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Effects and safety of periconceptional folate supplementation for preventing birth defects

  1. Luz Maria De-Regil1,*,
  2. Ana C Fernández-Gaxiola2,
  3. Therese Dowswell3,
  4. Juan Pablo Peña-Rosas1

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 6 OCT 2010

DOI: 10.1002/14651858.CD007950.pub2


How to Cite

De-Regil LM, Fernández-Gaxiola AC, Dowswell T, Peña-Rosas JP. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.: CD007950. DOI: 10.1002/14651858.CD007950.pub2.

Author Information

  1. 1

    World Health Organization, Micronutrients Unit, Department of Nutrition for Health and Development, Geneva, Geneva, Switzerland

  2. 2

    Instituto Nacional de Salud Pública, Cuernavaca, Morelos, Mexico

  3. 3

    The University of Liverpool, Cochrane Pregnancy and Childbirth Group, School of Reproductive and Developmental Medicine, Division of Perinatal and Reproductive Medicine, Liverpool, UK

*Luz Maria De-Regil, Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, 20 Avenue Appia, Geneva, Geneva, 1211, Switzerland. deregillu@who.int.

Publication History

  1. Publication Status: New
  2. Published Online: 6 OCT 2010

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Characteristics of included studies [ordered by study ID]
Czeizel 1994

MethodsRCT 2-arm parallel-group design.


Participants7905 women attending prenatal care at the Hungarian Family Planning Program (HFPP) in Hungary. Inclusion criteria were: (I) no delayed conception or infertility (i.e. no conception after more than 12 months of sexual activity without contraception), (II) not currently pregnant, (III) voluntary participation and a promise of compliance. In the first 4 years of the HFPP, there were 2 other criteria: age under 35 (women over 35 were referred to a genetic counselling clinic) and no previous wanted pregnancy.


InterventionsWomen were randomly assigned to 1 of 2 groups:

Group 1: women received a supplement (Elevit Pronatal®) containing 800 µg (0.8 mg) folic acid, in addition to 6000 IU (until the end of 1989) and 4000 IU (in 1990 to 1991) vitamin A; 1.6 mg vitamin B1; 1.8 mg vitamin B2; 19 mg nicotinamide; 2.6 mg vitamin B6; 10 mg pantothenic acid (as calcium pantothenate); 0.2 mg biotin; 4.0 pg vitamin B12; 100 mg vitamin C; 500 IU vitamin D; 15 mg vitamin E (as alpha-tocopherol-tocopherol acetate); 125 mg calcium; 125 mg phosphorus; 100 mg magnesium;60 mg elemental iron; 1 mg copper; 1 mg manganese; and 7.5 mg zinc.

Group 2: women received a supplement containing 1 mg copper; 1 mg manganese; 7.5 mg zinc; 7.5 mg (calcium ascorbate) vitamin C and lactose 736.27 mg.

A single tablet in either group was to be taken daily for 1 month before planned conception until 12 weeks of pregnancy (confirmed by sensitive pregnancy test after the first missed menstrual period and by ultrasonography within 2 weeks). Women were asked to ingest the tablet each day before recording the basal body temperature and to leave unused tablets in the box.


OutcomesMaternal: weight gain, increased appetite, lack of appetite, nausea and vomiting, vertigo, heartburn, constipation, diarrhoea, ectopic pregnancy, miscarriage, spontaneous abortion, multiple birth, twin birth.

Infant: NTDs and other congenital anomalies (congenital limb deficiency, cardiovascular congenital abnormalities, congenital pyloric stenosis, cleft lip, cleft palate) stillbirths, infant mortality, prenatally terminated fetuses, birthweight, low birthweight, gestational age, weight, length, and head circumference at 8 to 16 months of age, functional development tests at 8 to 16 months.


NotesExclusion criteria not clear. The final database included 5502 women with confirmed pregnancy.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?YesWomen were asked about whether they agreed to their allocation on the basis of a randomisation table.

Allocation concealment?UnclearNot described. It was not clear whether staff carrying out recruitment were aware of randomisation group.

Blinding?
Women
YesWomen were informed about the "blind' use of 1 of 2 kinds of tablets.

Blinding?
Clinical staff
UnclearNot clear if staff were blind.

Blinding?
Outcome assessors
UnclearCertificates were filled in by mothers and signed by physicians. If certificates were not sent back one of the co-workers visited the participants at home.

Incomplete outcome data addressed?
All outcomes
UnclearOf 7905 women randomised 69.6% had confirmed pregnancies.

Loss to follow up for women with confirmed pregnancies 1%.

Free of selective reporting?UnclearNot apparent.

Free of other bias?UnclearIn a comment in Czeizel 1992 it is stated that randomisation was broken twice; 1 to evaluate teratogenic effect of vitamin A and the second at the end of the trial in 1991.

ICMR 2000

MethodsRCT 2-arm parallel-group design.


Participants466 women with a history of giving birth to a child with open NTD and planning to have another child from 5 centres: Bangalore, Mumbai, Lucknow, New Delhi and Pune, in India. Previous NTDs included anencephaly, encephalocoele, meningocoele/meningomyelocoele, cranio rachischisis, and their combinations, including complicating hydrocephalus; but isolated cases of hydrocephalus were not included in the trial. Women with a history of giving birth to a child with closed spina bifida, women with a history of diabetes mellitus or abnormal fasting and post-prandial blood sugar, epilepsy, congenital anomalies indicative of a genetic syndrome in previous NTD, or vitamin intake during 3 months prior to the enrolment and pregnancy were excluded.


