Effects and safety of periconceptional folate supplementation for preventing birth defects

  • Review
  • Intervention

Authors

  • Luz Maria De-Regil,

    Corresponding author
    1. World Health Organization, Micronutrients Unit, Department of Nutrition for Health and Development, Geneva, Geneva, Switzerland
    • 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.

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  • Ana C Fernández-Gaxiola,

    1. Instituto Nacional de Salud Pública, Cuernavaca, Morelos, Mexico
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  • Therese Dowswell,

    1. The University of Liverpool, Cochrane Pregnancy and Childbirth Group, School of Reproductive and Developmental Medicine, Division of Perinatal and Reproductive Medicine, Liverpool, UK
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  • Juan Pablo Peña-Rosas

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

Background

It has been reported that neural tube defects can be prevented with periconceptional folic acid supplementation. The effects of different doses, forms and schemes of folate supplementation for the prevention of other birth defects and maternal and infant outcomes are unclear.

Objectives

This review updates and expands a previous Cochrane Review assessing the effects of periconceptional supplementation with folic acid to reduce neural tube defects (NTDs). We examined whether folate supplementation before and during early pregnancy can reduce neural tube and other birth defects (including cleft palate) without causing adverse outcomes for mothers or babies.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2010). Additionally, we searched the international clinical trials registry platform and contacted relevant organisations to identify ongoing and unpublished studies.

Selection criteria

We included all randomised or quasi-randomised trials evaluating the effect of periconceptional folate supplementation alone, or in combination with other vitamins and minerals, in women independent of age and parity.

Data collection and analysis

We assessed trials for methodological quality using the standard Cochrane criteria. Two authors independently assessed the trials for inclusion, one author extracted data and a second checked for accuracy.

Main results

Five trials involving 6105 women (1949 with a history of a pregnancy affected by a NTD and 4156 with no history of NTDs) were included. Overall, the results are consistent in showing a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.15 to 0.52). Only one study assessed the incidence of NTDs and the effect was not statistically significant (RR 0.08, 95% CI 0.00 to 1.33) although no events were found in the group that received folic acid. Folic acid had a significant protective effect for reoccurrence (RR 0.32, 95% CI 0.17 to 0.60). There is no statistically significant evidence of any effects on prevention of cleft palate, cleft lip, congenital cardiovascular defects, miscarriages or any other birth defects. There were no included trials assessing the effects of this intervention on maternal blood folate or anaemia at term.

We found no evidence of short-term side effects.

Authors' conclusions

Folic acid, alone or in combination with vitamins and minerals, prevents NTDs but does not have a clear effect on other birth defects.

Resumen

Antecedentes

Efectos y seguridad de la administración periconcepcional de suplementos de folato para la prevención de los defectos congénitos

Se ha informado que los defectos del tubo neural se pueden prevenir mediante la administración periconcepcional de suplementos de ácido fólico. Los efectos de diferentes dosis, formas y esquemas de administración de suplementos de folato para la prevención de otros defectos congénitos y en los resultados maternos e infantiles son inciertos.

Objetivos

Esta revisión actualiza y amplía una revisión Cochrane anterior que evaluó los efectos de la administración periconcepcional de suplementos con ácido fólico para reducir los defectos del tubo neural (DTN). Se examinó si la administración de suplementos de folato antes y durante el primer trimestre del embarazo puede reducir los defectos del tubo neural y otros defectos congénitos (incluido el paladar hendido) sin provocar resultados adversos para las madres o los recién nacidos.

Estrategia de búsqueda

Se hicieron búsquedas en el registro de ensayos del Grupo Cochrane de Embarazo y Parto (Cochrane Pregnancy and Childbirth Group) (julio 2010). Además, se buscó en la plataforma internacional del registro de ensayos clínicos y se estableció contacto con organizaciones relevantes para identificar estudios en curso y no publicados.

Criterios de selección

Se incluyeron todos los ensayos aleatorios o cuasialeatorios que evaluaran el efecto de la administración periconcepcional de suplementos de folato solos o en combinación con otras vitaminas y minerales en mujeres, independientemente de la edad y la paridad.

Obtención y análisis de los datos

La calidad metodológica de los ensayos se evaluó mediante los criterios Cochrane estándar. Dos revisores evaluaron de forma independiente los ensayos para la inclusión, un revisor extrajo los datos y otro verificó la exactitud.

Resultados principales

Se incluyeron cinco ensayos con 6105 mujeres (1949 con antecedentes de un embarazo afectado por un DTN y 4156 sin antecedentes de DTN). En general, los resultados son coherentes en mostrar un efecto protector de la administración diaria de suplementos de ácido fólico (solos o en combinación con otras vitaminas y minerales) para prevenir los DTN en comparación con ninguna intervención/placebo o vitaminas y minerales sin ácido fólico (cociente de riesgos [CR] 0,28; intervalo de confianza [IC] del 95%: 0,15 a 0,52). Sólo un estudio evaluó la incidencia de los DTN y el efecto no fue estadísticamente significativo (CR 0,08; IC del 95%: 0,00 a 1,33), aunque no se encontraron eventos en el grupo que recibido ácido fólico. El ácido fólico tuvo un efecto protector significativo para la recurrencia (CR 0,32; IC del 95%: 0,17 a 0,60). No existen pruebas estadísticamente significativas de ningún efecto sobre la prevención del paladar hendido, el labio leporino, los defectos cardiovasculares congénitos, los abortos espontáneos u otros defectos congénitos. No se incluyeron ensayos que evaluaran los efectos de esta intervención sobre los niveles maternos de folato en sangre ni la anemia al término.

No se encontraron pruebas de efectos secundarios a corto plazo.

Conclusiones de los autores

El ácido fólico solo o en combinación con vitaminas y minerales previene los DTN pero no tiene un efecto claro sobre otros defectos congénitos.

Traducción

Traducción realizada por el Centro Cochrane Iberoamericano

摘要

背景

在懷孕期間使用葉酸補充劑避免先天缺陷的效果及安全性

已經有報告指出懷孕中使用葉酸補充劑可以避免神經管缺陷的發生。但目前對葉酸補充劑在不同劑量、劑型及使用方案,用於預防其它先天性缺陷的效果,及其對產婦和新生兒的影響並不清楚。

目標

本篇回顧針對先前的Cochrane Review做更新及延伸討論,評估在懷孕期間使用葉酸補充劑以減少神經管缺陷 (NTDs) 的發生。我們針對在懷孕前或懷孕早期使用葉酸補充劑,是否可以減少神經管缺陷或其他先天性缺陷 (包含上顎裂) 的發生率,且不會對母親及嬰兒造成不良反應作討論。

搜尋策略

我們搜尋了the Cochrane Pregnancy and Childbirth Group's Trials Register (2010年7月) 。此外,我們也搜尋國際臨床試驗登記平台,並和相關機構聯絡,以取得進行中及未發表的研究。

選擇標準

受試的婦女沒有年齡及其他條件的限制,我們收錄隨機或半隨機對照試驗,比較懷孕中單獨使用葉酸補充劑和合併其它維生素或礦物質補充劑一起使用作的試驗。

資料收集與分析

我們利用standard Cochrane criteria評估試驗的方法品質。2位作者分別評估試驗並加以收錄,1位作者擷取數據,由第二位作者檢查數據的正確性。

主要結論

我們收錄了5個試驗,包含6105位婦女 (其中1949位曾經在懷孕時發生新生兒神經管缺陷,而另外4156位則沒有) 。整體而言,研究結果都很一致的顯示每天服用葉酸補充劑 (不論單獨使用或合併其它維生素或礦物質一起服用) ,比無干預/安慰劑或只服用維生素及礦物質而不服用葉酸更有保護的效果 (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.15 to 0.52) 。只有一個研究顯示對神經管缺陷的發生率,其影響在統計學上並不顯著 (RR 0.08, 95% CI 0.00 to 1.33) ,雖然在有服用葉酸的組別上,沒有神經管缺陷的發生案例。葉酸對復發有很顯著的保護效果 (RR 0.32, 95% CI 0.17 to 0.60) 。沒有統計上的顯著證據顯示葉酸對顎裂、唇裂、先天性心血管缺陷、流產或其它新生兒缺陷上有預防作用。收錄的試驗中沒有任何一篇評估服用葉酸對產婦血中葉酸濃度或貧血發生率的影響。我們沒有找到任何和短期副作用相關的證據。

作者結論

單獨服用葉酸或合併維生素及其他礦物質補充劑一起服用,可以預防神經管缺陷,但目前並不清楚葉酸對其它先天性缺陷的預防效果。

翻譯人

本摘要由朱奕蓁翻譯。

此翻譯計畫由臺灣國家衛生研究院 (National Health Research Institutes, Taiwan) 統籌。

總結

在懷孕前或懷孕早期服用葉酸補充劑 (持續12週以上) 以預防先天性缺陷:葉酸是一種合成物,可以用來做為營養補充劑或添加在食物中 (例如小麥和玉米粉) 以增加食物的營養成分,可以減低神經管缺陷 (NTDs) 的發生率。包括脊柱裂 (or cleft spine), 這種情況會有一塊或多塊脊柱的骨骼 (脊椎) 末閉合,以及先天無腦無脊椎畸形,是一種頭部末端的神經管閉合失敗,國際間目前都建議婦女可以在決定懷孕時開始服用葉酸補充劑,一直服用到懷孕12週。世界衛生組織 (WHO) 也提出的其它建議,認為生育年齡的女性應該每周補充鐵和葉酸,特別是在貧血發生率高於20% 的族群中的婦女更應該補充。營養補充劑也可以減少其它先天缺陷的發生率,像是唇裂,或唇顎裂以及先天性心血管缺陷。最近,5methyltetrahydrofolate (5MTHF) 被認為可以作為葉酸補充劑的替代品。這是因為許多食物中的葉酸及合成葉酸都會在體內代謝成5MTHF。有些婦女有特定的基因,會減少血中葉酸濃度。本篇回顧確定了葉酸預防第一、二期神經管缺陷的發生,目前沒有足夠的證據確定葉酸是否可以預防其它先天性缺陷。也缺乏關於現有和替代的補充方案安全性的資訊,以及其對於其它產婦和新生兒結果影響的資訊。本篇回顧收錄了5個試驗,包含6105位婦女 (其中1949位曾經在懷孕時發生新生兒神經管缺陷,而另外4156位則沒有) ,研究結果顯示在懷孕前開始每天服用0.36毫克 (360微克) 到4毫克 (4000微克) 的葉酸補充劑,不論是否併服其它維生素及礦物質補充劑,直到懷孕12週,對這些缺陷再復發的預防是有效的。現有的數據不足以拿來評估其對於唇顎裂等其它結果的影響。還需要更多的研究,針對各種營養補充方案以及不同種類的營養補充劑 (例如5methyltetrahydrofolate −5MTHF) 做討論,特別應該針對不是以小麥、玉米粉等會添加葉酸的食品為主食的地方,以及神經管缺陷發生率高的地方做討論。

摘要

妊娠期补充叶酸预防出生缺陷的效果及安全性

研究背景

已有报告指出: 妊娠期间补充叶酸可以预防胎儿神经管畸形。但目前尚不清楚不同剂量、剂型及使用方案的叶酸补充剂对预防其它出生缺陷的效果,及其对孕产妇和新生儿结局的影响。

研究目的

本篇系统评价是基于先前的Cochrane Review所做的更新及扩展,评估妊娠期间使用叶酸补充剂对减少NTDs(神经管畸形)的效果。我们评估了在妊娠前和妊娠早期补充叶酸能否减少NTDs和其他出生缺陷 (包含腭裂),同时也不对母婴造成不良反应。

检索策略

检索了Cochrane Pregnancy and Childbirth Group's Trials Register(2010年7月)数据库。此外,也检索了国际临床试验注册平台,并联系相关组织以获取正在进行的和未发表的研究信息。

标准/纳入排除标准

纳入了随机或半随机试验,这些试验比较了妊娠期单独补充叶酸或与其它维生素和矿物质一起补充两种方案的效果,受试妇女没有年龄及其他条件的限制。

数据收集与分析

我们使用标准的Cochrane标准来评价试验的方法学质量。两位评价者独立筛选文献,由一位评价者提取数据,另一位评价者核查数据的准确性。

主要结果

共纳入5个试验,涉及6105例妇女(其中1949例有生产NTDs胎儿病史,另外4156例则没有)。总的来说,研究结果一致认为: 每天补充叶酸(不论是单独补充还是和其它维生素、矿物质一起补充),与无干预/服用安慰剂或只服用维生素和矿物质相比,其预防NTDs的保护效果更好(RR(危险比): 0.28,95% CI(可信区间): 0.15∼0.52)。只有一个研究评估了NTDs的发生率,虽然服用叶酸组没有发生NTDs,但效果无统计学意义(RR: 0.08,95% CI: 0.00∼1.33)。叶酸对NTDs复发也有显著的保护效果(RR: 0.32,95% CI: 0.17∼0.60)。服用叶酸在预防腭裂、唇裂、先天性心血管缺陷、流产或其它出生缺陷上的效果,证据显示无统计学意义。纳入的试验中没有一篇评价叶酸补充对孕产妇血中叶酸浓度或贫血发生率的影响。

没有发现叶酸补充的短期副作用。

作者结论

单独补充叶酸或与维生素、矿物质一起补充,可以预防NTDs,但叶酸对其它出生缺陷的预防效果目前尚不清楚。

Résumé scientifique

Effets et tolérance de la supplémentation périconceptionnelle en folate pour prévenir les anomalies congénitales

Contexte

Il a été rapporté que les lésions du tube neural pouvaient être prévenues grâce à une supplémentation périconceptionnelle en acide folique. Les effets des différentes doses, des différentes formes et des différents programmes de supplémentation en folate pour la prévention des autres anomalies congénitales et les résultats pour la mère et l'enfant sont incertains.

