2 (n = 14) received 80 mg elemental iron slow release as ferrous sulphate + 350 μg (0.35 mg) folic acid (gino‐Tardyferon®) until term. Women who had already taken multiple micronutrient supplements containing folic acid were excluded from the study. This study was excluded because both groups received iron. The type of intervention is outside the scope of this review.
West 2014	28,516 pregnant women were provided supplements containing 15 micronutrients (14,374) or iron‐folic acid alone (14,142), taken daily from early pregnancy to 12 weeks postpartum, to assess the effects of antenatal multiple micronutrient vs iron‐folic acid supplementation on 6‐month infant mortality and adverse birth outcomes. Surveillance included 127,282 women; 44,567 became pregnant and were included in the analysis and delivered 28,516 live‐born infants. Median gestation at enrolment was 9 weeks. The study was excluded because it was conceived to assess the effects of antenatal multiple micronutrient vs iron‐folic acid supplementation on 6‐month infant mortality and adverse birth outcomes, and it was not possible to evaluate the role of iron alone in the proposed outcomes. This type of intervention is outside the scope of this review.
Willoughby 1966	350 consecutive pregnant women attending an antenatal care clinic were allocated to 1 of 5 groups: Group 1 received no hematinic supplements. Group 2 received 105 mg of elemental iron daily (as iron chelate aminoates). Group 3 received 105 mg of elemental iron daily with 100 μg (0.1 mg) of folic acid. Group 4 received 105 mg of elemental iron daily with 300 μg (0.3 mg) of folic acid. Group 5 received 105 mg of elemental iron daily with 450 μg (0.45 mg) of folic acid. All women received a multivitamin preparation (Vivatel®) free of folic acid. This study was excluded because it was not a randomised trial.
Willoughby 1968	68 pregnant women attending an antenatal care clinic in Queen Mother's Hospital in Scotland were randomly allocated to receive 195 mg of elemental iron alone daily or 195 mg of elemental iron in conjunction with 300 μg (0.3 mg) of folic acid daily. This study was excluded because both groups received iron.
Winichagoon 2003	484 healthy pregnant women with 13 to 17 weeks of gestation who had not received iron supplements before enrolling in the study, and who had a Hb concentration > 80 g/L, attending antenatal care clinics at the district hospital and 7 health centres from 54 villages in the Province of Khon‐Kaen in north‐east Thailand. The villages were grouped according to size and then randomised in 4 clusters to 1 of 3 interventions: Group 1 received a daily regimen providing 60 mg of elemental iron (as ferrous sulphate) with 250 μg (0.25 mg) of folic acid daily. Group 2 received 120 mg of elemental iron with 3500 μg (3.5 mg) of folic acid once a week. Group 3 received 180 mg of elemental iron (as ferrous sulphate) with 3500 μg (3.5 mg) of folic acid once a week. Supplementation started at 15 ± 2 weeks until delivery. This study was excluded because all groups received iron in different regimens (weekly versus daily) or doses.
Wu 1998	369 pregnant women attending antenatal care at Beijing Hospital, China were divided into 2 groups according to their initial Hb concentrations. Women with Hb 110 g/L or above were randomly assigned to 1 of 2 groups: Group 1 (n = 96) received 1 daily tablet of maternal supplement containing 60 mg of elemental iron in addition to other micronutrients including calcium and magnesium. Group 2 (n = 95) served as control and received no supplements. Another group of women with Hb < 110 g/L (treatment group) were randomly assigned to 1 of 3 groups: Group 1 received 1 tablet of maternal supplement daily. Group 2 received 0.9 g of ferrous sulphate daily. Group 3 received 1 tablet of Ferroids, a sustained released preparation daily. In the preventive group, women entered the study from 20 to 24 gestational weeks. In the treatment groups, women less than 36 gestational weeks were accepted. This study was excluded because it was not a randomised trial.
Xu 2022	This study evaluated the effect of iron‐rich foods (IRFs) on iron status and biomarkers of iron metabolism in the third trimester of pregnancy. 240 pregnant women at 11 to 13 weeks of gestation without iron‐deficiency anaemia (IDA) in South China were recruited to this single‐blind clinical trial (non‐IDA referred to both haemoglobin (Hb) ≥ 110g/L and serum ferritin (SF) ≥ 15 ng/mL), randomly assigned to 1) control, 2) IRFs containing 20 mg iron/d (IRF‐20), or 3) IRFs containing 40 mg iron/d (IRF‐40). The IRFs were consumed 3 days a week, including pork liver, chicken/duck blood, soybean, and agaric. This trial was excluded because the trial assessed dietary interventions.
Yecta 2011	210 pregnant women with 17 to 20 weeks' gestation and singleton pregnancies, no known disease, and Hb levels higher than 110 g/L attending local public healthcare centres at 7 prenatal healthcare clinics between September 2007 and February 2009 in the urban regions of Urmia city North West Iran were randomly assigned to 1 of 3 groups: Group 1 (n = 70) received 2 iron supplementation tablets once‐weekly providing 100 mg elemental iron per week (as ferrous sulfate). Group 2 (n = 70) received 1 tablet twice‐weekly providing 100 mg elemental iron per week (as ferrous sulfate). Group 3 (n = 70) received 1 tablet daily containing 50 mg elemental iron per day (as ferrous sulfate). No additional micronutrients were supplied. Hb and serum ferritin levels were measured at 20, 28, and 38 weeks. Pregnancy and birth outcomes (pregnancy termination, method of delivery, birthweight, stillbirth) were reported. This study was excluded because all participants received iron in different regimens.
Young 2000	413 healthy, non‐severely anaemic pregnant women attending antenatal care at Ekwendeni Hospital or its mobile clinics in northern Malawi with less than 30 weeks of gestation at their first visit, stratified by initial Hb concentration before randomisation. Supplementation starting time variable (22.2 ± 4.8 weeks) and ending time variable (32.2 ± 4.4 weeks of gestation). Participants were randomly assigned within each anaemia grade category to 1 of 2 interventions: Group 1 received 120 mg of elemental iron (as ferrous sulphate) with 500 ?g (0.5 mg) of folic acid once a week. Group 2 received 60 mg of elemental iron (as ferrous sulphate) with 250?g (0.25 mg) of folic acid daily. Outcomes: maternal: Hb concentration at baseline and after 8 weeks of supplementation; compliance, presence of side effects, and prevalence of anaemia. This study was excluded because all women received iron and folic acid in different regimens (daily versus weekly).
Young 2010	This trial examines the relative differences in heme (animal‐based) and non‐heme (ferrous sulphate) iron utilisation in 20 non‐smoking, pregnant women (19 yeas or older; n = 10) and adolescents (18 years of age or younger; n = 10) from the Strong Midwifery Group and the Rochester Adolescent Maternity Program in Rochester, NY, USA and 12 healthy, non‐smoking, non‐pregnant women ages 18 to 27 years recruited in 2009 from Ithaca, NY, USA. Women were randomly assigned to receive both an animal‐based heme meal (intrinsically labelled 58Fe pork) and labelled ferrous sulphate (57Fe) fed on alternate days. This study was excluded because it was not a prospective, parallel, randomised controlled trial.
Yu 1998	51 healthy pregnant women with 18 to 22 weeks of gestation who had not taken supplements or medication in the previous 6 months attending a public health centre in Ulsan, South Korea were randomly assigned to 1 of 2 groups: Group 1 received 160 mg of elemental iron (as ferrous sulphate) in 1 intake once a week. Group 2 received 80 mg of elemental iron (as ferrous sulphate) daily. Women with low Hb were assigned by the trialists to a daily regimen. Supplementation started at 20.1 weeks and 20.2 weeks of gestation for groups 1 and 2, respectively. This study was excluded because both groups received iron in different regimens (weekly versus daily).
Zamani 2008	152 healthy, non‐anaemic pregnant women aged 18 to 38 years, 15 to 16 weeks’ gestation (gestation estimated by menstrual dates and ultrasound) attending 2 clinics for prenatal care in Isfahan, Iran. ("In Iran, it is mandatory to prescribe iron (1 tablet containing 45 mg elemental iron (as ferrous sulphate) per day) and folic acid supplements to pregnant women after the 15th‐ 18th week of gestation"). Exclusion criteria: current anaemia (Hb < 110 g/L), past history of anaemia, thalassaemia, or other blood disorders, history of previous obstetric problems (haemorrhage, pregnancy‐induced hypertension, diabetes) or any other chronic systemic disorder. Participants were assigned to 1 of 2 groups: Group 1 (experimental group) received 2 tablets of 45 mg elemental iron (as ferrous sulphate) taken on a single day each week. “Women in the trial group were instructed to choose any day of the week and to take 2 tablets of 45 mg elemental iron (as ferrous sulphate) each on the same day every week, 1 in the morning and 1 before dinner” i.e. 90 mg of “elemental iron (as ferrous sulphate) 1 day per week in 2 takes”. (Supplied as 8 tablets every 4 weeks) for 16 weeks (from recruitment at 16 to 18 weeks). Group 2 (control group) were to take 1 tablet containing 45 mg elemental iron (as ferrous sulphate) daily for 16 weeks (from recruitment at 16 to 18 weeks). Supplied as 28 tablets every 4 weeks. This study was excluded because both groups received iron in different regimens (weekly versus daily).
Zhou 2009	180 anaemic women (Hb < 110 g/L) attending antenatal care at the Children, Youth and Women's Health Service, Adelaide, Australia with 24 to 32 weeks of gestation and a singleton pregnancy. Women were excluded if they were taking iron or vitamins and minerals supplements, had a presumptive diagnosis of non iron‐deficiency‐related anaemia, history of thalassaemia, drug or alcohol abuse, and/or diabetes requiring insulin or a known fetal abnormality. Women were randomly assigned to receive a daily dose of 20, 40, or 80 mg of elemental iron (as ferrous sulphate) for 8 weeks or until birth. The primary outcomes measured were Hb levels, anaemia at the end of the intervention, and gastrointestinal side effects during treatment. This study was excluded because all participants received different doses of iron.
Zutschi 2004	200 apparently pregnant women with 24 to 26 weeks of gestation, with singleton pregnancy and moderate anaemia (Hb > 80 g/L and < 110 g/L) were randomly assigned to receive injectable iron‐sorbitol‐citrate in 3 intramuscular doses of 150 mg each at 4 weeks intervals or 100 mg of elemental iron daily. Hb concentrations were measured at baseline, every 4 weeks, and at delivery. This study was excluded because it compared two routes of iron administration; both groups received iron.