InterventionsWomen were randomly assigned to 1 of 2 groups:

Group 1: received a supplement containing 4000 µg (4 mg) folic acid, iron (120 mg ferrous sulphate), 240 mg calcium phosphate; 10 mg zinc; 4000 IU vitamin A; 2.5 mg vitamin B1; 2.5 mg vitamin B2; 2 mg vitamin B6; 40 mg vitamin C; 400 IU vitamin D and 15 mg niacin (nicotinamide).

Group 2: received a supplement containing iron (120 mg ferrous sulphate and 240 mg calcium phosphate.

Both tablets were to be taken by mouth daily.

Supplementation started at least 1 month before conception up to 12 weeks of pregnancy. Compliance with supplement intake was checked with the help of a dietary card maintained by the women and number of capsules returned.


OutcomesMaternal: parity, spontaneous abortion, induced abortion.

Infant: livebirth, stillbirth, NTD (anencephaly, complicated spina bifida, other combination).


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?UnclearStudy described as randomised.

Allocation concealment?YesContainers were given a random number and sent to each centre.

Blinding?
Women
YesBoth capsules were identical and packed in similar containers.

Blinding?
Clinical staff
YesParticipants and care providers reported as blinded.

Blinding?
Outcome assessors
UnclearAll women were instructed to inform the outcome of pregnancy personally or by post. In absence of the report a social worker contacted the participant to record the outcome.

Incomplete outcome data addressed?
All outcomes
Unclear466 women were randomised and 305 had a confirmed pregnancy during the study period (65.5%). Loss to follow up after pregnancy confirmation less than 10%.

Free of selective reporting?UnclearNot apparent.

Free of other bias?UnclearAfter publication of MRC (1991) trial the study was stopped.

Comment: calculated sample size (250 per arm, including 20% of losses to follow up) was almost completed.

Kirke 1992

MethodsRCT 3-arm parallel-group design plus a second non-randomised control group.


Participants354 women with a previously affected pregnancy, who were not pregnant but planning to have another pregnancy attending 12 hospitals in Ireland. Women with conditions likely to result in impaired absorption from the gastrointestinal tract were excluded.


InterventionsWomen were randomly assigned to one of three groups:

Group 1: received supplement of 360 µg (0.36 mg) folic acid only (0.12 mg/tablet) daily.

Group 2: received supplements (Pregnavite Forte®) containing 4000 IU vitamin A; 400 IU vitamin D (calciferol); 1.5 mg vitamin B1 (thiamine hydrochloride); 1.5 mg vitamin B2 (riboflavin); 1 mg vitamin B6 (pyridoxine hydrochloride); 15 mg niacin (nicotinamide); 40 mg vitamin C; 480 mg calcium phosphate, and iron (252 mg ferrous sulphate) daily.

Group 3: received supplements (Pregnavite Forte F®) containing 360 µg (0.36 mg) folic acid in addition to 4000 IU vitamin A; 400 IU vitamin D (as calciferol); 1.5 mg vitamin B1 (thiamine hydrochloride); 1.5 mg vitamin B2 (riboflavin); 1 mg vitamin B6 (pyridoxine hydrochloride); 15 mg niacin (nicotinamide); 40 mg vitamin C; 480 mg calcium phosphate, and iron (252 mg ferrous sulphate) daily. Participants were instructed to take 1 tablet 3 times daily for at least 2 months before conception and until the date of the third missed period. Compliance was based on tablet counts and blood tests.


OutcomesMaternal: spontaneous abortion, ectopic pregnancy.

Fetal/infant: livebirth, stillbirth, occurrence and recurrence of NTD (major malformations: anencephalus, cleft lip, bilateral corneal ectasia with agenesis of the corpus callosum, polycystic kidneys with cleft lip, congenital mitral insufficiency, polydactyly, pyloric stenosis, urethral obstruction, cystic fibrosis, hydrocephalus without spina bifida, oesophageal atresia, and transposition of the great vessels; minor malformations: congenital dislocation of the hip, talipes, and scaphocephaly).


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?YesBlock randomisation was employed, 12 subjects per block, stratified by hospital.

Allocation concealment?YesRandomisation: achieved by using consecutively numbered, opaque, sealed envelopes.

Blinding?
Women
YesWomen initially received similarly presented white pills. After 1 year supplements with multiple micronutrients with folic acid were changed to commercially available tablet (colour purple) and the tablets containing multiple micronutrients without folic acid, produced by a different supplier were white. Authors stated that "It is felt that this partial loss of blinding did not materially affect the study outcome".

Blinding?
Clinical staff
YesStudy reported as double-blind.

Blinding?
Outcome assessors
UnclearNot clear if outcome assessors were aware of group allocation.

Incomplete outcome data addressed?
All outcomes
UnclearOf the 354 women randomised 281 had confirmed pregnancies (79.3%).

Free of selective reporting?UnclearNot apparent.

Free of other bias?UnclearNot apparent.

Laurence 1981

MethodsRCT 2-arm parallel-group design.