Objectifs

Cette revue constitue une mise à jour et un complément d'une revue Cochrane précédente évaluant les effets de la supplémentation périconceptionnelle en acide folique pour réduire les lésions du tube neural (LTN). Nous avons examiné si la supplémentation en folate avant et au début de la grossesse pouvait réduire les lésions du tube neural et autres anomalies (y compris palatoschisis) sans causer de résultats indésirables chez la mère ou le bébé.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre des essais cliniques du groupe Cochrane sur la grossesse et la naissance (juillet 2010). Par ailleurs, nous avons effectué des recherches dans le système d'enregistrement international des essais cliniques et contacté les organisations concernées pour identifier les études en cours et non publiées.

Critères de sélection

Nous avons inclus tous les essais randomisés ou quasi-randomisés évaluant l'effet de la supplémentation périconceptionnelle en folate seul, ou en association avec d'autres vitamines et minéraux, chez les femmes indépendamment de leur âge et du nombre de bébés qu'elles avaient portés.

Recueil et analyse des données

Nous avons évalué la qualité méthodologique des essais à l'aide des critères Cochrane standard. Deux auteurs ont indépendamment sélectionné les essais à inclure, un auteur a extrait les données et un deuxième a vérifié leur exactitude.

Résultats principaux

Cinq essais portant sur 6 105 femmes (1 949 ayant des antécédents de grossesse affectée par des LTN et 4 156 sans antécédents de LTN) ont été inclus. Globalement, les résultats sont cohérents et montrent un effet protecteur de la supplémentation quotidienne en acide folique (seul ou en association avec d'autres vitamines et minéraux) dans la prévention des LTN par rapport à l'absence d'intervention/placebo ou à la supplémentation en vitamines et minéraux sans acide folique (risque relatif (RR) 0,28, intervalle de confiance (IC) à 95 % 0,15 à 0,52). Seule une étude a évalué l'incidence des LTN et l'effet n’était pas statistiquement significatif (RR 0,08, IC à 95 % 0,00 à 1,33) bien qu'aucun événement n'ait été trouvé dans le groupe qui recevait de l'acide folique. L'acide folique avait un effet protecteur significatif pour la récidive (RR 0,32, IC à 95 % 0,17 à 0,60). Il n'existe aucune donnée statistiquement significative indiquant un quelconque effet sur la prévention du palatoschisis, de la fente labiale, des anomalies cardiovasculaires congénitales, des fausses couches ou de toute autre anomalie congénitale. Aucun essai évaluant les effets de cette intervention sur le taux sanguin de folate chez la mère ou l'anémie maternelle à terme n'a été inclus.

Nous n'avons trouvé aucune preuve d'effets secondaires à court terme.

Conclusions des auteurs

L'acide folique, seul ou en association avec des vitamines et minéraux, prévient les LTN mais n'a pas d'effet clair sur les autres anomalies congénitales.

アブストラクト

先天異常を防止するための葉酸受胎前後補充の効果と安全性

背景

神経管奇形は葉酸受胎前後補充により防止できることが報告されている。他の先天異常や母体・乳児アウトカムを防止するための様々な用量、剤形、計画の葉酸補充の効果は不明である。

目的

本レビューは、神経管奇形(NTD)を減じるための葉酸受胎前後補充の効果を評価している以前のコクラン・レビューを更新し拡大する。妊娠前と妊娠初期における葉酸補充は、母体や乳児に有害アウトカムを生じることなく、神経管奇形や他の先天異常(口蓋裂)を減じることができるかどうかを検討した。

検索戦略

Cochrane Pregnancy and Childbirth Group's Trials Registerを検索した(2010年7月)。さらに、進行中や未発表の研究を同定するため、国際的な臨床試験登録プラットフォームを検索し、関連する組織に連絡を取った。

選択基準

年齢や出産歴とは無関係に、女性を対象として、受胎前後の葉酸補充のみまたは他のビタミンやミネラルと併用での補充の効果を評価している全てのランダム化試験または準ランダム化試験を選択した。

データ収集と分析

標準的なコクラン基準を用いて、方法論的質について試験を評価した。2人のレビューアが独自にこれらの試験を組み入れるべきか否か評価し、1人のレビューアがデータを抽出し、2人目のレビューアが正確かどうかチェックした。

主な結果

6105例の女性(NTDを伴った妊娠歴あり1949例、NTD歴がない4156例)を対象とした5件の試験を選択した。全体では、NTD防止において葉酸の連日補充(単独または他のビタミンやミネラルと併用)が、無介入/プラセボまたは葉酸なしのビタミンとミネラルと比較して保護効果を示している点で結果は一貫している(リスク比(RR)0.28、95%信頼区間(CI)0.15~0.52)。1件の研究のみがNTDの発生率を評価し、葉酸投与を受けた群においてイベントは認められなかったものの、効果は統計学的に有意でなかった(RR 0.08、95%CI 0.00~1.33)。葉酸は再発に対して有意な保護効果を有していた(RR 0.32、95%CI 0.17~0.60)。口蓋裂、口唇裂、先天性心血管系欠損、流産、その他のあらゆる先天異常の防止に効果を有するという統計学的に有意なエビデンスはない。選択された試験はいずれもこの介入によって満期時の母体血中葉酸や貧血に及ぼす効果を評価しなかった。短期の副作用のエビデンスは見つからなかった。

著者の結論

葉酸は単独あるいはビタミンやミネラルと併用でNTDを防止するが、他の先天異常に対しての明瞭な効果はない。

訳注

監  訳: 江藤 宏美,2011.7.12

実施組織: 厚生労働省委託事業によりMindsが実施した。

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Plain language summary

Folic acid supplements before conception and in early pregnancy (up to 12 weeks) for the prevention of birth defects

Folic acid is a synthetic form of folate used in supplements and fortified foods (like wheat and maize flour) to reduce the occurrence of neural tube defects (NTDs). These include spina bifida (or cleft spine), where there is an opening in one or more of the bones (vertebrae) of the spinal column, and anencephaly where the head (cephalic) end of the neural tube fails to close. Supplementation with folic acid is internationally recommended to women from the moment they are trying to conceive until 12 weeks of pregnancy. Another option recommended by the World Health Organization (WHO) is that women of reproductive age take weekly iron and folic acid supplements, especially in populations where the prevalence of anaemia is above 20%. Supplementation may also reduce other birth defects such as cleft lip with or without cleft palate and congenital cardiovascular defects. Recently, 5-methyl-tetrahydrofolate (5-MTHF) has been proposed as an alternative to folic acid supplementation. This is because most dietary folate and folic acid are metabolised to 5-MTHF. Some women have gene characteristics which reduce folate concentration in blood.

This review confirms that folic acid supplementation prevents the first and second time occurrence of NTDs and shows there is not enough evidence to determine if folic acid prevents other birth defects. Information about the safety of other current and alternative supplementation schemes and any possible effects on other outcomes for mothers and babies is also lacking. This review of five trials, involving 6105 women (1949 with a history of a pregnancy affected by a NTD and 4156 with no history of NTDs), shows the protective effect of daily folic acid supplementation in doses ranging from 0.36 mg (360 µg) to 4 mg (4000 µg) a day, with and without other vitamins and minerals, before conception and up to 12 weeks of pregnancy, for preventing the recurrence of these diseases. There were insufficient data to evaluate the effects on other outcomes such as cleft lip and palate. More research is needed on different types of supplementation programmes and the use of different types of supplements (such as 5-methyl-tetrahydrofolate -5-MTHF), particularly in countries where folic acid fortification of staple foods like wheat or maize flour is not mandatory and where the prevalence of NTDs is still high.

概要

在妊娠前或妊娠早期(持续到12周)补充叶酸预防出生缺陷

叶酸是一种合成物,可以作为营养补充剂或者强化食品(例如小麦和玉米粉),以降低NTDs(神经管畸形)的发生率。NTDs包括脊柱裂(会有一块或多块脊椎骨未闭合)以及先天无脑畸形(末端神经管未闭合)。国际上推荐,妇女从准备怀孕到怀孕12周,应该一直补充叶酸。世界卫生组织也推荐,育龄妇女应该每周补充铁和叶酸,特别是在贫血发生率高于20% 的人群中的妇女更应该补充。补充叶酸还可能减少其它出生缺陷的发生,如唇裂、唇颚裂及先天性心血管缺陷。最近,5-MTHF(5-甲基四氢叶酸)被推荐作为叶酸补充剂的替代品。这是因为大多数膳食叶酸和合成叶酸都会在体内代谢成5-MTHF。有些妇女含有特定基因,会减少血中叶酸浓度。

本系统评价证实了补充叶酸能够预防NTDs的发生和复发,但没有足够的证据证明叶酸能够预防其它出生缺陷。对其他现有的替代补充方案,我们缺少安全性评价资料。叶酸补充对孕产妇和新生儿结局影响的评估资料也不足。本系统评价共纳入了5个试验,包含6105例妇女(其中1949例有生产NTDs胎儿病史,另外4156例则没有)。研究结果显示: 从怀孕前到怀孕12周,每天服用0.36毫克(360微克)到4毫克(4000微克)的叶酸补充剂,不论是是单独补充,还是和其它维生素、矿物质一起补充,对预防NTDs的复发都具有保护作用。现有的数据不足以评价叶酸对唇裂或唇腭裂等先天缺陷的影响作用。我们还需要开展进一步研究,探讨不同营养补充方案以及不同种类营养补充剂(如5-MTHF)的效果,尤其是在不以叶酸强化食品(如小麦和面粉)为主食,且NTDs发生率仍然很高的国家。

翻译注解

本摘要由重庆医科大学中国循证卫生保健协作网(China Effective Health Care Network)翻译。

Translated by: China Effective Health Care Network

Résumé simplifié

Supplémentation en acide folique avant la conception et au début de la grossesse (jusqu'à 12 semaines) pour la prévention des anomalies congénitales

L'acide folique est une forme synthétique de folate utilisée dans les compléments alimentaires et les aliments enrichis (tels que la farine de blé et de maïs) pour réduire les cas de lésions du tube neural (LTN). Celles-ci comprennent le spina bifida, où l'un ou plusieurs des os (vertèbres) de la colonne vertébrale présente une ouverture, et l'anencéphalie où l'extrémité côté tête (céphalique) du tube neural présente un défaut de fermeture. La supplémentation en acide folique est internationalement recommandée chez les femmes à partir du moment où elles essaient de concevoir et jusqu'à 12 semaines de grossesse. Une autre option recommandée par l'Organisation mondiale de la Santé (OMS) est la supplémentation hebdomadaire en fer et en acide folique chez les femmes en âge de procréer, en particulier dans les populations où la prévalence de l'anémie est supérieure à 20 %. La supplémentation peut également réduire d'autres anomalies congénitales telles que la fente labiale avec ou sans palatoschisis et les anomalies cardiovasculaires congénitales. Récemment, le 5-méthyl-tétrahydrofolate (5-MTHF) a été proposé comme alternative à la supplémentation en acide folique. Cela tient au fait que la majeure partie du folate et de l'acide folique alimentaires est métabolisée en 5-MTHF. Certaines femmes présentent des caractéristiques génétiques qui réduisent la concentration en folate du sang.