BMI: body mass index
BRAC: Bangladesh Rehabilitation Assistance Committee
FA: folic acid
Fe: iron
FCM: ferric carboxymaltose
FS: ferrous sulfate
Hb: haemoglobin
HCT: haematocrit (same as PCV: packed cell volume)
ID: iron‐deficiency
IDA: iron‐deficiency anaemia
IDE: iron‐deficient erythropoiesis
IFA: iron and folic acid
IU: international units
IV: intravenous
MCHC: mean corpuscular (or cell) haemoglobin concentration
MCV: mean corpuscular (or cell) haemoglobin concentration
MUAC: mid‐upper arm circumference
RBC: red blood cell
RCT: randomised controlled trial
RDA: recommended dietary allowance
SES: socioeconomic status
SF: serum ferritin
UIE: urinary iodine excretion
UNIMMAP: United Nations International Multiple Micronutrient Antenatal Preparation Multiple Micronutrient Supplements
vs: versus
WIC: Special Supplemental Nutrition Program for Women, Infants, and Children
WHO: World Health Organization

Characteristics of studies awaiting classification [ordered by study ID]

Akyol 2014.

Methods	Randomised controlled study; pregnant women were randomly allocated to iron replacement and non‐replacement group
Participants	85 healthy women, aged 20 to 35, chosen from the intake to the Department of Gynecology and Obstetrics Center at Private Bogazici Hospital
Interventions	Not stated
Outcomes	All of the serum iron and complement parameters were found to be better and statistically significant in the replacement group (P < 0.05).
Notes	Not included in 2024 update because of a trustworthiness red flag discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flag: abstract only We reached out to the authors, asking for clarification, but have had no response.

Alizadeh 2016.

Methods	Double‐blind, controlled randomised clinical trial
Participants	140 non‐smoker healthy pregnant women with gestational age of 14 to 18 weeks and singleton pregnancy with Hb > 13.2 g/dL and ferritin > 15 μg/L
Interventions	Mothers were randomly assigned to 50 mg ferrous sulfate and placebo groups from the 20th week of pregnancy.
Outcomes	There was a significant difference between the 2 groups in Hb (P = 0.03) and ferritin (P = 0.04) levels after the intervention, but no significant difference was found between the 2 groups in the incidence of anaemia (Hb < 11 g/dL) (P < 0.001). In addition, the incidence of neonatal jaundice was more in the interventional group than the placebo (P = 0.005). The incidence of neonatal jaundice was associated with first‐trimester ferritin (P = 0.01).
Notes	Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: the numbers of participants in the trial registration documents do not agree with the numbers given in the publication; two different randomisation methods given in methods section; P values recalculation show different results. We reached out to the authors, asking for clarification, but have had no response.

Corrigan 1936.

Methods	Quasi‐randomised trial with allocation by odd or even numbers; 2‐arm trial
Participants	200 normal pregnant women attending antenatal care clinic with 3 to 7 months of gestational age at Boston City Hospital, Boston, USA
Interventions	Participants were assigned a number in order. Patients who had been assigned an odd number received 0.2 g of ferrous sulphate (3 tablets daily to be taken after meals ‐ total daily dose 0.6 g); patients with even numbers received a placebo that was identical in appearance and size and contained lactose but not ferrous sulphate. Supplements were from recruitment until delivery. Women who took less than 1 of the 2 tablets prescribed daily were excluded. Setting and health worker cadre: the intervention was performed by physicians at the antepartum clinic of Boston City Hospital, Boston, Massachusetts, United States of America.
Outcomes	Number of women with anaemia at 1‐week postpartum. (Figures were also provided for the mean Hb level at 1‐week postpartum but no SD was provided and we were not able to include these data in the analysis.)
Notes	Mean Hb in the intervention group 117 g/L and 112 g/L in the control group Gestational age at start of supplementation: mixed gestational age Anaemic status at start of supplementation: not specified Daily iron dose: higher daily dose (60 mg or more) Iron release formulation: not specified Iron compound: ferrous sulphate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: no mention of ethics or consent; no baseline data; exactly 100 participants in each group with no dropouts; no trial dates. It was not possible for us to reach out to the authors because of the age of the study.

