Vitamin B12 supplementation during pregnancy for maternal and child health outcomes

Julia L Finkelstein; Amy Fothergill; Sudha Venkatramanan; Alexander J Layden; Jennifer L Williams; Krista S Crider; Yan Ping Qi

doi:10.1002/14651858.CD013823.pub2

. 2024 Jan 8;2024(1):CD013823. doi: 10.1002/14651858.CD013823.pub2

Vitamin B12 supplementation during pregnancy for maternal and child health outcomes

Julia L Finkelstein ^1,^✉, Amy Fothergill ^1,², Sudha Venkatramanan ¹, Alexander J Layden ³, Jennifer L Williams ², Krista S Crider ², Yan Ping Qi ²

Editor: Cochrane Pregnancy and Childbirth Group

PMCID: PMC10772977 PMID: 38189492

Abstract

Background

Vitamin B₁₂ deficiency is a major public health problem worldwide, with the highest burden in elderly people, pregnant women, and young children. Due to its role in DNA synthesis and methylation, folate metabolism, and erythropoiesis, vitamin B₁₂ supplementation during pregnancy may confer longer‐term benefits to maternal and child health outcomes.

Objectives

To evaluate the benefits and harms of oral vitamin B₁₂ supplementation during pregnancy on maternal and child health outcomes.

Search methods

We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) on 2 June 2023, and reference lists of retrieved studies.

Selection criteria

Randomised controlled trials (RCTs), quasi‐RCTs, or cluster‐RCTs evaluating the effects of oral vitamin B₁₂ supplementation compared to placebo or no vitamin B₁₂ supplementation during pregnancy.

Data collection and analysis

We used standard Cochrane methods. Four review authors independently assessed trial eligibility. Two review authors independently extracted data from included studies and conducted checks for accuracy. Three review authors independently assessed the risk of bias of the included studies using the Cochrane RoB 1 tool. We used GRADE to evaluate the certainty of evidence for primary outcomes.

Main results

The review included five trials with 984 pregnant women. All trials were conducted in low‐ and middle‐income countries, including India, Bangladesh, South Africa, and Croatia. At enrolment, 26% to 51% of pregnant women had vitamin B₁₂ deficiency (less than 150 pmol/L), and the prevalence of anaemia (haemoglobin less than 11.0 g/dL) ranged from 30% to 46%. The dosage of vitamin B₁₂ supplementation varied from 5 μg/day to 250 μg/day, with administration beginning at 8 to 28 weeks' gestation through to delivery or three months' postpartum, and the duration of supplementation ranged from 8 to 16 weeks to 32 to 38 weeks. Three trials, involving 609 pregnant women, contributed data for meta‐analyses of the effects of vitamin B₁₂ supplementation compared to placebo or no vitamin B₁₂ supplementation.

Maternal anaemia: there may be little to no difference for maternal anaemia by intervention group, but the evidence is very uncertain (70.9% versus 65.0%; risk ratio (RR) 1.08, 95% confidence interval (CI) 0.93 to 1.26; 2 trials, 284 women; very low‐certainty evidence).

Maternal vitamin B₁₂ status: vitamin B₁₂ supplementation during pregnancy may reduce the risk of maternal vitamin B₁₂ deficiency compared to placebo or no vitamin B₁₂ supplementation, but the evidence is very uncertain (25.9% versus 67.9%; RR 0.38, 95% CI 0.28 to 0.51; 2 trials, 272 women; very low‐certainty evidence). Women who received vitamin B₁₂ supplements during pregnancy may have higher total vitamin B₁₂ concentrations compared to placebo or no vitamin B₁₂ supplementation (mean difference (MD) 60.89 pmol/L, 95% CI 40.86 to 80.92; 3 trials, 412 women). However, there was substantial heterogeneity (I² = 85%).

Adverse pregnancy outcomes: the evidence is uncertain about the effect on adverse pregnancy outcomes, including preterm birth (RR 0.97, 95% CI 0.55 to 1.74; 2 trials, 340 women; low‐certainty evidence), and low birthweight (RR 1.50, 95% CI 0.93 to 2.43; 2 trials, 344 women; low‐certainty evidence). Two trials reported data on spontaneous abortion (or miscarriage); however, the trials did not report quantitative data for meta‐analysis and there was no clear definition of spontaneous abortion in the study reports. No trials evaluated the effects of vitamin B₁₂ supplementation during pregnancy on neural tube defects.

Infant vitamin B₁₂ status: children born to women who received vitamin B₁₂ supplementation had higher total vitamin B₁₂ concentrations compared to placebo or no vitamin B₁₂ supplementation (MD 71.89 pmol/L, 95% CI 20.23 to 123.54; 2 trials, 144 children).

Child cognitive outcomes: three ancillary analyses of one trial reported child cognitive outcomes; however, data were not reported in a format that could be included in quantitative meta‐analyses. In one study, maternal vitamin B₁₂ supplementation did not improve neurodevelopment status (e.g. cognitive, language (receptive and expressive), motor (fine and gross), social‐emotional, or adaptive (conceptual, social, practical) domains) in children compared to placebo (9 months, Bayley Scales of Infant and Toddler Development Third Edition (BSID‐III); 1 trial; low‐certainty evidence) or neurophysiological outcomes (72 months, event‐related potential measures; 1 trial; low‐certainty evidence), though children born to women who received vitamin B₁₂ supplementation had improved expressive language domain compared to placebo (30 months, BSID‐III; 1 trial; low‐certainty evidence).

Authors' conclusions

Oral vitamin B₁₂ supplementation during pregnancy may reduce the risk of maternal vitamin B₁₂ deficiency and may improve maternal vitamin B₁₂ concentrations during pregnancy or postpartum compared to placebo or no vitamin B₁₂ supplementation, but the evidence is very uncertain. The effects of vitamin B₁₂ supplementation on other primary outcomes assessed in this review were not reported, or were not reported in a format for inclusion in quantitative analyses. Vitamin B₁₂ supplementation during pregnancy may improve maternal and infant vitamin B₁₂ status, but the potential impact on longer‐term clinical and functional maternal and child health outcomes has not yet been established.

Keywords: Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Pregnancy; Abortion, Spontaneous; Anemia; Dietary Supplements; Outcome Assessment, Health Care; Vitamin B 12; Vitamins

Plain language summary

Vitamin B₁₂ supplementation for women during pregnancy

Key messages

– Women who took vitamin B₁₂ supplements during pregnancy may have improved vitamin B₁₂ status during pregnancy or postpartum, including less vitamin B₁₂ deficiency and higher vitamin B₁₂ levels, compared to women who did not take vitamin B₁₂ supplements, but the evidence is uncertain.

– The effects of taking vitamin B₁₂ supplements during pregnancy on other health outcomes in pregnant women or their children are not known.

Public health implications

Vitamin B₁₂ is an important nutrient that helps keep your body's blood and nerve cells healthy. Vitamin B₁₂ deficiency is an important public health problem, particularly in low‐ and middle‐income countries, with a high burden amongst pregnant women and children. Lower vitamin B₁₂ levels in pregnancy have been linked to greater risk of some adverse pregnancy outcomes such as miscarriage, poor growth of the baby in the womb, problems with the baby's brain or spinal cord (called neural tube defects), and lower vitamin B₁₂ status in infants.

Vitamin B₁₂ supplementation during pregnancy may help improve the health and nutrition of women and their babies. However, this has not been examined in well‐conducted reviews, and vitamin B₁₂ is not part of supplements recommended by the World Health Organization (WHO; a specialised agency of the United Nations responsible for international public health) for women during pregnancy.

What did we want to find out?

We wanted to find out if taking vitamin B₁₂ supplements during pregnancy would improve the health and nutrition of women and their babies.

What did we do?

We searched for clinical trials that looked at vitamin B₁₂ supplementation during pregnancy. We compared and summarised the results of the trials and rated our confidence in the information, based on factors such as trial methods and sizes.

What did we find?

We included five trials with 984 pregnant women. Three trials, including 609 pregnant women, had data included in analyses. Women who took vitamin B₁₂ supplements during pregnancy had less vitamin B₁₂ deficiency and higher vitamin B₁₂ levels compared to women who did not take vitamin B₁₂ supplements, but the evidence is uncertain. There were no differences between groups for maternal anaemia. We could not assess the effects of vitamin B₁₂ supplementation on other outcomes such as miscarriage, neural tube defects, and child cognition (a child's ability to gain knowledge through thought, understanding, and the senses) due to limited or no availability of results for analysis.

What are the limitations of the evidence?

The small number of trials and small size of trials were limitations in this review. Not all the trials provided data about the outcomes we were interested in. We are very unsure about the results.

How up to date is this evidence?

The evidence is up to date as of June 2023.

Summary of findings

Summary of findings 1. Summary of findings table ‐ Vitamin B12 supplementation compared to placebo/no vitamin B12 supplementation in pregnant women.

Vitamin B12 supplementation compared to placebo/no vitamin B12 supplementation in pregnant women
Patient or population: pregnant women Setting: Bangladesh, India, South Africa Intervention: vitamin B12 supplementation Comparison: placebo/no vitamin B12 supplementation
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with placebo/no vitamin B12 supplementation	Risk with vitamin B12 supplementation	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Maternal anaemia	448 per 1000	483 per 1000 (416 to 564)	RR 1.08 (0.93 to 1.26)	284 (2 RCTs)	⊕⊝⊝⊝ Very low^a
Maternal vitamin B12 deficiency	679 per 1000	258 per 1000 (190 to 346)	RR 0.38 (0.28 to 0.51)	272 (2 RCTs)	⊕⊝⊝⊝ Very low^b	Sensitivity analysis using random‐effects model: RR 0.30, 95% CI 0.09 to 0.96
Spontaneous abortion or miscarriage	See comments			448 (2 RCTs)	⊕⊝⊝⊝ Very low^c	2 trials reported spontaneous abortion or miscarriage. However, the trials did not report quantitative data required for meta‐analysis and there was no clear definition of spontaneous abortion in the study reports.
Low birthweight (< 2500 g)	109 per 1000	164 per 1000 (101 to 265)	RR 1.50 (0.93 to 2.43)	334 (2 RCTs)	⊕⊕⊝⊝ Low^d
Preterm birth (< 37 weeks)	107 per 1000	104 per 1000 (59 to 186)	RR 0.97 (0.55 to 1.74)	340 (2 RCTs)	⊕⊕⊝⊝ Low^d
Child cognitive outcomes	See comments			178 (1 RCT)	⊕⊕⊝⊝ Low^e	Maternal vitamin B12 supplementation did not improve neurodevelopment status (e.g. cognitive, language (receptive and expressive), motor (fine and gross), social‐emotional, or adaptive (conceptual, social, practical) domains) in children (9 months, BSID‐III; 1 RCT) or neurophysiological outcomes (72 months, ERP measures; 1 RCT), although children born to women who received vitamin B12 supplementation had improved expressive language domain (30 months, BSID‐III; 1 RCT)^f
Neural tube defects ‐ not reported	See comments			‐	‐	No trial reported this outcome
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_432822657927146558.

Open in a new tab

^a Downgraded one level for risk of bias due to serious concerns with selection bias, performance bias, and detection bias; one level due to imprecision because of small samples from these trials; and one level due to indirectness because of assessment at different timepoints and population. ^b Downgraded one level for risk of bias due to serious concerns with selection bias, performance bias, and detection bias; one level due to imprecision because of small samples from these trials; and one level due to inconsistency because of moderate statistical heterogeneity. ^c Downgraded one level for risk of bias due to serious concerns with selection bias, performance bias, and detection bias; one level for inconsistency as were unable to conduct meta‐analyses as quantitative data were not reported in a format for inclusion in analyses; and one level for imprecision, as only limited studies contributed data. ^d Downgraded one level for risk of bias due to serious concerns with selection bias, performance bias, and detection bias; and one level for imprecision due to the small sample size of the two trials. ^e Downgraded one level for inconsistency as we were unable to conduct meta‐analyses as quantitative data were not reported in a format for inclusion in analyses; and one level for imprecision, as only one study contributed data. ^f BSID‐III: Bayley Scales of Infant and Toddler Development, Third Edition; ERP: event‐related potential; RCT: randomised controlled trial.

Background

Description of the condition

Vitamin B₁₂ is required for DNA synthesis and methylation, and it plays a critical role in one‐carbon metabolism (Finkelstein 2015; Green 2017a). Vitamin B₁₂ is required for the conversion of folate to its active form (tetrahydrofolate (THF)) and purine synthesis; and for the methylation of homocysteine to methionine and production of S‐adenosyl methionine (SAM), which is a methyl donor in over 100 methylation reactions (Guéant 2013; Stover 2011). Due to these biological requirements, vitamin B₁₂ is essential for the production of red blood cells (erythropoiesis) (Green 2017a; Stabler 2013), and normal neurological development (Venkatramanan 2016). The classical presentation of vitamin B₁₂ deficiency is haematological (Aaron 2005; Green 2017b; IOM 1998). Insufficient vitamin B₁₂ supply may also lead to neurological manifestations (Venkatramanan 2016), which, although less common, may be irreversible without timely treatment (Green 2017a; Green 2017b; Stabler 2013).

Vitamin B₁₂ deficiency is an important public health problem worldwide, with the highest burden in pregnant women, young children, and elderly people (Allen 2010; Allen 2018; Green 2017a). The prevalence of vitamin B₁₂ deficiency is particularly high in low‐ and middle‐income countries (Green 2017a): approximately 40% in Latin America (Allen 2004; Brito 2015); 70% in Sub‐Saharan Africa (McLean 2007; Siekmann 2003); and 50% to 80% in South Asia (Finkelstein 2017; Gonmei 2018; Taneja 2007). Vitamin B₁₂ deficiency is common in pregnancy and has been associated with increased risk of adverse pregnancy outcomes (Finkelstein 2015), including spontaneous abortion (Hubner 2008; Reznikoff‐Etievant 2002), low birthweight (Rogne 2017), intrauterine growth restriction (IUGR) (Muthayya 2006), neural tube defects (NTDs) (Gu 2012; Molloy 2009; Molloy 2018; Ratan 2008; Ray 2007; Wilson 1999), and lower vitamin B₁₂ status in infants (Finkelstein 2015; Finkelstein 2017). Inadequate vitamin B₁₂ status during pregnancy and early in life has been associated with deficits in cognitive development (Venkatramanan 2016). It may also have lasting effects on infant growth and brain development, which may be irreversible (Black 2008; Pepper 2011; Venkatramanan 2016).