Cette revue confirme que la supplémentation en acide folique prévient le premier et le deuxième type de LTN et indique que les preuves sont insuffisantes pour déterminer si l'acide folique prévient les autres anomalies congénitales. Il existe également une pénurie de données sur l'innocuité des autres programmes de supplémentation actuels et alternatifs et sur les éventuels effets possibles sur les autres résultats pour les mères et les bébés. Cette revue de cinq essais, portant sur 6 105 femmes (1 949 ayant des antécédents de grossesse affectée par des LTN et 4 156 sans antécédents de LTN), illustre l'effet protecteur de la supplémentation quotidienne en acide folique à des doses allant de 0,36 mg (360 µg) à 4 mg (4 000 µg) par jour, avec ou sans autres vitamines et minéraux, avant la conception et jusqu'à 12 semaines de grossesse, pour prévenir la récurrence de ces maladies. Les données étaient insuffisantes pour évaluer les effets sur les autres résultats tels que la fente labiale et le palatoschisis. Des recherches supplémentaires sont nécessaires sur différents types de programmes de supplémentation et sur l'utilisation des différents types de suppléments (tels que le 5-méthyl-tétrahydrofolate - 5-MTHF), en particulier dans les pays où l'enrichissement en acide folique des aliments de base tels que la farine de blé ou de maïs n'est pas obligatoire et où la prévalence des LTN est toujours élevée.

Notes de traduction

Traduit par: French Cochrane Centre 12th November, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Background

The main focus of this review is on the provision of folate as folic acid or 5-MTHF (with or without other vitamins and minerals) in the periconceptional period (prior to conception and in early pregnancy, before 12 weeks’ gestation) to reduce the first and second time occurrence of neural tube defects (NTDs) and other birth defects. Other Cochrane Reviews and protocols focus on related topics such as oral iron with or without folic acid during pregnancy (Pena-Rosas 2009); treatment for iron deficiency and anaemia (Reveiz 2007); the use of various vitamin and multivitamin/micronutrient supplements for women during pregnancy (Haider 2006) and the effectiveness of oral folate supplementation alone during pregnancy on haematological and biochemical parameters during pregnancy and on pregnancy outcomes (Haider 2008). This review updates and expands the scope of a previously published Cochrane Review on periconceptional supplementation with folate with or without multivitamins for preventing NTDs (Lumley 2001).

Introduction

Folate is a water-soluble B vitamin present in legumes, leafy green vegetables (such as spinach and turnip greens) and some fruits (such as citrus fruits and juices). Folic acid is the synthetic and most stable form of folate and the form often used in supplements and in fortified foods. The bioavailability of folic acid is approximately 70% higher than that of folate naturally contained in foods, although there are wide variations depending on the methodology used in the measurement (McNulty 2004). 

Folate status in populations is generally assessed using static biochemical tests that directly measure folate in serum or in red blood cells (WHO 2008). Cut-off points to assess folate status have been proposed with an approach that relies on the combination of blood concentrations of the vitamin and the functional indicators in populations (Selhub 2008). The cut-off suggested to define deficiency is below 10 nmol/L (below 4 ng/mL) for serum folate, an indicator sensitive to recent usual intake; and below 340 nmol/L (below 151 ng/L) for red blood cell folate, an indicator of folate storage (WHO 2008). There are no universally accepted cut-off points to define deficiency during pregnancy, as concentrations decline over gestation and recover at delivery (WHO 2008), probably due to the physiologic haemodilution. Folate concentration measurements differ depending on the method used for assessment, particularly at the lower range of concentrations (CDC 2008a; Fazili 2007; Life Sciences Research Office 1994). 

Description of the condition

Insufficient periconceptional folate and folic acid intake is associated with a number of birth defects that may also relate to genetic and environmental factors (IOM 2003) operating before conception or during early pregnancy. Birth defects can cause lifelong problems affecting health, growth and learning and may be immediately apparent after birth, or manifest later in life (Murray 1997; WHO 1999; WHO 2000). Environmental factors, including nutrition, are thought to contribute to about 5% to 10% of total birth defects (IOM 2003).  

NTDs, which include anencephaly, spina bifida and encephalocoele, are congenital malformations that arise during the structural development of the neural tube, a process that is completed within 28 days after conception. In 1991, one randomised controlled trial (RCT) demonstrated that periconceptional folic acid supplementation prevented the recurrence of NTDs (MRC 1991) and in 1992 another RCT showed that a multiple micronutrient supplement containing folic acid prevented the occurrence of NTDs (Czeizel 1992). The latter results were confirmed in a public health campaign among women preparing for marriage conducted between 1993 and 1995 in China after which the risk of neural tube defects among the fetuses or infants of the women who took a folic acid supplement more than 80% of the time decreased by between 40% and 85% (Berry 1999).

While maternal intake of folate and folic acid is specifically associated with a decreased risk for NTDs they may also provide protection for other selected birth defects. There is suggestive evidence of protection from cardiovascular defects, Down syndrome, limb defects, cleft lip with or without cleft palate, urinary tract anomalies and congenital hydrocephalus (Coppede 2009; Eskes 2006; Goh 2006; Wilcox 2007). In the case of orofacial clefts, there are several similarities with NTDs: their occurrence at a similar time during embryogenesis, their involvement with the midline of the embryo, their near identical population characteristics and similar gene contributions. There is also some evidence of a suggested protective effect of folic acid use, especially for cleft lip with or without cleft palate (Wehby 2010), although this remains controversial, possibly because of the differences in dosage and type of supplementation (e.g. folic acid alone or with other micronutrients) used among studies (Botto 2004; Botto 2006). No effects have been shown in preventing pyloric stenosis, undescended testis or hypospadias. Approximately half of birth defects are limited to a single organ and the other half frequently present additional birth defects, such as heart malformations (Shibuya 1998).

Suspicion of a NTD may be raised by a maternal serum screening test during the second trimester of pregnancy which detects an elevated concentration of alpha-feto-protein. The diagnosis is confirmed by ultrasound examination during the second trimester of pregnancy. Cleft lip and palate can be identified on detailed ultrasound examination, but if there is only involvement of the palate, diagnosis by ultrasound can be difficult, and often not established until after birth. Unfortunately, these tests are not yet routinely done in most developing countries. Today, as infant mortality rates fall, birth defects are responsible for an increasing proportion of infant mortality and morbidity (Modell 1989; WHO 1997; WHO 2004). Affected infants have difficulty with feeding and later with speech development, hearing and tooth formation. Stigmatisation and discrimination may pose lifelong problems. Malnutrition and infection resulting from cleft lip or cleft palate, or both, can lead to severe illness and, in some cases, death (Shibuya 1998).

The impact of folate insufficiency on birth defects in different populations varies with each healthcare system. It partly relates to the use and coverage of preventive strategies including education and awareness of the importance of folic acid intake among women of reproductive age, access to and/or distribution of pre-pregnancy folic acid supplements, and/or fortification of staple foods with folic acid, in some cases with mandatory regulations for fortification of foods such as wheat and maize flour (CDC 2008b). Recent evidence demonstrates that public health policies which include folic acid fortification of staple foods are likely to result in a large-scale prevention of NTDs (Botto 2005; De Wals 2007; Berry 2010). It would seem reasonable to implement both interventions fully, especially in countries with a high prevalence of birth defects.

Several gene polymorphisms affect folate metabolism and are associated with reduced folate absorption and therefore increased folate needs. Some of the most studied mutations are the methylene-tetrahydrofolate reductase (MTHFR) gene and the reduced folate carrier (RFC1) gene (Chango 2000). The former affects 8% to 35% of the population, depending on ethnicity (Botto 2000; Guéant-Rodriguez 2006). In the absence of a folate-sufficient diet, these mutations are associated with increased risk of NTDs and conotruncal defects in the offspring (Van der Put 1998; Van Beynum 2006).

Folic acid intake may also affect fetal and child growth. Observational and controlled trials have showed a positive effect of periconceptional folic acid supplementation on fetal growth (Iyengar 1975; Relton 2005; Rolschau 1999), although the evidence for this association remains controversial.

Description of the intervention

In 1992, after evidence establishing the protective effect of folic acid supplementation against the first occurrence of NTDs emerged, the United States Public Health Service recommended daily supplementation with 400 µg of folic acid for all women of reproductive age (CDC 1992). The US Preventive Services Task Force (USPSTF) recommends that all women planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid (US Preventive Services Task Force 2009). The World Health Organization recommends that women take 400 µg of folic acid from the moment they are trying to conceive until 12 weeks of pregnancy (WHO 2006). For women with a history of delivery of a baby with a NTD, have diabetes, or are receiving an anticonvulsant treatment, the recommended daily dose is 5 mg of folic acid in addition to dietary advice to increase food folate intake (IOM 2003; WHO 2006). Daily supplementation with 400 µg of folic acid in addition to iron is routinely recommended for all pregnant women (universal supplementation) to prevent anaemia (WHO/UNICEF/UNU 2001). The World Health Organization (WHO) also recommends weekly iron and folic acid supplementation (containing 2.8 mg of folic acid per week) in population groups where the prevalence of anaemia is above 20% among women of reproductive age, and where mass fortification programs of staple food-stuffs with iron and folic acid are unlikely to be implemented within the next one to two years (WHO 2009). The evidence of the effectiveness of the folic acid content of the supplements in a weekly regimen is limited, and little attention was given to the change in folic acid intake when supplements were given on a weekly as opposed to daily basis. 

Recently, the use of 5-methyl-tetrahydrofolate (5-MTHF) has been proposed as an alternative to folic acid supplementation. The rationale for this is that most dietary folate and folic acid are metabolised to 5-MTHF during its passage across the intestinal mucosa. The 5-MTHF may be an adequate alternative for supplementation in the presence of MTHFR gene mutation. Four controlled trials using different doses have shown that supplementation with 5-MTHF is at least as effective as folic acid in improving folate status in women of childbearing age (Houghton 2006; Lamers 2004; Venn 2002; Venn 2003). This form of folate may also be less likely to mask haematological symptoms of severe vitamin B12 deficiency and it exhibits a lower interaction potential with antifolate antimalarial drugs (Nduati 2008; Pietrzik 2010), specifically sulphadoxine-pyrimethamine (SP), which might be affected by folic acid supplementation (Carter 2005; English 2006; Van Eijk 2008).

How the intervention might work

The main function of folate is as coenzyme in one-carbon transfer during the methylation cycle, a process essential for the syntheses of nucleic acids, which form part of DNA and the neurotransmitters. From these reactions it is immediately apparent why folate is so important to gene expression. Folate also plays an important role in protein synthesis and metabolism and other processes related to cell multiplication and tissue growth (WHO 2008). The main consequence of folate deficiency in adults is megaloblastic anaemia, characterised by abnormally large red-cell precursors in the bone marrow and larger than normal red cells in the peripheral blood.

The methylation of homocysteine to produce methionine (both essential amino acids) uses 5-MTHF as the methyl donor in the reaction. In folate deficiency, homocysteine accumulates in the serum resulting in negative effects for health. Elevated circulating homocysteine concentrations have been associated with an increased risk in cardiovascular disease (Refsum 2008) and late pregnancy complications such as pre-eclampsia (Makedos 2007; Patrick 2004; Tamura 2006), and possibly NTDs. Therefore, elevated plasma homocysteine may be a risk factor or, alternatively, merely a marker of risk (WHO 2008).

From the safety perspective, an observational study on the fetal origins of disease has proposed that normal to high maternal folate status coupled with low vitamin B12 status was associated with higher adiposity and insulin resistance in Indian babies (Yajnik 2008) which could probably have a long-term effect in the fetus later in life. Additional potentially undesired effects of folic acid supplementation come from the possible association of the use of multivitamins containing folic acid and an increase in twin pregnancies (Vollset 2005) as well as the ambiguous findings on the effects of folic acid supplementation on colonic lesions (Fife 2009; Jaszewski 2008; Wu 2009).

Why it is important to do this review

There seems to be sufficient evidence of known benefits of folic acid supplementation on NTDs (Lumley 2001) but not on other birth defects or on benefits to the mother. Furthermore, the best scheme (daily versus weekly), dose and/or form (5-MTHF versus folic acid) for providing folate supplements to women of childbearing age or during the periconceptional period are not yet established. It is also not known whether supplementation is of any benefit in places where wheat or maize flour fortification is mandatory and has proven to be effective for reducing NTDs rates. Additionally, concerns raised by some authors about the potential harm associated with high intake of folic acid merit exploration (Cole 2007; Mason 2007). This review aims to assess the evidence to respond these questions.