CTRI/2016/10/007373 (first received 2016).

Methods	Not stated
Participants	Pregnant patients completing 5th month of pregnancy
Interventions	Intervention 1: iron and calcium supplements: Group B: 15 patients; calcium carbonate 500 mg and ferrous sulphate 200 mg (containing 60 mg of elemental iron) given daily once Control intervention 1: Madhuraushadha siddha avaleha: Group A: 15 patients; Madhuraushadha siddha avaleha is administered at a dosage of 12 g, twice a day, once in the morning and in the evening, on an empty stomach with ksheera as anupana
Outcomes	Outcome: to evaluate the efficacy of Madhuraushadha siddha avaleha as rasayana in pregnant women and infants Time point: 2 months of drug administration Secondary outcome: efficacy of Madhuraushadha siddha avaleha on fetal and maternal immune system Time point: maternal immunity at end of 7th month; fetal immunity during delivery by cord blood analysis
Notes	Both primi and multi gravida will be included. Participants at 20 to 24 weeks of pregnancy are selected. Participants with Hb% between 8 and 11 g. Not included in 2024 update because it is unclear whether this is a suitable trial intervention, and there are no associated reports yet.

Dixit 2023.

Methods	RCT, 4‐arm trial with individual randomisation
Participants	400 pregnant women, 12 to 30 weeks gestation with anaemia recruited from antenatal or healthcare facilities in India Inclusion criteria: gestational age between 12 and 30 weeks, confirmed diagnosis of anaemia based on haemoglobin levels below a specified threshold, and willingness to participate in the study Exclusion criteria: pre‐existing conditions that could confound the study outcomes or affect iron absorption, such as haemoglobinopathies or chronic diseases Age range of pregnant women reported as: iron: 28.8 ± 3.5 vs placebo: 28.9 ± 3.1 years
Interventions	Participants were randomly allocated to 1 of 4 groups: Group 1 (n = 100): intravenous iron sucrose at prescribed dose and frequency Group 2 (n = 100): oral ferrous ascorbate at prescribed dose and frequency at prescribed dose and frequency Group 3 (n = 100): traditional oral iron supplementation alone, following standard clinical practice guidelines Group 4 (n = 100): placebo For the purposes of this review, traditional oral iron supplementation will be compared with placebo. Setting and health worker cadre: pregnant women were recruited from antenatal clinics or healthcare facilities. Duration of supplementation not reported. No information is reported on the dose of iron supplementation ("The dosing regimen for each intervention group was predetermined based on established guidelines or literature evidence.")
Outcomes	Primary: haemoglobin (baseline to specific time points during study), proportion of participants achieving target haemoglobin levels, and adverse effects/tolerability of the interventions. Secondary: preterm birth, low birthweight, perinatal mortality, quality of life assessments, compliance rates, and patient satisfaction. Insufficient information on time point and tools used in measurement of outcomes
Notes	Compliance: monitored through regular follow‐up visits, participant self‐reporting, and medication reconciliation; ion: 89% vs placebo: 95% Gestational age at start of supplementation: 12 to 30 weeks Anaemic status at start of supplementation: anaemic Daily iron dose: not reported Iron release formulation: not reported Iron compound: not reported ("traditional iron group") Malaria setting: malarial risk. As of 2022: "The WHO South‐East Asia Region had nine malaria endemic countries in 2022, accounting for 5.2 million cases and contributing to 2% of the burden of malaria cases globally (Table 3.3). In 2022, India accounted for about 65.7% of all malaria cases in the region (Fig. 3.5c). Almost 46% of all cases in the region were due to P. vivax." Dates of study: not reported Funding sources: not reported Declarations of interest: not reported Ethical approval: "The trial adhered to ethical principles, including informed consent procedures, protection of participants' privacy and confidentiality, and data handling in accordance with applicable regulations." Outcome data were not reported in a form for inclusion in statistical meta‐analysis; no data from this trial contributed data. Trial author was contacted for additional information (pending). Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: no trial registration; no ethical supervisory body mentioned; recruitment centre unclear; exactly 100 in each group with no participant dropouts; no trial dates given; does not state dosing, rather that "the dosing regimen for each intervention group was predetermined based on established guidelines or literature evidence". We reached out to the corresponding author twice but have had no response.

Hamzehgardeshi 2009.

Methods	A randomised, double‐blind, placebo‐controlled trial
Participants	87 pregnant women 17 to 35 years of age, Hb more than or equal to 132 g/L and ferritin ≥ 143 g/L with 13 to 18 weeks of gestation, body mass index (BMI) between 19.8 and 26 kg/m2 and singleton pregnancy
Interventions	Participants will be randomly assigned to 1 of 2 groups: group 1 ferrous sulphate, 150 mg tablet with 50 mg ferrous elemental, daily, from 20th gestational week to the end of pregnancy and group 2 placebo tablets, 1 tablet daily, from 20th gestational week to the end of pregnancy.
Outcomes	Hb, HCT, MCV, MCH, MCHC, and RBCs were measured in gestational weeks 24 to 28 and 32 to 36
Notes	Source of funding: Tarbiat Modarres University. Not included in 2024 update because of a trustworthiness red flag discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flag: no associated reports. We reached out to the authors twice but have had no response.

Han 2011.

Methods	Quasi‐randomised controlled trial with 3 arms and individual allocation to groups by order of enrolment
Participants	153 anaemic pregnant women 12 to 24 weeks' gestation, age range 20 to 30 years, with 80 ≤ Hb <110 g/L, no dietary supplements used during the previous 2 months and no abnormal pregnancy response, recruited from the communities of Shen county, Shandong province, China
Interventions	Participants were allocated to 1 of the 3 groups in the order of enrolment: Group 1 (n = 51) was the placebo control. Group 2 (n = 51) received a supplement daily containing 60 mg elemental iron (as ferrous sulphate). Group 3 (n = 51) received a supplement daily containing 60 mg elemental iron (as NaFeEDTA). The capsules were labelled in red, yellow, and blue colours and manufactured by Hurun’s company (a Chinese food‐additive company, Beijing). The intervention lasted 2 months. Women were visited at home once each week by the village nurse to replenish supplements and to monitor compliance by counting and recording the number of supplements that were taken. Setting and health worker cadre: the intervention was performed by village nurses in house visits to the participants in the communities of Shen county, Shandong province, China.
Outcomes	Hb concentration; plasma iron; soluble transferrin receptor; total iron‐binding capacity; MDA; SOD; glutathione peroxidase
Notes	The participants in the placebo group in this study were given iron supplementation with NaFeEDTA or foods rich in iron, such as the haemachrome‐iron from animal foodstuffs, such as meat, fish, and seafoods, immediately after the trial. Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: anaemic status Daily iron dose: higher daily dose (60 mg or more elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate and iron EDTA Malaria setting: yes. As of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine–pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas. Not included in 2024 update because of a trustworthiness red flag discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flag: no registration We reached out to the authors, asking for clarification, but have had no response.