Vitamin B₁₂ status can be evaluated using biomarkers in the blood such as total vitamin B₁₂ and holotranscobalamin (Allen 2018; Yetley 2011). Most vitamin B₁₂ (approximately 70%) is bound to haptocorrin in the circulation as holohaptocorrin. Holotranscobalamin (approximately 30%) is the form of cobalamin that actively binds to transcobalamin receptors for cellular uptake (Quadros 2010; Quadros 2013). Methylmalonic acid (MMA) and total homocysteine measure the concentrations of metabolites accumulated in biological reactions in the presence of inadequate vitamin B₁₂ status. Elevated MMA concentrations are an important functional and specific indicator of vitamin B₁₂ deficiency (Allen 2018; Yetley 2011). However, plasma total homocysteine is influenced by a number of additional nutritional factors (e.g. folate, folate‐mediated one‐carbon metabolism), and non‐nutritional factors (e.g. inflammation), and is a non‐specific biomarker for vitamin B₁₂ status.

In research to date, the utilisation of different biomarkers of vitamin B₁₂ status, and different cut‐offs to define deficiency and insufficiency, has constrained interpretation of findings across studies. In addition to total vitamin B₁₂, the use of functional biomarkers (e.g. MMA) is recommended for assessment of vitamin B₁₂ status in populations (Allen 2018; Yetley 2011).

Evidence from observational studies to date demonstrated that maternal vitamin B₁₂ deficiency during gestation is associated with increased risk of adverse pregnancy outcomes (Finkelstein 2015), such as spontaneous abortion (Hubner 2008; Reznikoff‐Etievant 2002), low birthweight (Rogne 2017), IUGR (Muthayya 2006), and NTDs (Gu 2012; Molloy 2009; Molloy 2018; Ratan 2008; Ray 2007; Wilson 1999); and lower vitamin B₁₂ status in infants (Finkelstein 2015; Finkelstein 2017). Inadequate vitamin B₁₂ status early in life has been associated with deficits in cognitive development (Venkatramanan 2016), and impaired growth and development (Black 2008; Pepper 2011; Venkatramanan 2016). However, there is limited information on the effects of vitamin B₁₂ supplementation on maternal and child health outcomes (Behere 2021).

The high burden of vitamin B₁₂ deficiency in pregnant women, and its links to increased risk of adverse health outcomes, have increased interest in fortification with vitamin B₁₂ (Allen 2010), and inclusion of vitamin B₁₂ in antenatal micronutrient supplementation. However, the efficacy and safety of vitamin B₁₂ supplementation in pregnancy for maternal and child health outcomes has not been established.

Description of the intervention

Supplemental vitamin B₁₂ may be administered through varying routes, regimens, and forms. These include: orally as supplements (tablets, dispersible tablets, capsules), syrups, or drops (Bahadir 2014); via intramuscular injection (Bakken 2023); or through consumption of fortified foods or food products (e.g. food fortification, multiple micronutrient powders) (Chandyo 2023; Devi 2017). This review focused on the effects of oral vitamin B₁₂ supplementation during pregnancy on maternal and child health outcomes. Vitamin B₁₂ tablets (i.e. soluble tablets, effervescent tablets, tablets for use in the mouth, and modified‐release tablets) and capsules (i.e. either hard or soft shells in various shapes and sizes) are both solid‐dosage forms containing one or more active ingredients, while dispersible tablets disintegrate in water or other liquids. Frequently used forms of vitamin B₁₂ include cyanocobalamin and methylcobalamin. This review did not include other types of interventions with vitamin B₁₂, such as oral syrups or drops, intramuscular injections, or fortification.

How the intervention might work

The goal of micronutrient supplementation during pregnancy is to improve maternal vitamin B₁₂ status and reduce the risk of adverse health outcomes for the mother and infant. Vitamin B₁₂ may be transferred to the foetus during pregnancy across the placenta (Layden 2016), and postpartum through breast milk (Dror 2018). Improving maternal vitamin B₁₂ status during pregnancy may influence foetal transfer of cobalamin and improve vitamin B₁₂ status in offspring (Finkelstein 2017). The underlying mechanisms on how vitamin B₁₂ influences the aetiology of maternal and child health outcomes have not yet been established. Evidence from laboratory studies indicate that vitamin B₁₂ deficiency can impair DNA methylation (Stover 2004), cell division (Stover 2011), erythropoiesis (Green 2017a), brain development (Black 2008; Arora 2019), and neurotransmitter synthesis (Green 2017a; Green 2017b; Stover 2004). Due to its essential role in DNA synthesis and methylation, and erythropoiesis, improving maternal and offspring vitamin B₁₂ status (via supplementation in pregnancy) may result in longer‐term benefits to maternal and child health outcomes, including anaemia and infant growth and development (Dror 2018; Finkelstein 2015).

Why it is important to do this review

The World Health Organization (WHO) currently recommends iron and folic acid (IFA) supplementation during pregnancy as part of routine antenatal care (WHO 2015). Emerging evidence suggests that maternal vitamin B₁₂ deficiency is a risk factor for adverse health outcomes for both the mother and infant (Finkelstein 2015).

No systematic reviews have been conducted to date to examine the specific effects of vitamin B₁₂ supplementation during pregnancy on maternal and child health outcomes. This Cochrane review will complement the findings of previous Cochrane reviews evaluating the effects of supplementation during pregnancy with multiple micronutrients (Keats 2019), IFA (Peña‐Rosas 2015), and folic acid (Lassi 2013); and a Campbell review evaluating the effects of vitamin and mineral supplementation during pregnancy on maternal, birth, and child health and development outcomes in low‐ and middle‐income countries (Keats 2021).

Objectives

To evaluate the benefits and harms of oral vitamin B₁₂ supplementation during pregnancy on maternal and child health outcomes.

Methods

Criteria for considering studies for this review

Types of studies

We considered the following types of studies for inclusion in this review.

Randomised controlled trials (RCTs)
Cluster‐RCTs
Quasi‐RCTs (i.e. where treatment was allocated by a quasi‐random method such as alternation, date of birth, or case record number)

The above study types were considered for inclusion if there was sufficient information provided to meet the eligibility criteria. Records that did not meet these inclusion criteria are described in the Characteristics of excluded studies table.

We did not include cross‐over studies or observational studies in the meta‐analyses. However, relevant evidence from observational studies is used in the Discussion to help identify gaps in research.

Types of participants

We included pregnant women, regardless of age, parity, or geographic location. We excluded studies of interventions targeted to participants with critical illnesses or severe comorbidity.

Types of interventions

We included studies that investigated oral supplementation of vitamin B₁₂ (alone or in combination with other micronutrients) compared to no supplementation, placebo, or other micronutrient supplements not containing vitamin B₁₂.

Vitamin B₁₂ supplementation included any cobalamin compound (e.g. cyanocobalamin, methylcobalamin) delivered in the form of a tablet, capsule, or dispersible tablet. Interventions including oral syrups or drops, intramuscular injections, or food fortification were not eligible for inclusion. There were no restrictions on dosage, frequency, or duration of vitamin B₁₂ supplementation.

Studies evaluating the effects of standard antenatal vitamin supplementation were eligible for inclusion provided that the supplement contained vitamin B₁₂ and was compared to a micronutrient supplement of the same composition without vitamin B_12. We included studies with co‐interventions (e.g. other micronutrients, education) if the co‐interventions were the same in both the intervention and control groups.

Types of outcome measures

Primary outcomes

Maternal

Anaemia (defined by trimester‐ and age‐appropriate cut‐offs, adjusted by altitude)
Vitamin B₁₂ deficiency/insufficiency (as measured by trial authors)
Spontaneous abortion or miscarriage (at less than 20 weeks' gestation or as defined by trial authors)

Child

Low birthweight (less than 2500 g)
Preterm birth (at less than 37 weeks' gestation)
Neural tube defects
Cognitive function (as defined by trial authors)

Secondary outcomes

Maternal

Vitamin B₁₂ status (serum/plasma vitamin B₁₂ (picomoles per litre (pmol/L)); holotranscobalamin (pmol/L); MMA (micromoles per litre (μmol/L)); total homocysteine concentrations (μmol/L); as measured by trial authors)
Haemoglobin (Hb) levels (grams per litre (g/L), as measured by trial authors)
Breast milk vitamin B₁₂ concentrations (pmol/L)
Megaloblastic anaemia (as defined by trial authors)
Hyperhomocysteinaemia (as measured by trial authors)
Pre‐eclampsia (as defined by trial authors)
Blood pressure, hypertension (as defined by trial authors)
Neurodegenerative pathology (as defined by trial authors)
Cognitive function (as defined by trial authors)
Depression (as defined by trial authors)
Any adverse effects (as defined by trial authors)

Child

Birthweight (in grams)
Very preterm birth (at less than 34 weeks' gestation)
Intrauterine growth restriction (as defined by trial authors)
Stillbirth (at 20 weeks' gestation or more or as defined by trial authors)
Other congenital anomalies (as defined by trial authors)
Vitamin B₁₂ status (serum/plasma vitamin B₁₂ (pmol/L); holotranscobalamin (pmol/L); MMA (μmol/L); total homocysteine concentrations (μmol/L); as measured by trial authors)
Hb levels (grams/litre; as measured by trial authors)
Anaemia (defined by age‐appropriate cut‐offs, adjusted by altitude)
Neonatal infection (as defined by trial authors)
Neonatal death (at less than 28 days of life)
Apgar score of less than seven at five minutes
Development and motor skills (as defined by trial authors)

Search methods for identification of studies

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

Electronic searches

We searched Cochrane Pregnancy and Childbirth's Trials Register by contacting their Information Specialist.

The Register is a database containing over 32,000 reports of controlled trials in the field of pregnancy and childbirth. It represents over 30 years of searching.

Briefly, Cochrane Pregnancy and Childbirth's Trials Register was maintained by their Information Specialist and contained trials identified from:

monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
weekly searches of MEDLINE (Ovid);
weekly searches of Embase (Ovid);
monthly searches of CINAHL (EBSCO);
handsearches 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 were screened by two people and the full text of all relevant trial reports identified through the searching activities described above was reviewed. Based on the intervention described, each trial report was assigned a number that corresponded to a specific Pregnancy and Childbirth review topic (or topics) and was then added to the Register. The Information Specialist searched 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 studies; Excluded studies; or Ongoing studies).

In addition, we searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for unpublished, planned, and ongoing trial reports (18 June 2022) using the search methods detailed in Appendix 1.

The initial search was conducted on 18 June 2022, and a search update was conducted on 2 June 2023.

Searching other resources

We searched the reference lists of retrieved studies. We did not apply any language or date restrictions.

Data collection and analysis

Screening eligible studies for trustworthiness

At least two review authors (AF, SV) evaluated all studies meeting our inclusion criteria against predefined criteria to select studies that, based on available information, were deemed to be sufficiently trustworthy to be included in the analysis. Cochrane Pregnancy and Childbirth has developed a Trustworthiness Screening Tool (CPC‐TST) which includes the following criteria.

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 published after 2010)? If not, was there a plausible reason?
When requested, did the trial authors provide/share the protocol or ethics approval letter (or both)?
Did the trial authors engage in communication with the Cochrane review authors within the agreed timelines?
Did the trial authors provide individual participants' data upon request? If not, was there a plausible reason?

Baseline characteristics

Was the study free from characteristics of the study participants that appeared too similar (e.g. the distribution of the mean (standard deviation (SD)) was excessively narrow or excessively wide, as noted by Carlisle 2017)?

Feasibility

Was the study free from characteristics that could be implausible (e.g. large numbers of women with a rare condition (such as severe cholestasis in pregnancy) recruited within 12 months)?
In cases with (close to) zero losses to follow‐up, was there a plausible explanation?

Results

Was the study free from results that could be implausible (e.g. massive risk reduction for main outcomes with small sample size)?
Did the numbers randomised to each group suggest that adequate randomisation methods were used (e.g. was the study free from issues such as unexpectedly even numbers of women 'randomised' including a mismatch between the numbers and the methods, if the authors said 'no blocking was used' but still ended up with equal numbers, or if the authors said they used 'blocks of 4' but the final numbers differ by 6)?

Studies assessed as being potentially 'high risk' were not included in the review. Where a study was classified as 'high risk', we attempted to contact the study authors to address any possible lack of information/concerns. In cases where we could not obtain contact details for the study authors, or where adequate information remained unavailable, the study remained in 'awaiting classification' and the reasons and communications with the author (or lack of) were described in detail.

Abstracts

Data from abstracts were included if, in addition to the trustworthiness assessment, the study authors had confirmed in writing that the data to be included in the review had come from the final analysis and would not change. If such information was not available/provided, the study remained in 'awaiting classification' (as above).

See Figure 1 for details of how we applied the trustworthiness screening criteria.

Cochrane Pregnancy and Childbirth trustworthiness screening tool (CPC‐TST)

Selection of studies

Four review authors (AF, SV, YPQ, AJL) independently assessed all the potential studies identified as a result of the search strategy in duplicate for inclusion. We resolved discrepancies through discussion and consultation with the senior review author (JLF). If studies were published only as abstracts or if study reports contained little information on methods, we attempted to contact study authors to obtain further details of the study design and results. A study flow diagram to summarise the number of records identified, included, and excluded is presented in Figure 2.

Data extraction and management

We developed and used a standardised form for data extraction. For eligible studies, two review authors (AF, SV) extracted data using this form. Extracted information included trial dates, sources of trial funding, and the trial authors' declarations of interest. We resolved discrepancies through discussion and consultation with the senior review author (JLF). We contacted study authors by the Cochrane Pregnancy and Childbirth Editorial Office to request missing data for inclusion in this review. When data required for meta‐analyses were only reported in figures, two review authors (AF, SV) extracted data from figures in duplicate. We estimated mean and SDs from the reported median and interquartile range if needed (which assumes the sample size was large enough and the distribution of outcome was similar to the normal distribution), using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Section 7.7.3.5; Higgins 2023). We entered data into Review Manager Web, and checked them for accuracy (RevMan 2022). When information was missing or unclear, we contacted study authors of the original reports for further information or clarification.

Assessment of risk of bias in included studies

Three review authors (YPQ, AF, SV) independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2023). We resolved disagreements through discussion and consultation with the senior review author (JLF).

1. Random sequence generation (checking for possible selection bias)

For each included study, we described the method used to generate the allocation sequence in detail to allow an assessment of whether it should produce comparable groups.

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); or
unclear risk of bias.

2. Allocation concealment (checking for possible selection bias)

For each included trial, we described the method used to conceal allocation to interventions prior to assignment 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 (e.g. open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or
unclear risk of bias.

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

For each included study, we described the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We provided any information relating to whether the intended blinding was effective for participants or personnel (or both) separately. We considered studies at low risk of bias if they were blinded, or if the lack of blinding would be unlikely to affect results. We classified blinding as high risk of bias if blinding status of a trial was unclear or the trial was open. We assessed blinding separately for different outcomes or classes of outcomes.

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)

For each included trial, we described the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We provided any information relating to whether the intended blinding was effective. We assessed blinding separately for different outcomes or classes of outcomes, with particular attention being paid to the objectivity of each outcome measure.