Participants905 women resident in Glamorgan and Gwent, Wales who had a pregnancy complicated by a fetal NTD (anencephaly, encephalocoele, and spina bifida cystica) between 1954 and 1969 were traced through malformation registers, maternal and paediatric records, local authority records, and other sources. Those under 35 years of age at the time of the study were visited in their homes by medically qualified field workers and invited to participate. 218 women agreed to participate in the intervention trial.


InterventionsWomen were randomly assigned to 1 of 2 groups:

Group 1: received supplements containing 4000 µg (4 mg) folic acid daily (each tablet contained 2000 µg folic acid).

Group 2: received placebo.

Women were asked to take a tablet twice a day starting from the time contraceptive precautions were stopped. Compliance among women in group 1 was monitored at the sixth to ninth week of estimated gestation; if the serum folate concentration at this stage was higher than 10 µg/L the woman's account of taking the tablets during the earlier part of the pregnancy could be accepted as valid. If the serum folate concentration was below 10 µg/L the woman was classified as non-compliant. Compliance was not tested among women in group 2.


OutcomesMaternal: diet, serum and red blood cell folate concentrations at 6 to 9 weeks of pregnancy, miscarriage, termination.

Infant: livebirth, NTD (anencephaly, spina bifida cystica).


NotesExclusion criteria not clear.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?YesRandom number tables.

Allocation concealment?UnclearWomen were allocated to receive treatment or placebo by random numbers.

Blinding?
Women
YesWomen did not know the content of the tablets.

Blinding?
Clinical staff
YesStudy reported as double-blind.

Blinding?
Outcome assessors
UnclearIt was not clear whether outcome assessors were blind to group allocation.

Incomplete outcome data addressed?
All outcomes
Unclear(Not clear, some discrepancies in figures in different papers) 218 women were randomised and there were 123 pregnancies reported (56.4%). The main study report describes outcomes for 111 women who had confirmed pregnancies.

Free of selective reporting?UnclearNot apparent.

Free of other bias?UnclearNot apparent.

MRC 1991

Methods2 by 2 factorial RCT.


Participants1817 participating women from 7 countries (UK, Hungary, Israel, Australia, Canada, Russia and France) at high risk of having a pregnancy with a NTD, because of a previous affected pregnancy (not associated with the autosomal recessive disorder Meckel’s syndrome), that were planning another pregnancy and were not already taking micronutrient supplements. Women were excluded if they had epilepsy in case the folic acid supplementation adversely affected their treatment.


InterventionsWomen were randomly assigned to one of 4 groups:

Group 1: received 4000 µg (4 mg) folic acid; iron (120 mg ferrous sulphate) and 240 dicalcium phosphate daily.

Group 2: received 4000 µg (4 mg) folic acid; iron (120 mg ferrous sulphate); 240 di-calcium phosphate; 4000 IU vitamin A; 400 IU vitamin D; 1.5 mg vitamin B1;1.5 mg vitamin B2; 10 mg vitamin B6; 40 mg vitamin C and 15 mg niacin (nicotinamide).

Group 3: received iron (120 mg ferrous sulphate);240 di-calcium phosphate; 4000 IU vitamin A; 400 IU vitamin D; 1.5 mg vitamin B1;1.5 mg vitamin B2; 10 mg vitamin B6; 40 mg vitamin C and 15 mg niacin (nicotinamide) daily with no folic acid.

Group 4 (control): received iron (120 mg ferrous sulphate) and 240 di-calcium phosphate daily.

Women were asked to take a single capsule each day from the date of randomisation until 12 weeks of pregnancy (estimated from the first day of the last menstrual period). The capsules used in the study were packaged in 2-week calendar "blister" packs.


OutcomesMaternal: serum folic acid at last visit before becoming pregnant, miscarriage, ectopic pregnancy, termination of pregnancy.

Infant: any fetal malformation (i.e. anencephaly, spina bifida cystica, or encephalocoele), sex, birthweight, head circumference.


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?UnclearRandomisation: method not clear.

Allocation concealment?YesWomen were allocated at random to each of the 4 groups. Separate set of random allocations were used for each centre.

Blinding?
Women
YesNeither the doctor nor the patient knew which regimen had been allocated.

Blinding?
Clinical staff
YesDouble-blind trial.

Blinding?
Outcome assessors
UnclearNot specified.

Incomplete outcome data addressed?
All outcomes
UnclearOf 1817 women randomised 1195 had confirmed pregnancies (65.7%). Subsequent loss to follow up 7%.

Free of selective reporting?UnclearNot apparent.

Free of other bias?UnclearNot apparent.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Atukorala 1994195 pregnant women aged 17 to 45 years and 14 to 24 weeks' gestation from tea plantations in 5 regions of Sri Lanka attending antenatal clinics were randomly assigned to receive either a iron-fortified food (thriposha) and advised to consume 50 g/day or supplements containing 60 mg elemental iron (as ferrous sulphate) + 250 µg (0.25 mg) folic acid . The types of participants and types of interventions are out of the scope of this review.

Bailey 2005This is a review paper and not an intervention trial. This meta-analysis included studies from 1995 to 2000.

Binns 2006This 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. This is not a randomised trial. The study design, types of participants and types of interventions are out of the scope of this review.

Botto 2006This 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 was to evaluate the effectiveness of policies and recommendations on folic acid aimed at reducing the occurrence of NTDs. The study design is out of the scope of this review.

Canfield 2005This 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.