Hankin 1963.

Methods	Quasi‐randomised trial, 2 arms with individual randomisation
Participants	174 primigravidae or secundigravidae at their first visit at the antenatal Clinic of Queen Elizabeth Hospital in Woodville, Australia with ability to write and speak English
Interventions	Participants were divided into a supplemented group receiving a daily dose of 100 mg of elemental iron (as ferrous gluconate) or a control group that was un supplemented. Supplementation started during 2nd trimester and ending time is unclear. Setting and health worker cadre: the intervention was performed by physicians at the Queen Elizabeth Hospital in Woodville, South Australia.
Outcomes	Maternal: Hb and HCT at 20 to 30 weeks, 30 to 40 weeks, at 5 days, at 6 weeks, and at 3 months postpartum Infant: Hb from umbilical cord, at 6 weeks, at 3 months, and at 6 months of age (not reported)
Notes	Unsupervised Compliance not reported Gestational age at start of supplementation: mixed/unspecified gestational age Anaemic status at start of supplementation: mixed/unspecified anaemia status Daily iron dose: higher daily dose (60 mg or more elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous gluconate Malaria setting: non‐malarial setting. As of 2011: Malaria: no risk. Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: no mention of ethics or consent; no trial dates; unclear randomisation; no dropouts mentioned It was not possible for us to reach out to the authors because of the age of the study.

Jafarbegloo 2010.

Methods	Double‐blind clinical trial with 2 arms
Participants	139 pregnant women with Hb higher than 132 g/L from the 20th week to the end of pregnancy
Interventions	Participants are randomly assigned to 1 of 2 groups: Group 1 (n = 88): 1 ferrous sulphate pill containing 50 mg elemental iron (as ferrous sulphate) daily Group 2 (n = 51): 1 placebo tablet daily Supplementation started from the 20th week to the end of pregnancy.
Outcomes	Side effects at 24th and 36th week of gestation.
Notes	Source of funding: researcher Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: study dates in the trial registration do not agree with the dates given in the paper; exactly the same numbers in each participant group; randomisation unclear. We reached out to the authors, asking for clarification, but have had no response.

Korkmaz 2014.

Methods	Randomised, double‐blind, placebo‐controlled trial with 3 arms
Participants	108 pregnant women with singleton pregnancies without a risk factor for poor pregnancy outcome, systemic disorder, any medication and any previous surgery attending outpatient clinic of Dr Sami Ulus Maternity and Women’s Health Training and Research Hospital, Ankara, Turkey, between November 2010 and January 2012. Women with iron‐deficiency anaemia (determined according to Hb lower than 110 g/L), pre‐existing diabetes, prior gestational diabetes, a history of stillbirth, multiple gestation, active chronic systemic disease, and smokers were excluded.
Interventions	Participants were randomly assigned to 1 of 3 groups: Group 1 (n = 36) received 400 μg (0.4 mg) folic acid daily. Group 2 (n = 36) received 60 mg elemental iron daily. Group 3 (n = 36) received placebo. Supplementation started at 6th week of gestation until term.
Outcomes	Antepartum, intrapartum, and neonatal information was abstracted from the antenatal medical records and from inpatient hospital records. Gestational age at delivery, Apgar (1st min), Apgar (5th min), birthweight (g), albumin (mg/dL), serum GGT (IU/L), weight gain (kg), post‐term deliveries (beyond the 42nd week of gestation), the preterm premature rupture of membranes (spontaneous membrane rupture before 37th week of gestation).
Notes	Gestational age at start of supplementation: early, if supplementation started before 20 weeks' gestation Anaemic status at start of supplementation: non‐anaemic Daily iron dose: 60 mg elemental iron Iron release formulation: normal release preparation/unspecified Iron compound: other/not specified Malaria setting: malaria‐free Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: no trial registration; exactly the same number of participants in each group, with no dropouts We reached out to the authors, asking for clarification, but have had no response.

Liu 2000.

Methods	RCT with 3 arms and individual randomisation
Participants	300 pregnant women at 24 to 28 weeks of gestation, with no organic disease and Hb level higher than 100 g/L who received antenatal examinations at the Second Affiliated Hospital, Zhujiang Hospital, the First Military Medical University, Guangzhou, China from January 1998 to January 1999
Interventions	Participants were randomly assigned to 1 of 3 groups: Group 1 received 1 tablet daily containing 100 mg elemental iron (as ferrous sulphate sustained‐release) with 500 mg vitamin C and B‐complex vitamins (amounts not reported) administered orally for 4 consecutive weeks. Group 2 received conventional iron supplement (as 300 mg ferrous sulphate) administered 3 times a day to meals for 4 consecutive weeks. Group 3 did not receive any iron supplementation. Setting and health worker cadre: intervention and outcome assessment were conducted by physicians from the Obstetric & Gynecology Department, Zhujiang Hospital, the First Military Medical University, Guangzhou, China.
Outcomes	RBC, Hb, and serum ferritin at baseline, after 4 weeks of intervention, and before delivery. Anaemia, iron deficiency, fatigue, dizziness, shortness of breath, and pale mucous membranes and skin, tinnitus, presence of stomatitis or glossitis, premature birth, average Apgar score, congenital malformations. Side effects reported: nausea and loss of appetite, severe gastrointestinal reactions including vomiting, abdominal pain, and diarrhoea, metallic taste in the mouth, black staining of their teeth. Blood tests and serum ferritin measurement were performed for the gravidas after 4 and 8 weeks of supplementation and before delivery. Apgar scoring and physical examinations were performed for the newborns after delivery.
Notes	Gestational age at start of supplementation: late gestational age (supplementation started at 20 weeks' gestation or later). Only groups included in the comparisons are group 2 and group 3, who did not receive supplements. Anaemic status at start of supplementation: non‐anaemic Daily iron dose: high daily dose (60 mg or more mg iron daily) Iron release formulation: normal and slow release preparation for group 1 (not included in the comparisons in this review) Iron compound: ferrous sulphate Malaria setting: yes. As of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine‐pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas. Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: no mention of ethics or consent; unclear randomisation; exactly the same number of participants in each group, with no dropouts mentioned We reached out to the authors, asking for clarification, but have had no response.

Ma 2010.