Objectives

This review updates the previous systematic review assessing the effects of periconceptional supplementation of folic acid to reduce neural tube defects (Lumley 2001) and aims to examine whether periconceptional folate supplementation can reduce the risk of neural tube and other birth defects (including cleft palate) without causing adverse outcomes for mothers or babies.

Methods

Criteria for considering studies for this review

Types of studies

We have included both randomised and quasi-randomised trials. We had planned to include cluster-randomised trials if they were otherwise eligible. Other levels of evidence (e.g. cohort or case-control studies) have not been included in meta-analyses nor have they contributed to the results or conclusions, but we have considered such evidence in the discussion where relevant.

Types of participants

We included studies with women who become pregnant or were 12 or less weeks' pregnant at the time of the intervention, independent of age and parity. We have included studies focusing on women who have had a previous pregnancy affected by a neural tube defect. We excluded women who continued supplementation throughout pregnancy as the effectiveness of oral folate supplementation alone during pregnancy on haematological and biochemical parameters during pregnancy and on pregnancy outcomes are evaluated in another Cochrane Review (Haider 2008).

Types of interventions

We have included a range of interventions including supplementation with folic acid alone (FA) and with other vitamins and minerals. We have included studies where supplementation is offered in the periconceptional period and during early pregnancy. Where data were available we planned to compare:

  • supplementation with FA versus no treatment/placebo/other micronutrients without folic acid;

  • supplementation with FA alone versus no treatment/placebo;

  • supplementation with FA + other micronutrients versus no treatment/placebo;

  • supplementation with FA + other micronutrients versus other micronutrients (without folic acid);

  • supplementation with 5-methyl-tetrahydrofolate (5MTHF) alone versus no treatment/placebo;

  • supplementation with 5MTHF + micronutrients versus no treatment/placebo;

  • supplementation with 5MTHF + micronutrients versus other micronutrients (without 5MTHF);

  • supplementation with 5MTHF versus supplementation with FA.

Types of outcome measures

Primary outcomes
Infant
  • Neural tube defects

  • Cleft lip  

  • Cleft palate

  • Congenital cardiovascular defects

  • Other birth defects (excluding neural tube defects, cleft lip, cleft palate and cardiovascular defects)

Maternal
  • Anaemia at term (defined as Hb less than 110 g/L)

  • Red blood cell folate at term (nmol/L)

  • Serum folate at term (nmol/L)

  • Miscarriage (as defined by trialists)

Secondary outcomes
Infant
  • Stillbirths (as defined by trialists)

  • Neonatal deaths (death occurring in days 0 to 28 of life)

  • Pregnancy termination for fetal abnormality (as defined by trialists)

  • Low birthweight (less than 2500 g)

  • Very low birthweight (less than 1500 g)

  • Infant optimal health status at birth (as defined by trialists)

  • Admission to special care for any cause (as defined by trialists)

  • Macrosomia (greater than 4000 g)

  • Infant insulin resistance (as defined by trialists)

  • Apgar at one minute after birth (8 or greater)

  • Apgar score at five minutes after birth (8 or greater)

  • Preterm birth (less than 37 weeks' gestation)

Maternal
  • Multiple pregnancy (2 or more fetuses at birth)

  • Homocysteine at term (µmol/L)

  • Serum vitamin B6 concentration at term (nmol/L)

  • Plasma or serum vitamin B12 concentration at term (pmol/L)

  • Pre-eclampsia (defined as gestational hypertension (blood pressure higher than 140/90 mmHg and proteinuria (more than 300 mg of protein in a 24-hour urine sample)

  • Any side effects (as defined by trialists)

Search methods for identification of studies

Electronic searches

We contacted the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register (July 2010). 

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. handsearches of 30 journals and the proceedings of major conferences;

  4. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords. 

Searching other resources

We contacted the World Health Organization, Centers for Disease Control and Prevention (CDC), and the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS) to identify ongoing studies and unpublished reports (correspondence is available upon request).

The international clinical trials registry platform (ICTRP) was also searched for any ongoing or planned trials. We did not apply any language restrictions.

Data collection and analysis

Selection of studies

One review author (LMR) screened all the titles and abstracts of all references identified as a result of the search strategy while JPR, AFG, and TD each assessed each a third. We resolved any disagreement through discussion.

In this version of the review all studies were reported in journal articles. In updates of the review if we identify trials published only as abstracts, or study reports containing insufficient information on methods, we will attempt to contact the trial authors to obtain further details of study design and results; if there is insufficient information for us to be able to assess risk of bias, studies will await assessment until further information is published, or made available to us.

Data extraction and management

We designed a form to extract data. For eligible studies, two review authors (TD, AFG) extracted the data using the agreed form. We resolved discrepancies through discussion. We entered data into Review Manager software (RevMan 2008) and TD and LMR carried out checks for accuracy.

When information regarding any of the above was unclear, we attempted to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). We resolved any disagreement by discussion or by involving a third assessor.

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

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

We assessed the method as:

  • adequate (any truly random process, e.g. random number table; computer random number generator);

  • inadequate (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear.   

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

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

We assessed the methods as:

  • adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear.   

(3) Blinding (checking for possible performance bias)

We have described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. For interventions involving the provision of nutritional supplements it may be possible to blind women, clinical staff and outcome assessors to group allocation by providing placebo preparations. Blinding has been assessed separately for different outcomes or classes of outcomes, and we have indicated where there was partial blinding (e.g. of outcome assessors).

We assessed the methods as:

  • adequate, inadequate or unclear for participants;

  • adequate, inadequate or unclear for personnel;

  • adequate, inadequate or unclear for outcome assessors.

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

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

Assessing bias associated with incomplete data may be particularly difficult in this topic area as the intervention may take place many months (or indeed years) before outcomes are assessed, and not all of those randomised may be eligible for all outcomes. For example, women randomised to receive supplements before conception may not become pregnant and therefore cannot experience outcomes that occur during pregnancy (such as miscarriage), or at birth (low birthweight infant). We decided that we would take a pragmatic approach and include in the denominators for pregnancy outcomes only for those women who became pregnant, rather than all women randomised. We are aware that this may introduce a serious source of bias, and we will note those outcomes likely to be affected by this, and advise caution in the interpretation of results.

We assessed methods as:

  • adequate;

  • inadequate;

  • unclear.

(5) Selective reporting bias

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

We assessed the methods as:

  • adequate (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study failed to include results of a key outcome that would have been expected to have been reported);

  • unclear.

(6) Other sources of bias

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

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

  • yes;

  • no;

  • unclear.

(7) Overall risk of bias

We made explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings.  We planned to explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratio with 95% confidence intervals. 

Continuous data

For continuous data, we used the mean difference if outcomes were measured in the same way between trials. We used the standardised mean difference to combine trials that measured the same outcome (e.g. serum folate concentration) but using different methods.  

Unit of analysis issues

Cluster-randomised trials

We planned to include cluster-randomised trials in the analyses along with individually-randomised trials. If in the future we identify any such trials, in updates of this review we will adjust the standard error of the effect estimate from cluster trials using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Meta-analyses will be carried out using the generic inverse-variance method available in RevMan (RevMan 2008). We will use an estimate of the intra cluster correlation co-efficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources are used, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs, and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a separate meta-analysis.

Cross-over trials

Cross-over trials are not an appropriate study design for the interventions considered in this review and have been excluded.

Studies with more than two treatment groups

For studies with more than two intervention groups (multi-arm studies) in the main analysis (comparison one) we combined groups to create a single pair-wise comparison (Higgins 2008).

Dealing with missing data

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

We planned to carry out analyses, as far as possible, on an intention-to-treat basis, i.e. by attempting to include all participants randomised to each group in the analyses, so the denominator for each outcome in each trial would be the number randomised minus any participants whose outcomes are known to be missing. In those studies where women were recruited before conception for outcomes relating to pregnancy we have taken a pragmatic approach and included in the denominators only those women known to become pregnant.

Assessment of heterogeneity

We examined the forest plots from meta-analysis to look for heterogeneity among studies, and used the I² and T² statistics to quantify the level of heterogeneity among the trials in each analysis. If we identified substantial heterogeneity (I² greater than approximately 50%) we noted this in the text and explored it by pre-specified subgroup analysis. We would advise caution in the interpretation of those results where there are high levels of unexplained heterogeneity.

Assessment of reporting biases

Where we suspected reporting bias (see 'Selective reporting bias' above) we attempted to contact study authors, asking them to provide missing outcome data. We have not explored possible publication bias by producing funnel plots as too few studies contributed data to the review.

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2008). We have used fixed-effect meta-analysis for combining data where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar. Where we suspected clinical or methodological heterogeneity between studies sufficient to suggest that treatment effects might differ between trials we repeated the analysis using a random-effects model.

Subgroup analysis and investigation of heterogeneity

Where data were available we had planned to carry out subgroup analysis for primary outcomes:

  1. by scheme: daily supplementation versus weekly supplementation;

  2. by dose: 400 µg/d or less of folic acid versus more than 400 µg folic acid per day;

  3. by start of supplementation: before pregnancy versus during first trimester versus mixed; 

  4. by assisted reproduction: assisted versus non-assisted reproduction;

  5. by mandatory folic acid fortification: places with mandatory flour fortification versus non-flour fortification or not mandatory;

  6. by history of a pregnancy affected by a neural tube defect (recurrence): yes versus no.

We planned that for both fixed- and random-effects meta-analyses we would examine differences between subgroups by inspection of the subgroup confidence intervals; non-overlapping confidence intervals indicating a statistically significant difference in treatment effect between the subgroups. We carried out few random-effects analyses as levels of heterogeneity were generally low.

Sensitivity analysis

We planned to carry out sensitivity analysis to examine the effects of removing studies at high risk of bias (studies with poor allocation concealment) from the analysis. In this version of the review none of the trials were assessed as having poor allocation concealment.

If, in updates of the review, cluster trials are included we will carry out sensitivity analysis using a range of intra cluster correlation values.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

Results of the search

The search strategy retrieved 117 references corresponding to 59 trials. Five trials (31 references) were included and one trial is still ongoing and its results are expected in 2011 (see Characteristics of ongoing studies).

Included studies

We included five trials involving 6105 women in the review, all of which met the pre-stated inclusion criteria. Most of the studies focused on infant outcomes and few of the results reported related to the maternal outcomes we had pre-specified in the protocol. All of the studies that we included were published before 2001. In all of them women were supplemented daily; in one trial women received less than 400 µg (0.4 mg) of folic acid per day (Kirke 1992), while in the remaining studies women consumed 800 µg (0.8 mg) (Czeizel 1994); 2000 µg (2.0 mg) per day (Laurence 1981) and 4000 µg (4.0 mg) per day (ICMR 2000; MRC 1991). In all trials women started supplementation before pregnancy and discontinued it after 12 weeks of pregnancy. Sample sizes varied among studies. All trials focused on the prevention of neural tube defects; four trials evaluated recurrence (ICMR 2000; Kirke 1992; Laurence 1981; MRC 1991) and only one occurrence (Czeizel 1994). Of the 6105 women included in the review, 1949 had a history of NTDs and 4156 had no history.

One trial compared folic acid supplementation with a placebo group (Laurence 1981), two trials compared folic acid plus multiple micronutrients versus multiple micronutrients (Czeizel 1994; ICMR 2000) although the control groups received different formulations. One trial included four comparison groups: one with folic acid with iron and calcium, one with folic acid plus iron, calcium and multiple micronutrients, another with iron, calcium and multiple micronutrients without folic acid and a control group that only received iron and calcium but did not receive multiple micronutrients nor folic acid (MRC 1991). In this study the iron and calcium in the capsules was provided as ferrous sulphate and dicalcium phosphate. In the another included study (Kirke 1992) there were three comparison groups: one with folic acid; another with multiple micronutrients and another with multiple micronutrients and folic acid. The allocation of women to the control group in this study (Kirke 1992) was not randomised but the comparison was still included in the analyses.

We did not identify any randomised controlled trials which examined either weekly supplementation or the use of 5-MTHF.

Excluded studies

We excluded 53 trials: 41 trials because their study design or scope did not match the objectives of this review; three trials reported studies performed in non-pregnant women; one trial was a non-randomised clinical trial, and eight trials were on folic acid supplementation that started in the first trimester of gestation and continued throughout pregnancy.

See Characteristics of excluded studies tables for a detailed description of the studies and the reasons for exclusion.

Risk of bias in included studies

Allocation

Sequence generation: Three trials adequately randomised the participants to the treatment groups (Czeizel 1994; Kirke 1992; Laurence 1981); one of them used block randomisation (Kirke 1992). Two multicentre trials did not report or did not state clearly the method used to generate the randomisation sequence (ICMR 2000; MRC 1991).

Allocation concealment: Two trials reported using sealed envelopes, opaque bottles or similar pills when doing the allocation of the women to treatment groups (ICMR 2000; Kirke 1992). In this last study pills were changed after one year resulting in a partial loss of blinding. The three remaining studies were reported as blinded, but were unclear in their method of concealment of treatment allocation.

Blinding

All of these trials were described as "double-blind" although it was not clear whether outcome assessors were blind to group allocation. Women in all treatment groups received capsules or tablets containing active treatment ingredients or placebo although it was not always clear whether the preparations were of identical appearance.

Incomplete outcome data

For those women becoming pregnant, loss to follow up ranged from 1% (Czeizel 1994; MRC 1991) to 20% (Kirke 1992). The remaining two trials lost less than 10% of the randomised participants.

We noted in the methods section above that for pregnancy outcomes we would include in the denominators only those women with confirmed pregnancies. In all studies women were randomised before conception and not all women became pregnant. For example, in the study by Czeizel 1994 of 7905 randomised, 5502 had confirmed pregnancy (69.6%); so 30% of those randomised did not become eligible to experience pregnancy and birth outcomes. We are aware that this makes results more difficult to interpret. Where data were available, we have provided information on the number of women randomised and the numbers with confirmed pregnancies in the Characteristics of included studies tables.

In some cases we did not find it simple to determine the denominators as detailed information on attrition at different stages was not reported. For some competing/overlapping outcomes (e.g. perinatal deaths, miscarriages and pregnancy termination for fetal abnormality) we have reported figures provided in the trial reports but we advise caution in interpreting such data.

Selective reporting

Assessing selective reporting bias was difficult as we did not have access to study protocols. We were not able to explore possible reporting bias as too few studies have been included to make allow us to carry out meaningful analyses.

Other potential sources of bias

In one study (Czeizel 1994) the randomisation code was broken twice: once to analyse the teratogenic effect of vitamin A and at the end of the trial to analyse the effect of the supplementation. One study (ICMR 2000) was terminated before expected as a consequence of the publication of the results from another trial (MRC 1991); however the calculated sample size was almost achieved.

See Characteristics of included studies tables for assessments of the methodological quality of each included trial and Figure 1 and Figure 2 for summaries of the quality of included studies.

Figure 1.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Effects of interventions

The summary of results is organised by comparisons and by infant and maternal outcomes. See the Data and analyses section for detailed results on primary and secondary outcomes.

Four of the five trials included in the review recruited women with a history of NTDs and subgroup analyses suggested no clear differences in trials examining first occurrence and recurrence of NTDs. However to aid interpretation of results, along with reporting overall findings from trials, we have described the results from the trials examining first occurrence and recurrence of NTDs separately.

(1) Supplementation with folic acid versus any other interventions/placebo (five trials)

Primary outcomes
Infant outcomes
Neural tube defects (NTDs) (all)

Five trials (Czeizel 1994; ICMR 2000; Kirke 1992; Laurence 1981; MRC 1991) with 6105 women examined the prevalence of NTDs in women receiving folic acid supplementation (alone or in combination with other vitamins and minerals) compared with women receiving placebo or other vitamins and minerals (not including folic acid) (Analysis 1.1). In all of these trials, supplementation started before pregnancy, continued throughout the first trimester, and involved daily supplementation. Periconceptional folate supplementation (alone, or in combination with other vitamins and minerals) reduces the prevalence of NTDs in comparison with no intervention, placebo or multiple micronutrients without folic acid (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.15 to 0.52).

Four trials recruited women with a history of NTDs (ICMR 2000; Kirke 1992; Laurence 1981; MRC 1991) and supplementation was associated with a reduction in the recurrence of a pregnancy affected by a NTD (RR 0.32, 95% CI 0.17 to 0.60). In the single trial (4156 women) (Czeizel 1994) recruiting women with no history of NTDs, and examining the first occurrence of NTDs, results favoured the group receiving supplementation, but evidence of a difference between groups did not reach statistical significance (RR 0.08, 95% CI 0.00 to 1.33); however, no cases of NTDs were observed in the supplemented group.

In one of the trials involving 364 women (Kirke 1992) the daily supplementation dose was 360 µg (0.36 mg); while results from this study favoured the intervention group they were not statistically significant (RR 0.12, 95% CI 0.01 to 2.29). In the remaining four trials (Czeizel 1994; ICMR 2000; Laurence 1981; MRC 1991) the daily dose of folic acid was more than 400 µg (0.4 mg) and NTDs were reduced in the intervention group; the difference between treatment groups was statistically significant (RR 0.30, 95% CI 0.16 to 0.56).

Cleft palate

Overall, only three babies were affected with cleft palate in the studies examining this outcome (Czeizel 1994; Kirke 1992; MRC 1991); there was no significant difference between the group receiving folic acid supplementation and controls (RR 0.66, 95% CI 0.11 to 3.92).

Cleft lip

In the three trials (Czeizel 1994; Kirke 1992; MRC 1991) reporting the number of babies affected by cleft lip, there was no evidence of a difference between groups; overall eight babies were affected by cleft lip, four in each treatment group (Analysis 1.5; Analysis 1.6).

Congenital cardiovascular defects

This outcome was reported in three trials (Czeizel 1994; Kirke 1992; MRC 1991). There was no significant evidence of a difference between experimental and control groups in the number of babies with congenital cardiovascular defects irrespective of dose of drug, or history of NTDs (Analysis 1.7; Analysis 1.8).

Other birth defects (excluding NTDs, cleft lip, cleft palate and cardiovascular defects)

Three trials reported the number of babies with other birth defects (Czeizel 1994; Kirke 1992; MRC 1991). Overall, when results from these three trials were pooled there was no significant evidence of a difference between groups (RR 0.72, 95% CI 0.48 to 1.07). However, for this outcome there was high heterogeneity (I2 = 63%) and we repeated the analysis using a random-effects model (average RR 0.81, 95% CI 0.38 to 1.77) and the lack of effect was confirmed. In the Czeizel 1994 trial which recruited women with no history of NTDs, the difference between groups, favouring women in the supplementation group, was statistically significant (RR 0.50, 95% CI 0.30 to 0.84).

Maternal outcomes
Maternal anaemia at term (defined as Hb less than 110 g/L); red blood cell folate at term; serum folate at term

No trials reported on these outcomes.

Miscarriage

All five trials examined the rate of miscarriage in women with confirmed pregnancy receiving daily folic acid supplements compared with controls (Czeizel 1994; ICMR 2000; Kirke 1992; Laurence 1981; MRC 1991); while the number of miscarriages was increased in the group receiving supplements containing folic acid the difference between groups did not reach statistical significance (RR 1.10, 95% CI 0.97 to 1.26). There were no significant differences between experimental and control groups for any of the subgroups we examined (Analysis 1.12).

Secondary outcomes
Infant outcomes
Stillbirths

Stillbirths were reported in four trials (Czeizel 1994; ICMR 2000; Kirke 1992; MRC 1991). There was no significant evidence of any difference between treatment groups in the pooled analysis (RR 0.96, 95% CI 0.51 to 1.83), or in any subgroup analyses (Analysis 1.14).

Pregnancy termination for fetal abnormality

Overall, in the four studies examining this outcome (Czeizel 1994; ICMR 2000; Laurence 1981; MRC 1991) there were 58 pregnancies terminated for fetal abnormality; 13/2978 in the experimental group and 45/2930 in the control group. The difference between groups was statistically significant in the pooled analysis (RR 0.30, 95% CI 0.16 to 0.54). In all of these studies daily supplementation was greater than 400 µg (0.4 mg) and women started supplements before pregnancy.

Low birthweight (less than 2500 g)

The number of babies with low birthweight was examined in one trial (186 babies) (ICMR 2000). There was no significant evidence of a difference between treatment groups (Analysis 1.19).

Other infant outcomes

No trials reported results for our other pre-specified secondary outcomes:

  • Very low birthweight (less than 1500 g)

  • Infant optimal health status at birth (as defined by trialists)

  • Neonatal deaths

  • Admission to special care for any cause (as defined by trialists)

  • Macrosomia (less than 4000 g)

  • Infant insulin resistance (as defined by trialists)

  • Apgar at one minute after birth (8 or greater)

  • Apgar score at five minutes after birth (8 or greater)

  • Preterm birth (less than 37 weeks' gestation)

  • Long-term outcomes (as defined by trialists)

Maternal
Multiple pregnancy  

The number of women affected by multiple pregnancy was examined in three trials (Czeizel 1994; ICMR 2000; MRC 1991). Overall, there was no evidence of any significant difference between women receiving supplements with folic acid and those in the controls (RR 1.32, 95% CI 0.88 to 1.98), nor was there evidence of differences between treatment groups in the subgroups we examined (Analysis 1.16).

Side effects

Only one study reported findings on side effects like nausea, vomiting, constipation or diarrhoea (Czeizel 1994) and the number of reported cases was very low in both the group of women receiving folic acid with multiple micronutrients and the control group during the pre-pregnancy and pregnancy period.

Other maternal outcomes

No trials reported on our other pre-specified secondary outcomes:

  • Homocysteine at term (µmol/L)

  • Serum vitamin B6 concentration at term (nmol/L)

  • Plasma or serum vitamin B12 concentration at term (pmol/L)

  • Pre-eclampsia (defined as gestational hypertension (blood pressure higher than 140/90 mmHg) and proteinuria (more than 300 mg of protein in a 24-hour urine sample)

(2) Supplementation with folic acid alone versus no treatment/placebo (two trials)

Primary outcomes
Infant outcomes
NTDs (all)

In two trials (Kirke 1992; Laurence 1981) involving 299 women, supplementation in the experimental group was with folic acid alone (rather than with folic acid plus other vitamins and minerals). Overall, the prevalence of NTDs was lower in the group receiving folic acid supplementation compared with controls; the difference between groups was statistically significant (RR 0.32, 95% CI 0.08 to 1.34). In all of these trials women had a history of a pregnancy affected by a NTD, supplementation started before pregnancy, continued throughout the first trimester, and involved daily supplementation.

One of the trials (Kirke 1992) involved a lower dose of folic acid (360 µg). In this study the difference between groups was not significant (Kirke 1992) for this outcome.

Cleft palate

In the only study reporting this outcome, with 188 women (Kirke 1992), there were no cases affected by a cleft palate (Analysis 2.3).

Cleft lip

No babies were affected with cleft lip in the only study reporting this outcome (Kirke 1992).

Congenital cardiovascular defects

This outcome was reported in one trial (Kirke 1992). Only one baby in the no treatment/placebo group was affected with a congenital cardiovascular defect (Analysis 2.7).

Maternal outcomes
Maternal anaemia at term (defined as Hb less than 110 g/L); red blood cell folate at term; serum folate at term

No trials reported on these outcomes.

Miscarriage

Two trials (299 women) examined the rate of miscarriage in women with confirmed pregnancies receiving folic acid supplements compared with controls (Kirke 1992; Laurence 1981); there was no significant evidence of a difference between treatment groups in the number of women having miscarriage (Analysis 2.11).

Secondary outcomes
Infant outcomes
Stillbirths

Stillbirths were reported in one trial (Kirke 1992). Overall there were four stillbirths in the no treatment/placebo group; the difference between groups was not statistically significant (RR 0.13, 95% CI 0.01 to 2.46).

Pregnancy termination for fetal abnormality

One study contributed data to this analysis (Laurence 1981); the number of pregnancy terminations for fetal abnormality was reduced in the folic acid group. The difference was not statistically significant (RR 0.28, 95% CI 0.06 to 6.83).

Other infant outcomes

No trials reported on our other pre-specified secondary outcomes.

Maternal

No trials reported on our pre-specified secondary outcomes:

(3) Supplementation with folic acid + other micronutrients versus no treatment/placebo (one trial)

Primary outcomes
Infant outcomes
NTDs (all)

One trial (Kirke 1992) involving 190 women contributed data to this comparison. The dose of folic acid was 360 µg (Kirke 1992). The risk of NTDs was lower in the group receiving supplementation with folic acid and other micronutrients compared with controls (RR 0.17, 95% CI 0.01 to 3.22). In this trial, women had a history of a pregnancy affected by a NTD, supplementation started before pregnancy, continued throughout the first trimester, and involved daily supplementation.

Cleft palate and cleft lip

No babies included in the comparison were affected by cleft lip or palate (Analysis 3.3; Analysis 3.5).

Congenital cardiovascular defects

This outcome was reported in one trial (Kirke 1992). There was only one baby (in the no treatment/placebo group) affected by a congenital cardiovascular defect (Analysis 3.7).

Other birth defects (excluding neural tube defects, cleft lip, cleft palate and cardiovascular defects)

Other birth defects were reported in one trial (Kirke 1992). There were two defects in the folic acid group (2/87) and two the control group (2/103) and the difference between groups was not statistically significant (RR 1.18, 95% CI 0.17 to 8.23).

Maternal outcomes
Maternal anaemia at term (defined as Hb less than 110 g/L); red blood cell folate at term; serum folate at term

No trials reported on these outcomes.

Miscarriage

There were two cases of confirmed pregnancy suffering miscarriage among the women who received the folic acid and none in the women who received no treatment/placebo (2/87 in the folic acid group compared with 0/103 in the no treatment/placebo group) although the difference between groups did not achieve statistical significance (RR 5.91, 95% CI 0.29 to 121.46). (Analysis 3.11).

Secondary outcomes
Infant outcomes
Stillbirths

Stillbirths were reported in one trial (Kirke 1992). Overall there were four stillbirths, all in the no treatment/placebo group. However, there was no significant evidence of any difference between groups (RR 0.13, 95% CI 0.01 to 2.41).

Other infant outcomes

No trials reported on our other pre-specified secondary outcomes.

Maternal

No trials reported on our pre-specified maternal secondary outcomes.

(4) Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid) (four trials)

Primary outcomes
Infant outcomes
NTDs (all)

Four of the trials (Czeizel 1994; ICMR 2000; Kirke 1992; MRC 1991) (5806 women) included comparisons of women receiving folic acid with other micronutrients compared with women receiving other micronutrients without folic acid. There was a statistically significant difference between groups favouring those who received the folic acid supplementation (RR 0.29, 95% CI 0.15 to 0.56). In all of these trials supplementation started before pregnancy, continued throughout the first trimester, and involved daily supplementation.

Results in subgroups are identical or similar to those in comparison one.

Cleft palate

Two babies (both in the control group) were affected with cleft palate in the three studies examining this outcome (Czeizel 1994; Kirke 1992; MRC 1991); the difference between groups was not statistically significant (RR 0.66, 95% CI 0.11 to 3.92).

Cleft lip

In the three trials (Czeizel 1994; Kirke 1992; MRC 1991) reporting the number of babies affected by cleft lip, there was no evidence of a difference between groups; overall eight babies were affected by cleft lip, four in each treatment group (Analysis 4.5).

Congenital cardiovascular defects

This outcome was reported in three trials (Czeizel 1994; Kirke 1992; MRC 1991). There was no statistically significant evidence of a difference between experimental and control groups in the number of babies with congenital cardiovascular defects irrespective of dose of drug, or history of NTDs (Analysis 4.7).

Other birth defects (excluding neural tube defects, cleft lip, cleft palate and cardiovascular defects)

Three trials reported the number of babies with other birth defects (Czeizel 1994; Kirke 1992; MRC 1991). There was no significant evidence of a difference between groups (RR 0.75, 95% CI 0.50 to 1.12). In the Czeizel 1994 trial which recruited women with no history of NTDs, the difference between groups, favouring women in the folate supplementation group, was significant (RR 0.53, 95% CI 0.31 to 0.89).

Maternal outcomes
Maternal anaemia at term (defined as Hb less than 110 g/L); red blood cell folate at term (nmol/L); serum folate at term (nmol/L)

No trials reported on these outcomes.

Miscarriage

Four trials reported the number of women with confirmed pregnancy suffering miscarriage (Czeizel 1994; ICMR 2000; Kirke 1992; MRC 1991); while the number of miscarriages was increased in the group receiving folic acid the difference between groups did not reach statistical significance (RR 1.10, 95% CI 0.96 to 1.26). There were no significant differences between experimental and control groups for any of the subgroups we examined (Analysis 4.12).

Secondary outcomes
Infant outcomes
Stillbirths

Stillbirths were reported in four trials included in this comparison (Czeizel 1994; ICMR 2000; Kirke 1992; MRC 1991). There was no significant evidence of any difference between treatment groups in the pooled analysis (RR 1.36, 95% CI 0.68 to 2.75), or in any subgroup analyses (Analysis 4.14).

Pregnancy termination for fetal abnormality

Overall, in the three studies examining this outcome (Czeizel 1994; ICMR 2000; MRC 1991) there were 57 pregnancies terminated for fetal abnormality; 13/2918 in the women who received folic acid with other micronutrients and 44/2879 in the control group who received other micronutrients supplements without folic acid. The difference between groups was statistically significant in the pooled analysis (RR 0.30, 95% CI 0.16 to 0.55).

Low birthweight (less than 2500 g)

The number of babies with low birthweight was examined in one trial (186 babies) (ICMR 2000). There was no significant evidence of a difference between treatment groups (Analysis 4.19).

Other infant outcomes

No trials reported results for our other pre-specified secondary outcomes.

Maternal
Multiple pregnancy  

The number of women affected by multiple pregnancy was examined in three trials (Czeizel 1994; ICMR 2000; MRC 1991). There was no significant evidence of a difference between women in the two treatment groups (RR 1.32, 95% CI 0.88 to 1.98).

Other maternal outcomes

No trials reported on our other pre-specified secondary outcomes.

(5) Supplementation with 5-methyl-tetrahydrofolate (5MTHF) alone versus no treatment/placebo

We did not identify any trials for inclusion in the review which examined this comparison.

(6) Supplementation with 5MTHF + micronutrients versus no treatment/placebo

We did not identify any trials for inclusion in the review which examined this comparison.

(7) Supplementation with 5MTHF + micronutrients versus other micronutrients (without 5MTHF)

We did not identify any trials for inclusion in the review which examined this comparison.

(8) Supplementation with 5MTHF versus supplementation with folic acid

We did not identify any trials for inclusion in the review which examined this comparison.

Discussion

Summary of main results

This review addresses the effects and safety of folic acid supplementation or folic acid with other micronutrients versus no treatment/placebo or other micronutrients (without folic acid) during the periconceptional period and the first trimester of pregnancy. This review updates and extends an earlier Cochrane Review (Lumley 2001).

To reduce the risk of neural tube defects (NTDs) for women capable of becoming pregnant, the recommendation is to take 400 μg of folic acid daily from fortified foods, supplements, or both, in addition to consuming food folate from a varied diet beginning at least one month before conception (IOM 1998; WHO/UNICEF/UNU 2001). Expert panels suggest that supplemental intake in this population should range between 400 μg and 800 μg (US Preventive Services Task Force 2009). The first recommendations were based on the amount needed to maintain an adequate haematological status, and the protective role of folic acid against NTDs was later confirmed with a public health supplementation trial carried out in China from 1993 to 1995 which showed a reduction in the occurrence of neural tube defects (NTDs) of 40% to 85% (from the south and north of the country, respectively) (Berry 1999). The results of this review clearly show that periconceptional folic acid supplementation reduces the recurrence of NTDs and although there is only one trial assessing first time occurrence of NTDs (with wide confidence intervals that cross the null value) no events were found among women supplemented with folic acid (Czeizel 1994). The evidence from early clinical trials designed to study the effect of folic acid supplementation around the time of conception on NTDs is so strong that this probably accounts for why we only found one additional RCT looking at this matter (ICMR 2000) and few observational studies published from 1995 to date that reinforce these findings (US Preventive Services Task Force 2009). There are no trials exploring the effect of 5MTHF during the periconceptional period, but it is very likely that the benefits of this intervention observed during the reproductive age and lactation (Houghton 2006; Lamers 2004) might extend to pregnancy.

Questions remain about the best dose and periodicity of folic supplementation as there is still a high prevalence of birth defects worldwide. Doses ranging from 360 μg (0.36 mg) (Kirke 1992) to 6000 μg (6 mg) (Chen 2008) a day have proven to be effective in preventing both occurrence and recurrence of NTDs; this wide response to supplementation may be determined by the baseline blood folate concentrations in each population. Improving nutrition surveillance in order to find the appropriate dose and supplementation scheme is crucial to promote a cost-effective public health policy that can reach a larger number of people.

It is very likely that the lack of results we observed on maternal and perinatal outcomes was related to the short exposure to the intervention. Currently, the World Health Organization recommends that women receive daily supplements of iron and folic acid throughout pregnancy. Some of the trials excluded in this review, where supplementation started before and continued beyond 12 weeks of pregnancy, showed positive effects on both maternal and infant outcomes and one of them also showed improved survival at seven years of age (Christian 2003). Therefore, it seems adequate to encourage periconceptional plus gestational supplementation to improve perinatal results.

All the trials included in this review were performed before many countries introduced mandatory flour fortification with folic acid. In the US, for example, the flour fortification programme was designed so that typical folic acid intake would be increased by approximately 100 µg/day and that the risk of intakes greater than 1000 µg/day (the FDA's tolerable upper level of daily intake) would be minimal (Daly 1997). Results showed that the typical intake of folic acid from fortified foods is more than twice as high as originally predicted (Quinlivan 2003). Even though the effectiveness of mandatory folic acid fortification programmes has been documented by a decline in the prevalence of NTDs in the United States, Canada, Costa Rica, Chile, and South Africa (Berry 2010), fortified foods (mandatory and not) might be providing relatively large amounts of folic acid to the entire population and some authors have suggested that the recommendation of supplementing 400 µg/day of folic acid in addition to dietary folate to women planning to become pregnant deserves to be reviewed. However, they acknowledge the lack of certainty on the minimum dose of supplemental folic acid that is effective for reducing NTDs occurrence (Dary 2009).

There are no clinical trials that review the effect of weekly periconceptional folate supplementation for the prevention of birth defects. The weekly iron and folic acid supplementation programme (WIFS) studies (WHO 2009) have proven that weekly supplementation is an effective preventive intervention to control iron deficiency among childbearing age women, with good compliance. There is no information on the impact of such schemes on birth defects. Two published studies have evaluated weekly folic acid supplementation before pregnancy (not randomised controlled trials). In the first one, carried out in Mexico, women received 5000 µg (5 mg) folic acid for three months, and their red blood cell and plasma folate concentrations significantly increased (Martinez-de Villareal 2001). This strategy was also associated with a 50% decrease in the incidence of anencephaly and spina bifida cases, and a significant reduction in infant mortality and disability after two years (Martinez-de Villareal 2002). In the second study, conducted in New Zealand, a weekly single supplement of 2800 µg (2.8 mg) of folic acid taken for 12 weeks increased women’s red blood cell folate to concentrations associated with a reduced risk of bearing a child with a NTD (Norsworthy 2004).

New studies have documented that MTHFR polymorphism may be considered a susceptible gene for cardiovascular birth defects (Brandalize 2009; Marinho 2009). If MTHFR is associated with congenital heart defects (i.e. Tetralogy of Fallot), this may in part explain the lack of effect of periconceptional folic acid supplementation on cardiovascular malformations, and may warrant further study for opportunities for preventing other birth defects.

This review found a protective effect against birth defects with the use of folic acid combined with other micronutrients. From a metabolic perspective, it is clear that niacin, thiamin, vitamin B6, and vitamin B12 influence reactions that include folate. The possibility that other micronutrients apart from folic acid may have an additional protective effect has been a matter considered in several more recent studies (Czeizel 2004; Goh 2006; Thompson 2009).

Overall completeness and applicability of evidence

Periconceptional folic acid supplementation has a strong protective effect on the incidence and recurrence of NTDs, but there is not sufficient evidence to assess its effect either on the occurrence or recurrence of other defects at birth, nor on most maternal primary and secondary outcomes.

The force of the results makes this an intervention that can be applied in most settings for reducing NTDs rates. However, the women in the trials included in this review had Caucasian, Anglo-Saxon, Anglo-American and Indian backgrounds and the evidence suggests that the presence of gene polymorphisms (i.e. MTHFR gene mutation) is more prevalent among people of Latin origins (Guéant-Rodriguez 2006), thus the findings may slightly differ across all population groups. Also, there is still a need to understand the applicability of these results in endemic malaria regions where antifolate antimalarial drugs are being used, and in women living with HIV/AIDS, receiving or not receiving antiretroviral therapy.

Women in the trials included in this review were actively planning pregnancy and attending for preconception care. It is estimated that 80 million women each year have unwanted or unintended pregnancies (Glasier 2006), and women seeking preconception care may be more affluent and more educated, or be seeking care as they are at high risk after previous pregnancy complications (Czeizel 1999b; Elsinga 2006). These women may be more likely to comply with prescribed supplementation schemes, and the same level of compliance and effect may not be achieved by other groups.

Quality of the evidence

The included trials were rated of medium to high quality in terms of allocation concealment and blinding, and pooling results in meta-analysis resulted in fairly low levels of between-study heterogeneity. Having said this, in trials where only a subset of the original randomised sample became eligible to experience many of the outcomes measured, results may be at risk of bias and not simple to interpret. In all the trials included in this review, studies recruited non-pregnant women (albeit women that may have been planning pregnancy) and inevitably only a proportion of those randomised had confirmed pregnancy during the study periods. As the focus of the review was on pregnancy outcomes, we decided that denominators would include only those women who became pregnant.

Restricting the analyses to pregnant women may have led to the size of the treatment effect for some outcomes being either over or under-estimated. It is possible that women who became pregnant may have been different in a number of respects from those that did not, and that the intervention may have had a different effect on those women that did or did not become pregnant. It is possible that the intervention may have an impact on the ability to become pregnant or to sustain a pregnancy during the very early stages (before pregnancy confirmation) although there is no strong evidence from the studies included in this review or in the literature to suggest that this was likely to have been the case. One study (Czeizel 1994) suggested small but statistically significant differences in confirmed pregnancy rates in women in the intervention and control groups (71.3% versus 67.9% respectively); however, this finding may have occurred by chance or been confounded by the use of in vitro fertilisation by some women (Berry 2004). The possible difference between groups in one trial (Czeizel 1994) was not borne out in other studies examining conception rates in the two treatment groups as the numbers of women with confirmed pregnancy were very similar in intervention and control groups (ICMR 2000; Kirke 1992; MRC 1991).

Interpreting the results from the review for potentially overlapping outcomes may not be straightforward and there was insufficient information in trial reports for us to be clear about whether outcomes were mutually exclusive. It was likely, but not certain, that the same fetus may have been counted in more than one outcome. For example, where NTDs were detected, these same pregnancies may have been included in the figures for pregnancy termination, but we cannot assume that all detected abnormalities led to pregnancy termination. Results for outcomes such as pregnancy termination for fetal abnormality therefore need to be interpreted with caution.

Potential biases in the review process

There were a number of potential biases in the review process. We attempted to minimise bias in several ways: two review authors independently assessed eligibility for inclusion, and data extraction, assessments of risk of bias and data entry were checked by two authors. However, carrying out reviews is not an exact science and may require a number of subjective judgements; it is possible that a different review team may have reached different decisions regarding assessments of eligibility and risk of bias. We would encourage readers to examine the Characteristics of included studies tables to assist in the interpretation of results.

Agreements and disagreements with other studies or reviews

The findings of the review are consistent with those of the previous Cochrane Review (Lumley 2001). As we have noted, the evidence from randomised trials provides only part of the available evidence in this matter. While the evidence from trials indicates the value of folate in the prevention and recurrence of neural tube defects, evidence from case-control and other types of studies provides additional evidence on population-wide supplementation schemes, and recent research is throwing some light on the most appropriate dosing regimens to achieve the greatest health gain for mothers and babies.

Authors' conclusions

Implications for practice

The beneficial effects of folic acid supplementation for preventing birth defects depend on the timing of the intervention (before pregnancy and up to 12 weeks of pregnancy). Adequate targeting is needed to ensure the effectiveness of periconceptional folate supplementation for the prevention on birth defects.

Implications for research

The included trials were published before international recommendations for periconceptional folic acid supplementation emerged. There is a need for clinical trials using the current internationally recommended doses to determine the effect of folic acid supplementation on birth defects. Considering the high compliance of the weekly supplementation regimen, it is worth considering. Recent studies suggest periconceptional micronutrient supplementation may have a potential protective effect against paediatric cancers and folic acid may be conferring the protective effect (Goh 2007); these areas also merit further research attention.

Acknowledgements

As part of the pre-publication editorial process this protocol has been commented on by three peers (an editor and two referees who are external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser. We would also like to thank Dr Robert J Berry and Dr Rafael Flores-Ayala from the US Centers for Disease Control and Prevention for their thorough comments on this review.

Data and analyses

Download statistical data

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)5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Daily supplementation scheme56105Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.15, 0.52]
2.2 Dose of 400 µg or less1364Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.01, 2.29]
2.3 Dose of more than 400 µg45741Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.56]
2.4 Started pre-pregnancy and continued during the first trimester56105Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.15, 0.52]
2.5 History of NTDs41949Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.17, 0.60]
2.6 No history of NTDs or unknown14156Risk 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)3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Daily supplementation scheme35715Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]
4.2 Dose of 400 µg or less1364Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.3 Dose of more than 400 µg25351Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]
4.4 Started pre-pregnancy and continued during first trimester35715Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]
4.5 History of NTDs21559Risk Ratio (M-H, Fixed, 95% CI)3.05 [0.12, 74.61]
4.6 No history of NTDs or unknown14156Risk 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)3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Daily supplementation scheme35715Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.27, 3.74]
6.2 Dose of 400 µg or less1364Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.02, 9.07]
6.3 Dose of more than 400 µg25351Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.29, 5.80]
6.4 Started pre-pregnancy and continued during first trimester35715Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.27, 3.74]
6.5 History of NTDs21559Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.02, 9.07]
6.6 No history of NTDs or unknown14156Risk 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)3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 Daily supplementation scheme35715Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.27, 1.14]
8.2 Dose of more than 400 µg25351Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.28, 1.26]
8.3 Dose of 400 µg or less1364Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.01, 4.62]
8.4 Started pre-pregnancy and continued35715Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.27, 1.14]
8.5 History of NTDs21559Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.07, 3.14]
8.6 No history of NTDs or unknown14156Risk 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)3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 Daily supplementation scheme35715Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.48, 1.07]
10.2 Dose of 400 µg or less1364Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.19, 3.69]
10.3 Dose of more than 400 µg25351Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.47, 1.07]
10.4 Started pre-pregnancy and continued during the first trimester35715Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.48, 1.07]
10.5 History of NTDs21559Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.67, 2.48]
10.6 No history of NTDs or unknown14156Risk 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)5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
12.1 Daily supplementation scheme57618Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.97, 1.26]
12.2 Dose of 400 µg or less1364Risk Ratio (M-H, Fixed, 95% CI)1.37 [0.68, 2.77]
12.3 Dose of more than 400 µg47254Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.96, 1.25]
12.4 Started pre-pregnancy and continued during first trimester57618Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.97, 1.26]
12.5 History of NTDs42116Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.79, 1.30]
12.6 No history of NTDs or unknown15502Risk 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)4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
14.1 Daily supplementation45994Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.51, 1.83]
14.2 Dose of 400 μg or less1364Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.00, 1.51]
14.3 Dose of more than 400 μg35630Risk Ratio (M-H, Fixed, 95% CI)1.38 [0.68, 2.81]
14.4 Started pre-pregnancy and continued45994Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.51, 1.83]
14.5 History of NTDs31838Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.25, 1.57]
14.6 No history of NTDs or unknown14156Risk 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)3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
16.1 Daily supplementation scheme36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]
16.2 Dose of 400 μg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.3 Dose of more than 400 μg36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]
16.4 Started pre-pregnancy and continued during first trimester36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]
16.5 History of NTDs21472Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.38, 2.70]
16.6 No history of NTDs or unknown14767Risk 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)4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
18.1 Daily supplementation scheme45908Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.54]
18.2 Dose of 400 μg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
18.3 Dose of more than 400 μg45908Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.54]
18.4 Started pre-pregnancy and continued during first trimester45908Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.54]
18.5 History of NTDs31752Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.16, 0.65]
18.6 No history of NTDs or unknown14156Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
20.1 Daily supplementation scheme1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]
20.2 Dose of 400 μg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.3 Dose of more than 400 μg1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]
20.4 Started pre-pregnancy and continue during first trimester1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]
20.5 History of NTDs1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]
20.6 No history of NTDs or unknown00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
Analysis 1.1.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 1 Neural tube defects (ALL).

Analysis 1.2.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 2 Neural tube defects (by subgroups).

Analysis 1.3.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 3 Cleft palate (ALL).

Analysis 1.4.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 4 Cleft palate (by subgroups).

Analysis 1.5.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 5 Cleft lip (ALL).

Analysis 1.6.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 6 Cleft lip (by subgroups).

Analysis 1.7.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 7 Congenital cardiovascular defects (ALL).

Analysis 1.8.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 8 Congenital cardiovascular defects (by subgroups).

Analysis 1.9.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 9 Other birth defects (any) (ALL).

Analysis 1.10.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 10 Other birth defects (by subgroups).

Analysis 1.11.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 11 Miscarriage (ALL).

Analysis 1.12.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 12 Miscarriage (by subgroups).

Analysis 1.13.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 13 Stillbirth (ALL).

Analysis 1.14.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 14 Stillbirth (by subgroups).

Analysis 1.15.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 15 Multiple pregnancy (ALL).

Analysis 1.16.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 16 Multiple pregnancy (by subgroups).

Analysis 1.17.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 17 Pregnancy termination for fetal abnormality (ALL).

Analysis 1.18.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 18 Pregnancy termination for fetal abnormality (by subgroups).

Analysis 1.19.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 19 Low birthweight (ALL).

Analysis 1.20.

Comparison 1 Supplementation with folic acid versus no treatment/other micronutrients/placebo, Outcome 20 Low birthweight (by subgroups).

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)2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Daily supplementation scheme2299Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.08, 1.34]
2.2 Dose of 400 µg or less1188Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 3.30]
2.3 Dose of more than 400 µg1111Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.08, 2.23]
2.4 Started pre-pregnancy and continued during the first trimester2299Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.08, 1.34]
2.5 History of NTDs2299Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.08, 1.34]
2.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Daily supplementation scheme1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.2 Dose of 400 µg or less1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.3 Dose of more than 400 µg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.4 Started pre-pregnancy and continued during first trimester1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.5 History of NTDs1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Daily supplementation scheme1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.2 Dose of 400 µg or less1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.3 Dose of more than 400 µg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.4 Started pre-pregnancy and continued during first trimester1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.5 History of NTDs1188Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 Daily supplementation scheme1188Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.02, 9.77]
8.2 Dose of 400 µg or less1188Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.02, 9.77]
8.3 Dose of more than 400 µg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
8.4 Started pre-pregnancy and continued1188Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.02, 9.77]
8.5 History of NTDs1188Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.02, 9.77]
8.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 Daily supplementation scheme1188Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.06, 6.57]
10.2 Dose of 400 µg or less1188Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.06, 6.57]
10.3 Dose of more than 400 µg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
10.4 Started pre-pregnancy and continued during the first trimester1188Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.06, 6.57]
10.5 History of NTDs1188Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.06, 6.57]
10.6 No history of NTDs or unknown00Risk 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)2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
12.1 Daily supplementation scheme2299Risk Ratio (M-H, Fixed, 95% CI)1.66 [0.66, 4.18]
12.2 Dose of 400 µg or less1188Risk Ratio (M-H, Fixed, 95% CI)1.82 [0.67, 4.90]
12.3 Dose of more than 400 µg1111Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.05, 13.25]
12.4 Started pre-pregnancy and continued during first trimester2299Risk Ratio (M-H, Fixed, 95% CI)1.66 [0.66, 4.18]
12.5 History of NTDs2299Risk Ratio (M-H, Fixed, 95% CI)1.66 [0.66, 4.18]
12.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
14.1 Daily supplementation1188Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.46]
14.2 Dose of 400 μg or less1188Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.46]
14.3 Dose of more than 400 μg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
14.4 Started pre-pregnancy and continued during first trimester1188Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.46]
14.5 History of NTDs1188Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.46]
14.6 No history of NTDs or unknown00Risk 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 scheme00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.2 Dose of 400 μg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.3 Dose of more than 400 μg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.4 Started pre-pregnancy and continued during first trimester00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.5 History of NTDs00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
18.1 Daily supplementation scheme1111Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.01, 6.83]
18.2 Dose of 400 μg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
18.3 Dose of more than 400 μg1111Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.01, 6.83]
18.4 Started pre-pregnancy and continued during first trimester1111Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.01, 6.83]
18.5 History of NTDs1111Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.01, 6.83]
18.6 No history of NTDs or unknown00Risk 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)0 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
20.1 Daily supplementation scheme00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.2 Dose of 400 μg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.3 Dose of more than 400 μg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.4 Started pre-pregnancy and continued during first trimester00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.5 History of NTDs00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.6 No history of NTDs or unknown00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
Analysis 2.1.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 1 Neural tube defects (ALL).

Analysis 2.2.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 2 Neural tube defects (by subgroups).

Analysis 2.3.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 3 Cleft palate (ALL).

Analysis 2.4.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 4 Cleft palate (by subgroups).

Analysis 2.5.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 5 Cleft lip (ALL).

Analysis 2.6.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 6 Cleft lip (by subgroups).

Analysis 2.7.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 7 Congenital cardiovascular defects (ALL).

Analysis 2.8.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 8 Congenital cardiovascular defects (by subgroups).

Analysis 2.9.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 9 Other birth defects (any) (ALL).

Analysis 2.10.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 10 Other birth defects (by subgroups).

Analysis 2.11.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 11 Miscarriage (ALL).

Analysis 2.12.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 12 Miscarriage (by subgroups).

Analysis 2.13.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 13 Stillbirth (ALL).

Analysis 2.14.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 14 Stillbirth (by subgroups).

Analysis 2.17.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 17 Pregnancy termination for fetal abnormality (ALL).

Analysis 2.18.

Comparison 2 Supplementation with folic acid alone versus no treatment/placebo, Outcome 18 Pregnancy termination for fetal abnormality (by subgroups).

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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Daily supplementation scheme1190Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 3.22]
2.2 Dose of 400 µg or less1190Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 3.22]
2.3 Dose of more than 400 µg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
2.4 Started pre-pregnancy and continued during first trimester1190Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 3.22]
2.5 History of NTDs1190Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 3.22]
2.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Daily supplementation scheme1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.2 Dose of 400 µg or less1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.3 Dose of more than 400 µg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.4 Started pre-pregnancy and continued during the first trimester1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.5 History of NTDs1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Daily supplementation scheme1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.2 Dose of 400 µg or less1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.3 Dose of more than 400 µg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.4 Started pre-pregnancy and continued during the first trimester1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.5 History of NTDs1190Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 Daily supplementation scheme1190Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.02, 9.55]
8.2 Dose of 400 µg or less1190Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.02, 9.55]
8.3 Dose of more than 400 µg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
8.4 Started pre-pregnancy and continued during the first trimester1190Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.02, 9.55]
8.5 History of NTDs1190Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.02, 9.55]
8.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 Daily supplementation scheme1190Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.17, 8.23]
10.2 Dose of 400 µg or less1190Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.17, 8.23]
10.3 Dose of more than 400 µg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
10.4 Started pre-pregnancy and continued during the first trimester1190Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.17, 8.23]
10.5 History of NTDs1190Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.17, 8.23]
10.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
12.1 Daily supplementation scheme1190Risk Ratio (M-H, Fixed, 95% CI)5.91 [0.29, 121.46]
12.2 Dose of 400 µg or less1190Risk Ratio (M-H, Fixed, 95% CI)5.91 [0.29, 121.46]
12.3 Dose of more than 400 µg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
12.4 Started pre-pregnancy and continued during the first trimester1190Risk Ratio (M-H, Fixed, 95% CI)5.91 [0.29, 121.46]
12.5 History of NTDs1190Risk Ratio (M-H, Fixed, 95% CI)5.91 [0.29, 121.46]
12.6 No history of NTDs or unknown00Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
14.1 Daily supplementation1190Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.41]
14.2 Dose of 400 μg or less1190Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.41]
14.3 Dose of more than 400 μg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
14.4 Started pre-pregnancy and continued1190Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.41]
14.5 History of NTDs1190Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.41]
14.6 No history of NTDs or unknown00Risk 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)0 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
16.1 Daily supplementation scheme00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.2 Dose of 400 μg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.3 Dose of more than 400 μg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.4 Started pre-pregnancy and continued during first trimester00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.5 History of NTDs00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.6 No history of NTDs or unknown00Risk 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)0 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
18.1 Daily supplementation scheme00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
18.2 Dose of 400 μg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
18.3 Dose of more than 400 μg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
18.4 Started pre-pregnancy and continued during first trimester00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
18.5 History of NTDs00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
18.6 No history of NTDs or unknown00Risk 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)0 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
20.1 Daily supplementation scheme00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.2 Dose of 400 μg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.3 Dose of more than 400 μg00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.4 Started pre-pregnancy and continued during first trimester00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.5 History of NTDs00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.6 No history of NTDs or unknown00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
Analysis 3.1.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 1 Neural tube defects (ALL).

Analysis 3.2.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 2 Neural tube defects (by subgroups).

Analysis 3.3.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 3 Cleft palate (ALL).

Analysis 3.4.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 4 Cleft palate (by subgroups).

Analysis 3.5.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 5 Cleft lip (ALL).

Analysis 3.6.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 6 Cleft lip (by subgroups).

Analysis 3.7.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 7 Congenital cardiovascular defects (ALL).

Analysis 3.8.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 8 Congenital cardiovascular defects (by subgroups).

Analysis 3.9.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 9 Other birth defects (any) (ALL).

Analysis 3.10.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 10 Other birth defects (by subgroups).

Analysis 3.11.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 11 Miscarriage (ALL).

Analysis 3.12.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 12 Miscarriage (by subgroups).

Analysis 3.13.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 13 Stillbirth (ALL).

Analysis 3.14.

Comparison 3 Supplementation with folic acid + other micronutrients versus no treatment/placebo, Outcome 14 Stillbirth (by subgroups).

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)4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Daily supplementation scheme45806Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.15, 0.56]
2.2 Dose of 400 µg or less1176Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.26]
2.3 Dose of more than 400 µg35630Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.14, 0.56]
2.4 Started pre-pregnancy and continued during the first trimester45806Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.15, 0.56]
2.5 History of NTDs31650Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.17, 0.66]
2.6 No history of NTDs or unknown14156Risk 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)3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Daily supplementation scheme35527Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]
4.2 Dose of 400 µg or less1176Risk Ratio (M-H, Fixed, 95% CI)Not estimable
4.3 Dose of more than 400 µg25351Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]
4.4 Started pre-pregnancy and continued during the first trimester35527Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.92]
4.5 History of NTDs21371Risk Ratio (M-H, Fixed, 95% CI)3.05 [0.12, 74.61]
4.6 No history of NTDs or unknown14156Risk 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)3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Daily supplementation scheme35527Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.27, 3.65]
6.2 Dose of 400 µg or less1176Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.26]
6.3 Dose of more than 400 µg25351Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.29, 5.80]
6.4 Started pre-pregnancy and continued during the first trimester35527Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.27, 3.65]
6.5 History of NTDs21371Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.6 No history of NTDs or unknown14156Risk 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)3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 Daily supplementation scheme35527Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.43, 2.22]
8.2 Dose of 400 µg or less1176Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.26]
8.3 Dose of more than 400 µg25351Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.46, 2.53]
8.4 Started pre-pregnancy and continued during the first trimester35527Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.43, 2.22]
8.5 History of NTDs21371Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.08, 4.61]
8.6 No history of NTDs or unknown14156Risk 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)3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 Daily supplementation scheme35527Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.50, 1.12]
10.2 Dose of 400 µg or less1176Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.15, 7.10]
10.3 Dose of more than 400 µg25351Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.49, 1.12]
10.4 Started pre-pregnancy and continued during the first trimester35527Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.50, 1.12]
10.5 History of NTDs21371Risk Ratio (M-H, Fixed, 95% CI)1.38 [0.70, 2.73]
10.6 No history of NTDs or unknown14156Risk 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)4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
12.1 Daily supplementation scheme47319Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.96, 1.26]
12.2 Dose of 400 µg or less1176Risk Ratio (M-H, Fixed, 95% CI)5.11 [0.25, 105.01]
12.3 Dose of more than 400 µg37143Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.96, 1.26]
12.4 Started pre-pregnancy and continued during the first trimester47319Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.96, 1.26]
12.5 History of NTDs31817Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.76, 1.30]
12.6 No history of NTDs or unknown15502Risk 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)4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
14.1 Daily supplementation scheme45806Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.68, 2.75]
14.2 Dose of 400 μg or less1176Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.20]
14.3 Dose of more than 400 μg35630Risk Ratio (M-H, Fixed, 95% CI)1.62 [0.77, 3.43]
14.4 Started pre-pregnancy and continued45806Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.68, 2.75]
14.5 History of NTDs31650Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.41, 3.36]
14.6 No history of NTDs or unknown14156Risk 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)3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
16.1 Daily supplementation scheme36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]
16.2 Dose of 400 μg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
16.3 Dose of more than 400 μg36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]
16.4 Started pre-pregnancy and continued during first trimester36239Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.98]
16.5 History of NTDs21472Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.38, 2.70]
16.6 No history of NTDs or unknown14767Risk 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 scheme35797Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.55]
18.2 Dose of 400 μg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
18.3 Dose of more than 400 μg35797Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.55]
18.4 Started pre-pregnancy and continued during first trimester35797Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.55]
18.5 History of NTDs21641Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.16, 0.67]
18.6 No history of NTDs or unknown14156Risk 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)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
20.1 Daily supplementation scheme1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]
20.2 Dose of 400 ɥg or less00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.3 Dose of more than 400 μg1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]
20.4 Started pre-pregnancy and continued during first trimester1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]
20.5 History of NTDs1186Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]
20.6 No history of NTDs or unknown00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
Analysis 4.1.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 1 Neural tube defects (ALL).

Analysis 4.2.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 2 Neural tube defects (by subgroups).

Analysis 4.3.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 3 Cleft palate (ALL).

Analysis 4.4.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 4 Cleft palate (by subgroups).

Analysis 4.5.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 5 Cleft lip (ALL).

Analysis 4.6.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 6 Cleft lip (by subgroups).

Analysis 4.7.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 7 Congenital cardiovascular defects (ALL).

Analysis 4.8.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 8 Congenital cardiovascular defects (by subgroups).

Analysis 4.9.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 9 Other birth defects (any) (ALL).

Analysis 4.10.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 10 Other birth defects (by subgroups).

Analysis 4.11.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 11 Miscarriage (ALL).

Analysis 4.12.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 12 Miscarriage (by subgroups).

Analysis 4.13.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 13 Stillbirth (ALL).

Analysis 4.14.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 14 Stillbirth (by subgroups).

Analysis 4.15.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 15 Multiple pregnancy (ALL).

Analysis 4.16.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 16 Multiple pregnancy (by subgroups).

Analysis 4.17.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 17 Pregnancy termination for fetal abnormality (ALL).

Analysis 4.18.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 18 Pregnancy termination for fetal abnormality (by subgroups).

Analysis 4.19.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 19 Low birthweight (ALL).

Analysis 4.20.

Comparison 4 Supplementation with folic acid + other micronutrients versus other micronutrients (without folic acid), Outcome 20 Low birthweight (by subgroups).

History

Protocol first published: Issue 3, 2009
Review first published: Issue 10, 2010

Contributions of authors

All review authors contributed to drafting the text of the review and commenting on drafts.

Disclaimer: Luz Maria de Regil and Juan Pablo Pena-Rosas are currently staff members of the World Health Organization. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the World Health Organization.

Declarations of interest

There are no known conflicts of interest.

Sources of support

Internal sources

  • The University of Liverpool, UK.

  • Universidad Iberoamericana, Ciudad de Mexico, Mexico.

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

External sources

  • National Institute for Health Research (NIHR), UK.

    TD is supported by a grant from the National Institute for Health Research (NIHR). UK NIHR NHS Cochrane Collaboration Programme Grant Scheme award for NHS prioritised, centrally managed, pregnancy and childbirth systematic reviews: CPGS02

  • Department of Reproductive Health and Research, World Health Organization, Switzerland.

  • Government of Luxembourg, Luxembourg.

    WHO acknowledges the Government of Luxembourg for their financial support to the Micronutrients Unit for conducting systematic reviews on micronutrient interventions.

Characteristics of studies

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.
Interventions

Women 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.

Outcomes

Maternal: 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
Unclear

Of 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.
Interventions

Women 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.

Outcomes

Maternal: 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?Unclear

After 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.
Interventions

Women 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.

Outcomes

Maternal: 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.
Interventions

Women 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.

Outcomes

Maternal: 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

  1. a

    NTD: neural tube defect
    RCT: randomised controlled trial

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.
Interventions

Women 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.

Outcomes

Maternal: 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
  1. a

    CLP: cleft palate
    MM: multiple micronutrient
    NTD: neural tube defect

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.
Participants

Women 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
Notes

Recruitment has recently finished (2009).

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

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