Chen 2008A randomised, population-based community intervention study was carried out in Henan, Guizhou, Hunan, and Jilin provinces of China. Ten intervention trial counties and 8 control counties were selected from these provinces. Current resident women planning a pregnancy who volunteered to participate in the follow up were included in the trial. 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 according to periconceptional supplementation for 2 years. Women who had a pregnancy were followed up from 28 weeks' gestation at least to pregnancy termination, and the outcome was recorded. During 2000 and 2002, all of the women having pregnancies with birth defects and women whose pregnancies were without any birth defects were interviewed. 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.

Christian 20034926 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 month post-partum in the case of live births of 5 weeks or more after a miscarriage or stillbirth.

Daly 199580 non-pregnant women attending Coombe Women's Hospital, Ireland were randomised to one of four groups: control, dietary advice, fortified milk (70 µg folic acid/100 mL), and fortified milk plus dietary advice. Milk fortification was effective to raise serum and red cell folate. The types of interventions are out of the scope of this review.

Daly 1997121 women of childbearing age employees in the Coombe Women's Hospital, Ireland were randomly allocated to 0, 100, 200, or 400 µg/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. The types of participants are out of the scope of this review.

Doyle 2001Fifty-five 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 randomised study in East London, UK. Multiple micronutrient supplementation started at 3 months postpartum and follow up lasted 6 months. The type of participants are out of the scope of this review.

Drazkowski 2002Case 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. The type of study, participants and interventions are out of the scope of the review.

Eichholzer 2006This is a review that addresses supplementation and fortification as public health policies. This is not an intervention trial.

Ejidokun 2000Qualitative 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. The type of study, participants and interventions are out of the scope of this review.

Elbourne 2002This is not an intervention trial. This paper addresses methodological issues relating to the meta-analysis of trials with cross-over designs.

Ellison 200431 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. The type of participants and type of interventions are out of the scope of this review.

Eskes 2000This paper reviews the relationship between low vitamin status (folic acid, vitamin B6 and B12), hyperhomocysteinemia, 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.

Field 1991This paper reviews the effect of folic acid in NTD in humans and animals. This is not an intervention trial.

Geisel 2003This 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.

Hague 2003This paper discusses the effects of changing levels of homocysteine in pregnancy. This is not an intervention trial.

Hayes 1996This is a case-control study examining factors associated with orofacial clefts. Case were mothers with babies with cleft lip with or without cleft palate, controls were mothers of babies with other congenital anomalies (except NTDs). The type of study is out of the scope of this review.

Itikala 2001Case-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 cleft palate 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 cleft palate or cleft palate 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 2008This paper reviews the effectiveness of cereal grain fortification with folic acid. This is not an intervention trial.

Khambalia 2009In this study of 88 women in rural Bangladesh, women were randomised before pregnancy to receive daily iron and 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.

Lee 2005A total of 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. Authors found that improvements in iron and folate nutriture were highly dependent on when the supplement program was initiated, but both supplement doses were equally effective. The influence of folic acid supplementation on maternal folate status was not as pronounced as was the influence of iron supplementation on iron status. The type of study and type of participants are out of the scope of this review.

Mandishona 1999112 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 2009In this trial in Iran 246 nulliparous women were randomised to receive daily folic acid from early pregnancy; either 0.5 mg per day or 5 mg per day. Both groups received folic acid, and supplements continued throughout pregnancy.

Mathews 1999Authors investigated the possibility of merging 2 studies: 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 analysis of secondary data. The type of study is out of the scope of this review.

Melli 2008203 nulliparous pregnant women with a singleton pregnancy in their first trimester, attending the antenatal outpatient clinic 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. The type of intervention is out of the scope of this review.

Molster 2007The 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.

Nelen 2000A case-control study. 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 2009Forty 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 (RBC) 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. The type of participants and comparisons are out of the scope of this review.

Pitkin 2007This 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.

Pritchard 1991This paper describes the causes of abruptio placentae. It was excluded because is out of the scope of this review.

Ramakrishnan 2003A randomised, double-blind clinical trial in semi-rural Mexico to compare the effects of multiple micronutrients 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 sulfate) and 252 mg magnesium; group 2 received 60 mg elemental iron (as ferrous sulfate). The supplements were provided 6 days a week at home. Routine antenatal care was provided to both groups until delivery. These findings suggest that multiple micronutrient supplementation during pregnancy does not lead to greater infant birth size than iron-only supplementation. The study was excluded because supplementation time surpassed 12 weeks of pregnancy.

Ray 2007A 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 2008A 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 2005232 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 (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. The type of participants and interventions are out of the scope of this review.

Rolschau 19998184 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 100 µg (1 mg) folic acid or  250 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. The type of interventions is out of the scope of this review.

Sayers 1997A cross-sectional community-based survey was conducted in Dublin, Ireland to document the knowledge and behavior 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 1993The 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 women. The type of study, participants and interventions are out of the scope of this review.

Schwarz 2008446 English-speaking women, aged 18 to 45 years from 2 urgent clinics in San Francisco, United States were randomly assigned received computerised counselling about periconceptional folate supplements, while women in the control group received computerized counselling about emergency contraception. After 6 months 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 type of participants is out of the scope of this review.