Methods	RCT with 4 arms including a placebo, and individual randomisation
Participants	164 anaemic pregnant women (80 g/L, Hb, 110 g/L), 12 to 24 weeks' gestation and 20 to 35 years old recruited between March 2004 and September 2006 from the community hospitals of Shen County in the central area of China
Interventions	Participants were randomly allocated to 1 of 4 groups for this 2‐month intervention in the order of recruitment: Group 1 (n = 41) received placebo. Group 2 (n = 41) received 60 mg elemental iron (as ferrous sulphate). Group 3 (n = 41) received 60 mg elemental iron (as ferrous sulphate) and 400 μg (0.4 mg) folic acid daily. Group 4 (n = 41) received 60 mg elemental iron (as ferrous sulphate), and 400 μg (0.4 mg) folic acid, 2 mg retinol and 1 mg riboflavin daily. Setting and health worker cadre: in each community, a local female community health worker called ‘village nurse’ was responsible for the recruitment and distribution of the supplements. Women were recruited from the community hospitals and then home‐visited once a week by the village nurse to replenish supplements and to monitor compliance by counting and recording the number of supplements that were taken. The nurse also provided counselling about the possible side effects.
Outcomes	Hb, plasma iron, ferritin, folic acid, retinol riboflavin after the 2 months intervention. Other outcomes included membrane fluidity, oxidative stress markers such as GSH‐Px, SOD, and MDA.
Notes	This study is included but does not provide any data that can be useful for purposes of this review. Gestational age at start of supplementation: unspecified or mixed gestational ages at the start of supplementation. Anaemic status at start of supplementation: anaemic. Daily iron dose: high daily dose (60 mg or more mg iron daily). Iron release formulation: normal. Iron compound: ferrous sulphate. Malaria setting: yes. Malaria as of 2011: Malaria risk, including P.falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P.falciparum resistance to chloroquine and sulphadoxine–pyrimethamine reported. Limited risk of P.vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas. Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: no trial registration; same dates and same setting for participants as the study Sun 2010, but no mention of each other in either publication, although both have almost exactly the same wording. We reached out to the authors, asking for clarification, but have had no response.

NCT04101461 (first received 2019 Sep 24).

Methods	Randomised, parallel assignment, open‐label clinical trial
Participants	Inclusion criteria: Pregnant woman with a singleton pregnancy (12 to 14 weeks) BMI (30 to 40 kg/m2) Normal haemoglobin level (> 11 g/dL) Normal haematocrit (Hct 31% to 41%) Normal ferritin level (6 to 130 ng/mL) Women willing to participate in the study Women living in the nearby area, to make follow‐up visits possible Exclusion criteria: Multiple gestations Women received a recent blood transfusion Women with threatened miscarriage Women known to have pathological blood loss Intolerant to oral iron form History of haematologic disorder Women who used iron in the past 3 months Women with chronic diseases (hypertension, diabetes, renal diseases, thyroid disease)
Interventions	Active comparator: Group I: 27 mg elemental iron; will receive PharaFerro27; Devart Lab Company, Egypt; once daily starting at 12 to 14 weeks until 37 to 38 weeks Active comparator: Group II: 54 mg elemental iron; will receive 2 tablets of PharaFerro27; Devart Lab Company, Egypt; daily starting at 12 to 14 weeks until 37 to 38 weeks
Outcomes	Primary outcome measures: The number of anaemic women at time of delivery (time frame: 6 months) Secondary outcome measures: The mean level of maternal haemoglobin at 37 to 38 weeks (time frame: 6 months) The incidence of patients' reported side effects (time frame: 6 months) The difference in serum ferritin (time frame: 6 months) The difference in serum hepcidin (time frame: 6 months)
Notes	No associated reports yet

NCT04810546 (first received 2021 Mar 23).

Methods	Interventional clinical, randomised, parallel assignment, single‐masked (outcomes assessor) trial
Participants	40 participants (obese women at risk of iron deficiency anaemia (Hb 11.0 to 12.0 g/dL (first trimester)/10.5 to 11.5 g/dL (second trimester) for non‐Black women and 10.2 to 11.2 g/dL (first trimester)/9.7 to 10.7 g/dL (second trimester) for Black women) from 15 to 20 weeks of gestation (WG) until the time of labour)
Interventions	Experimental: Jarrow Formulas Oral Bovine Lactoferrin Supplement Once daily Oral Lf (250 mg). Women assigned to this group will be instructed to consume an oral Lf capsule 1 hour prior to their afternoon meal and 2 prenatal vitamin/mineral supplement gummies without iron with omega‐3 fatty acids before bed from early second trimester (15 to 20 WG) up through delivery. Women are advised to consume the Lf prior to meals, given our team member Valenti's unpublished work shows its superior efficacy for improving iron and haematological parameters among pregnant women with hereditary thrombophilia versus when consumed with meals. The prenatal vitamin/mineral gummies will be a commercially available product (One‐a‐Day Women's Prenatal Gummies with omega‐3 fatty acids, Bayer Healthcare, Whippany, NJ). Women in both groups will be advised to consume an iron‐rich diet and provided a handout detailing foods rich in heme and non‐heme iron. Dietary Supplement: Jarrow Formulas Oral Bovine Lactoferrin Supplement Lactoferrin (Apolactoferrin) 250 mg contains ~17.6 mg/100 g of iron No intervention: usual care "Women assigned to this group will be instructed to consume a commercially available prenatal vitamin/mineral supplement with iron and omega‐3 fatty acids (Prenatal 1, Bayer Healthcare, Whippany, NJ) before bed from early second trimester (15‐20 WG) through delivery. To minimize variability in prenatal vitamin/supplement use across the participants, we have opted to standardize the prenatal vitamin/mineral supplement by providing women in the usual care arm a supplement that is nutritionally like what is prescribed by the Center for Women's Health providers. Women will be advised to consume an iron‐rich diet and provided a handout describing foods rich in heme and non‐heme iron."
Outcomes	—
Notes	No associated papers yet

NCT05423249 (first received 2022).

Methods	Randomised, parallel assignment, double‐masked interventional trial
Participants	150 pregnant females Inclusion criteria: English speaking Age 18 to 55 Less than 20 weeks gestational age Low ferritin level (< 30 μg/L) in the first trimester Normal haemoglobin level (> 11 g/dL) in the first trimester Exclusion criteria: Women with anaemia diagnosed in the first trimester (HgB ≤ 11 g/dL) Women with antepartum iron supplementation, except prenatal vitamins, within 3 months Women with iron overload or hypersensitivity Women with significant vaginal bleeding prior to enrolment Women with chronic illness: SLE, haemoglobinopathies, HIV, inflammatory bowel disease, active cancer, prior bariatric surgery
Interventions	The treatment group will receive oral ferrous sulfate 325 mg (containing 65 mg of elemental iron) once daily, an oral prenatal vitamin once daily, oral ascorbic acid 500 mg once daily, and oral docusate sodium 100 mg twice daily as needed. The placebo group will receive a placebo pill, the same oral prenatal vitamin, and oral docusate sodium 100 mg twice daily as needed.
Outcomes	Primary outcome measures : Delivery admission haemoglobin (time frame: from date of randomisation until to 42 weeks); haemoglobin value < 11 mg/dL Third trimester haemoglobin (time frame: 28 weeks to 36 weeks); incidence of anaemia, haemoglobin value < 11 mg/dL, in the third trimester Secondary outcome measures: Maternal anaemia (time frame: enrolment to 30 days postpartum); timing of diagnosis Incidence of preterm delivery (time frame: enrolment to 30 days postpartum); preterm delivery rate Incidence of maternal haemorrhage (time frame: enrolment to 30 days postpartum); postpartum haemorrhage rate Incidence of treatment of anaemia (time frame: enrolment to 30 days postpartum); need for IV iron or blood transfusion Incidence of infection (time frame: enrolment to 30 days postpartum); infection rate Maternal hospital stay (time frame: enrolment to 30 days postpartum); length of hospital stay Infant weight (time frame: time of birth to 30 days of life) Incidence of neonatal intensive care unit admission (time frame: time of birth to 30 days of life) Rate of poor perinatal outcome (time frame: time of birth to 30 days of life)
Notes	No associated reports yet

Ouladsahebmadarek 2011.