We assessed methods used to blind outcome assessment as:

low, high, or unclear risk of bias.

4. Incomplete outcome data (checking for possible attrition bias due to the amount, nature, and handling of incomplete outcome data)

For each included study and for each outcome or class of outcomes, we described the completeness of data, including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or was supplied by the trial authors, we re‐included missing data in the analyses which we undertook.

We assessed methods as:

low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; 'as treated' analysis done with substantial departure of intervention received from that assigned at randomisation); or
unclear risk of bias.

5. Selective reporting (checking for reporting bias)

We described how we investigated the possibility of selective outcome reporting bias for each included study. We examined protocols and methods sections to assess if all prespecified outcomes were reported. In the case of inadequate reporting of outcomes, or if non‐significant results did not have adequate information provided, we contacted study authors.

We assessed the methods as:

low risk of bias (where it was clear that all the study's prespecified outcomes and all expected outcomes of interest to the review had been reported);
high risk of bias (where not all the study's prespecified outcomes had been reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely so could not be used; or the study failed to include results of a key outcome that would have been expected to have been reported); or
unclear risk of bias.

6. Other bias (checking for bias due to problems not covered by 1. to 5. above)

We described any important concerns we have about other possible sources of bias for each included trial.

We assessed if:

a potential source of bias was related to the specific study design;
there was extreme baseline imbalance;
the study was claimed to be fraudulent;
the trial was stopped early due to some data‐dependent process.

Each study was classified as:

low risk of other bias;
high risk of other bias; or
unclear whether there was risk of other bias.

7. Overall risk of bias

We evaluated whether studies were at high overall risk of bias according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2023). With reference to 1. to 6. above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact the findings. We were unable to conduct sensitivity analyses to examine the potential impact of the level of bias on findings.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented proportions. For two‐group comparisons, we presented results as risk ratios (RR) with 95% confidence intervals (CI).

Continuous data

For continuous data, we reported the mean difference (MD) with 95% CIs if all included trials measured outcomes on the same scale.

Unit of analysis issues

Cluster‐randomised controlled trials

We identified no cluster‐RCTs for inclusion in this review.

Cross‐over trials

We identified no cross‐over trials in this review.

Other unit of analysis issues

None of the trials included multiple pregnancies. For multiple‐armed trials, we selected one pair of interventions and excluded the others. All intervention groups of a multiple‐intervention study are mentioned in the Characteristics of included studies table. However, we only provided detailed descriptions of the intervention groups relevant to the review, and only those groups were used in analyses. We checked that the data were presented for each of the groups to which participants were randomised (Higgins 2023).

Dealing with missing data

For included studies, we noted levels of attrition. Due to the limited number of trials (fewer than 10 studies established a priori), data were not available to conduct sensitivity analyses to examine the potential impact of including studies with high levels of missing data, or the impact of including studies identified at high risk of bias.

For all outcomes, we conducted analyses on an intention‐to‐treat basis (i.e. we attempted to include all participants randomised to each group in the analyses), and all participants were analysed in the group to which they were allocated, regardless of whether they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta‐analysis using the Tau², I², and Chi² statistics. We considered heterogeneity as substantial if I² was greater than 30% and either Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity (Higgins 2023).

Assessment of reporting biases

For each trial, we checked for the existence of trial registrations published before or after reports of the study were published. We did not investigate reporting biases using funnel plots, as the number of included trials was fewer than 10.

Data synthesis

We conducted statistical analysis using Review Manager Web (RevMan 2022). We used fixed‐effect meta‐analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect (i.e. where trials were examining the same intervention, and the trials' populations and methods were judged to be sufficiently similar).

Subgroup analysis and investigation of heterogeneity

We planned to conduct subgroup analyses (i.e. dose, administration, form, micronutrient composition, baseline vitamin B₁₂ deficiency, baseline maternal folate status) for primary outcomes for which there were at least three trials contributing data. However, we were unable to conduct the preplanned subgroup analyses due to the limited number of included trials.

Sensitivity analysis

We planned to conduct sensitivity analyses to investigate the impact of trial quality, by excluding studies assessed at high risk of bias (as determined by concealment of allocation, high attrition rates, or both); and to explore the effects of fixed‐ or random‐effects analyses for outcomes with statistical heterogeneity, and the effects of any assumptions made (such as the value of the intracluster correlation coefficient (ICC) used for cluster‐RCTs); and evaluate quasi‐RCTs separately in sensitivity analyses by certainty of evidence. However, we were unable to conduct any predefined sensitivity analyses, due to the limited number of included trials and data reported.

Summary of findings and assessment of the certainty of the evidence

Two review authors (AF, SV) assessed the certainty of the evidence using the GRADE approach, as outlined in the GRADE handbook (Schünemann 2013), in order to assess the certainty of the body of evidence relating to the primary outcomes for the main comparison.

We used the GRADEpro GDT to import data from Review Manager Web to create a summary of findings table (GRADEpro GDT; RevMan 2022). We produced a summary of the intervention effect and a measure of certainty for each of the primary outcomes using the GRADE approach.

Maternal outcomes

Anaemia (defined by trimester‐ and age‐appropriate cut‐offs, adjusted by altitude)
Vitamin B₁₂ deficiency/insufficiency (as measured by trial authors)
Spontaneous abortion or miscarriage (at less than 20 weeks' gestation or as defined by trial authors)

Child outcomes

Low birthweight (less than 2500 g)
Preterm birth (at less than 37 weeks' gestation)
NTDs
Cognitive function (as defined by trial authors)

The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence for each outcome. We downgraded the evidence from 'high certainty' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates, or potential publication bias.

Results

Description of studies

Results of the search

The study flow is depicted in Figure 2. The search identified 97 records; after deduplication, we screened 90 records, and assessed the full text of 32 records for eligibility.

Of the 32 records, we included five trials (16 reports) in this review (Duggan 2014; Edelstein 1968; Metz 1965; Siddiqua 2016; Zec 2020). Three trials contributed data and were included in quantitative analyses (Duggan 2014; Edelstein 1968; Siddiqua 2016).

We excluded nine trials (15 reports) (Bhowmik 2021; Chandyo 2023; CTRI/2020/01/022713; CTRI/2020/10/028330; Devi 2017; Li 2020; Mearns 2014; Nagpal 2020; NCT03258385), and identified one ongoing trial (one report) (Winje 2018).

Included studies

This review included five trials (Duggan 2014; Edelstein 1968; Metz 1965; Siddiqua 2016; Zec 2020). Three trials involving 609 pregnant women contributed data for the meta‐analyses (Duggan 2014; Edelstein 1968; Siddiqua 2016).

Two trials were eligible for inclusion but did not contribute data because the results were not presented in a form that allowed for inclusion (e.g. numbers were not reported, results were not reported separately for intervention groups) (Metz 1965; Zec 2020).

Duggan 2014 contained three ancillary analyses (Srinivasan 2017; Srinivasan 2020; Thomas 2019); they did not contribute to the quantitative analyses due to limited availability of data for comparisons.

Details of all the included studies are presented in the Characteristics of included studies table.

Country settings

The included trials were conducted in India (Duggan 2014), Bangladesh (Siddiqua 2016), South Africa (Edelstein 1968; Metz 1965), and Croatia (Zec 2020).

Participants

The trials had sample sizes of pregnant women ranging from 82 (Siddiqua 2016) to 366 (Duggan 2014).

The pregnant women and their babes were presenting for antenatal care. Most pregnant women were aged 18 years or older at enrolment (Duggan 2014) or aged 18 to 35 years (Siddiqua 2016). Two trials did not report participant age (Edelstein 1968; Metz 1965) and one trial only reported the mean age of participants was 31.1 years (Zec 2020).

At enrolment, the prevalence of vitamin B₁₂ deficiency (less than 150 pmol/L) was 26% (Siddiqua 2016) and 51% (Duggan 2014); three studies did not report vitamin B₁₂ status at enrolment (Edelstein 1968; Metz 1965; Zec 2020).

At baseline, the prevalence of anaemia (Hb less than 11.0 g/dL) was 30% (Duggan 2014) and 46% (Siddiqua 2016); three studies did not report prevalence of anaemia (Edelstein 1968; Metz 1965; Zec 2020).

One trial in Croatia, enroled pregnant women at eight to 10 weeks' gestation (Zec 2020). Two trials enroled pregnant women at 14 weeks' gestation or less (mean 11 weeks' gestation) (Duggan 2014; Siddiqua 2016). Two trials from South Africa enroled pregnant women after 24 (Metz 1965) or 28 (Edelstein 1968) weeks' gestation.

Interventions

Daily dose of vitamin B₁₂

All trials administered vitamin B₁₂ as a daily oral supplement. Daily doses were 5 μg/day (Zec 2020), 250 μg/day (Siddiqua 2016), and 50 μg/day (Duggan 2014; Edelstein 1968; Metz 1965).

Vitamin B₁₂ supplements were administered as capsules (Duggan 2014; Siddiqua 2016) or as dispersible tablets (Edelstein 1968; Metz 1965). One trial did not specify the type of administration method for vitamin B₁₂ supplements (Zec 2020).

Type of vitamin B₁₂ compound

One trial reported the form of vitamin B₁₂ compound as cyanocobalamin (Duggan 2014); four trials did not specify the type of vitamin B₁₂ compound.

Duration of intervention

Daily vitamin B₁₂ supplementation was provided to participants beginning 14 weeks' gestation or less (Duggan 2014; Siddiqua 2016; Zec 2020), after 24 weeks' gestation (Metz 1965), and 28 weeks' gestation (Edelstein 1968). Daily vitamin B₁₂ supplementation was administered until the third trimester (Zec 2020), delivery (Edelstein 1968; Metz 1965), six weeks' postpartum (Duggan 2014), or three months' postpartum (Siddiqua 2016). The duration of intervention was eight weeks (Edelstein 1968), 12 to 16 weeks (Metz 1965; Zec 2020), or 32 to 38 weeks (Duggan 2014; Siddiqua 2016).

Intervention settings

The trials recruited pregnant women during routine antenatal care appointments. Intervention settings included gynaecological primary care practises (Zec 2020), urban maternity clinics in the Maternal and Child Health Training Institute (MCHTI) (Siddiqua 2016), a maternity healthcare centre predominantly catering to women from lower socioeconomic strata (Duggan 2014), and two hospitals in Johannesburg (Edelstein 1968; Metz 1965).

Comparisons: vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation

Two trials compared vitamin B₁₂ supplementation to placebo (Duggan 2014; Siddiqua 2016); all women also received IFA supplementation as standard of care (Duggan 2014: iron 60 mg and folic acid 500 μg; Siddiqua 2016: iron 60 mg and folic acid 400 μg).

Three trials compared vitamin B₁₂ supplementation with IFA to IFA alone (i.e. no vitamin B₁₂ supplementation) (Zec 2020: ferrous iron 350 mg (70 mg elemental iron) and folic acid 5 mg; Edelstein 1968; Metz 1965: iron 200 mg and folic acid 5 mg).

In meta‐analyses, we combined data from these trials to evaluate the comparison of 'vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation'.

Standard of care

All trials provided IFA supplementation to all pregnant women as standard of care. The dose of iron supplementation administered was 60 mg (Duggan 2014; Siddiqua 2016), 70 mg (350 mg ferrous iron; Edelstein 1968; Zec 2020), or 200 mg elemental iron (Metz 1965). The doses of folic acid supplementation were 400 μg (Siddiqua 2016), 500 μg (Duggan 2014), or 5.0 mg (5000 μg; Edelstein 1968; Metz 1965; Zec 2020).

Outcomes

Primary outcomes

Maternal anaemia

Three trials reported maternal anaemia (Duggan 2014; Metz 1965; Siddiqua 2016). Two trials defined anaemia as Hb less than 11.0 g/dL (second or third trimester of pregnancy, Duggan 2014; three months' postpartum, Siddiqua 2016), while one trial did not specify the cut‐off for anaemia (six weeks' postpartum, Metz 1965).

Maternal vitamin B₁₂ deficiency

Three trials reported data on maternal vitamin B₁₂ deficiency (Duggan 2014; Metz 1965; Siddiqua 2016). Two trials defined vitamin B₁₂ deficiency as total vitamin B₁₂ less than 150 pmol/L (third trimester of pregnancy, Duggan 2014; three months' postpartum, Siddiqua 2016), and one trial did not define vitamin B₁₂ deficiency (12 to 24, 25 to 28, 29 to 32, 33 to 36, or 37 to 40 weeks' gestation or six weeks' postpartum, Metz 1965).

Spontaneous abortion or miscarriage

Two trials reported data for spontaneous abortion or miscarriage (Duggan 2014; Siddiqua 2016).

Low birthweight

Two trials reported data on low birthweight, defined as less than 2500 g (Duggan 2014; Siddiqua 2016).

Preterm birth

Two trials reported data on preterm birth, defined as delivery at less than 37 weeks' gestation (Duggan 2014; Siddiqua 2016).

Neural tube defects

No trials reported data on NTDs.

Child cognitive function

Duggan 2014 reported cognitive outcomes in children in India in three ancillary analyses (Srinivasan 2017; Srinivasan 2020; Thomas 2019). One study performed neurocognitive assessment in children at nine months of age (Srinivasan 2017) and one at 30 months of age (Thomas 2019), using the Bayley Scales of Infant Development, Third Edition (BSID‐III). One study assessed neurophysiological measures in children at 72 months of age using event‐related potentials (ERPs) of positive waveform of approximately 300 ms after stimulus (P300) and mismatch negativity (MMN), using a wireless system, Enobio (Neuroelectrics) to capture ERP signals (Srinivasan 2020).

Secondary outcomes

Maternal vitamin B₁₂ status

Four trials reported maternal vitamin B₁₂ status (second or third trimester, Duggan 2014; 72 hours after delivery and three months' postpartum, Siddiqua 2016; third trimester, Edelstein 1968; third trimester, Metz 1965). Biomarkers of vitamin B₁₂ status included concentrations of total vitamin B₁₂ (Duggan 2014; Edelstein 1968; Metz 1965; Siddiqua 2016), MMA (Duggan 2014; Siddiqua 2016), and homocysteine (Duggan 2014; Siddiqua 2016). Two trials reported data on elevated MMA, defined as greater than 0.26 μmol/L (Duggan 2014) or greater than 0.271 μmol/L (Siddiqua 2016).

Two trials evaluated vitamin B₁₂ concentrations by electrochemiluminescence (Elecsys 2010; Roche Diagnostics) (plasma, Duggan 2014; plasma, Siddiqua 2016), and one trial via microbiological assay (Lactobacillus leishmanii; serum, Edelstein 1968). One trial did not specify assessment methods (Metz 1965). Trials assessed MMA concentrations by gas chromatography–mass spectrometry (GC‐MS; model 3800; Varian) (plasma, Duggan 2014) or by liquid chromatography–tandem mass‐spectrometry (UPLC‐MS/MS) (plasma, Siddiqua 2016). Trials assessed total homocysteine concentrations using GC‐MS (model 3800; Varian) (plasma, Duggan 2014) or by high‐performance liquid chromatography with fluorescence detection (HPLC‐FLD) (plasma, Siddiqua 2016).