Shaw 1995Case-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 2006Population-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 2002Commentary about the advantages of supplementation in different age groups. This is not an intervention trial.

van der Put 1998aCase-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 2004Case-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 2004A letter to the editor addressing the expediency of folic acid fortification to prevent NTDs versus masking vitamin B12 status. The letter was excluded because does not contain results from clinical trials.

Walsh 2007Cross-sectional population study looking at blood folate status of over 400 sequential primigravid Caucasian women with a singleton pregnancy, booking at less than or equal to 20 weeks' gestation. The type of study is out of the scope of the review.

Watson 1999This 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.

Wen 2005Review 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.

Westphal 2004A double-blind control study to determine the effects of a commercial blend that includes folic acid on progesterone level, basal body temperature, menstrual cycle and pregnancy rate. The type of interventions is out of the scope of this review.

Wilcox 2007National 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 cleft palate, especially among women with folate rich diets who also took folic acid supplements and multivitamins. Folic acid provided no protection against cleft palate. The type of study is out of the scope of the review.

Zeng 20085828 pregnant women in 2 rural counties in Shaanxi Province, in north west China. 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. Multiple micronutrients 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.

 
Characteristics of ongoing studies [ordered by study ID]
Javois 2006

Trial name or titleOral cleft prevention trial in Brazil.

MethodsRandomised, double-blind, dose comparison, parallel assignment, efficacy study.

ParticipantsWomen 16 to 45 years.

Inclusion criteria: all women must reside in the state where the clinic is located. Can include women with non-syndromic cleft lip with or without clef palate (NSCL/P) who attend the craniofacial clinics, and women who have at least one natural child of any age with NSCL/P.

InterventionsThe hypothesis was that folic acid supplementation of 4 mg/day at preconception and during the first 3 months of pregnancy will decrease the recurrence of non-syndromic cleft lip with or without cleft palate (NSCL/P) in a high-risk group of women when compared to women taking 0.4 mg per day of folic acid. The total sample will include 2000 women (that either have NSCL/P or that have at least 1 child with NSCL/P) randomly assigned to the 4 mg versus the 0.4 mg folic acid study groups. The study will also compare the recurrence rates of NSCL/P in the total sample of subjects as well as the 2 study groups (4 mg, 0.4 mg) to that of a historical control group.

OutcomesThe primary outcome is the recurrence of non-syndromic cleft lip with or without cleft palate (NSCL/P) in offspring of trial mothers. Secondary outcomes include: recurrence of NSCL/P compared to a historical control group; overall and high versus low dose, serum and red blood cell folate levels, severity of NSCL/P in offspring of trial mothers, twinning rate, miscarriage rate, pre-eclampsia, rates of other birth defects, birthweight, gestational age at delivery.

Starting dateJanuary 2004.

Contact informationLorette Javois, Ph.D. javoisl@mail.nih.gov

NotesRecruitment has recently finished (2009).

http://clinicaltrials.gov/ct2/show/NCT00098319

 
Comparison 1. Supplementation with folic acid versus no treatment/other micronutrients/placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neural tube defects (ALL)56105Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.15, 0.52]

 2 Neural tube defects (by subgroups)5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Daily supplementation scheme
56105Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.15, 0.52]

    2.2 Dose of 400 µg or less
1364Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.01, 2.29]

    2.3 Dose of more than 400 µg
45741Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.56]

    2.4 Started pre-pregnancy and continued during the first trimester
56105Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.15, 0.52]

    2.5 History of NTDs
41949Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.17, 0.60]

    2.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)0.08 [0.00, 1.33]

 3 Cleft palate (ALL)35715Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]

 4 Cleft palate (by subgroups)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Daily supplementation scheme
35715Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]

    4.2 Dose of 400 µg or less
1364Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.3 Dose of more than 400 µg
25351Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]

    4.4 Started pre-pregnancy and continued during first trimester
35715Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]

    4.5 History of NTDs
21559Risk Ratio (M-H, Fixed, 95% CI)3.05 [0.12, 74.61]

    4.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.06]

 5 Cleft lip (ALL)35715Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.27, 3.74]

 6 Cleft lip (by subgroups)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Daily supplementation scheme
35715Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.27, 3.74]

    6.2 Dose of 400 µg or less
1364Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.02, 9.07]

    6.3 Dose of more than 400 µg
25351Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.29, 5.80]

    6.4 Started pre-pregnancy and continued during first trimester
35715Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.27, 3.74]

    6.5 History of NTDs
21559Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.02, 9.07]

    6.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.29, 5.80]

 7 Congenital cardiovascular defects (ALL)35715Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.27, 1.14]

 8 Congenital cardiovascular defects (by subgroups)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Daily supplementation scheme
35715Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.27, 1.14]

    8.2 Dose of more than 400 µg
25351Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.28, 1.26]

    8.3 Dose of 400 µg or less
1364Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.01, 4.62]

    8.4 Started pre-pregnancy and continued
35715Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.27, 1.14]

    8.5 History of NTDs
21559Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.07, 3.14]

    8.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.26, 1.25]

 9 Other birth defects (any) (ALL)35715Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.48, 1.07]

 10 Other birth defects (by subgroups)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Daily supplementation scheme
35715Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.48, 1.07]

    10.2 Dose of 400 µg or less
1364Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.19, 3.69]

    10.3 Dose of more than 400 µg
25351Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.47, 1.07]

    10.4 Started pre-pregnancy and continued during the first trimester
35715Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.48, 1.07]

    10.5 History of NTDs
21559Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.67, 2.48]

    10.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.30, 0.84]