Methods	RCT with 2 arms and individual randomisation
Participants	960 healthy women in the first trimester of pregnancy with Hb > 120 g/L and blood pressure < 140/90 mmHg from Alzahra University dependent hospital in Vanak,Tehran, Iran
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1 received daily 1 multiple micronutrient + 30 mg elemental iron from week 13 of gestation until delivery. Group 2 received daily 1 daily multiple micronutrient + placebo tablet from 13 weeks of pregnancy until delivery. Setting and health worker cadre: the intervention was conducted by obstetricians and gynaecologists from the Alzahra hospital, in Iran.
Outcomes	Hb concentrations, HCT, serum iron, serum ferritin, total iron binding capacity at baseline and at delivery, birthweight, gestational age at birth, prematurity, intrauterine growth retardation, 1 min Apgar score, 5 min Apgar score, admission duration in neonatal care intensive unit, premature rupture of membranes, placenta abruption, pre‐eclampsia, periventricular‐intraventricular haemorrhage (PIH), gestational diabetes, intrauterine fetal death (IUFD), oligohydramnios
Notes	Both groups were matched for mother's age, BMI, parity, previous obstetric history and iron parameters. Gestational age at start of supplementation: early gestational age (less than 20 weeks' gestation at the start of supplementation) Anaemic status at start of supplementation: non‐anaemic status at the start of supplementation Daily iron dose: 30 mg elemental iron Iron release formulation: normal release preparation/not specified Iron compound: not specified Malaria setting: yes. As of 2011: Malaria risk due to P. vivax and P. falciparum exists from March to November inclusive in rural areas of the provinces of Hormozgan and Kerman (tropical part) and the southern part of Sistan‐Baluchestan. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported. Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: no trial registration; no mention of ethics; unclear randomisation; no trial dates; P values re‐calculable and sample shows errors The Cochrane office was unable to contact the authors, so we could not enquire about these red flags.

PACTR201804003188338 (first received 2018).

Methods	Randomised controlled trial
Participants	Subjects willing and able to give informed consent for participation in the trial. Pregnant women who have a singleton fetus. Aged 18 to 44 years. Gestational age between 14 and 27 weeks of pregnancy.
Interventions	Tablet ferrous sulphate (200 mg tablet containing 60 mg of elemental iron), Spatone iron‐plus solution
Outcomes	Primary outcome: haemoglobin concentration on day 28 post‐randomisation Secondary outcome: serum ferritin concentration on day 28 post‐randomisation
Notes	Unclear whether this is a suitable intervention for this review. No associated reports yet.

Sun 2010.

Methods	Quasi‐randomised trial with individual assignment in order of enrolment
Participants	186 anaemic pregnant women, 12 to 24 weeks' gestation, age between 20 and 30 years with Hb concentration ≥ 80 and < 110 g/L, no dietary supplements during the previous 2 months, and no abnormal pregnancy response from the communities of Shen County in a central rural area of China.
Interventions	Participants were randomly allocated in the order of enrolment to 1 of 4 groups: Group 1 (n = 47) was supplemented daily with 60 mg elemental iron (as ferrous sulphate). Group 2 (n = 46) received 60 mg elemental iron (as ferrous sulphate) and 400 μg (0.4 mg) folic acid. Group 3 (n = 46) received 60 mg elemental iron (as ferrous sulphate), 2 mg retinol, and 400 μg (0.4 mg) folic acid. Group 4 (n = 47) was the placebo control group. The capsules were coloured red, yellow, green, and blue during manufacture by Hurun (a Chinese food‐additive company, Beijing). The capsules were to be taken daily for 2 months. Setting and health worker cadre: the study was carried out in communities of Shen County in a central rural area of China. Women were home‐visited once a week by the village nurse to replenish supplements and to monitor compliance by counting and recording the number of supplements that were taken.
Outcomes	Hb concentration; plasma iron; plasma retinol and plasma folate; erythrocyte protoporphyrin; interleukin 2; lymphocyte proliferation at baseline and after 2 months intervention.
Notes	Relevant comparisons for this review: group 1 (n = 47) was supplemented daily with 60 mg elemental iron (as ferrous sulphate) vs group 4 (n = 47) was the placebo control group. group 2 (n = 46) received with 60 mg elemental iron (as ferrous sulphate) and 400 μg (0.4 mg) folic acid vs group 4 (n = 47) was the placebo control group. Gestational age at start of supplementation: mixed gestational age at the start of supplementation (12‐24 weeks' gestation). Anaemic status at start of supplementation: anaemic at the start of supplementation (Hb < 110 g/L). Daily iron dose: higher daily dose (60 mg elemental iron). Iron release formulation: normal release preparation/not specified. Iron compound: ferrous sulphate. Malaria setting: yes. As of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine–pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas. Supported by Danone Nutrition Institute China. Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: no trial registration; same dates and same setting for participants as the study Ma 2010, but no mention of each other in either publication, although both have almost exactly the same wording. We reached out to the authors, asking for clarification, but have had no response.

Ziaei 2007.

Methods	RCT, 2 arms with individual randomisation
Participants	750 apparently healthy, non‐smoking, non‐anaemic (with Hb higher or equal to 132 g/L) pregnant women in the early stage of second trimester, BMI 19.8 to 26 kg/m2 and age 17 to 35 years with singleton pregnancy attending prenatal care in Tehran, Iran. Women with history of threatened abortion in the present pregnancy or diseases related to polycythaemia such as asthma and chronic hypertension were not included.
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1 received 50 mg of elemental iron (as ferrous sulphate) + 1000 μg (1 mg) folic acid daily. Group 2 received placebo and 1000 μg (1 mg) of folic acid daily. Setting and health worker cadre: the intervention was performed by midwives and physicians at multiple urban clinical centres in Tehran, Iran.
Outcomes	Maternal: Hb at 24 to 28 weeks, 32 to 36 weeks, premature delivery, weight gain, caesarean sections, hypertensive disorders, severe anaemia, high Hb concentrations, iron deficiency, iron‐deficiency anaemia, MCV, MCH, and MCHC at term, severe anaemia and high Hb concentrations at any time during 2nd to 3rd trimesters, symptomatic tract infection, puerperal infection, antepartum and postpartum haemorrhage, transfusion provided, side effects (any), diarrhoea, constipation, nausea, heartburn, vomiting, placental abruption, premature rupture of membranes. Infant: birthweight, perinatal mortality rate, low Apgar at 10th minute, small‐for‐gestational age.
Notes	Unsupervised Supplementation started 13.07 ± 2.02 weeks' gestation for group 1 and 13.66 ± 3.45 weeks' gestation for the placebo group and lasted until after delivery. No compliance reported Gestational age at start of supplementation: early gestational age at the start of supplementation (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: medium iron dose (50 mg elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: yes. As of 2011: Malaria risk due to P. vivax and P. falciparum exists from March to November inclusive in rural areas of the provinces of Hormozgan and Kerman (tropical part) and the southern part of Sistan‐Baluchestan. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported. Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: no mention of consent; randomisation method unclear; no trial dates; sample of P values recalculated and shows errors The Cochrane office was unable to contact the authors, so we could not enquire about these red flags.

