Effects and safety of periconceptional oral folate supplementation for preventing birth defects

. 2015 Dec 14;2015(12):CD007950. doi: 10.1002/14651858.CD007950.pub3

Study	Reason for exclusion
Angeles‐Agdeppa 2005	744 pregnant and non‐pregnant women of reproductive age from the Philippines participated in this community‐based longitudinal study. The non‐pregnant participants were encouraged to buy and take weekly iron‐folic acid supplements with 60 mg elemental iron and 3500 µg (3.5 mg) (though a social marketing campaign); those who were pregnant in the first 20 weeks of gestation were given free weekly iron‐folic acid supplements until 3 months postpartum; those who were pregnant with at least 20 weeks of gestation were given free daily iron‐folic acid tablets with 60 mg iron and 0.4 mg folic acid. All study participants were given folic acid. The types of interventions and participants are out of scope for this review.
Atukorala 1994	95 pregnant women aged 17 to 45 years at 14 to 24 weeks' gestation from tea plantations in 5 regions of Sri Lanka attending antenatal clinics participated in this cohort and received iron‐fortified food (thriposha) and were advised to consume 50 g/day or supplements containing 60 mg elemental iron (as ferrous sulphate) + 250 µg (0.25 mg) folic acid. The participants were at least at the 14th week of gestation (none of the participants were recruited in the first trimester) and the interventions were given throughout the rest of pregnancy (in the second and third trimesters). The types of participants, types of interventions and type of study are out of the scope of this review.
Bailey 2005	This is a review paper and not an intervention trial. This meta‐analysis included studies from 1995 to 2000. The type of study is out of scope of this review.
Berger 2005	864 pregnant women in Vietnam were given iron‐folic acid supplements at either daily (60 mg elemental iron and 250 µg (0.25 mg) folic acid or weekly (120 mg iron and 3500 µg (3.5 mg) folic acid frequency. The interventions were started pre‐pregnancy and continued until 3 months postpartum. All study participants were given folic acid. The types of interventions and participants are out of scope for this review.
Binns 2006	587 women who delivered their infants in 1 of 2 maternity hospitals in Australia and who completed a self‐administered questionnaire while in hospital or within 3 days of discharge participated in the study. This is not a randomised trial. This is a cross‐sectional study that documented the prevalence of mothers taking folic acid as supplements or added in fortified foods, and explored determinants of folic acid intake. The study design, types of participants and types of interventions are out of the scope of this review.
Bortolus 2014	This is a study among women of reproductive age in Italy and The Netherlands who intend to become pregnant in the next 12 months. Participants are randomised to receive either 4000 µg (4 mg) or 400 µg (0.4 mg) of folic acid until the 12th week of gestation (from pre‐pregnancy until the end of the first trimester). The participants from Italy stop taking folic acid after the first trimester. Those from The Netherlands are assigned to take either 200 µg (0.2 mg) or 800 µg (0.8 mg) of folic acid until the end of the pregnancy (during the second and third trimesters). All the participants take folic acid. The types of interventions are out of scope of this review.
Botto 2006	This is a retrospective cohort study of births monitored through 13 birth defects registries monitoring rates of NTDs from 1988 to 1998 in Norway, Finland, Northern Netherlands, England and Wales, Ireland, France (Paris, Strasbourg, and Central East), Hungary, Italy (Emilia Romagna and Campania), Portugal, and Israel. The aims were to evaluate the effectiveness of policies and recommendations on folic acid aimed at reducing the occurrence of NTDs by comparing the incidence of NTDs before and after the year of the recommendation in each country. The study design is out of the scope of this review.
Canfield 2005	This is a secondary data‐analysis using data reported from states to the National Birth Defects Prevention Network and examined the effect of enriched cereal‐grains products fortification with folic acid on birth defects in the United States. Periods were 1995 to 1996 (pre‐fortification) and 1999 to 2000 (post‐fortification). The results suggest some modest benefit from the folic acid fortification on the prevalence of a number of non‐NTD birth defects. The study design is out of the scope of this review.
Cavalli‐Sforza 2005	This is a review of studies on compliance and purchase behaviour of women of reproductive age after a social mobilisation and communication campaign on weekly iron‐folic acid supplementation. This is not an intervention trial. The type of study is out of scope for this review.
Chen 2008	52,043 women residing in these counties who were planning a pregnancy were included in the trial. A population‐based community intervention study was carried out in Henan, Guizhou, Hunan, and Jilin provinces of China. Ten intervention counties and 8 control counties were selected from these provinces. Women from intervention counties received a supplement (Forceval®) containing 400 µg (0.4 mg) folic acid; 563 IU vitamin A; 200 IU vitamin D₂; 1.4 mg vitamin B₁; 1.4 mg vitamin B₂; 3 µg vitamin B₁₂; 60 mg vitamin C; 8 mg vitamin E, 100 µg biotin (bioepiderm); 14 mg niacin (niacinamide); 4 mg pantothenic acid, 100 mg calcium; 10 mg iron; 2 mg copper (cuprum); 10 mg zinc, 77 mg phosphorus, 30 mg magnesium, 3 mg manganese, 30 µg selenium, 100 µg molybdenum, and 4 mg potassium. Women in the control counties did not receive supplementation. Participants were followed up for 2 years. NTDs were recorded for all births from 28 weeks of gestation to 7 days after birth. 9 NTDs were recorded from 25,444 pregnancies (NTD birth prevalence of 0.35/1000 pregnancies) in the intervention group and 48 NTDs among 26,599 pregnancies (NTD birth prevalence of 1.80/1000 pregnancies) in the control group. The protective rate was 80.4%. This is not a randomised trial. The type of study is out of the scope of this review.
Christian 2003	4926 pregnant women in rural Nepal participated in a cluster‐randomised, double‐masked, controlled trial with 5 arms. The following groups were evaluated: group 1 received 400 µg (0.4 mg) folic acid and 1000 µg retinol equivalents (RE) vitamin A; group 2 received 400 µg (0.4 mg) folic acid; 60 mg elemental iron and 1000 µg retinol equivalents (RE) vitamin A; group 3 received 400 µg (0.4 mg) folic acid; 60 mg elemental iron; 30 mg zinc and 1000 µg retinol equivalents (RE) vitamin A; group 4 received 400 µg (0.4 mg) folic acid; 60 mg elemental iron; 30 mg zinc; 10 mg vitamin D; 10 mg vitamin E; 1.6 mg vitamin B₁; 1.8 mg vitamin B₂; 20 mg niacin; 2.2 mg vitamin B₆; 2.6 mg vitamin B₁₂; 100 mg vitamin C; 65 mg vitamin K; 2 mg copper; 100 mg magnesium and 1000 µg retinol equivalents (RE) vitamin A; and group 5, 1000 µg retinol equivalents (RE) vitamin A alone as the control. All participating women were offered deworming treatment (albendazole 400 mg single dose) in the second and third trimester. Short‐ and long‐term effects of antenatal supplementation were evaluated, showing a protective effect of iron‐folic acid supplementation on infant mortality at age 7 years. Supplementation started at recruitment and continued until 3 months postpartum in the case of live births of 5 weeks or more after a miscarriage or stillbirth. In each of the intervention groups, 46% to 50% of the participants started supplements at less than 9 weeks of gestation, 41% to 46% at 9 to 16 weeks of gestation, and 8% to 10% on at least 17 weeks of gestation. Supplements were continued through to 3 months postpartum. The types of participants are out of the scope of this review.
Daly 1995	80 non‐pregnant women attending Coombe Women's Hospital, Ireland were randomised to 1 of 4 groups: control, dietary advice, fortified milk (76 µg [0.076 mg] folic acid/100 mL), and fortified milk plus dietary advice. Milk fortification was effective to raise serum and red cell folate. None of the participants became pregnant. The types of interventions and types of participants are out of the scope of this review.
Daly 1997	121 women of childbearing age employees in the Coombe Women's Hospital, Ireland were randomly allocated to 0, 100 µg (0.1 mg)/day, 200 µg (0.2 mg)/day, or 400 µg (0.4 mg)/day of folic acid. Red cell folate and plasma homocysteine were measured at baseline and after 10 weeks supplementation. Compliance was monitored by having the women sign a dated sheet when taking the tablet. 95 women completed the 6‐month study. Double‐blind randomised controlled trial to find the lowest folic acid dose that effectively reduces plasma homocysteine levels in premenopausal women. None of the participants became pregnant. The types of participants are out of the scope of this review.
Doyle 2001	55 women who had given birth to a low birthweight baby (less than 2500 g), and who planned to have a further pregnancy, were recruited to a prospective study in East London, UK. The participants were assigned into 3 groups: group 1 were assessed to have adequate diets and were given dietary advice; group 2 were assessed to have inadequate diets and were given a vitamin‐mineral supplement with 400 µg (0.4 mg) folic acid and dietary advice; and group 3 were assessed to have inadequate diet and were given dietary advice. MM supplementation started at 3 months postpartum and follow‐up lasted 6 months. None of the participants became pregnant during the duration of the study. The type of participants are out of the scope of this review.
Drazkowski 2002	Case reports from 4 women with epilepsy identified with low B₁₂ levels using data from electronic medical records of the Barrow Neurologic Institute, Epilepsy Specialty Clinic, United States. They received supplements of either 4 or 5 mg synthetic folic acid and parenteral B₁₂. 2 were supplemented up for more than 18 months; the other 2 were supplemented for an unknown length of time. All cases resolved their B₁₂ deficiency symptoms after parenteral B₁₂ administration. The type of study, participants and interventions are out of the scope of the review.
Eichholzer 2006	This is a review that addresses supplementation and fortification as public health policies. This is not an intervention trial. The type of study is out of scope of this review.
Ejidokun 2000	Qualitative study using focus group discussions, observational data and in‐depth interview to identify community perspectives and attitudes to pregnancy, anaemia, iron and folate supplements during pregnancy amongst women (n = 23), and 2 healthcare providers in Lagos, Nigeria. Maternal anaemia was not perceived as a priority health problem by pregnant women. This is not an intervention trial. The type of study, participants and interventions are out of the scope of this review.
Elbourne 2002	This is not an intervention trial. This paper addresses methodological issues relating to the meta‐analysis of trials with cross‐over designs. The type of study is out of scope of this review.
Ellison 2004	31 women with singleton pregnancy were randomised to receive 400 µg (0.4 mg) folic acid once daily until 16 weeks' gestation or until the end of pregnancy. Authors found that folic acid supplementation throughout pregnancy maintains plasma homocysteine concentration. All participants received folic acid. The type of participants and type of interventions are out of the scope of this review.
Eskes 2000	This paper reviews the relationship between low vitamin status (folic acid, vitamin B₆ and B₁₂), hyperhomocysteinaemia, the MTHFR gene mutation C677T, and thrombotic factors like Protein C, Protein S, antithrombin III, factor V Leiden and Activated Protein C, either alone or in combination as high‐risk factors for obstetrical vascular disease. This is not an intervention trial. The type of study is out of scope of this review.
Field 1991	This paper reviews the effect of folic acid in NTD in humans and animals. This is not an intervention trial. The type of study is out of scope of this review.
Geisel 2003	This paper reviews the effect of folic acid in NTD in humans, and ways in which knowledge of folic acid can be increased. This is not an intervention trial. The type of study is out of scope of this review.
Gunaratna 2015	802 non‐pregnant women in Tanzania were randomly assigned to receive either 1) folic acid; 2) folic acid and iron; or 3) folic acid, iron and multivitamins. All treatment groups received folic acid. New pregnancies were withdrawn from the study. The type of participants and interventions are out of scope of this review.
Hague 2003	This paper discusses the effects of changing levels of homocysteine in pregnancy. This is not an intervention trial. The type of study is out of scope of this review.
Hayes 1996	This is a case‐control study examining factors associated with orofacial clefts. Participants were mothers with babies with cleft lip with or without CLP, controls were mothers of babies with other congenital anomalies (except NTDs). The type of study is out of the scope of this review.
Itikala 2001	Case‐control study to evaluate the relation between regular multivitamin use and the birth prevalence of orofacial clefts. There was a 48% risk reduction for cleft lip with or without CLP among mothers who used multivitamins during the periconceptional period or who started multivitamin use during the first postconceptional month. No reductions for cleft lip with or without CLP or CLP alone were found for women who began multivitamin use in the second or third month after conception. The type of study is out of the scope of the review.
Johnston 2008	This paper reviews the effectiveness of cereal grain fortification with folic acid. This is not an intervention trial. The type of study is out of scope of this review.
Khambalia 2009	88 women in rural Bangladesh, women were randomised before pregnancy to receive daily 60 mg elemental iron (as ferrous fumarate) and 400 µg (0.4 mg) folic acid or folic acid only. Both treatment groups received folic acid. Once pregnancy was confirmed women were withdrawn from the study and received routine care which included folic acid supplements. The types of interventions and types of participants are out of scope of this review.
Lee 2005	131 apparently healthy pregnant women were assigned to 1 of 5 groups: group 1 (control) received no supplement; group 2 received 30 mg elemental iron (as ferrous sulphate) plus 175 µg (0.17 mg) folic acid daily from the first trimester until delivery; group 3 received 60 mg elemental iron (as ferrous sulphate) plus 350 µg (0.35 mg) folic acid from the first trimester until delivery; group 4 received 30 mg elemental iron (as ferrous sulphate) plus 175 µg (0.17 mg) folic acid daily from the 20th week gestation until delivery and group 5 received 60 mg elemental iron (as ferrous sulphate) plus 350 µg (0.35 mg) folic acid from the 20th week gestation until delivery. The participants in the groups 2 and 3 received their supplements starting in the first trimester (mean ± SD = 9.1 ± 2.3 weeks) and continued until delivery. The type of study and type of participants are out of the scope of this review.
Li 2014	4052 women in China undergoing prenatal consultations were divided into 2 ethnic groups, Han or Mongolian, and were further assigned into 1 of 4 groups: group 1 received folic acid tablets before pregnancy and drank liquid milk (containing folate which ranged in concentration from 1.68 to 5.69 µg/100ml); group 2 did not take folic acid tablets before pregnancy but drank milk daily once pregnancy was confirmed; group 3 received folic acid but did not drink milk throughout the trial; and, group 4 (control) did not take folic acid tablets and did not drink milk throughout the trial. Women who received folic acid tablets (groups 1 and 3) and/or milk (groups 1 and 2) continued their interventions throughout pregnancy. The type of intervention is out of the scope of the review.
Mandishona 1999	112 women aged between 12 and 50 years from a population of 425 rural people participating in ongoing family genetic studies in the Murehwa and Zaka districts of Zimbabwe and in Mpumalanga Province, South Africa to assess the effect of consumption of a traditional beer, rich in iron, in the regular diet for preventing iron deficiency. The type of study, participants and interventions are out of the scope of this review.
Manizheh 2009	246 nulliparous women attending outpatient antenatal clinic in Alzahra Hospital in Iran were randomised to receive daily folic acid from early pregnancy; either 500 µg (0.5 mg) per day or 5000 µg (5 mg) per day. Folic acid was started in the first trimester and supplements continued throughout pregnancy. All participants received folic acid. The types of interventions and participants are out of scope of this review.
Mathews 1999	The authors merged 2 studies in order to investigate the association between folic acid supplementation and twinning: the MRC Vitamin study, a randomised controlled trial of folic acid supplementation (4 mg/day) among women in whom a previous pregnancy had been affected by NTD; and the Prospective Study of Nutrition, Smoking and Pregnancy Outcome, an observational study that gathered detailed information on periconceptional nutrition from nulliparous women in the UK (women who had undergone infertility treatment were excluded). This is an analysis of secondary data. None of the outcomes of interest for this review were included in this study. The type of study is out of the scope of this review.
McNulty 2013	119 women attending antenatal clinic in Northern Ireland and who reported taking folic acid supplements during the first trimester were assigned in the second trimester to receive either 400 µg (0.4 mg) of folic acid or a placebo everyday until the end of pregnancy. The types of intervention and participants are out of the scope of the review.
Melli 2008	203 nulliparous pregnant women with a singleton pregnancy in their first trimester, attending the antenatal outpatient clinic in Tabriz, Iran with no history of hypertension and folic acid supplementation. Women were divided into 2 groups: group 1 was given 5000 µg (5 mg) per day and group 2 received 500 µg (0.5 mg/day) folic acid. In addition to the plasmatic homocysteine concentrations during the first trimesters and at delivery, the incidence of pregnancy‐induced hypertension, pre‐eclampsia and eclampsia and were compared. The incidence of any type of hypertension was 2% with regimen 1 compared to 11% with routine regimen. All the study participants received folic acid. The type of intervention is out of the scope of this review.
Molster 2007	The paper reported the results of a survey of knowledge, attitudes and behaviour with regard to food fortification with folic acid amongst a randomly selected sample aged 18 years or older in Australia. This is not an intervention trial. The type of study is out of scope of this review.
Nelen 2000	This is a case‐control study where homocysteine (fasting and afterload), folate (serum and red cells), pyridoxal 5*‐phosphate, and cobalamin concentrations were measured in 123 white women who had at least 2 consecutive spontaneous early pregnancy losses each and compared with 104 healthy controls from the University Hospital Nijmegen St. Radboud, The Netherlands. Elevated homocysteine and reduced serum folate concentrations were risk factors for recurrent spontaneous early pregnancy losses. The type of study is out of the scope of this review.
Nguyen 2009	40 non‐pregnant women aged between 18 and 45 years, who had not taken folic acid supplements, from the Motherisk Program, The Hospital for Sick Children, Canada were randomly assigned to 1 of 2 groups: group 1 received a daily supplement (PregVit®) containing 1100 µg (1.1 mg) folic acid; 2700 IU b‐carotene; 30 IU vitamin E; 12 µg vitamin B₁₂; 120 mg vitamin C; 250 IU vitamin D; 3 mg thiamine; 300 mg calcium; 3.4 mg riboflavin; 20 mg niacinamide; 10 mg vitamin B‐6; 5 mg pantothenic acid; 50 mg magnesium; 0.15 mg iodine; 35 mg iron (as ferrous fumarate); 2 mg copper and 15 mg zinc; or group 2 received 5000 µg (5 mg) folic acid 5 mg (PregVit‐folic 5®); 2700 IU b‐carotene; 30 IU vitamin E; 12 µg vitamin B₁₂; 120 mg vitamin C; 250 IU vitamin D; 3 mg thiamine; 300 mg calcium; 3.4 mg riboflavin; 20 mg niacinamide; 10 mg vitamin B6; 5 mg pantothenic acid; 50 mg magnesium; 0.15 mg iodine; 35 mg iron (as ferrous fumarate); 2 mg copper and 15 mg zinc. The women were instructed to take the supplement for 30 weeks. Plasma and red blood cell folate concentrations were measured at baseline and at weeks 2, 4, 6, 12, and 30. The use of 5 mg folic acid among women of childbearing age produced higher blood folate concentrations, with a faster rate of folate accumulation, compared with 1.1 mg folic acid. None of the participants became pregnant. All participants were given folic acid. The types of participants and interventions are out of the scope of this review.
Pitkin 2007	This is not an intervention trial. This review includes prospective and retrospective studies. In the clinical trials section the conclusion is that folic acid supplementation was useful to prevent occurrence (only 1 trial) and recurrence of NTD. The type of study is out of scope of this review.
Pritchard 1991	This paper describes the causes of abruptio placentae. It was excluded because the type of study is out of the scope of this review.
Ramakrishnan 2003	A randomised, double‐blind clinical trial in semi‐rural Mexico to compare the effects of MMs supplements with those of iron supplements during pregnancy on birth size. 873 pregnant women were recruited before 13 weeks of gestation and randomly assigned to 1 of 2 groups: group 1 received supplements containing 2150 IU vitamin A; 309 IU vitamin D₃; 5.73 IU vitamin E; 0.93 mg thiamine; 1.87 mg riboflavin; 15.5 mg niacin; 215 µg (0.21 mg) folic acid; 1.94 mg vitamin B₆; 2.04 µg vitamin B₁₂; 66.5 mg vitamin C; 12.9 mg zinc; 62.4 mg elemental iron (as ferrous sulphate) and 252 mg magnesium; group 2 received 60 mg elemental iron (as ferrous sulphate). The supplements were provided 6 days a week at home. Routine antenatal care was provided to both groups until delivery. These findings suggest that MM supplementation during pregnancy does not lead to greater infant birth size than iron‐only supplementation. The supplementation was started at a mean ± SD gestational age of 9.24 ± 2.51 weeks in the first group (MMs) and 9.31 ± 3.00 weeks in the second group (iron‐only supplements). Supplements were continued until delivery. The study was excluded because supplementation time surpassed 12 weeks of pregnancy. The type of intervention is out of scope of this review.
Ray 2007	A population‐based case‐control study in Ontario, Canada (89 NTD cases and 422 controls). The outcome was serum holotranscobalamin (holoTC) at 15 to 20 weeks' gestation. There was a trend of increasing risk with lower levels of holoTC. The type of study and intervention are out of the scope of this review.
Ray 2008	A cross‐sectional study among 10,622 women in Ontario, Canada. Authors determined the prevalence of biochemical B₁₂ deficiency and found that 1 in 20 women may be deficient in B₁₂ in early pregnancy. The type of study is out of the scope of this review.
Robbins 2005	232 non‐pregnant women from 2 clinics in Arkansas, United States were assigned randomly to receive brief folic acid counselling, a reminder phone call, and 30 folic acid tablets containing 400 µg (0.4 mg) of folic acid (n = 162 women; intervention group) or to receive counselling about other preventive health behaviours and a folic acid informational pamphlet (n = 160 women; control group). Self‐reported folic acid use was compared at baseline and at 2 months. Weekly folic acid intake increased in the intervention group by 68%, compared with 20% in the control group. No significant differences were found in daily intake. None of the participants became pregnant during the duration of this study. The type of participants and interventions are out of the scope of this review.
Rolschau 1999	8184 Danish female citizens resident in the county of Funen, Denmark planning a pregnancy or already pregnant were offered a free supplement of folic acid of either 1000 µg (1 mg) folic acid or 2500 µg (2.5 mg) folic acid in a double‐blind randomised study to determine whether a supplement of folic acid given preconceptionally or early in pregnancy had any influence on birthweight, incidence of preterm labour, low birthweight and small‐for‐gestational age. Folic acid given preconceptionally or in the first half of pregnancy slightly increased birthweight and a decreased the incidence of preterm labour, infants with low birthweight and small‐for‐gestational age. All the study participants received folic acid. The types of interventions are out of the scope of this review.
Rosenthal 2008	140 female factory workers aged 18 to 49 years in Choloma, Honduras were randomly assigned to 1 of 2 groups: group 1 received a daily dosage of 1000 μg (1 mg) folic acid; group 2 received a once weekly dosage of 5000 μg (5 mg). Serum folate and red blood cell folate levels were determined by radioimmunoassay at baseline, 6 weeks and 12 weeks. Although both folate supplementation regimens increased serum and red blood cell folate levels significantly among the women studied, blood folate levels that are considered to be protective of NTD were reached faster with the daily dosage of 1000 μg (1 mg) folic acid. Both groups received folic acid at different doses and regimens. The types of interventions are out of the scope of this review.
Sayers 1997	A cross‐sectional community‐based survey was conducted in Dublin, Ireland to document the knowledge and behaviour of 335 women of childbearing age to periconceptional folic acid. Approximately two‐thirds (213/ 335, 63.6%) had heard of folic acid. Knowledge was significantly associated with higher social class and higher education; few were advised to take folic acid before pregnancy. The type of study, participants and interventions are out of the scope of this review.
Schorah 1993	The authors studied the impact of folate fortification of food on folate intake in women of childbearing age. Folic acid intake was measured by a 7‐day weighed procedure from 1986 to 1988. The results show that the consumption of fortified cereals considerably increased the intake of folic acid in the 10 women consuming fortified cereals compared to the intake of the 14 women not consuming fortified cereals. The type of study, participants and interventions are out of the scope of this review.
Schwarz 2008	446 English‐speaking women, aged 18 to 45 years from 2 urgent clinics in San Francisco, United States were randomly assigned to receive computerised counselling about either periconceptional folate supplements (intervention group) or emergency contraception (control group). After 6 months the women in the intervention group were more likely to know that folate prevents birth defects, that folate is most important in early pregnancy, and to report the recent use of a folate supplement. The types of participants and interventions are out of the scope of this review.
Shaw 1995	This is a case‐control study to investigate if periconceptional use of multivitamins containing folic acid was associated with a reduced risk of orofacial clefts (n = 734 per group). Women who used multivitamins containing periconceptional folic acid had a 25% to 50% reduction in risk for offspring with orofacial clefts compared to women who did not use such vitamins. Maternal daily consumption of cereal containing folic acid produced similar results. The type of study is out of the scope of this review.
Shaw 2006	Population‐based case‐control study investigating whether periconceptional intakes of supplemental folic acid, dietary folate, and several other nutrients were associated with orofacial clefts. There was no association detected. The type of study is out of the scope of this review.
Shrimpton 2002	Commentary about the advantages of supplementation in different age groups. This is not an intervention trial. The type of study is out of scope of this review.
van der Put 1998a	Case‐control study which suggests that the combined heterozygosity for the 2 methylenetetrahydrofolate reductase (MTHFR) gene common mutations accounts for a proportion of folate‐related NTDs. The type of study, participants, and interventions are out of the scope of this review.
van Rooij 2004	Case‐control study (n = 174) to investigate the association between maternal folate intake by supplement and food and the risk of cleft lip with or without CLP. Dietary folate intake reduced CLP risk independently in a dose‐response manner. The largest risk reductions were found in those mothers who had a diet of more than 200 µg folate per day in combination with a folic acid supplement. The type of study is out of the scope of this review.
Wald 2004	A letter to the editor addressing the expediency of folic acid fortification to prevent NTDs versus masking vitamin B12 status. The study was excluded because the letter does not contain results from clinical trials. The type of study is out of scope of this review.
Walsh 2007	Cross‐sectional population study looking at blood folate status of over 400 sequential primigravid Caucasian women with a singleton pregnancy, at less than or equal to 20 weeks' gestation. The type of study is out of the scope of the review.
Watson 1999	This study explores different methods of communicating information to increase folate awareness in women of childbearing age, who participated in a community randomised trial. The type of interventions is out of the scope of this review.
Wehby 2012	2508 non‐pregnant women of reproductive age from craniofacial clinics in Brazil who had nonsyndromic or isolated oral clefts or had at least 1 natural child with nonsyndromic or isolated oral clefts were assigned to receive either a single pill of 4000 µg (4 mg) folic acid or 400 µg (0.4 mg) of folic acid daily to be continued until the end of the first trimester. From these, there were 234 live births with recorded infant outcomes. All study participants took folic acid. The type of intervention is out of the scope of the review.
Wen 2005	Review of 65 studies to examine the biological basis of why folic acid may have health effects beyond its proven effect of reducing NTDs; and to explore controversial policies of folic acid supplementation and food fortification. This is not an intervention trial. The type of study is out of scope of this review.
Westphal 2004	This is a placebo‐controlled study among 30 women to determine the effects of taking for 3 months a commercial supplement that includes folate (amount unspecified) on progesterone level, basal body temperature, menstrual cycle and pregnancy rate. None of the participants became pregnant during the duration of the supplementation. None of the outcomes of interest for this review were reported in the study. The type of interventions is out of the scope of this review.
Wilcox 2007	National population based case‐control study to measure the possible association of facial clefts with maternal intake of folic acid supplements, multivitamins, and folates in diet. Results show that 400 µg (0.4 mg) folic acid supplementation daily during early pregnancy was associated with a reduced risk of isolated cleft lip with or without CLP, especially among women with folate rich diets who also took folic acid supplements and multivitamins. Folic acid provided no protection against CLP. The type of study is out of the scope of the review.
Zeng 2008	5828 pregnant women in 2 rural counties in Shaanxi Province, in north west China participated in this study. Villages were randomly assigned to 1 of 3 groups: group 1 received supplements containing 400 µg (0.4 mg) folic acid; group 2 received 30 mg elemental iron, 400 µg (0.4 mg) folic acid; and group 3 received 30 mg elemental iron, 400 µg (0.4 mg) folic acid; 15 mg zinc; 2 mg copper; 65 µg selenium; 150 µg iodine; 800 µg vitamin A; 1.4 mg vitamin B₁ (thiamine); 1.4 mg vitamin B₂ (riboflavin); 1.9 mg vitamin B₆; 2.6 µg vitamin B₁₂; 5 µg vitamin D; 70 mg vitamin C; 10 mg vitamin E; and 18 mg niacin. Authors found that antenatal supplementation with iron‐folic acid was associated with longer gestation and a reduction in early neonatal mortality compared with folic acid. MMs supplements were associated with modest increase in birthweight compared with folic acid. All women received folic acid. The type of interventions is out of the scope of this review.

CLP: cleft palate  MM: multiple micronutrient  MTHFR: methylenetetrahydrofolate reductase  NTD: neural tube defect  SD: standard deviation