 11 Miscarriage (ALL)57618Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.97, 1.26]

 12 Miscarriage (by subgroups)5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 Daily supplementation scheme
57618Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.97, 1.26]

    12.2 Dose of 400 µg or less
1364Risk Ratio (M-H, Fixed, 95% CI)1.37 [0.68, 2.77]

    12.3 Dose of more than 400 µg
47254Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.96, 1.25]

    12.4 Started pre-pregnancy and continued during first trimester
57618Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.97, 1.26]

    12.5 History of NTDs
42116Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.79, 1.30]

    12.6 No history of NTDs or unknown
15502Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.97, 1.34]

 13 Stillbirth (ALL)45994Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.51, 1.83]

 14 Stillbirth (by subgroups)4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 Daily supplementation
45994Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.51, 1.83]

    14.2 Dose of 400 μg or less
1364Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.00, 1.51]

    14.3 Dose of more than 400 μg
35630Risk Ratio (M-H, Fixed, 95% CI)1.38 [0.68, 2.81]

    14.4 Started pre-pregnancy and continued
45994Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.51, 1.83]

    14.5 History of NTDs
31838Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.25, 1.57]

    14.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)1.53 [0.60, 3.95]

 15 Multiple pregnancy (ALL)36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]

 16 Multiple pregnancy (by subgroups)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    16.1 Daily supplementation scheme
36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]

   16.2 Dose of 400 μg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    16.3 Dose of more than 400 μg
36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]

    16.4 Started pre-pregnancy and continued during first trimester
36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]

    16.5 History of NTDs
21472Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.38, 2.70]

    16.6 No history of NTDs or unknown
14767Risk Ratio (M-H, Fixed, 95% CI)1.39 [0.89, 2.18]

 17 Pregnancy termination for fetal abnormality (ALL)45908Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.54]

 18 Pregnancy termination for fetal abnormality (by subgroups)4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    18.1 Daily supplementation scheme
45908Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.54]

   18.2 Dose of 400 μg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    18.3 Dose of more than 400 μg
45908Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.54]

    18.4 Started pre-pregnancy and continued during first trimester
45908Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.54]

    18.5 History of NTDs
31752Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.16, 0.65]

    18.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.06, 0.79]

 19 Low birthweight (ALL)1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]

 20 Low birthweight (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    20.1 Daily supplementation scheme
1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]

   20.2 Dose of 400 μg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    20.3 Dose of more than 400 μg
1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]

    20.4 Started pre-pregnancy and continue during first trimester
1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]

    20.5 History of NTDs
1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]

   20.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 
Comparison 2. Supplementation with folic acid alone versus no treatment/placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neural tube defects (ALL)2299Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.08, 1.34]

 2 Neural tube defects (by subgroups)2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Daily supplementation scheme
2299Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.08, 1.34]

    2.2 Dose of 400 µg or less
1188Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 3.30]

    2.3 Dose of more than 400 µg
1111Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.08, 2.23]

    2.4 Started pre-pregnancy and continued during the first trimester
2299Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.08, 1.34]

    2.5 History of NTDs
2299Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.08, 1.34]

   2.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 3 Cleft palate (ALL)1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 4 Cleft palate (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Daily supplementation scheme
1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.2 Dose of 400 µg or less
1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   4.3 Dose of more than 400 µg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.4 Started pre-pregnancy and continued during first trimester
1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.5 History of NTDs
1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   4.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 5 Cleft lip (ALL)1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 6 Cleft lip (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Daily supplementation scheme
1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    6.2 Dose of 400 µg or less
1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   6.3 Dose of more than 400 µg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    6.4 Started pre-pregnancy and continued during first trimester
1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    6.5 History of NTDs
1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   6.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 7 Congenital cardiovascular defects (ALL)1188Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.02, 9.77]

 8 Congenital cardiovascular defects (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Daily supplementation scheme
1188Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.02, 9.77]

    8.2 Dose of 400 µg or less
1188Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.02, 9.77]

   8.3 Dose of more than 400 µg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    8.4 Started pre-pregnancy and continued
1188Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.02, 9.77]

    8.5 History of NTDs
1188Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.02, 9.77]

   8.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 9 Other birth defects (any) (ALL)1188Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.06, 6.57]

 10 Other birth defects (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Daily supplementation scheme
1188Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.06, 6.57]

    10.2 Dose of 400 µg or less
1188Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.06, 6.57]

   10.3 Dose of more than 400 µg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    10.4 Started pre-pregnancy and continued during the first trimester
1188Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.06, 6.57]

    10.5 History of NTDs
1188Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.06, 6.57]

   10.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 11 Miscarriage (ALL)2299Risk Ratio (M-H, Fixed, 95% CI)1.66 [0.66, 4.18]

 12 Miscarriage (by subgroups)2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 Daily supplementation scheme
2299Risk Ratio (M-H, Fixed, 95% CI)1.66 [0.66, 4.18]

    12.2 Dose of 400 µg or less
1188Risk Ratio (M-H, Fixed, 95% CI)1.82 [0.67, 4.90]

    12.3 Dose of more than 400 µg
1111Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.05, 13.25]

    12.4 Started pre-pregnancy and continued during first trimester
2299Risk Ratio (M-H, Fixed, 95% CI)1.66 [0.66, 4.18]

    12.5 History of NTDs
2299Risk Ratio (M-H, Fixed, 95% CI)1.66 [0.66, 4.18]

   12.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 13 Stillbirth (ALL)1188Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.46]