Ziaei 2008.

Methods	RCT, 2 arms with individual randomisation
Participants	244 pregnant women 17 to 35 years of age attending prenatal care in Tehran, Iran, with BMI between 19.8 and 26 kg/m2, and 13 to 18 weeks of gestation, with singleton pregnancy and non‐anaemic (Hb 132 g/L or higher) and normal serum ferritin (15 μg/L or higher). Women who smoked, had a history of diseases such as polycythaemia, asthma, or chronic hypertension, or a history or threatened abortion in the present pregnancy were excluded.
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1 received 50 mg of elemental iron (as ferrous sulphate) daily. Group 2 received placebo from 20th week of gestation until delivery. All women received 50 mg elemental iron (as ferrous sulphate) after delivery for 6 weeks. Setting and health worker cadre: the intervention was performed by midwives and physicians at a prenatal clinic in Tehran, Iran.
Outcomes	Maternal: Hb, HCT, serum ferritin at baseline, at time of delivery, 1 week postpartum and 6 weeks postpartum, postpartum haemorrhage, caesarean sections.
Notes	Unsupervised No compliance reported Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) Anaemic status at start of supplementation: non‐anaemic Daily iron dose: medium dose (50 mg elemental iron) Iron release formulation: normal release preparation/unspecified Iron compound: ferrous sulphate Malaria setting: yes. As of 2011: Malaria risk due to P. vivax and P. falciparum exists from March to November inclusive in rural areas of the provinces of Hormozgan and Kerman (tropical part) and the southern part of Sistan‐Baluchestan. P. falciparum resistant to chloroquine and sulphadoxine‐pyrimethamine reported. Not included in 2024 update because of trustworthiness red flags discovered by using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (Alfirevic 2023). Trustworthiness red flags: no mention of ethics or consent; randomisation method unclear; no trial dates The Cochrane office was unable to contact the authors, so we could not enquire about these red flags.

BMI: body mass index
EDTA: ethylenediaminetetraacetic acid
GSH‐Px: glutathione peroxidase
Hb: haemoglobin
HCT: haematocrit (same as PCV: packed cell volume)
IV: intravenous
MCH: mean corpuscular (or cell) haemoglobin
MCHC: mean corpuscular (or cell) haemoglobin concentration
MCV: mean corpuscular (or cell) volume
MDA: malondialdehyde
NaFeEDTA: sodium ferric ethylenediaminetetraacetate
RBC: red blood cell
RCT: randomised controlled trial
SD: standard deviation
SLE: systemic lupus erythematosus
SOD: superoxide dismutase
WG: weeks of gestation

Characteristics of ongoing studies [ordered by study ID]

ISRCTN16425597 2023.

Study name	Prevention of anaemia with oral iron supplementation
Methods	Double‐blind, placebo‐controlled, randomised trial
Participants	11,020 pregnant women aged at least 18 years, at 12 weeks' gestation will be recruited from hospitals in the United Kingdom. Women will be randomly assigned to 1 of 2 groups. Inclusion criteria: Healthy non‐anaemic pregnant women of all parities (haemoglobin concentration (Hb) ≥ 110 g/L measured by the first‐trimester blood profile) at booking or screening A live fetus on a first‐trimester ultrasound scan carried out for viability or dating 15 weeks + 6 days gestation or less Aged 18 years and above Able to give informed consent and willing to fulfil trial requirements Exclusion criteria: Known haemoglobinopathies (women with haemoglobinopathy trait are still eligible) Anaemia of any type, defined by British Society for Haematology guidelines Severe gastrointestinal disease requiring ongoing treatment and potentially affecting tolerability of oral iron Allergies to iron Multiple pregnancies, given the higher iron demands Known haemochromatosis Recent red cell transfusion, within 30 days
Interventions	Intervention 1. Iron group: ferrous sulphate 200 mg daily Control 2. Placebo Duration: 34 weeks (approximately 12 weeks' gestation to 6+ weeks post‐delivery)
Outcomes	Primary outcome measure: A composite outcome of the proportion of pregnancies with pre‐term birth (< 37 completed weeks gestation), stillbirth (at 24 weeks gestation or above), neonatal death (up to 28 days) and small for gestational age (SGA) (< 10th centile sex‐specific weight for age, defined by UK growth charts) Secondary outcome measures: Secondary outcomes relating to the mother are as follows: 1. Components of the composite primary outcome measured using case report form (CRF): 1.1. Pre‐term birth (< 37 completed weeks gestation) 1.2. Small for gestational age (< 10th centile sex‐specific weight for age) 1.3. Stillbirth (at 24 weeks gestation or above) 1.4. Neonatal death (up to 28 days) 2. Proportion of women developing anaemia during pregnancy measured using CRF 3. Mean transitions in haemoglobin measured using CRF from recruitment to 28 weeks and birth 4. Proportion of women with primary postpartum haemorrhage (PPH) measured using CRF 5. Proportion of women requiring red cell transfusions measured using CRF prior to discharge but not more than 48 hours post‐birth 6. Proportion of women receiving an iron infusion measured using CRF prior to discharge and up to 6 weeks after birth 7. Proportion of women with an infection and/or sepsis measured using CRF before discharge and up to 6 weeks after birth 8. Proportion of women breastfeeding or providing breast milk for pre‐term infant or baby measured using CRF at discharge from maternity care and at 6 weeks 9. Proportion of women with postpartum depression/psychosis measured using CRF at 6 weeks post‐birth 10. Mean adherence to medication measured using the MGL‐4 score at 28 weeks 11. Health‐related quality of life (HRQoL) measured using EQ‐5D‐5L at baseline, 28 weeks and at 6 weeks post‐birth 12. Healthcare utilisation measured using CRF over the trial period Secondary outcomes relating to the infant are as follows: 1. Mean birthweight measured using CRF 2. Mean gestation at birth measured using CRF 3. Apgar score at 5 minutes post‐birth 4. Proportion of infants treated for possible neonatal early‐onset infection, measured using CRF up to 6 weeks post‐birth 5. Proportion of infants with culture‐positive neonatal early‐onset infection, measured using CRF up to 6 weeks post‐birth 6. Proportion of infants admitted to neonatal/transitional care, measured using CRF up to 6 weeks post‐birth 7. Healthcare utilisation including initial hospital stay, subsequent hospital readmissions, measured using CRF up to 6 weeks post‐birth
Starting date	16 October 2023 to 1 August 2025
Contact information	Dr Catherine Bain (Scientific) Long Road Cambridge CB2 0PT United Kingdom +44 (0)1223 588182 Catherine.bain@nhsbt.nhs.uk Dr Simon Stanworth (Principal Investigator) John Radcliffe Hospital Oxford OX3 9BQ United Kingdom +44 (0)1865 381037 simon.stanworth@nhsbt.nhs.uk
Notes	Ethics approval(s): Approved 17/11/2023, North of Scotland Research Ethics Committee 1 (Summerfield House, 2 Eday Road, Aberdeen, AB15 6RE, United Kingdom; +44 (0)1224 558458; gram.nosres@nhs.scot), ref: 23/NS/0123 Funding source: National Institute for Health Research, NIHR Research, NIHRresearch, NIHR ‐ National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR

IFA: iron and folic acid
Hb: haemoglobin
HCT: haematocrit (same as PCV: packed cell volume)
MCH: mean cell haemoglobin
MCHC: mean cell haemoglobin concentration
MCV: mean cell volume
MM: multiple micronutrient
RBC: red blood cell
PCR: polymerase chain reaction

Differences between protocol and review

In this review update, we incorporated the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (CPC‐TST).

This review updates Peña‐Rosas 2015. It includes five new trials and excludes 10 previously included studies as they did not meet the pre‐defined trustworthiness criteria based on the CPC‐TST. Studies were categorised as 'Awaiting classification' if they did not meet the trustworthiness criteria, authors could not be contacted and/or no author correspondence was received in response to study design queries. Studies that meet the aforementioned criteria will be reassessed in the next update of this review.

The previous versions of this review (Peña‐Rosas 2015; Peña‐Rosas 2012) updated part of Peña‐Rosas 2009 to only evaluate the effects of a daily oral iron supplementation regimen (with or without folic acid or other vitamins and minerals). A separate review addresses the efficacy of intermittent iron and folic acid supplementation regimens for women during pregnancy (Peña‐Rosas 2015a).

Outcomes

In the previous versions of this review, the following outcomes were updated:

• Only pre‐specified primary and secondary outcomes were reported.

• We retained a description of the lay health worker cadre and setting for each trial.

• We continued to include a time frame for haematological variables: at or near term (34 weeks or more gestational age) and at term (37 weeks or more of gestational age).

• We retained the outcome 'congenital anomalies (including neural tube defects)' instead of birth defects.

• Comparisons were changed to evaluate the effects of daily tablets containing iron (alone or with any other micronutrients) versus no iron; iron alone; iron and folic acid; as well as the additional effects of iron alone or iron + folic acid in combination with other vitamins and minerals.

Methods

In this review update, we assessed all studies using the CPC‐TST for assessing trustworthiness.

In the previous versions of this review, methods were updated to include the Cochrane methodological guidance (Higgins 2011), and the Methodological Expectations of Cochrane Intervention Reviews (MECIR) standards (Higgins 2021), including on:

• the use of formal tests for subgroup analyses using random‐effects models;

• reporting relevant intervention groups from included studies with multiple treatment arms;

• the adjustment of cluster trials;

• assessing risk of bias in included studies with additional considerations for cluster‐randomised trials, using the RoB 1 tool;

• the inclusion of summary of findings tables to assess the overall certainty of the evidence for primary outcomes.

Contributions of authors

Juan Pablo Peña‐Rosas wrote the initial protocol and led the first three versions of the review; and Juan Pablo Peña‐Rosas, Maria Nieves Garcia‐Casal, Luz Maria De‐Regil, and Therese Dowswell conducted the previous review update. The methods' section of this protocol was based on a standard protocol provided by Cochrane Pregnancy and Childbirth.

In this review update, Cochrane Pregnancy and Childbirth conducted the updated search, and Anna Cuthbert and Jo Weeks applied the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool to the previous and new trials, and drafted these sections of the methods and results. Jo Weeks, Anna Cuthbert, Sudha Venkatramanan, and Doreen Larvie conducted data extraction and risk of bias assessments for the additional trials in the search, and Anna Cuthbert developed the GRADE evidence profiles for the critical outcomes. Jo Weeks, Anna Cuthbert, Sudha Venkatramanan, Doreen Larvie, and Julia Finkelstein updated the results section. Julia Finkelstein, Sudha Venkatramanan, and Doreen Larvie developed the revised background and discussion sections. All authors revised the review draft, and contributed to and approved the final version of the review. Julia Finkelstein has responsibility for the final content.

Sources of support

Internal sources

• Department of Nutrition for Health and Development, World Health Organization, Switzerland

  Maria Nieves Garcia‐Casal and Luz Maria De‐Regil are full‐time staff of the World Health Organization.

• University of Liverpool, UK

  The University of Liverpool provided support for Jo Weeks and Anna Cuthbert to work on this review update.

External sources

• Children's Investment Foundation Fund (CIFF) Project, UK

  The Children's Investment Foundation Fund (CIFF) provided funding to the University of Liverpool. This funding provided salary support for Jo Weeks and Anna Cuthbert to work on this review update.

Declarations of interest

We certify that we have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of the review (e.g. employment, consultancy, stock ownership, honoraria, expert testimony).

Dr Julia L Finkelstein is a principal investigator on research grants to examine the burden and aetiology of anaemia in women of reproductive age (U.S. Centers for Disease Control and Prevention), biomarkers of nutritional status in women of reproductive age (National Institutes of Health), and to conduct randomised trials with micronutrient interventions to improve the health of women of reproductive age (U.S. Centers for Disease Control and Prevention). Dr. Finkelstein has no known conflicts of interest to declare.

Anna Cuthbert was employed by the Cochrane Pregnancy and Childbirth Group, at the University of Liverpool, for a project that included work on this review. The project was also funded by the Children’s Investment Foundation Fund (CIFF). Anna Cuthbert has no known conflicts of interests to declare.

Jo Weeks was employed by the University of Liverpool for a project that included the work on this review. The project was also funded by the Children’s Investment Foundation Fund (CIFF). Jo Weeks has no known conflicts of interests to declare.

Sudha Venkatramanan has no known conflicts of interest to declare.

Doreen Y Larvie has no known conflicts of interest to declare.

Luz Maria De‐Regil is a full‐time staff member of the World Health Organization. The authors alone are responsible for the views expressed in this publication, and they do not necessarily represent the decisions, policy or views of the World Health Organization. Luz Maria De‐Regil has no known conflicts of interest to declare.

Maria Nieves Garcia‐Casal is a full‐time staff member of the World Health Organization. The authors alone are responsible for the views expressed in this publication, and they do not necessarily represent the decisions, policy or views of the World Health Organization. Maria Nieves Garcia‐Casal has no known conflicts of interest to declare.

None of the authors are investigators in any trials included in this review.

New search for studies and content updated (no change to conclusions)