Maternal haemoglobin concentrations

All trials reported maternal Hb concentrations (second or third trimester of pregnancy, Duggan 2014; three months' postpartum, Siddiqua 2016; 34 to 36 weeks' gestation, Zec 2020; at delivery and six and 12 weeks' postpartum, Edelstein 1968; 12 to 20, 21 to 24, 25 to 28, 29 to 32, 33 to 36, 37 to 40 weeks' gestation and six weeks' postpartum, Metz 1965).

Trials analysed Hb via automated Coulter counter (ABX Pentra C+; Horiba Medicals) (Duggan 2014), spectrophotometry (SIGMA kit) (Siddiqua 2016), haematological analyser ADVIA 2120 (Zec 2020), or estimated as oxyhaemoglobin in a photoelectric colorimeter (Edelstein 1968; Metz 1965).

Breast milk vitamin B₁₂ concentrations

Two trials reported vitamin B₁₂ concentrations in breast milk (six weeks, three months, and six months' postpartum, Duggan 2014; three months' postpartum, Siddiqua 2016).

Both trials analysed breast milk vitamin B₁₂ concentrations by competitive protein binding immunoassay using an Immulite 1000 automated analyser (Duggan 2014; Siddiqua 2016).

Maternal megaloblastic anaemia

No trials reported data on maternal megaloblastic anaemia.

Hyperhomocysteinaemia

Two trials reported elevated maternal homocysteine, defined as greater than 15.0 μmol/L (second or third trimester, Duggan 2014) or greater than 10.0 μmol/L (three months' postpartum, Siddiqua 2016).

Other maternal secondary outcomes

No trials reported data on other secondary outcomes, including pre‐eclampsia, blood pressure or hypertension, neurodegenerative pathology, cognitive function, depression, or adverse events.

Child outcomes

Birthweight

Two trials reported birthweight (Duggan 2014; Siddiqua 2016).

Intrauterine growth restriction

One trial reported IUGR (Duggan 2014).

Vitamin B₁₂ status

Two trials reported vitamin B₁₂ status (Duggan 2014; Siddiqua 2016). Biomarkers of vitamin B₁₂ status included total vitamin B₁₂, MMA, and homocysteine concentrations, evaluated at six weeks of age (Duggan 2014) or three months of age (Siddiqua 2016).

The trials evaluated child vitamin B₁₂ biomarkers in venous blood using the same methods and instruments as maternal biomarkers, namely: total vitamin B₁₂ via electrochemiluminescence (Duggan 2014; Siddiqua 2016), MMA via GC‐MS (Duggan 2014) or UPLC‐MS/MS (Siddiqua 2016), and homocysteine via GC‐MS (Duggan 2014) or HPLC‐FLD (Siddiqua 2016).

Haemoglobin concentrations

Two trials reported Hb concentrations in children (Duggan 2014; Siddiqua 2016).

The trials evaluated Hb concentrations in venous blood via spectrophotometry (SIGMA kit) in children at three months of age (Siddiqua 2016) and via automated Coulter counter (ABX Pentra C+; Horiba Medicals) in children at six weeks of age (Duggan 2014).

Anaemia

Two trials reported anaemia in children, defined as Hb less than 10.5 g/dL at three months of age (Siddiqua 2016) or as Hb less than 11.0 g/dL at six weeks of age (Duggan 2014).

Other secondary outcomes

No trials reported data on other secondary child outcomes, including very preterm birth, stillbirth, other congenital anomalies, neonatal infection, neonatal death, Apgar scores, or development and motor skills.

Missing data

We contacted study authors through the Cochrane Pregnancy and Childbirth Editorial Office to request missing data for inclusion in this review.

Sources of trial funding

Four trials reported funding sources (Duggan 2014; Edelstein 1968; Metz 1965; Siddiqua 2016), and one trial reported no funding sources (Zec 2020). The included trials were supported by research grants from the Indian Council of Medical Research and the National Institutes of Health (Duggan 2014), the WHO (Edelstein 1968; Metz 1965), and the Nuffield Foundation (Edelstein 1968). One trial was funded by Nestlé Foundation, the Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency, and an intramural USDA‐ARS Project (Siddiqua 2016).

Trial authors' declarations of interest

Three trials reported authors' declarations of interest (Duggan 2014; Siddiqua 2016; Zec 2020). Two trials did not provide information on authors' conflicts of interest (Edelstein 1968; Metz 1965).

Screening eligible studies for trustworthiness

We screened all trials for trustworthiness using the CPC‐TST screening tool, and contacted trial authors through the Cochrane Pregnancy and Childbirth Editorial Office for clarification. All studies were at low risk for research governance, baseline characteristics, feasibility, and results. We contacted two trial authors for additional information (pending) (Siddiqua 2016; Zec 2020).

Excluded studies

We excluded nine study records from this review (Bhowmik 2021; Chandyo 2023; CTRI/2020/01/022713; CTRI/2020/10/028330; Devi 2017; Li 2020; Mearns 2014; Nagpal 2020; NCT03258385).

Three were registries for trials, which were not eligible for inclusion in this review (CTRI/2020/10/028330; CTRI/2020/01/022713; NCT03258385).

One trial was excluded based on the participant population (Mearns 2014).

Five trials were excluded based on ineligible comparison group (Bhowmik 2021; Nagpal 2020), ineligible intervention (Chandyo 2023), or ineligible intervention and comparison group (Devi 2017; Li 2020).

Ongoing studies

We identified one ongoing trial (Winje 2018).

Risk of bias in included studies

A summary of the risk of bias assessment of the included trials is presented in Figure 3 and Figure 4.

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

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

Sequence generation

Two trials were at low risk of bias; one trial conducted random sequence generation via permuted blocks of variable size (Duggan 2014), and one sequence generation was not developed a priori with the intervention allocated by rolling a die (Zec 2020). Two trials were at unclear risk of bias as they provided insufficient information regarding the sequence generation process to permit evaluation (Edelstein 1968; Metz 1965). One trial reported a quasi‐random sequence generation process using alternate sequence allocation and was at high risk of bias (Siddiqua 2016).

Allocation concealment

One trial reported adequate methods for allocation concealment and was at low risk of bias (Duggan 2014). Two trials did not describe or clearly describe the methods for allocation concealment and were at unclear risk of bias (Edelstein 1968; Metz 1965). Two trials were at high risk of bias; one reported inadequate methods for allocation concealment (Siddiqua 2016); and one did not use any allocation concealment (Zec 2020).

Blinding of participants and staff (performance bias)

One trial was at low risk of performance bias as blinding of participants and study staff was by using a placebo, and intervention and placebo tablets were indistinguishable by appearance, taste, or smell, and stored in coded opaque bottles (Duggan 2014).

Three trials were at unclear risk of performance bias (Edelstein 1968; Metz 1965; Siddiqua 2016). Siddiqua 2016 used a placebo that was indistinguishable from the intervention by appearance, taste, or smell. However, there was insufficient information available to determine whether participants or staff could have been unblinded to intervention groups, due to alternate allocation of the intervention or other methods used. Metz 1965 used no placebo, and information was insufficient to determine if participants or staff could have been unblinded to intervention groups. Although tablets administered (vitamin B₁₂ supplementation with IFA versus IFA alone) were identical in appearance, the number of tablets in each group or methods to ensure blinding of participants and staff were not described. Edelstein 1968 provided no information on methods for blinding of study participants or personnel.

One trial was at high risk of performance bias as participants or study staff were not blinded to the intervention group (Zec 2020).

Blinding of outcome assessors (detection bias)

All trials were at low risk of detection bias as the outcome measurements (e.g. vitamin B₁₂ biomarkers) were unlikely to be influenced by lack of blinding (Duggan 2014; Edelstein 1968; Metz 1965; Siddiqua 2016; Zec 2020).

Incomplete outcome data

We considered trials with more than 25% loss to follow‐up or with imbalanced loss to follow‐up in trial arms to have a high risk of incomplete outcome data.

One trial was at low risk of attrition bias (Siddiqua 2016). Three trials were at unclear risk of attrition bias, due to a lack of information provided for missing outcome data, and uncertainty if the proportion of outcome data missing would result in a clinically relevant impact on the observed effect sizes (Duggan 2014; Edelstein 1968; Metz 1965). One trial was at high risk of attrition bias due to the proportion of missing outcome data (greater than 50%) (Zec 2020).

Selective reporting

Clinical trials registrations were examined to confirm a priori outcomes for trials and evaluate potential reporting bias. All the included trials reported all prespecified outcomes. Data for some outcomes were not reported in sufficient detail for inclusion in quantitative analyses.

Other potential sources of bias

Three trials were at low risk of other bias (Duggan 2014; Metz 1965; Zec 2020). Two trials had other potential sources of bias (Edelstein 1968; Siddiqua 2016).

Effects of interventions

See: Table 1

The primary outcomes of the effect of vitamin B₁₂ supplementation during pregnancy on primary maternal and child health outcomes are summarised in Table 1.

In this review, three trials, involving 609 pregnant women, contributed data on primary outcomes for inclusion in meta‐analyses (Duggan 2014; Edelstein 1968; Siddiqua 2016).

Vitamin B₁₂ supplementation versus placebo/no vitamin B₁₂ supplementation

Primary outcomes

See Table 1.

In this review, two trials evaluated the effects of vitamin B₁₂ supplementation compared to placebo, and all women received IFA as standard of care (Duggan 2014; Siddiqua 2016). Three trials compared vitamin B₁₂ supplementation with IFA to IFA alone (i.e. no vitamin B₁₂ supplementation) (Edelstein 1968; Metz 1965; Zec 2020). However, two trials did not contribute data because the results were not presented in a form that allowed for inclusion (Metz 1965; Zec 2020). Therefore, in the meta‐analyses, we combined three trials to evaluate the comparison of 'vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation' (Duggan 2014; Edelstein 1968; Siddiqua 2016).

Maternal anaemia

Three trials reported data on maternal anaemia (Duggan 2014; Siddiqua 2016; Metz 1965).

In individual trials, the prevalence of anaemia did not differ between groups when assessed in the second or third trimester in one trial (Duggan 2014), at three months' postpartum in one trial (Siddiqua 2016), or at various time points during gestation (i.e. 25 to 28, 29 to 32, 33 to 36, or 37 to 40 weeks' gestation) or at six weeks' postpartum in one trial (Metz 1965).

Two trials with 448 women contributed data to meta‐analyses for maternal anaemia (Duggan 2014; Siddiqua 2016). There may be little to no difference for maternal anaemia by intervention group, but the evidence was uncertain (70.9% with vitamin B₁₂ versus 65.0% with placebo/no vitamin B₁₂ supplementation; RR 1.08, 95% CI 0.93 to 1.26; 2 trials, 284 women; very low‐certainty evidence; Analysis 1.1).

1.1 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 1: Maternal anaemia

Maternal vitamin B₁₂ deficiency

Three trials reported data for maternal vitamin B₁₂ deficiency (Duggan 2014; Metz 1965; Siddiqua 2016).

One trial reported data for vitamin B₁₂ deficiency (less than 150 pmol/L) during the third trimester of pregnancy (33.3% with vitamin B₁₂ versus 81.4% with placebo; 204 participants; Duggan 2014). One trial reported data on vitamin B₁₂ deficiency (less than 150 pmol/L) at three months' postpartum (3.0% with vitamin B₁₂ versus 28.6% with placebo; 68 participants; Siddiqua 2016). One trial found the prevalence of 'subnormal' maternal vitamin B₁₂ status (not defined, measured at various time points during gestation (i.e. 25 to 28, 29 to 32, 33 to 36, or 37 to 40 weeks' gestation) or at six months' postpartum) decreased following the initiation of vitamin B₁₂ supplementation; however, there were no direct comparisons between the intervention and control groups (Metz 1965).

Two trials with 448 women contributed data to the meta‐analysis for maternal vitamin B₁₂ deficiency (Duggan 2014; Siddiqua 2016). Vitamin B₁₂ supplementation may reduce risk of maternal vitamin B₁₂ deficiency compared to placebo or no vitamin B₁₂ supplementation, but the evidence is very uncertain (25.9% with vitamin B₁₂ versus 67.9% with placebo/no vitamin B₁₂ supplementation; RR 0.38, 95% CI 0.28 to 0.51; 2 trials, 272 women; very low‐certainty evidence; Analysis 1.2). Sensitivity analyses were conducted using a random‐effects mode based on the moderate heterogeneity (I² = 46%) (RR 0.30, 95% CI 0.09 to 0.96).

1.2 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 2: Maternal vitamin B₁₂ deficiency or insufficiency

Spontaneous abortion or miscarriage

Two trials with 448 women reported spontaneous abortion (or miscarriage) (Duggan 2014; Siddiqua 2016). In one trial, we extracted the data from the study flow chart (Duggan 2014); however, the study did not provide the definition and timing of spontaneous abortion (i.e. less than 20 weeks). The second trial did not clearly define the outcome ("aborted") as spontaneous abortion or induced abortion, and the definition and timing for spontaneous abortion was not defined (i.e. less than 20 weeks) (Siddiqua 2016).

The trials reported no quantitative data for inclusion in meta‐analyses and were downgraded to very low‐certainty evidence.

Low birthweight

Two trials with 448 women reported data on low birthweight (Duggan 2014; Siddiqua 2016).

The evidence is uncertain about the effect of vitamin B₁₂ supplementation on low birth weight (RR 1.50, 95% CI 0.93 to 2.43; 2 trials, 334 women; low‐certainty evidence; Analysis 1.3).

1.3 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 3: Low birthweight (< 2500 g)

Preterm birth

Two trials with 448 women reported data on preterm birth (Duggan 2014; Siddiqua 2016).

The evidence is uncertain about the effect of vitamin B₁₂ supplementation on preterm birth (RR 0.97, 95% CI 0.55 to 1.74; 2 trials, 340 women; low‐certainty evidence; Analysis 1.4).

1.4 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 4: Preterm birth (< 37 weeks)

Neural tube defects

No trials reported data for NTDs.

Child cognitive outcomes

Three ancillary analyses conducted in one trial (Duggan 2014) reported cognitive outcomes in children at nine months of age (Srinivasan 2017), 30 months of age (Thomas 2019), and 72 months of age (Srinivasan 2020).

In individual studies, maternal vitamin B₁₂ supplementation did not improve neurodevelopment status in domains assessed by BSID‐III in children at nine months of age (178 children) compared to placebo, including the following domains: cognitive (mean: 38.92 (SD 2.89) with vitamin B₁₂ versus 39.94 (SD 2.82) with placebo), receptive language (mean: 11.13 (SD 0.93) with vitamin B₁₂ versus 11.19 (SD 0.85) with placebo), expressive language (mean: 10.02 (SD 2.18) with vitamin B₁₂ versus 11.00 (SD 2.18) with placebo), fine motor skill (mean: 25.98 (SD 1.53) with vitamin B₁₂ versus 26.04 (SD 1.56) with placebo), or gross motor skill (mean: 36.01 (SD 5.04) with vitamin B₁₂ versus 33.90 (SD 5.85) with placebo) (low‐certainty evidence) (Srinivasan 2017).

Vitamin B₁₂ supplementation during pregnancy did not improve neurophysiological outcomes at 72 months of age (132 children) compared to placebo using ERP measures (positive waveform 300 ms), including latency (mean: 324 (SD 144) with vitamin B₁₂ versus 352 (SD 137) with placebo), amplitude (mean: 5001 (SD 3341) with vitamin B₁₂ versus 5552 (SD 4636) with placebo), or after stimulus and mismatch negativity 1100 ms, including latency (mean: 251 (SD 79) with vitamin B₁₂ versus 290 (SD 104) with placebo) and amplitude (mean: −1558 (SD 1527) with vitamin B₁₂ versus −2187 (SD 1936) with placebo) (low‐certainty evidence) (Srinivasan 2020).

In an assessment at 30 months of age, children born to women who received vitamin B₁₂ supplementation had improved expressive language domain of the BSID‐III compared to placebo (218 children) (mean: 36.01 (SD 3.85) vitamin B₁₂ versus 34.78 (SD 4.49) with placebo) (low‐certainty evidence) (Thomas 2019).

Secondary outcomes

Maternal vitamin B₁₂ status

Four trials reported maternal vitamin B₁₂ status, including total vitamin B₁₂ (four trials; Duggan 2014; Edelstein 1968; Metz 1965; Siddiqua 2016), MMA (two trials; Duggan 2014; Siddiqua 2016), and homocysteine (two trials) concentrations (Duggan 2014; Siddiqua 2016).

Total vitamin B₁₂

In individual trials, vitamin B₁₂ supplementation increased total vitamin B₁₂ concentrations in the second or third trimester of pregnancy (Duggan 2014), and at 72 hours after delivery and three months' postpartum (Siddiqua 2016), compared to placebo. In two other trials, although vitamin B₁₂ concentrations increased in the third trimester of pregnancy amongst women who received vitamin B₁₂ supplements, there were no differences between intervention groups (i.e. vitamin B₁₂ supplementation versus no vitamin B₁₂ supplementation) (Edelstein 1968; Metz 1965).

Three trials involving 609 pregnant women contributed data for meta‐analyses (Duggan 2014; Edelstein 1968; Siddiqua 2016). Vitamin B₁₂ supplementation may improve vitamin B₁₂ status. Women who received vitamin B₁₂ supplementation may have higher total vitamin B₁₂ concentrations compared to placebo or no vitamin B₁₂ supplementation (MD 60.89 pmol/L, 95% CI 40.86 to 80.92; 3 trials, 412 women; Analysis 1.5). There was substantial heterogeneity (I² = 85%). We conducted sensitivity analysis using a random‐effects model (MD 55.37 pmol/L, 95% CI −12.85 to 123.60). We repeated the analysis after removing Edelstein 1968. In sensitivity analyses of data from two trials with 448 pregnant women, women who received vitamin B₁₂ supplementation had higher total vitamin B₁₂ concentrations compared to placebo or no vitamin B₁₂ supplementation (MD 84.51 pmol/L, 95% CI 60.81 to 108.21; 2 trials, 272 women) and there was no heterogeneity (Analysis 1.6; Duggan 2014; Siddiqua 2016). Edelstein 1968 had several methodological limitations, including lack of information regarding randomisation, limited duration (less than eight weeks) of vitamin B₁₂ supplementation, low adherence, and limited statistical analyses reported for a priori comparisons of interests.

1.5 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 5: Maternal total vitamin B₁₂ concentrations

1.6 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 6: Maternal total vitamin B₁₂ concentrations

Methylmalonic acid

Two trials evaluated MMA, a functional biomarker of vitamin B₁₂ status that is elevated in the context of vitamin B₁₂ deficiency (Duggan 2014; Siddiqua 2016).

In individual trials, there were no differences in MMA concentrations amongst women who received vitamin B₁₂ supplementation compared to placebo, when assessed during the second (243 women) or third (207 women) trimester of pregnancy (Duggan 2014). MMA concentrations were lower amongst women who received vitamin B₁₂ supplementation compared to placebo, when assessed at three months' postpartum (68 women) (Siddiqua 2016).

There were no quantitative data reported in these trials for inclusion in meta‐analyses.

Maternal haemoglobin levels

All included trials evaluated maternal Hb concentrations (second or third trimester of pregnancy, Duggan 2014; three months' postpartum, Siddiqua 2016; 34 to 36 weeks' gestation, Zec 2020; delivery and at six and 12 weeks' postpartum, Edelstein 1968; 12 to 20, 21 to 24, 25 to 28, 29 to 32, 33 to 36, 37 to 40 weeks' gestation and at six weeks' postpartum, Metz 1965).

In individual trials, there were no differences by intervention group for maternal Hb concentrations.

Three trials involving 609 pregnant women contributed data to meta‐analyses for this outcome (Duggan 2014; Edelstein 1968; Siddiqua 2016). The evidence suggests that vitamin B₁₂ supplementation results in little to no difference in Hb concentrations compared to placebo or no vitamin B₁₂ supplementation (MD 0.00 g/dL, 95% CI −0.06 to 0.05; 3 trials, 424 women; Analysis 1.7). Sensitivity analyses were conducted using random‐effects models, based on the moderate statistical heterogeneity (I² = 54%) (MD −0.10 g/dL, 95% CI −0.45 to 0.25).

1.7 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 7: Maternal haemoglobin concentrations

Breast milk vitamin B₁₂ concentrations

Two trials evaluated vitamin B₁₂ concentrations in breast milk (Duggan 2014; Siddiqua 2016).

In one trial, vitamin B₁₂ supplementation during pregnancy (until six weeks' postpartum) increased breast milk vitamin B₁₂ concentrations at six weeks' postpartum (141 women) compared to placebo. However, there were no differences in breast milk vitamin B₁₂ concentrations between groups at three months' (104 women) or six months' (81 women) postpartum (Duggan 2014). In the second trial, women who received vitamin B₁₂ supplementation during pregnancy (until three months' postpartum) had higher breast milk vitamin B₁₂ concentrations at three months' postpartum (68 women) compared to placebo (Siddiqua 2016).

There were no quantitative data reported in these studies for inclusion in meta‐analyses.

Maternal megaloblastic anaemia

No trials reported data on maternal megaloblastic anaemia.

Maternal hyperhomocysteinaemia

Two trials reported maternal hyperhomocysteinaemia or homocysteine concentrations (Duggan 2014; Siddiqua 2016).

In one trial, there were no differences between groups in the prevalence of hyperhomocysteinaemia (greater than 10.0 μmol/L) at three months' postpartum (Siddiqua 2016). In the second trial, hyperhomocysteinaemia (greater than 15.0 μmol/L) was not compared by intervention group during gestation; however, there were no differences between intervention groups in continuous homocysteine concentrations evaluated during the second or third trimester of pregnancy (Duggan 2014).

Two trials involving 448 pregnant women contributed data to meta‐analyses for this outcome (Duggan 2014; Siddiqua 2016). It is uncertain whether vitamin B₁₂ supplementation has an effect on the risk of maternal hyperhomocysteinaemia (defined as greater than 15.0 μmol/L at trimester three in pregnancy or as greater than 10.0 μmol/L at three months' postpartum), compared to placebo or no vitamin B₁₂ supplementation (RR 0.81, 95% CI 0.41 to 1.62; 2 trials, 274 women; Analysis 1.8).

1.8 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 8: Maternal hyperhomocysteinaemia

Other maternal secondary outcomes

No trials reported data on other secondary outcomes, including pre‐eclampsia, blood pressure or hypertension, neurodegenerative pathology, cognitive function, depression, or adverse events.

Birthweight

Two trials reported infant birthweight (Duggan 2014; Siddiqua 2016).

Siddiqua 2016 reported no differences in birthweight between vitamin B₁₂ and placebo groups (68 children; P = 0.87), although the specific data (e.g. mean and SD) were not reported by intervention group. Duggan 2014 reported that maternal vitamin B₁₂ supplementation during pregnancy did not increase birthweight compared to placebo (mean: 2.85 (SD 0.46) kg with vitamin B₁₂ versus 2.83 (SD 0.45) kg with placebo; 252 children).

Intrauterine growth restriction

One trial reported IUGR (Duggan 2014). Maternal vitamin B₁₂ supplementation during pregnancy did not reduce the risk of IUGR compared to placebo (33/131 (25%) women with vitamin B₁₂ versus 43/125 (34%) women with placebo).

Child vitamin B₁₂ status

Two trials reported vitamin B₁₂ status in children, including total vitamin B₁₂, MMA, and homocysteine concentrations (Duggan 2014; Siddiqua 2016).

Total vitamin B₁₂

In individual trials, maternal vitamin B₁₂ supplementation during pregnancy increased vitamin B₁₂ concentrations compared to placebo in children at six weeks of age (77 women; Duggan 2014) and three months of age (68 women; Siddiqua 2016).

1.9 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 9: Infant total vitamin B₁₂ concentrations

Methylmalonic acid

In individual trials, maternal vitamin B₁₂ supplementation during pregnancy reduced MMA concentrations compared to placebo in children at six weeks of age (76 women; Duggan 2014) and three months of age (68 women; Siddiqua 2016).

Data were not available in these trials for inclusion in a meta‐analysis.

Homocysteine

In individual trials, maternal vitamin B₁₂ supplementation during pregnancy reduced homocysteine concentrations compared to placebo in children at six weeks of age (77 women; Duggan 2014), and three months of age (68 women; Siddiqua 2016).

Two trials with 448 pregnant women contributed data to the meta‐analysis (Duggan 2014; Siddiqua 2016). Children born to women who received vitamin B₁₂ supplementation may have lower total homocysteine concentrations compared to placebo or no vitamin B₁₂ supplementation (MD −4.42 μmol/L, 95% CI −7.25 to −1.59; 2 trials, 145 children; Analysis 1.10). We conducted a sensitivity analysis using a random‐effects model based on moderate‐to‐substantial heterogeneity (I² = 60%) (MD −4.88 μmol/L, 95% CI −9.55 to −0.22).

1.10 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 10: Infant homocysteine concentrations

Child haemoglobin concentrations

Two trials reported Hb concentrations in children at six weeks of age (Duggan 2014), and three months of age (Siddiqua 2016).

In one trial, there were no differences in Hb concentrations between children whose mothers received vitamin B₁₂ supplementation during pregnancy compared to placebo (Siddiqua 2016). The second trial did not compare Hb concentrations in children by intervention group (Duggan 2014).

Two trials involving 448 pregnant women contributed data to the meta‐analysis (Duggan 2014; Siddiqua 2016). There may be little to no effect on Hb concentrations amongst children born to women who received vitamin B₁₂ supplementation compared to placebo or no vitamin B₁₂ supplementation (MD −0.43 g/dL, 95% CI −1.11 to 0.25; 2 trials, 141 children; Analysis 1.11).

1.11 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 11: Infant haemoglobin concentrations

Child anaemia

Two trials reported data on infant anaemia (Duggan 2014; Siddiqua 2016).

One trial found no differences between intervention groups in the prevalence of anaemia (Hb less than 10.5 g/dL) in infants at three months of age (Siddiqua 2016). The second trial did not compare the prevalence of anaemia (Hb less than 11.0 g/dL) in infants at six weeks of age by intervention group (Duggan 2014).

Two trials involving 448 pregnant women contributed data to the meta‐analysis (Duggan 2014; Siddiqua 2016). It is uncertain if maternal vitamin B₁₂ supplementation during pregnancy has an impact on anaemia in children compared to placebo or no vitamin B₁₂ supplementation (odds ratio 0.74, 95% CI 0.37 to 1.47; 2 trials, 141 children; Analysis 1.12).

1.12 — Comparison 1: Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation, Outcome 12: Infant anaemia

Other child secondary outcomes

No trials reported data on other child secondary outcomes, including very preterm birth, stillbirth, other congenital anomalies, neonatal infection, neonatal death, Apgar scores, or development and motor skills.

Discussion

Summary of main results

This review was conducted to evaluate the effects of oral vitamin B₁₂ supplementation during pregnancy on maternal and child health outcomes. We included five trials involving 984 pregnant women from India, Bangladesh, South Africa, and Croatia. Three trials, including 609 pregnant women, contributed data for meta‐analyses of primary outcomes, and compared the effects of vitamin B₁₂ supplementation to placebo or no vitamin B₁₂ supplementation.

Maternal vitamin B₁₂ status

Vitamin B₁₂ supplementation during pregnancy may reduce the risk of maternal vitamin B₁₂ deficiency (two trials) compared to placebo or no vitamin B₁₂ supplementation, but the evidence is very uncertain. Women who received vitamin B₁₂ supplements may have higher vitamin B₁₂ concentrations (three trials) in the third trimester of pregnancy or at three months' postpartum compared to placebo or no vitamin B₁₂ supplementation.

Maternal anaemia

In contrast, there may be little or no difference for maternal anaemia by intervention groups at any time point assessed, including during gestation (i.e. at various time points in pregnancy, second or third trimester of pregnancy) or at six weeks' or three months' postpartum, but the evidence is very uncertain.

Adverse pregnancy outcomes

The evidence is uncertain about the effect on adverse pregnancy outcomes, including low birthweight (low‐certainty evidence) or preterm birth (low‐certainty evidence). No trials reported the effects of vitamin B₁₂ supplementation during pregnancy on NTDs.

Additionally, only one trial reported other primary maternal and child health outcomes, including spontaneous abortion (or miscarriage) (very low‐certainty evidence) and child cognition (low‐certainty evidence), and data were not presented in a format for inclusion in quantitative analyses.

Overall completeness and applicability of evidence

This review included five RCTs, conducted in India (one trial), Bangladesh (one trial), South Africa (two trials), and Croatia (one trial). Two trials were conducted in the mid‐2000s, and three trials did not specify study dates. One trial was conducted amongst pregnant women with anaemia at enrolment, while the other four trials included pregnant women irrespective of baseline micronutrient status. Three trials evaluated vitamin B₁₂ supplementation administered beginning at 14 weeks' gestation or less, while two trials assessed vitamin B₁₂ supplementation later in gestation (greater than 24 weeks' gestation).

Two trials evaluated the effects of vitamin B₁₂ supplementation compared to placebo, and all women received IFA supplementation as standard of care. Three trials evaluated the effects of vitamin B₁₂ supplementation in combination with IFA supplementation compared to IFA alone. Three trials, including 609 pregnant women, contributed data for meta‐analyses on the effects of vitamin B₁₂ supplementation compared to placebo (two trials) or vitamin B₁₂ in combination with IFA compared to IFA alone (one trial). In meta‐analyses, we combined these trials to evaluate the effects of vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation on primary maternal and child health outcomes.

Maternal vitamin B₁₂ deficiency (three trials) and maternal vitamin B₁₂ concentrations (four trials) were the most frequently reported outcomes in the included trials. Vitamin B₁₂ supplementation during pregnancy reduced the risk of vitamin B₁₂ deficiency (vitamin B₁₂ versus placebo; overall: 25.9% versus 67.9%; pregnancy: 33.3% versus 81.4%; postpartum: 3.0% versus 28.6%) and increased maternal vitamin B₁₂ concentrations by an average of 60.89 pmol/L (95% CI 40.86 to 80.92) during the third trimester of pregnancy or at three months' postpartum. Meta‐analyses included measures of maternal vitamin B₁₂ status during two distinct physiological periods: pregnancy and postpartum, which constrains the interpretation of findings. However, the 42% difference in the prevalence of vitamin B₁₂ deficiency between intervention groups (ranging from 48.1% during pregnancy to 25.3% postpartum) and the corresponding mean magnitude of increase in maternal vitamin B₁₂ concentrations (60.89 pmol/L) indicates that maternal vitamin B₁₂ supplementation during pregnancy may lead to clinically meaningful improvements in maternal vitamin B₁₂ status.

Maternal vitamin B₁₂ supplementation during pregnancy also increased vitamin B₁₂ concentrations in children (two trials), by an average of 71.89 pmol/L (95% CI 20.23 to 123.54), at six weeks or three months of age. The magnitude of increase in child vitamin B₁₂ concentrations is comparable to the reported increases in maternal vitamin B₁₂ status, indicating that vitamin B₁₂ supplementation during pregnancy improved the vitamin B₁₂ status of both women and their children. Despite the limited availability of data for inclusion in meta‐analyses and variation in timing of assessment, vitamin B₁₂ supplementation improved maternal vitamin B₁₂ status during the pregnancy and postpartum periods and increased child vitamin B₁₂ status across trials.

The duration of vitamin B₁₂ supplementation during pregnancy and through the postpartum period may be a clinically relevant consideration for improving vitamin B₁₂ status and health outcomes in women and their children. Vitamin B₁₂ supplementation during pregnancy improved maternal vitamin B₁₂ status during gestation, and in both women and their children at six weeks' to three months' postpartum.

In contrast, the effects of vitamin B₁₂ supplementation on breast milk concentrations of vitamin B₁₂ varied with the timing of cessation of daily supplementation during the postpartum period: vitamin B₁₂ supplementation during pregnancy (beginning at 14 weeks' gestation or less) increased breast milk concentrations of vitamin B₁₂ at six weeks' postpartum (but not three or six months' postpartum) in one trial and at three months' postpartum in a second trial, corresponding to the cessation of daily vitamin B₁₂ supplementation, respectively. These findings suggest that the effects of vitamin B₁₂ supplementation on breast milk concentrations may not be sustained after cessation of daily vitamin B₁₂ supplementation.

The implications for improvements in maternal or child vitamin B₁₂ status for maternal and child health outcomes are less clear. In meta‐analyses of data from two trials, there were no effects of vitamin B₁₂ supplementation during pregnancy, low birthweight, or preterm birth, compared to placebo. Data were not reported or not available for other maternal and child health outcomes for inclusion in quantitative analyses.

The included trials were conducted to evaluate the effects of vitamin B₁₂ supplementation during pregnancy on maternal vitamin B₁₂ status, with most trials including maternal vitamin B₁₂ concentrations during gestation as the primary outcome. These studies were not designed to evaluate the effects of maternal vitamin B₁₂ supplementation on specific pregnancy outcomes or longer‐term child health outcomes and may not have had sufficient power to evaluate these outcomes.

The search identified one ongoing trial evaluating the effects of maternal vitamin B₁₂ supplementation on child cognitive function that will add to the body of evidence on the effects of maternal vitamin B₁₂ supplementation on child health outcomes (Winje 2018).

Quality of the evidence

All trials were at low risk of detection bias (blinding of outcome assessment), and reporting bias. One trial was at low risk of bias for all domains except attrition bias, which was unclear based on the information provided. One trial was at high risk of bias for selection bias due to non‐random sequence generation and lack of allocation concealment. One trial was at high risk of selection bias due to lack of allocation concealment, performance bias, and attrition bias. The two remaining trials were at unclear risk of bias in several domains, due to the limited methodological information provided.

The overall certainty of evidence for maternal vitamin B₁₂ deficiency, maternal anaemia, and spontaneous abortion or miscarriage was determined to be very low, and for low birthweight and preterm birth to be low (see Table 1). The certainty of evidence for maternal vitamin B₁₂ deficiency and maternal anaemia was downgraded three times due to concerns about risk of bias, imprecision, and indirectness due to different time points and population. The certainty of evidence for spontaneous abortion or miscarriage was downgraded three times due to serious concerns about risk of bias, inconsistency, and imprecision. The certainty of evidence for low birthweight and preterm birth was downgraded twice due to serious concerns of bias and imprecision of estimates. Overall certainty of evidence was downgraded twice for child cognitive outcomes, due to serious concerns about inconsistency and imprecision.

Potential biases in the review process

There are several potential biases in the review process. We attempted to minimise them in three ways: 1. an information specialist conducted the search for this review through the Cochrane Pregnancy and Childbirth's Trials Register using standardised methods, and applied no date or language restrictions; 2. two review authors independently evaluated search results for potential inclusion based on established a priori criteria; and 3. two review authors independently extracted data using a structured form, and three review authors independently evaluated risk of bias. We resolved discrepancies through discussion and consultation with the senior review author. Additional information summarised from the Included studies is provided for additional context in interpreting results from this review.

Agreements and disagreements with other studies or reviews

No systematic reviews to date have been conducted to evaluate the effects of vitamin B₁₂ supplementation during pregnancy on maternal and child health outcomes to which findings from this review are directly comparable.

Systematic reviews

Two prior systematic reviews were conducted to examine the role of vitamin B₁₂ in the development of perinatal outcomes, summarising findings from primarily observational studies (Behere 2021; Finkelstein 2015). In Finkelstein 2015, vitamin B₁₂ supplementation during pregnancy improved maternal vitamin B₁₂ status (one study), which is consistent with findings from the current review. However, based on a synthesis of evidence from observational studies (primarily case‐control and cross‐sectional design), lower maternal vitamin B₁₂ status during gestation was associated with increased risk of adverse pregnancy outcomes (Finkelstein 2015). Behere 2021 evaluated the association of maternal vitamin B₁₂ during pregnancy and perinatal and child health outcomes, focusing on evidence from observational studies and RCTs conducted in India. Based on observational studies synthesised in the review, low maternal vitamin B₁₂ status during pregnancy was associated with higher risk of NTDs and low birthweight, and lower maternal vitamin B₁₂ status during pregnancy was associated with impaired cognitive outcomes in children (Behere 2021).

Meta‐analyses of observational studies

In meta‐analyses of observational studies, maternal vitamin B₁₂ concentrations during pregnancy were associated with a higher risk of early recurrent pregnancy loss (Bala 2021), preterm birth (Rogne 2017), low birthweight (Rogne 2017; Sukumar 2016), and NTDs (Wang 2012). In addition to these primary outcomes, meta‐analyses of observational studies reported lower maternal vitamin B₁₂ concentrations during pregnancy were associated with higher risk of gestational diabetes mellitus (Kouroglou 2019; Wang 2021) and pre‐eclampsia (Mardali 2020), but not maternal neurocognitive outcomes (e.g. depression and restless leg syndrome; Ramadan 2021). Findings from our review are not directly comparable to meta‐analyses of observational studies.

Other reviews

One recent Campbell systematic review evaluated the effects of vitamin and mineral supplementation during pregnancy on maternal, birth, child health, and development outcomes in low‐ and middle‐income countries (Keats 2021). Findings in this review demonstrated that multiple micronutrient supplementation improved maternal and child health outcomes, including maternal anaemia, low birthweight, preterm birth, small‐for‐gestational age, stillbirths, and micronutrient deficiencies (Keats 2021). Evidence from systematic reviews of observational studies that did not include quantitative analyses indicated that lower maternal vitamin B₁₂ status was associated with a higher risk of NTDs (Molloy 2018; Ray 2003; Wahbeh 2021), while higher vitamin B₁₂ status during pregnancy may be associated with improved cognition in children (Venkatramanan 2016).

Additional studies

In addition to the trials included in this review, trials evaluating the effects of different doses of vitamin B₁₂ supplementation during pregnancy may provide additional context for interpretation of findings from this review. For example, Devi 2017 compared different combinations of vitamin B₁₂ supplementation in milk. Vitamin B₁₂ supplementation in milk did not increase maternal vitamin B₁₂ concentrations compared to milk alone, but reduced concentrations of homocysteine in the third trimester of pregnancy, which is a functional biomarker of vitamin B₁₂ and folate metabolism (Devi 2017). One ongoing trial is comparing the effects of different vitamin B₁₂ supplements (cyanocobalamin 400 μg plus folic acid 1 mg and methylcobalamin 500 μg plus folic acid 5 mg) to folic acid 5 mg alone on birth outcomes (CTRI/2020/01/022713). A third trial is comparing the effects of different doses of oral vitamin B₁₂ supplementation during pregnancy (50 µg/day versus 250 µg/day) on motor and mental outcomes in children (Nagpal 2020).

Authors' conclusions

Implications for practice.

Evidence suggests that oral vitamin B₁₂ supplementation during pregnancy may reduce the risk of maternal vitamin B₁₂ deficiency and may improve vitamin B₁₂ status in women during pregnancy or postpartum compared to placebo or no vitamin B₁₂ supplementation, but the evidence is very uncertain. The data on vitamin B₁₂ supplementation during pregnancy on other maternal and child health outcomes are limited.

Although vitamin B₁₂ supplementation during pregnancy may have improved maternal vitamin B₁₂ status, its effects on longer‐term maternal and child health outcomes are unknown.

Implications for research.

This review emphasises the importance of conducting rigorous and larger trials for longer durations to better understand the role of vitamin B₁₂ supplementation during pregnancy on maternal and child health outcomes. Future research could consider investigating the following.

Prospective evaluation of maternal and child vitamin B₁₂ biomarkers, folate status, and haematological indicators.
Inclusion of additional maternal health outcomes, including pre‐eclampsia, depression, and cognition, using standardised instruments and time points.
Appropriately powered trials to examine specific pregnancy outcomes, including spontaneous abortion, intrauterine growth restriction, birthweight, low birthweight, preterm birth, and congenital defects.
Inclusion of specific child health outcomes, including cognitive outcomes and developmental milestones using standardised and validated instruments at various time points.
Assessment of the effects of vitamin B₁₂ supplementation through the postpartum period.

Evaluation of the effects of vitamin B₁₂ supplementation during pregnancy on maternal and child health outcomes to inform recommendations for vitamin B₁₂ supplementation as part of standard antenatal care could also be considered.

History

Protocol first published: Issue 12, 2020

Acknowledgements

We would like to thank the staff at the editorial office of Cochrane Pregnancy and Childbirth for their support in the preparation of this review.

The protocol for this review was initially developed during the World Health Organization (WHO)/Cochrane/Cornell University Summer Institute for Systematic Reviews in Nutrition for Global Policy Making, hosted at the Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA. The WHO has partially supported this programme beginning in 2014.

Individuals from the US Centers for Disease Control and Prevention (US Government employees) contributed to this review, and their work is in the public domain in the US. The findings and conclusions in this report are those of the review authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to Cochrane Pregnancy and Childbirth. The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the Evidence Synthesis Programme, the NIHR, National Health Service (NHS), or the Department of Health and Social Care.

Appendices

Appendix 1. ICTRP and ClinicalTrials.gov – search methods

ICTRP

(each line was run separately and all synonyms were searched)

B12 AND pregnant

B12 AND pregnancy

ClinicalTrials.gov

Advanced search

pregnancy | Interventional Studies | Vitamin B 12

pregnant | Interventional Studies | Vitamin B 12

antenatal | Interventional Studies | Vitamin B 12

Interventional Studies | Pregnancy | Cobalamins

Data and analyses

Comparison 1. Vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Maternal anaemia	2	284	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.93, 1.26]
1.2 Maternal vitamin B₁₂ deficiency or insufficiency	2	272	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.28, 0.51]
1.3 Low birthweight (< 2500 g)	2	334	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.93, 2.43]
1.4 Preterm birth (< 37 weeks)	2	340	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.55, 1.74]
1.5 Maternal total vitamin B₁₂ concentrations	3	412	Mean Difference (IV, Fixed, 95% CI)	60.89 [40.86, 80.92]
1.6 Maternal total vitamin B₁₂ concentrations	2	272	Mean Difference (IV, Fixed, 95% CI)	84.51 [60.81, 108.21]
1.7 Maternal haemoglobin concentrations	3	424	Mean Difference (IV, Fixed, 95% CI)	‐0.00 [‐0.06, 0.05]
1.8 Maternal hyperhomocysteinaemia	2	274	Odds Ratio (M‐H, Fixed, 95% CI)	0.81 [0.41, 1.62]
1.9 Infant total vitamin B₁₂ concentrations	2	144	Mean Difference (IV, Fixed, 95% CI)	71.89 [20.23, 123.54]
1.10 Infant homocysteine concentrations	2	145	Mean Difference (IV, Fixed, 95% CI)	‐4.42 [‐7.25, ‐1.59]
1.11 Infant haemoglobin concentrations	2	141	Mean Difference (IV, Fixed, 95% CI)	‐0.43 [‐1.11, 0.25]
1.12 Infant anaemia	2	141	Odds Ratio (M‐H, Fixed, 95% CI)	0.74 [0.37, 1.47]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Duggan 2014.

*Study characteristics*
Methods	Double‐blind, randomised, placebo‐controlled trial in India Trial conducted between December 2008 to December 2010 Pregnant women were enroled ≤ 14 weeks' gestation and randomised to either vitamin B₁₂ supplements (50 μg/day cyanocobalamin) or placebo
Participants	Included: 366 pregnant women aged ≥ 18 years who presented for antenatal care ≤ 14 weeks' gestational age (based on the date of the last menstrual period) at a maternity healthcare centre predominantly catering for women from lower socioeconomic strata were eligible to enrol. Excluded: women who anticipated moving out of the area before study completion; who had twin or multiple pregnancies; who were treated for infertility; who tested positive for hepatitis B (hepatitis B surface antigen), HIV, or syphilis infections (Venereal Disease Research Laboratory test); who were taking daily vitamin supplements in addition to folic acid and iron; with a serious pre‐existing medical condition (defined as the need for chronic or daily medication use); with a history of previous caesarean section.
Interventions	Intervention: vitamin B₁₂ supplementation 50 μg/day Control: placebo Duration: enrolment through 6 weeks' postpartum All women received iron–folic acid supplementation (iron 60 mg, folic acid 500 mg) per standard of care.
Outcomes	Maternal anaemia (second or third trimester of pregnancy), spontaneous abortion or miscarriage, birthweight (and LBW), maternal vitamin B₁₂ status (third trimester), child cognitive assessment (9, 30, and 72 months of age), child vitamin B₁₂ status (6 weeks of age), breast milk vitamin B₁₂ concentrations (6 weeks', 3 months', and 6 months' postpartum), maternal hyperhomocysteinaemia (second or third trimester), and child Hb concentrations (6 weeks of age).
Notes	Funded by Indian Council of Medical Research grant 5/7/192/06‐RHN and Eunice Kennedy Shriver National Institute of Child Health and Human Development grants NIH R03 HD054123 and K24HD058795
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A randomization list from 1 to 370 was prepared by the study biostatistician using permuted blocks of variable size, and women enrolled at the study clinic were provided the next consecutive number on the list."
Allocation concealment (selection bias)	Low risk	Quote: "Women were randomly assigned to receive a daily oral dose of vitamin B‐12 (50 μg) or a placebo identical in appearance … The randomization list was provided to the pharmacy department in Bangalore [Bengaluru], with each number corresponding to a code denoting 1 of the 2 treatment groups. Onsite study pharmacists stored the coded randomization list in a locked file cabinet and concealed allocation by only displaying the woman's identification number on the label of the bottle."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Capsules of the regimen were distributed in bottles containing 40 each. The placebo and vitamin B₁₂ supplement were indistinguishable in terms of taste, smell, and appearance. Study physicians, research nurses, and participants were unaware of treatment groups. Blinding of participants and personnel was ensured.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Study physicians, research nurses, and participants were unaware of treatment groups." Comment: blinding of outcome assessors was ensured. Measurement of outcomes unlikely to be influenced by blinding.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Loss to follow‐up was clearly described. Reasons for missing outcome data (e.g. withdrawing from study, migration) was unlikely to be related to outcome data (biochemical indicators). Missing outcome data were relatively balanced in numbers across the intervention groups. Unclear if the proportion of missing outcomes (20% to 25%) would have a clinically relevant impact on the effect estimates for the intervention.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported. Reported primary outcomes for the trial were clearly documented.
Other bias	Low risk	Study appeared free of other evident sources of bias.

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Edelstein 1968.

*Study characteristics*
Methods	Randomised trial in South Africa Pregnant women were randomly allocated to 1 of 2 groups.
Participants	161 Pregnant Bantu women attending Baragwanath Hospital in Johannesburg, South Africa, who were ≥ 24 weeks' gestation
Interventions	Intervention: vitamin B₁₂ supplementation (50 μg/day) plus IFA (iron 200 mg, folic acid 5 mg) per standard of care Control: IFA alone Duration: 28 weeks' gestation until delivery
Outcomes	Maternal vitamin B₁₂ status (third trimester), maternal Hb concentrations (6 and 12 weeks' postpartum)
Notes	Funded by a research grant from the World Health Organization and Nuffield Foundation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information about sequence generation to permit evaluation.
Allocation concealment (selection bias)	Unclear risk	Method of concealment not described.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information on blinding of study participants and personnel to permit evaluation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Insufficient information on blinding of outcome assessment provided to permit evaluation. However, blinding of outcome assessment (laboratory biomarkers) unlikely to be influenced by unblinding.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Information on missing outcome data or reasons for missing data were not reported. Insufficient reporting of outcome data, exclusions, or attrition to permit evaluation.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported.
Other bias	Unclear risk	Trial partially funded by the Nuffield Foundation (an independent trust) and no details on their involvement in design or interpretation of results were explicitly mentioned.

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Metz 1965.

*Study characteristics*
Methods	Randomised controlled trial in South Africa Pregnant women presenting for antenatal care were randomised to 1 of 3 groups
Participants	175 White pregnant women attending antenatal care at South Rand Hospital in Johannesburg, South Africa
Interventions	Intervention: vitamin B₁₂ supplementation (50 μg/day) plus IFA (iron 200 mg, folic acid 5 mg) per standard of care Control: IFA alone Additional group: iron (200 mg) alone Duration: 24 weeks' gestation to delivery
Outcomes	Maternal vitamin B₁₂ status (third trimester), maternal Hb concentrations (6 weeks' postpartum)
Notes	Funded by a research grant from the World Health Organization.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "In the antenatal clinic, patients in early pregnancy were allocated by random numbers to one of three groups." Comment: insufficient information about the sequence generation process to permit evaluation.
Allocation concealment (selection bias)	Unclear risk	Method of concealment not described.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "All tablets were dispensed in identical gelatin capsules." Comment: blinding of study participants and personnel was described. However, insufficient information provided to permit evaluation, and how blinding of study participants and personnel was maintained during the study.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Insufficient information provided to permit evaluation of blinding of outcome assessment. However, outcome assessment (biomarkers) was unlikely to be influenced by unblinding.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Enrolment of participants in intervention groups at baseline was described (iron alone: 57 participants; IFA: 60 participants; IFA and vitamin B₁₂: 58 participants). However, there was insufficient information of attrition/exclusions or outcome data to evaluate completeness.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported. Outcomes of interest were reported in figures and data were not provided in tables.
Other bias	Low risk	Study appeared free of other evident sources of bias.

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Siddiqua 2016.

*Study characteristics*
Methods	Placebo‐controlled randomised trial in Bangladesh Conducted from June 2010 to August 2012
Participants	82 pregnant women 11–14 weeks' gestation, aged 18–35 years, who were anaemic (Hb < 11.0 g/dL) and willing to deliver their child at the Maternal and Child Health Training Institute
Interventions	Intervention: vitamin B₁₂ supplementation (250 μg/day) Control: placebo Duration: 11–14 weeks' gestation to 3 months' postpartum All women received IFA (iron 60 mg, folic acid 400 μg) per standard of care
Outcomes	Maternal anaemia (3 months' postpartum), vitamin B₁₂ deficiency (< 150 pmol/L; (3 months' postpartum)), spontaneous abortion or miscarriage, LBW, preterm birth, maternal vitamin B₁₂ concentrations (72 hours after delivery and 3 months' postpartum), maternal Hb concentrations (3 months' postpartum), breast milk vitamin B₁₂ concentrations (3 months' postpartum), maternal hyperhomocysteinaemia (3 months' postpartum), birthweight, child vitamin B₁₂ concentrations (3 months of age), and child Hb concentrations (3 months of age).
Notes	Funded by the Nestlé Foundation (GR‐00745), Swedish International Development Cooperation Agency (GR‐00599), Bill & Melinda Gates Foundation (OPP1061055), and intramural USDA‐ARS Project (5306‐51000‐003‐00D). We contacted trial authors for additional information (pending).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Non‐random component in sequence generation process. The intervention received by the first participant was determined by lottery, and thereafter, every alternate participant received that type of tablet.
Allocation concealment (selection bias)	High risk	Allocation was based on alternation; investigators enroling participants could foresee allocation assignments. The vitamin B₁₂ and placebo supplements were prepared, packaged, and blinded by the Incepta Pharmaceuticals Company in Bangladesh and delivered in small bottles of 10 tablets. Bottles were labelled as A and B, and the identity was kept confidential until the end of the study. The tablet, either A or B, to be received by the first participant was determined by lottery, and thereafter, every alternate participant received that type of tablet.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of study participants and personnel was attempted: enroled women were randomly assigned to receive either vitamin B₁₂ supplements or a placebo tablet identical in appearance and taste. The vitamin B₁₂ and placebo supplements were prepared, packaged, and blinded by the Incepta Pharmaceuticals Company in Bangladesh and delivered in small bottles of 10 tablets. Bottles were labelled as A and B, and the identity was kept confidential until the end of the study. The tablet, either A or B, to be received by the first participant was determined by lottery, and thereafter, every alternate participant received that type of tablet. The vitamin B₁₂ tablets were indistinguishable in appearance, colour, and taste from the placebo tablet. Participants and caregivers were blinded to the randomisation until laboratory work and statistical analysis were completed. However, randomisation was assigned to the first participant; subsequently, each alternate participant thereafter received the same intervention. If participant or personnel were unblinded for 1 participant, then knowledge of intervention assignments could have been obtained for the other participants.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Participants and caregivers were blinded to the randomization until laboratory work and statistical analysis were completed." Comment: outcome assessment was blinded and unlikely to be influenced by unblinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Losses to follow‐up were clearly described. Reasons for missing outcome data were unlikely to be related to outcomes. Missing outcome data were relatively balanced across intervention groups. The proportion of missing outcomes (15–20%) was unlikely to have a clinically relevant impact on the intervention effect estimates.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported.
Other bias	Unclear risk	Trial partially funded by the Nestlé Foundation, where grant applications are reviewed by a group of "independent international scientists." No details on their involvement in design or interpretation of results were explicitly mentioned.

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Zec 2020.

*Study characteristics*
Methods	Randomised controlled trial 8 gynaecological primary care practises in Split‐Dalmatian County, Croatia Investigators rolled a die to determine to which group a participant would be assigned
Participants	Healthy pregnant women aged 18–36 years Inclusion criteria: no signs of anaemia (Hb < 110 g/L in the first trimester and Hb < 105 g/L in the second and third trimesters), and otherwise healthy pregnancy
Interventions	Intervention: vitamin B₁₂ supplementation (5 μg/day) plus IFA (iron 350 mg, folic acid 5 mg) per standard of care Control: IFA alone Duration: 8 weeks' gestation to third trimester
Outcomes	Maternal Hb concentrations (34–36 weeks' gestation)
Notes	No funding reported. Trial authors were contacted for additional information (pending).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random sequence was generated, but was not determined a priori. A simple randomisation was conducted by tossing a die. For each participant enroled in the study, investigators threw a die to determine to which group a participant would be allocated. Numbers 1–3 of the dice allocated participants into the control group, and numbers 4–6 allocated participants into the intervention group. Randomisation sequence was not concealed. Study investigators, gynaecologists, and participants were aware of the group allocation.
Allocation concealment (selection bias)	High risk	Randomisation sequence and allocation were not concealed (see above).
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and study personnel were not blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessment was not blinded. However, measurement of outcomes (laboratory biomarkers) was unlikely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias) All outcomes	High risk	Loss to follow‐up and reasons for missing outcome data were not clearly described; unclear if reasons for missing outcome data were likely to be related to outcome. The proportion of missing data was likely enough to have a clinically relevant impact on the effect estimates for the intervention. In the 34th week of pregnancy, 62 participants in the control group and 50 participants in the intervention group did not attend for final testing. Finally, the number of participants analysed were 38 in the control group and 50 in the intervention group. The authors indicated that (quote) "after performing post hoc power analysis and taking into consideration observed effect sizes for included outcomes, we found that major findings of this study were adequately powered."
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported.
Other bias	Low risk	Study appeared free of other evident sources of bias.

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Hb: haemoglobin; IFA: iron‐folic acid; LBW: low birthweight.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Bhowmik 2021	Ineligible comparison group. Randomised trial of vitamin D or vitamin B₁₂ (or both) supplementation to correct respective micronutrient deficiencies at enrolment; with an additional observational arm without vitamin D or vitamin B₁₂ deficiencies.
Chandyo 2023	Ineligible intervention: randomised trial of vitamin B₁₂‐fortified biscuits compared to placebo
CTRI/2020/01/022713	Trial registry. Ineligible intervention and comparison group: randomised trial of 1. cyanocobalamin 400 μg plus folic acid 1 mg plus pyridoxine hydrochloride 10 mg; 2. methylcobalamin 500 μg plus folic acid 5 mg plus pyridoxine hydrochloride 10 mg; and 3. folic acid 5 mg.
CTRI/2020/10/028330	Trial registry. Ineligible comparison: randomised trial of vitamin B₁₂ supplementation compared to milk.
Devi 2017	Ineligible intervention and comparison group. Partially open‐labelled randomised trial, in which pregnant women with serum vitamin B₁₂ < 200 pmol/L were randomly assigned to 1. balanced protein‐energy supplementation of 500 mL milk/day (containing an estimated vitamin B₁₂ 2 μg) plus vitamin B₁₂ supplement (vitamin B₁₂ 10 mg), 2. milk 500 mL/day plus placebo tablet, or 3. placebo supplement.
Li 2020	Ineligible intervention and comparison group. Randomised trial of multiple micronutrient supplementation (including vitamin B₁₂) compared to iron supplementation or placebo.
Mearns 2014	Ineligible population. Randomised trial was not conducted amongst pregnant women.
Nagpal 2020	Ineligible comparison group. Randomised trial comparing different doses of vitamin B₁₂ supplements.
NCT03258385	Trial registry. Ineligible intervention: randomised trial of vitamin B₁₂‐fortified UHT milk (200 mL milk fortified with vitamin B₁₂ 100 μg) or unfortified UHT milk.

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UHT: ultra heat treatment.

Characteristics of ongoing studies [ordered by study ID]

Winje 2018.

Study name	Does early vitamin B₁₂ supplementation improve neurodevelopment and cognitive function in childhood and into school age: a study protocol for extended follow‐ups from randomised controlled trials in India and Tanzania
Methods	Follow‐up study for randomised controlled trials in India and Tanzania.
Participants	Children whose mothers participated in a vitamin B₁₂ supplementation trial during pregnancy, or children who participated in a vitamin B₁₂ supplementation trial in infancy/early childhood 4 trials: 1 in Bangalore (Bengaluru), India (pregnancy); 2 in Delhi, India (infancy/early childhood); 1 in Dar es Salaam, Tanzania (pregnancy and infancy)
Interventions	None
Outcomes	Child neurodevelopment, cognitive function, and linear growth
Starting date	Varied by initial randomised controlled trial: 2015–2016
Contact information	Tor A Strand; Email tor.strand@uib.no
Notes	Study protocol for follow‐up of completed trials

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Differences between protocol and review

Any differences between our published protocol (Finkelstein 2020) and the full review are listed below.

We incorporated the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool (CPC‐TST).

Contributions of authors

JLF co‐ordinated the review and wrote the first draft of the review.

YPQ and AF developed the background section and initial draft of the protocol. The methods' section of this protocol was based on a standard protocol provided by the Cochrane Pregnancy and Childbirth group.

AF and SV conducted data extraction in duplicate and developed the results section.

AF, SV, and YPQ conducted risk of bias assessment in duplicate.

AJL and JLF developed the discussion section.

AF, SV, YPQ, AJL, JLF, and KSC revised the review.

All protocol authors contributed to and approved the final version of the review.

JLF has responsibility for final content.

Sources of support

Internal sources

None, Other

Not applicable

External sources

None, Other

Not applicable

Declarations of interest

The protocol for this review was initially developed during the World Health Organization (WHO)/Cochrane/Cornell University Summer Institute for Systematic Reviews in Nutrition for Global Policy Making, held annually at the Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA (Finkelstein 2020). The WHO has partially supported this programme beginning in 2014. The protocol was not directly supported by the WHO.

JLF is a principal investigator on research grants to examine the burden and aetiology of anaemia in women of reproductive age (US Centers for Disease Control and Prevention), biomarkers of anaemia and 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 (US Centers for Disease Control and Prevention). JLF has no known conflicts of interest to declare.

AF is an employee of the US Government at the Centers for Disease Control and Prevention and has no known conflicts of interest to declare.

SV has no known conflicts of interest to declare.

YPQ is an employee of the US Government at the Centers for Disease Control and Prevention and has no known conflicts of interest to declare.

AJL has no known conflicts of interest to declare.

JLW is an employee of the US Government at the Centers for Disease Control and Prevention working as a PhD nurse epidemiologist and family nurse practitioner for the US Public Health Service and has no known conflicts of interest to declare.

KSC is an employee of the US Government at the Centers for Disease Control and Prevention and has no known conflicts of interest to declare.

None of the authors are investigators on any trials included in this review.

New

References

References to studies included in this review

Duggan 2014 {published and unpublished data}

Duggan C, Srinivasan K, Thomas T, Samuel T, Rajendran R, Muthayya S, et al. Vitamin B-12 supplementation during pregnancy and early lactation increases maternal, breast milk, and infant measures of vitamin B-12 status. Journal of Nutrition 2014;144(5):758-64. [CENTRAL: CN-00989010] [EMBASE: 2014273285] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
Finkelstein JL, Kurpad AV, Bose B, Thomas T, Srinivasan K, Duggan C. Anaemia and iron deficiency in pregnancy and adverse perinatal outcomes in Southern India. European Journal of Clinical Nutrition 2019;74(1):112-25. [CENTRAL: CN-01960913] [EMBASE: 628527912] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
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Srinivasan K, Thomas S, Anand S, Jayachandra M, Thomas T, Strand TA, et al. Vitamin B-12 supplementation during pregnancy and early lactation does not affect neurophysiologic outcomes in children aged 6 years. Journal of Nutrition 2020;150(7):1951-7. [CENTRAL: CN-02132685] [EMBASE: 631937845] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
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Thomas S, Thomas T, Bosch RJ, Ramthal A, Bellinger DC, Kurpad AV, et al. Effect of maternal vitamin B12 supplementation on cognitive outcomes in south Indian children: a randomized controlled clinical trial. Maternal and Child Health Journal 2019;23(2):155-63. [CENTRAL: CN-01913436] [PMID: ] [DOI] [PubMed] [Google Scholar]

Edelstein 1968 {published data only}

Edelstein T, Stevens K, Baumslag N, Metz J. Folic acid and vitamin B12 supplementation during pregnancy in a population subsisting on a sub-optimal diet. Journal of Obstetrics and Gynaecology of the British Commonwealth 1968;75(2):133-7. [CENTRAL: CN-00231500] [DOI] [PubMed] [Google Scholar]

Metz 1965 {published data only}

Metz J, Festenstein H, Welch P. Effect of folic acid and vitamin B12 supplementation on tests of folate and vitamin B12 nutrition in pregnancy. American Journal of Clinical Nutrition 1965;16:472-9. [CENTRAL: CN-00233439] [DOI] [PubMed] [Google Scholar]

Siddiqua 2016 {published data only (unpublished sought but not used)}

NCT01795131. Vitamin B12 supplementation during pregnancy [Role of vitamin B12 supplementation during pregnancy and postpartum to reduce nutritional anemia and improve immunity in Bangladeshi women and their infants]. clinicaltrials.gov/show/NCT01795131 (first received 20 February 2013). [CENTRAL: CN-01579081]
Siddiqua T, Ahsan K, Ahmed S, Allen L, Raqib R. Vitamin B12 supplementation during pregnancy and postpartum increases maternal plasma anti-influenza IgA and ameliorates infant's plasma AGP response. FASEB Journal 2014;28(1 Suppl 1):Abstract 392.8. [CENTRAL: CN-01060790] [EMBASE: 71420840] [Google Scholar]
Siddiqua T, Ahsan K, Rashid M, Shahab-Ferdows S, Hampel D, Ahmed T, et al. Vitamin B12 supplementation of Bangladeshi women during pregnancy and lactation increases vitamin B12 in breast milk and improves infant status. Annals of Nutrition & Metabolism 2013;63(Suppl 1):164-5. [Google Scholar]
Siddiqua TJ, Ahmad SM, Ahsan KB, Rashid M, Roy A, Rahman SM, et al. Vitamin B12 supplementation during pregnancy and postpartum improves B12 status of both mothers and infants but vaccine response in mothers only: a randomized clinical trial in Bangladesh. European Journal of Nutrition 2016;55(1):281-94. [CENTRAL: CN-01139211] [EMBASE: 20160116872] [PMID: ] [DOI] [PubMed] [Google Scholar]
Siddiqua TJ, Akhtar E, Hossain MB, Allen LH, Ahmed T, Raqib R. Vitamin B12 supplementation during pregnancy and postpartum of Bangladeshi women: effects on oxidative stress, pro-inflammatory cytokines and global DNA methylation. FASEB Journal 2017;31:1. [CENTRAL: CN-01778126] [EMBASE: 616959238] [Google Scholar]

Zec 2020 {published data only}

NCT03522428. Vitamin B12 pregnancy supplementation [Vitamin B12 supplementation in addition to folic acid and iron improves hematological and biochemical markers in pregnancy: a randomized controlled trial]. clinicaltrials.gov/show/nct03522428 (first received 6 April 2018). [CENTRAL: CN-01599500] [DOI] [PubMed]
Zec M, Roje D, Matovinovic M, Anticevic V, Librenjak Skare L, Jeroncic A, et al. Vitamin B12 supplementation in addition to folic acid and iron improves hematological and biochemical markers in pregnancy: a randomized controlled trial. Journal of Medicinal Food 2020;23(10):1054-9. [CENTRAL: CN-02102515] [EMBASE: 631567545] [PMID: ] [DOI] [PubMed] [Google Scholar]

References to studies excluded from this review

Bhowmik 2021 {published data only}

Bhowmik B, Siddiquee T, Mdala I, Quamrun NL, Jahan SS, Hassan Z, et al. Vitamin D3 and B12 supplementation in pregnancy. Diabetes Research and Clinical Practice 2021;174:108728. [CENTRAL: CN-02277248] [PMID: ] [DOI] [PubMed] [Google Scholar]

Chandyo 2023 {published data only}

Chandyo RK, Kvestad I, Ulak M, Ranjitkar S, Hysing M, Shrestha M, et al. The effect of vitamin B12 supplementation during pregnancy on infant growth and development in Nepal: a community-based, double-blind, randomised, placebo-controlled trial. Lancet 2023;401:1508-17. [DOI] [PubMed] [Google Scholar]
Chandyo RK, Ulak M, Kvestad I, Shrestha M, Ranjitkar S, Basnet S, et al. The effects of vitamin B12 supplementation in pregnancy and postpartum on growth and neurodevelopment in early childhood: study protocol for a randomized placebo controlled trial. BMJ Open 2017;7(8):e016434. [CENTRAL: CN-01599811] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
NCT03071666. Vitamin B12 supplementation during pregnancy on cognitive development [Supplementation of vitamin B12 in pregnancy and postpartum on growth and cognitive functioning in early childhood: a randomized, placebo controlled trial]. clinicaltrials.gov/show/nct03071666 (first received 23 February 2017). [CENTRAL: CN-01577322]

CTRI/2020/01/022713 {published data only}CTRI/2020/01/02271

CTRI/2020/01/022713. Effect of vitamin B12 supplementation on growth of the baby [Supplementation of vitamin B12 to improve B12-folate ratio in pregnancy and its effect on birth outcome]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2020/01/022713 (first received 13 January 2020). [CENTRAL: CN-02166696]

CTRI/2020/10/028330 {published data only}CTRI/2020/10/028330

CTRI/2020/10/028330. Daily milk intake by pregnant lactovegetarian women improves the vitamin B12 status of offsprings as compared to the intake of vitamin B12 pills [Daily milk intake by pregnant lactovegetarian women improves the vitamin B12 status of offsprings as compared to the intake of synthetic B12: an intervention trial – pilot study]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2020/10/028330 (first received 9 October 2020). [CENTRAL: CN-02186245]

Devi 2017 {published data only}

CTRI/2016/01/006578. Vitamin B12 during pregnancy [Vitamin B12: its bioavailability and effect in a balanced protein supplement on sulfur amino acid and methyl transfer kinetics in Indian pregnancy]. www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=3636 (first received 29 January 2016). [CENTRAL: CN-02279601]
Devi S, Mukhopadhyay A, Dwarkanath P, Thomas T, Crasta J, Thomas A, et al. Combined vitamin B-12 and balanced protein-energy supplementation affect homocysteine remethylation in the methionine cycle in pregnant South Indian women of low vitamin B-12 status. Journal of Nutrition 2017;147(6):1094-103. [CENTRAL: CN-01381542] [PMID: ] [DOI] [PubMed] [Google Scholar]

Li 2020 {published data only}

Li S, Mi B, Qu P, Liu D, Lei F, Wang D, et al. Association of antenatal vitamin B complex supplementation with neonatal vitamin B12 status: evidence from a cluster randomized controlled trial. European Journal of Nutrition 2020;60(2):1031-9. [CENTRAL: CN-02141659] [EMBASE: 2005286662] [PMID: ] [DOI] [PubMed] [Google Scholar]

Mearns 2014 {published data only}

Mearns GJ, Koziol-McLain J, Obolonkin V, Rush EC. Preventing vitamin B12 deficiency in South Asian women of childbearing age: a randomised controlled trial comparing an oral vitamin B12 supplement with B12 dietary advice. European Journal of Clinical Nutrition 2014;68(8):870-5. [CENTRAL: CN-00998235] [EMBASE: 2014534487] [PMID: ] [DOI] [PubMed] [Google Scholar]

Nagpal 2020 {published data only}

CTRI/2018/07/015048. A study to evaluate the utility of Vitamin B-12 supplementation of pregnant women in improving the brain development of their infants [A randomised controlled trial to compare two different doses of maternal B12 supplementation in improving infant B12 deficiency and neurodevelopment – MATCOBIND]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2018/07/015048 (first received 25 July 2018). [CENTRAL: CN-01907527]
NCT03783104. Maternal B12 supplementation to improve infant B12 deficiency and neurodevelopment [A randomised controlled trial to compare two different doses of maternal B12 supplementation in improving infant B12 deficiency and neurodevelopment]. clinicaltrials.gov/show/nct03783104 (first received 20 December 2018). [CENTRAL: CN-01795553]
NCT04083560. A comparison of two different doses of maternal B12 supplementation in improving infant B12 deficiency and neurodevelopment. clinicaltrials.gov/show/nct04083560 (first received 10 September 2019). [CENTRAL: CN-01984158]
Nagpal J, Mathur MR, Rawat S, Nagrath D, Lee C, Singhal A, et al. Efficacy of maternal B12 supplementation in vegetarian women for improving infant neurodevelopment: protocol for the MATCOBIND multicentre, double-blind, randomised controlled trial. BMJ Open 2020;10(5):e034987. [CENTRAL: CN-02132169] [EMBASE: 631869239] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

NCT03258385 {published data only}

NCT03258385. Vitamin B12 supplementation to improve B12 status and child development [Effects of vitamin B12 fortified milk supplementation during pregnancy and 6 month postpartum to improve B12 status and child development]. clinicaltrials.gov/show/NCT03258385 (first received 2017 August 23). [CENTRAL: CN-01495971]

References to ongoing studies

Winje 2018 {published data only}

Winje BA, Kvestad I, Krishnamachari S, Manji K, Taneja S, Bellinger DC, et al. Does early vitamin B12 supplementation improve neurodevelopment and cognitive function in childhood and into school age: a study protocol for extended follow-ups from randomised controlled trials in India and Tanzania. BMJ Open 2018;8(2):e018962. [CENTRAL: CN-01627287] [EMBASE: 623793700] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

Additional references

Aaron 2005

Aaron S, Kumar S, Vijayan J, Jacob J, Alexander M, Gnanamuthu C. Clinical and laboratory features and response to treatment in patients presenting with vitamin B12 deficiency-related neurological syndromes. Neurology India 2005;53(1):55-8; discussion 59. [DOI] [PubMed] [Google Scholar]

Allen 2004

Allen LH. Folate and vitamin B12 status in the Americas. Nutrition Reviews 2004;62(6 pt 2):S29-S33. [DOI] [PubMed] [Google Scholar]

Allen 2010

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PERMALINK

Vitamin B12 supplementation during pregnancy for maternal and child health outcomes

Julia L Finkelstein

Amy Fothergill

Sudha Venkatramanan

Alexander J Layden

Jennifer L Williams

Krista S Crider

Yan Ping Qi

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Summary of findings table ‐ Vitamin B12 supplementation compared to placebo/no vitamin B12 supplementation in pregnant women.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Maternal

Child

Secondary outcomes

Maternal

Child

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Screening eligible studies for trustworthiness

Research governance

Baseline characteristics

Feasibility

Results

Abstracts

1.

Selection of studies

2.

Data extraction and management

Assessment of risk of bias in included studies

1. Random sequence generation (checking for possible selection bias)

2. Allocation concealment (checking for possible selection bias)

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

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

4. Incomplete outcome data (checking for possible attrition bias due to the amount, nature, and handling of incomplete outcome data)

5. Selective reporting (checking for reporting bias)

6. Other bias (checking for bias due to problems not covered by 1. to 5. above)

7. Overall risk of bias

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cluster‐randomised controlled trials

Cross‐over trials

Other unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Maternal outcomes

Child outcomes

Results

Description of studies

Results of the search

Daily dose of vitamin B₁₂

Type of vitamin B₁₂ compound

Comparisons: vitamin B₁₂ supplementation versus placebo or no vitamin B₁₂ supplementation

Maternal vitamin B₁₂ deficiency

Maternal vitamin B₁₂ status

Breast milk vitamin B₁₂ concentrations

Vitamin B₁₂ status

Vitamin B₁₂ supplementation versus placebo/no vitamin B₁₂ supplementation

Maternal vitamin B₁₂ deficiency

Maternal vitamin B₁₂ status

Total vitamin B₁₂