 14 Stillbirth (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 Daily supplementation
1188Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.46]

    14.2 Dose of 400 μg or less
1188Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.46]

   14.3 Dose of more than 400 μg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    14.4 Started pre-pregnancy and continued during first trimester
1188Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.46]

    14.5 History of NTDs
1188Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.46]

   14.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

15 Multiple pregnancy (ALL)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

16 Multiple pregnancy (by subgroups)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.1 Daily supplementation scheme
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.2 Dose of 400 μg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.3 Dose of more than 400 μg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.4 Started pre-pregnancy and continued during first trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.5 History of NTDs
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 17 Pregnancy termination for fetal abnormality (ALL)1111Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.01, 6.83]

 18 Pregnancy termination for fetal abnormality (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    18.1 Daily supplementation scheme
1111Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.01, 6.83]

   18.2 Dose of 400 μg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    18.3 Dose of more than 400 μg
1111Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.01, 6.83]

    18.4 Started pre-pregnancy and continued during first trimester
1111Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.01, 6.83]

    18.5 History of NTDs
1111Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.01, 6.83]

   18.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

19 Low birthweight (ALL)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

20 Low birthweight (by subgroups)0Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   20.1 Daily supplementation scheme
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   20.2 Dose of 400 μg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   20.3 Dose of more than 400 μg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   20.4 Started pre-pregnancy and continued during first trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   20.5 History of NTDs
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   20.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 
Comparison 3. Supplementation with folic acid + other micronutrients versus no treatment/placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neural tube defects (ALL)1190Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 3.22]

 2 Neural tube defects (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Daily supplementation scheme
1190Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 3.22]

    2.2 Dose of 400 µg or less
1190Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 3.22]

   2.3 Dose of more than 400 µg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    2.4 Started pre-pregnancy and continued during first trimester
1190Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 3.22]

    2.5 History of NTDs
1190Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 3.22]

   2.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 3 Cleft palate (ALL)1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 4 Cleft palate (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Daily supplementation scheme
1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.2 Dose of 400 µg or less
1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   4.3 Dose of more than 400 µg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.4 Started pre-pregnancy and continued during the first trimester
1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.5 History of NTDs
1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   4.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 5 Cleft lip (ALL)1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 6 Cleft lip (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Daily supplementation scheme
1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    6.2 Dose of 400 µg or less
1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   6.3 Dose of more than 400 µg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    6.4 Started pre-pregnancy and continued during the first trimester
1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    6.5 History of NTDs
1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   6.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 7 Congenital cardiovascular defects (ALL)1190Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.02, 9.55]

 8 Congenital cardiovascular defects (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Daily supplementation scheme
1190Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.02, 9.55]

    8.2 Dose of 400 µg or less
1190Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.02, 9.55]

   8.3 Dose of more than 400 µg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    8.4 Started pre-pregnancy and continued during the first trimester
1190Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.02, 9.55]

    8.5 History of NTDs
1190Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.02, 9.55]

   8.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 9 Other birth defects (any) (ALL)1190Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.17, 8.23]

 10 Other birth defects (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Daily supplementation scheme
1190Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.17, 8.23]

    10.2 Dose of 400 µg or less
1190Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.17, 8.23]

   10.3 Dose of more than 400 µg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    10.4 Started pre-pregnancy and continued during the first trimester
1190Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.17, 8.23]

    10.5 History of NTDs
1190Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.17, 8.23]

   10.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 11 Miscarriage (ALL)1190Risk Ratio (M-H, Fixed, 95% CI)5.91 [0.29, 121.46]

 12 Miscarriage (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 Daily supplementation scheme
1190Risk Ratio (M-H, Fixed, 95% CI)5.91 [0.29, 121.46]

    12.2 Dose of 400 µg or less
1190Risk Ratio (M-H, Fixed, 95% CI)5.91 [0.29, 121.46]

   12.3 Dose of more than 400 µg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    12.4 Started pre-pregnancy and continued during the first trimester
1190Risk Ratio (M-H, Fixed, 95% CI)5.91 [0.29, 121.46]

    12.5 History of NTDs
1190Risk Ratio (M-H, Fixed, 95% CI)5.91 [0.29, 121.46]

   12.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 13 Stillbirth (ALL)1190Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.41]

 14 Stillbirth (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 Daily supplementation
1190Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.41]

    14.2 Dose of 400 μg or less
1190Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.41]

   14.3 Dose of more than 400 μg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    14.4 Started pre-pregnancy and continued
1190Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.41]

    14.5 History of NTDs
1190Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.41]

   14.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

15 Multiple pregnancy (ALL)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

16 Multiple pregnancy (by subgroups)0Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   16.1 Daily supplementation scheme
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.2 Dose of 400 μg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.3 Dose of more than 400 μg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.4 Started pre-pregnancy and continued during first trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.5 History of NTDs
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

17 Pregnancy termination for fetal abnormality (ALL)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

18 Pregnancy termination for fetal abnormality (by subgroups)0Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   18.1 Daily supplementation scheme
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   18.2 Dose of 400 μg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   18.3 Dose of more than 400 μg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   18.4 Started pre-pregnancy and continued during first trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   18.5 History of NTDs
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   18.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

19 Low birthweight (ALL)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

20 Low birthweight (by subgroups)0Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   20.1 Daily supplementation scheme
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   20.2 Dose of 400 μg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   20.3 Dose of more than 400 μg
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   20.4 Started pre-pregnancy and continued during first trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   20.5 History of NTDs
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   20.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 
Comparison 4. Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neural tube defects (ALL)45806Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.15, 0.56]

 2 Neural tube defects (by subgroups)4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Daily supplementation scheme
45806Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.15, 0.56]

    2.2 Dose of 400 µg or less
1176Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.26]

    2.3 Dose of more than 400 µg
35630Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.14, 0.56]

    2.4 Started pre-pregnancy and continued during the first trimester
45806Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.15, 0.56]

    2.5 History of NTDs
31650Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.17, 0.66]

    2.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)0.08 [0.00, 1.33]

 3 Cleft palate (ALL)35527Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]

 4 Cleft palate (by subgroups)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Daily supplementation scheme
35527Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]

    4.2 Dose of 400 µg or less
1176Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.3 Dose of more than 400 µg
25351Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]

    4.4 Started pre-pregnancy and continued during the first trimester
35527Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]

    4.5 History of NTDs
21371Risk Ratio (M-H, Fixed, 95% CI)3.05 [0.12, 74.61]

    4.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.06]

 5 Cleft lip (ALL)35527Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.27, 3.65]

 6 Cleft lip (by subgroups)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Daily supplementation scheme
35527Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.27, 3.65]

    6.2 Dose of 400 µg or less
1176Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.26]

    6.3 Dose of more than 400 µg
25351Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.29, 5.80]

    6.4 Started pre-pregnancy and continued during the first trimester
35527Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.27, 3.65]

    6.5 History of NTDs
21371Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    6.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.29, 5.80]

 7 Congenital cardiovascular defects (ALL)35527Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.43, 2.22]

 8 Congenital cardiovascular defects (by subgroups)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Daily supplementation scheme
35527Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.43, 2.22]

    8.2 Dose of 400 µg or less
1176Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.26]

    8.3 Dose of more than 400 µg
25351Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.46, 2.53]

    8.4 Started pre-pregnancy and continued during the first trimester
35527Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.43, 2.22]

    8.5 History of NTDs
21371Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.08, 4.61]

    8.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.44, 2.66]

 9 Other birth defects (any) (ALL)35527Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.50, 1.12]

 10 Other birth defects (by subgroups)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Daily supplementation scheme
35527Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.50, 1.12]

    10.2 Dose of 400 µg or less
1176Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.15, 7.10]

    10.3 Dose of more than 400 µg
25351Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.49, 1.12]

    10.4 Started pre-pregnancy and continued during the first trimester
35527Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.50, 1.12]

    10.5 History of NTDs
21371Risk Ratio (M-H, Fixed, 95% CI)1.38 [0.70, 2.73]

    10.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.31, 0.89]

 11 Miscarriage (ALL)47319Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.96, 1.26]

 12 Miscarriage (by subgroups)4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 Daily supplementation scheme
47319Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.96, 1.26]

    12.2 Dose of 400 µg or less
1176Risk Ratio (M-H, Fixed, 95% CI)5.11 [0.25, 105.01]

    12.3 Dose of more than 400 µg
37143Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.96, 1.26]

    12.4 Started pre-pregnancy and continued during the first trimester
47319Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.96, 1.26]

    12.5 History of NTDs
31817Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.76, 1.30]

    12.6 No history of NTDs or unknown
15502Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.97, 1.34]

 13 Stillbirth (ALL)45806Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.68, 2.75]

 14 Stillbirth (by subgroups)4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 Daily supplementation scheme
45806Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.68, 2.75]

    14.2 Dose of 400 μg or less
1176Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.20]

    14.3 Dose of more than 400 μg
35630Risk Ratio (M-H, Fixed, 95% CI)1.62 [0.77, 3.43]

    14.4 Started pre-pregnancy and continued
45806Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.68, 2.75]

    14.5 History of NTDs
31650Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.41, 3.36]

    14.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)1.53 [0.60, 3.95]

 15 Multiple pregnancy (ALL)36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]

 16 Multiple pregnancy (by subgroups)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    16.1 Daily supplementation scheme
36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]

   16.2 Dose of 400 μg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    16.3 Dose of more than 400 μg
36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]

    16.4 Started pre-pregnancy and continued during first trimester
36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]

    16.5 History of NTDs
21472Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.38, 2.70]

    16.6 No history of NTDs or unknown
14767Risk Ratio (M-H, Fixed, 95% CI)1.39 [0.89, 2.18]

 17 Pregnancy termination for fetal abnormality (ALL)35797Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.55]

 18 Pregnancy termination for fetal abnormality (by subgroups)323188Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.22, 0.40]

    18.1 Daily supplementation scheme
35797Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.55]

   18.2 Dose of 400 μg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    18.3 Dose of more than 400 μg
35797Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.55]

    18.4 Started pre-pregnancy and continued during first trimester
35797Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.55]

    18.5 History of NTDs
21641Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.16, 0.67]

    18.6 No history of NTDs or unknown
14156Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.06, 0.79]

 19 Low birthweight (ALL)1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]

 20 Low birthweight (by subgroups)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    20.1 Daily supplementation scheme
1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]

   20.2 Dose of 400 ɥg or less
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    20.3 Dose of more than 400 μg
1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]

    20.4 Started pre-pregnancy and continued during first trimester
1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]

    20.5 History of NTDs
1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]

   20.6 No history of NTDs or unknown
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable