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Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes

  1. Zohra S Lassi1,
  2. Rehana A Salam2,
  3. Batool A Haider3,
  4. Zulfiqar A Bhutta1,*

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 2 JAN 2013

DOI: 10.1002/14651858.CD006896.pub2


How to Cite

Lassi ZS, Salam RA, Haider BA, Bhutta ZA. Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD006896. DOI: 10.1002/14651858.CD006896.pub2.

Author Information

  1. 1

    Aga Khan University Hospital, Division of Women and Child Health, Karachi, Pakistan

  2. 2

    Aga Khan University Hospital, Department of Paediatrics, Division of Women and Child Health, Karachi, Sind, Pakistan

  3. 3

    Harvard School of Public Health, Departments of Epidemiology and Nutrition, Boston, MA, USA

*Zulfiqar A Bhutta, Division of Women and Child Health, Aga Khan University Hospital, Stadium Road, PO Box 3500, Karachi, 74800, Pakistan. zulfiqar.bhutta@aku.edu.

Publication History

  1. Publication Status: New
  2. Published Online: 28 MAR 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms
 

Description of the intervention

Folate is a generic term for both the endogenous form of the vitamin occurring naturally in food and the synthetic form found in supplements and fortified foods (Bailey 1995). It should be noted, however, that folate is a naturally occurring vitamin while folic aid is the synthetic replacement of folate used in most supplements and in fortified foods. Humans are fully dependent on dietary sources or dietary supplements and microorganisms in their intestinal tract for their folate supply. Folate derivatives are essential for the synthesis of nucleic acid, amino acids, cell division, tissue growth, and DNA methylation (Krishnaswamy 2001; Morrison 1998; Scholl 2000).

Inadequate folate intake leads to a decrease in serum folate concentration, resulting in a decrease in erythrocyte (red blood cell) folate concentration, a rise in homocysteine (Hcy) concentration, and megaloblastic changes in the bone marrow and other tissues with rapidly dividing cells (Dietary Ref 1998; Willoughby 1968). During pregnancy, fetal growth causes an increase in the total number of rapidly dividing cells, which leads to increased requirements for folate (Bailey 1995). With inadequate folic acid intake, concentrations of folate in maternal serum, plasma, and red blood cells decrease from the fifth month of pregnancy onwards (Açkurt 1995; Bates 1986). If inadequate folate intake is sustained during pregnancy, megaloblastic anaemia (a blood disorder characterised by anaemia, with red blood cells that are larger than normal and cell contents that are not completely developed) occurs (Willoughby 1968). Folate concentrations continue to decrease for several weeks after pregnancy (Bruinse 1995; Smith 1983), and by the second to third month postpartum, a third of all mothers can have subnormal concentrations of folate in serum and red blood cells (Açkurt 1995). Possible causes for the decline in blood folate during pregnancy include increased folate demand for growth of the fetus due to an increase in the number of rapidly dividing cells (Bailey 1995) and growth of uteroplacental organs, decreased folate absorption, low folate intake, hormonal influence on folate metabolism as a physiologic response to pregnancy (Chanarin 1969), and dilution of folate due to blood volume expansion (Bruinse 1995). Folate demands may be further increased in women with sickle cell disease and women living in areas where malaria is endemic (Lawson 1988); in these areas, anaemia in pregnancy is a major health problem. Increased folate catabolism and urinary folate excretion (Fleming 1972; Landon 1971) may also contribute to increased folate needs in pregnancy (Caudill 1998; Gregory 2001b; Higgins 2000; McPartlin 1993), but the findings are controversial. As a consequence of folate deficiency, Hcy accumulates in the serum and is found to be associated with an increased risk in cardiovascular disease (Refsum 2008), late pregnancy complications such as pre-eclampsia (Makedos 2007; Patrick 2004; Tamura 2006), and neural tube defects around the time of conception (De Benoist 2008).

The recommended folate intake for pregnant women is 400 µg/day (Food and Nutrition Board 1970). It was revised in 1999 after evaluating its bioavailability from food and synthetic folate, and the recommendation was increased to 450 µg (600 DFEs/day (dietary folate equivalent)) (Institute of Medicine 2000). It should be noted that as per NICE guidelines, this amount of folic acid when supplemented to pregnant women (and those intending to become pregnant), before conception and throughout the first 12 weeks, reduces the risk of having a baby with a neural tube defect (NICE 2008). However, the Food and Nutrition Board of the Institute of Medicine have suggested that an increased folate intake might delay the diagnosis of vitamin B-12 deficiency by correcting the anaemia, or even exacerbate its neurologic and neuropsychiatric effects (Food and Nutrition Board 1998; Herbert 1997; Rush 1994). Further research is still needed in this area.

 

How the intervention might work

The relationship between pregnancy outcome and maternal blood folate concentrations, folate intake and hyperhomocysteinaemia cannot be ignored (Smits 2001). Plasma total homocysteine (tHcy) is regulated by folate status (Selhub 1993), and hyperhomocysteinaemia is linked to vaso-occlusive disease (Green 1995). Impaired placental perfusion due to hyperhomocysteinaemia is implicated in having a negative effect on pregnancy outcome, as are inadequate folate intake and low serum folate concentrations (Scholl 2000). Folate has long been used as a supplement in combination with iron during pregnancy, largely on the basis of haematological benefits (Fleming 1968), although deficiency has also been associated with pregnancy complications and congenital malformations (Scholl 2000). Periconceptional supplementation with folic acid, three months before and early in pregnancy is recommended (Czeizel 1992; MRC 1991), and has been shown to reduce the risk of neural tube defects by almost three-quarters (De-Regil 2010). Although still unproven, folic acid supplementation has also been suggested to help prevent other fetal malformations such as congenital heart defects (Botto 1996; Czeizel 1993; Czeizel 1996; Shaw 1995), urinary tract anomalies (Li 1995), limb defects (Czeizel 1993), oro-facial clefts (Czeizel 1993; Li 1995; Shaw 1995), and pyloric stenosis (Shaw 1995).

 

Why it is important to do this review

The role of folate deficiency in increasing the risk of spontaneous abortion and birth outcomes such as low birthweight, preterm birth, and perinatal mortality is unclear (Bukowski 2009; Scholl 2000). Hence, the aim of this review is to assess the effect of folic acid supplementation alone in pregnant women on haematological and biochemical parameters, adverse events during pregnancy, and on pregnancy outcomes. We did not assess periconceptional folic acid supplementation, or supplementation of folic acid along with iron during pregnancy and with other micronutrients, as these have been addressed by other reviews (Haider 2006; De-Regil 2010; Pena-Rosas 2006).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms

To assess the effectiveness of oral folic acid supplementation alone or with other micronutrients versus no folic acid (placebo or same micronutrients but no folic acid) during pregnancy on haematological and biochemical parameters during pregnancy and on pregnancy outcomes.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We included randomised or quasi-randomised controlled trials of folic acid supplementation alone or with other micronutrients versus no folic acid (placebo or same micronutrients but no folic acid).

 

Types of participants

We included pregnant women of any age and parity.

 

Types of interventions

  1. Folic acid alone versus no treatment/placebo (no folic acid)
  2. Folic acid+ iron versus iron (no folic acid)
  3. Folic acid + other vitamins and minerals versus other vitamins and minerals (but no folic acid)

We excluded studies that supplemented folic acid in the form of fortification or home fortification alone or in combination with other micronutrients. We also excluded studies in which women were supplemented during periconception.

 

Types of outcome measures

 

Primary outcomes

 
Maternal outcomes

  • Pre-delivery anaemia (less than 10 g/dL haemoglobin or haematocrit below 30%
  • Mean pre-delivery haemoglobin level
  • Low pre-delivery serum folate (less than 3 mg/L or 7 nmol/L or 3 ng/mL)
  • Mean pre-delivery serum folate level
  • Low pre-delivery red cell folate (less than 100 mg/L or 300 nmol/L or 140 ng/mL)
  • Mean pre-delivery red cell folate

 
Pregnancy outcome

  • Preterm birth (delivery before 37 weeks of gestation)

 
Infant outcome

  • Low birthweight (birthweight less than 2500 g)

 

Secondary outcomes

  • Miscarriage (loss of pregnancy before 22 weeks of gestation)
  • Perinatal mortality - includes stillbirth (deaths after 22 weeks of gestation) and mortality in the first seven days of life
  • Pre-eclampsia- defined as blood pressure of > 140 mmHg systolic or > 90 mmHg diastolic after 20 weeks of gestation, and proteinuria of more than 0.3 g in 24 hours
  • Respiratory disease in child
  • Allergic disease in child
  • Megaloblastic anaemia
  • Hyperhomocysteinaemia (more than 16 micromol/L)

 

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 (31 December 2012)

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

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
  2. weekly searches of MEDLINE;
  3. weekly searches of EMBASE;
  4. handsearches of 30 journals and the proceedings of major conferences;
  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and EMBASE, 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

For identification of ongoing or unpublished studies, we contacted major organisations working in micronutrient supplementation, including UNICEF Nutrition Section, World Health Organization (WHO) Maternal and Reproductive Health, WHO Nutrition Division, and National Center on Birth defects and Developmnetal Disabilities, US Centers for Disease Control and Prevention (CDC).

We did not apply any language restrictions.

 

Data collection and analysis

 

Selection of studies

Two review authors, Zohra Lassi (ZSL) and Rehana Salam (RAS), independently assessed for inclusion all the potential studies we identified as a result of the search strategy. We resolved any disagreement through discussion and, if required, we consulted the third review author, Zulfiqar Bhutta (ZAB)

 

Data extraction and management

We designed a form to extract data. For eligible studies, two review authors (RAS and ZL) extracted the data using the agreed form. We resolved discrepancies through discussion and, if required, we consulted the third review author. Data were entered into ReviewManager software (RevMan 2011) and checked 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 (ZSL and RAS) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement was resolved by discussion or by involving a third assessor (ZAB).

 

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

We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it produced comparable groups. We assessed the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);
  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);
  • unclear risk of bias.

 

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

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

We assessed the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
  • unclear risk of bias.   

 

(3.1) Blinding (checking for possible performance bias)

We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies were at low risk of bias if they were blinded, or if we judged that the lack of blinding would be unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

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

 

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

We 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 stated 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 exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we re-included missing data in the analyses which we undertook. We assessed methods as:

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

 

(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:

  • low risk of bias (where it was clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
  • high risk of bias (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 were reported incompletely and so could not be used; study failed to include results of a key outcome that would have been expected to have been reported);
  • unclear risk of bias.

 

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

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

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

  • low risk of other bias;
  • high risk of other bias;
  • unclear whether there is risk of other bias.

 

(7) Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). 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. 

 

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, but used different methods.  

 

Unit of analysis issues

 

Cluster-randomised trials

We included cluster-randomised/quasi-randomised trials in the analyses along with individually-randomised trials. We incorporated the data of cluster-randomised/quasi-randomised trials using generic inverse variance method in which logarithms of risk ratio estimates were used along with the standard error of the logarithms of risk ratio estimates.

 

Cross-over trials

We also looked for any cross-over trials on this topic, and such trials were deemed eligible for inclusion, However, we did not find any eligible cross-over trials.

 

Dealing with missing data

We noted levels of attrition for included studies. We also planned to explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis. For all outcomes, we carried out analyses, as far as possible, on an intention-to-treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and all participants were analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

 

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We regarded heterogeneity as substantial if the I² was greater than 30% and either T² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity. 

 

Assessment of reporting biases

If there were 10 or more studies in the meta-analysis, we investigated reporting biases (such as publication bias) using funnel plots. We assessed funnel plot asymmetry visually, If asymmetry was suggested by a visual assessment, we performed exploratory analyses to investigate it.

Mostly studies were old and we suspected reporting bias, therefore, we attempted to contact study authors, where possible, asking them to provide missing outcome data.

 

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2011). We used fixed-effect Mantel-Hanzel meta-analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. trials were examining the same intervention, and the trials’ populations and methods were judged to be sufficiently similar. If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random-effects meta-analysis to produce an overall summary if an average treatment effect across trials was considered clinically meaningful. The random-effects summary was treated as the average range of possible treatment effects and we discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we did not combine trials.

If we used random-effects analyses, the results were presented as the average treatment effect with 95% confidence intervals, and the estimates of  T² and I².

 

Subgroup analysis and investigation of heterogeneity

We planned to carry out subgroup analyses based on following factors.

• Different doses of folate used (< 400 μg and > 400 μg)
• Different durations of folate supplementation
• Haemoglobin level of participants
• Co-interventions

Not all included studies mentioned the baseline haemoglobin levels of participants and since duration and start of folic acid supplementation in women during pregnancy varied, we, therefore, did not carry out these subgroup analyses. However, subgroup analyses were carried out on studies in which iron was additionally provided with folic acid. We also performed subgroup analyses on the dosage of folic acid.

We also reported the outcomes based on how the outcome was defined in the individual study.

We assessed subgroup differences by the interaction tests available within RevMan (RevMan 2011). We reported the results of subgroup analyses quoting the χ² statistic and the P value, and the interaction test I² value.

 

Sensitivity analysis

We did not perform sensitivity analyses as studies were old and of mediocre quality.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms
 

Description of studies

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

 

Results of the search

A total of 94 trial reports were considered for inclusion into this review, finally 31 studies involving 17,771 women were included in this review (Figure 1).

 FigureFigure 1. Study flow diagram.

 

Included studies

Thirty-one studies have been included in this review. The majority of these studies were quite old and were conducted during the 1960s (Castren 1968; Chanarin 1965; Chanarin 1968; Chisholm 1966; Dawson 1962; Edelstein 1968; Fleming 1968; Hibbard 1969a; Menon 1962; Metz 1965; Willoughby 1967); the 1970s (Balmelli 1974; Batu 1976; Baumslag 1970; Fletcher 1971; Giles 1971; Iyengar 1975; Rae 1970; Rolschau 1979; Trigg 1976; Weil 1977), and the 1980s (Blot 1981; Harrison 1985; Lira 1989; Roth 1980; Srisupandit 1983; Tchernia 1982; Pack 1980). Three studies were published in 2005 (Charles 2005; Christian 2003; Decsi 2005), however, Charles 2005 re-analysed data that were collected in 1966. Seven studies (Chanarin 1965; Christian 2003; Dawson 1962; Decsi 2005; Hibbard 1969a; Metz 1965; Pack 1980) were were not included in the meta-analyses because they either did not mention their standard deviations/standard errors; or they reported the rise or fall in the haematological and biochemical levels.

Most of the outcomes were defined in the same way across different trials except for preterm birth, pre-delivery anaemia, and low birthweight which were defined differently, however, we still included them and they were presented in subgroup according to their defined cut-offs (Refer to  Table 1). The majority of the studies were conducted in Europe (Balmelli 1974; Blot 1981; Castren 1968; Chanarin 1965; Chanarin 1968; Charles 2005; Chisholm 1966; Dawson 1962; Decsi 2005; Fletcher 1971; Hibbard 1969a; Rae 1970; Rolschau 1979; Tchernia 1982; Trigg 1976; Weil 1977; Willoughby 1967), Africa (Baumslag 1970; Edelstein 1968; Fleming 1968; Harrison 1985; Metz 1965) and Asia (Batu 1976; Christian 2003; Iyengar 1975; Menon 1962; Srisupandit 1983). One study was conducted in South America (Lira 1989), one in Australia (Giles 1971) and one in New Zealand (Pack 1980). One study (Roth 1980) did not mention the setting. The time for initiation of supplementation varied from 8th week of pregnancy till three days postpartum. Most of the studies supplemented women with folic acid in combination with iron (Balmelli 1974; Batu 1976; Baumslag 1970; Blot 1981; Castren 1968; Chanarin 1965; Chanarin 1968; Chisholm 1966; Christian 2003; Edelstein 1968; Fletcher 1971; Giles 1971; Harrison 1985; Iyengar 1975; Lira 1989; Menon 1962; Metz 1965; Rae 1970; Rolschau 1979; Roth 1980; Srisupandit 1983; Tchernia 1982; Trigg 1976; Weil 1977; Willoughby 1967) however, only a few compared folic acid alone with placebo (Charles 2005; Chisholm 1966; Decsi 2005; Fleming 1968; Pack 1980).

Please refer to the Characteristics of included studies table for more details.

 

Excluded studies

A total of 25 studies were excluded from the review as they did not satisfy the inclusion criteria. Hamilton 1973 was not a randomised controlled trial. There were four studies in which folic acid was given in combination with other micronutrients compared with a no supplement group (Bjerre 1967; Ma 2008; Wang 2012; Zeng 2008). Similarly, Giles 1960 compared the intervention group with historical controls; Gregory 2001 compared pregnant women with non pregnant women; Khanna 1977 evaluated the therapeutic use of folic acid in women with anaemia; and there were a few studies in which the association of folic acid supplementation was observed, with breast cancer, fetal apoptosis (Klinger 2006), congenital anomalies (Ulrich 1999) and with malaria when given with sulphadoxine pyrimethamine (Ouma 2006). We excluded studies in which therapy of iron and folic acid was compared with no therapy at all (Taylor 1979; Taylor 1981). We also excluded studies in which folic acid was given in a fortification form (Colman 1974; Colman 1975). We excluded studies that compared the duration of folic acid supplements (Ellison 2004; Polatti 1992), and different dosage of folic acid supplements (Hekmatdoost 2011; Hibbard 1969; Manizheh 2009). Trials were also excluded that were in the form of published abstracts only and had insufficient information to extract (Hague 1998; Kristoffersen 1979; Melli 2008; Thomson 1982). Also, one study in which results from three trials were re analysed was excluded (Tchernia 1982a).

Please refer to Characteristics of excluded studies table for more details.

 

Risk of bias in included studies

Most of the studies were conducted over 30 to 45 years ago, and we found poor subjective and objective compliance with random allocation, adequate concealment and blinding. Bias and confounding thus seem to us the likely explanation for our findings.

Figure 2 and Figure 3 provide a graphical summary of the results of risk of bias for the included studies.

 FigureFigure 2. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
 FigureFigure 3. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

 

Allocation

Sequence generation and adequate allocation concealment was a problem in almost all the studies and control of selection bias at entry was often difficult to assess as many authors stated that women were 'randomly allocated' without actually describing the technique, still there were studies that managed to report the methods of allocation concealment adequately (Blot 1981; Edelstein 1968; Fleming 1968; Giles 1971; Rolschau 1979).

 

Blinding

Blinding was the another issue which was rarely discussed in depth, and only few reported them adequately including Blot 1981; Edelstein 1968; Fleming 1968; Giles 1971; Harrison 1985; Weil 1977.

 

Incomplete outcome data

Mostly studies provided insufficient information regarding attrition rates, which meant we were unable to make any judgment. There were only a few studies that discussed their exclusion and attrition rates and reported their reasons. (Balmelli 1974; Batu 1976; Blot 1981 Castren 1968; Fleming 1968; Giles 1971 Harrison 1985; Iyengar 1975; Srisupandit 1983; Tchernia 1982).

 

Selective reporting

Again, studies provided insufficient information, which limited us from making any judgment (Balmelli 1974; Blot 1981; Castren 1968; Harrison 1985; Iyengar 1975; Srisupandit 1983).

 

Other potential sources of bias

No other bias was identified but we had insufficient information available to fully assess this 'Risk of bias' domain. Consequently, we assessed all included studies as being at 'unclear' risk of other bias.

 

Effects of interventions

 

a. Clinical measures of untoward events during pregnancy and of pregnancy outcome

 

Preterm birth

None of the included studies reported preterm birth in accordance with our definition of the outcome. We found two studies, of which one defined it as birth of a baby between 36 to 38 weeks, and another defined it as birth before 38 weeks of pregnancy. We pooled them both to look for an association with folic acid supplementation in pregnancy. Our analysis showed that administration of folic acid supplementation during pregnancy has no impact on reducing preterm birth (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.73 to 1.38; three studies, 2959 participants ( Analysis 1.1)).

 

Stillbirths/neonatal deaths

None of the included studies reported perinatal mortality. However, three studies reported stillbirth and neonatal mortality as a composite outcome, hence we pooled them to obtain data for perinatal mortality. Folic acid supplementation during pregnancy did not show any impact on reducing stillbirths/neonatal deaths (RR 1.33, 95% CI 0.96 to 1.85; three studies, 3110 participants ( Analysis 1.2)).

 

Birthweight

Folic acid supplementation during pregnancy did not show any impact on reducing low birthweight (less than 2500 g) (RR 0.83, 95% CI 0.66 to 1.04; four studies, 3113 participants ( Analysis 1.3)).

We also attempted to look at the impact of folic acid supplementation during pregnancy on mean birthweight (g) of newborns and found no association (mean difference (MD) 104.96 g, 95% CI -0.25.50 g to 235.41 g; five studies, 774 participants; random-effects, T² = 21694.29, I² = 90% ( Analysis 1.4)). All the studies pooled for this outcome compared folic acid + iron versus iron alone.

The standard errors for Trigg 1976 were very small as compared to the other trials for being plausible, therefore, we conducted a sensitivity analysis after removing this study. Heterogeneity was reduced from 90% to 50% (MD 135.76, 95% CI 47.85 to 223.68; four studies, 625 participants; random-effects, T² = 4841.10, I² = 50% ( Analysis 1.5)

 

Outcomes not reported in the included studies

The included studies did not report on the impact of folic acid supplementation on miscarriage, pre-eclampsia, respiratory disease or allergic disease in children.

 

b. Haematological and biochemical parameters

 

Pre-delivery anaemia

The included studies used different definitions of anaemia. Eight studies reported pre-delivery anaemia as an outcome, but only two studies used our definition of anaemia. We included all studies reporting anaemia but pooled them separately according to the definition of anaemia used. Folic acid supplementation did not show any impact on reducing pre-delivery anaemia (any cut-off point) (average RR 0.62, 95% CI 0.35 to 1.10; eight studies, 4149 participants; random-effects, T² = 0.51, I² = 90% ( Analysis 1.6)). When studies were separately pooled according to the definition described in the earlier section of this review, we found that supplementation had no impact on reducing anaemia (haemoglobin less than 10 g/dL) (average RR 0.35, 95% CI 0.05 to 2.42; two studies, 2448 participants; random-effects, T² = 1.86, I² = 97% ( Analysis 1.6)).

We also looked at the impact of folic acid supplementation in pregnancy on mean pre-delivery haemoglobin level, and found no difference in the mean haemoglobin concentration among those in the intervention arm compared with those in the placebo arm (MD -0.03, 95% CI -0.25 to 0.19; 12 studies, 1806 participants; random-effects, T² = 0.12, I² = 95% ( Analysis 1.7)). All the studies pooled for this outcome compared folic acid + iron versus iron alone.

With regard to subgroup analysis based on dosage of folic acid supplementation, we found no differences on improving haemoglobin concentrations and the interaction test was insignificant (Chi² = 1.18, df = 1 (P = 0.28), I² = 15.1%).  Analysis 1.8

We also ran a funnel plot to assess the publication bias and we found studies were equally distributed on each side except for two outliers Figure 4.

 FigureFigure 4. Funnel plot of comparison: 1 Folic acid versus no folic acid, outcome: 1.7 Mean pre-delivery haemoglobin level.

 

Pre-delivery serum folate

Folic acid supplementation in pregnancy showed a reduction in the incidence of low pre-delivery serum folate by 62% (RR 0.38, 95% CI 0.25 to 0.59; two studies, 696 participants ( Analysis 1.11)).

We found non-significantly higher mean pre-delivery serum folate levels among those in the folic acid supplementation arm compared with those in the placebo arm (standardised mean difference (SMD) 2.03, 95% CI 0.80 to 3.27; eight studies, 1250 participants; random-effects, T² = 2.96, I² = 98% ( Analysis 1.9)). All the studies pooled for this outcome compared folic acid + iron versus iron alone.

For subgroup analysis based on dosage of folic acid supplementation, we found significant improvements in mean serum folate concentration when the dose was less than 400 μg (SMD 3.70, 95% CI: 0.28 to 7.11, four studies n = 253, random effects, I² = 99%), however, no impact was seen of folic acid > 400 μg (SMD 0.68, 95% CI: -0.75 to 2.10, four studies n = 997, random effects, I² = 98%)  Analysis 1.10. The interaction test for the overall estimate was not significant (Chi² P value = 0.11, I² = 61%) suggesting no difference between groups.

 

Pre-delivery red cell folate

None of the included studies reported data for pre-delivery red cell folate deficiency status. However, mean red cell folate levels were reported in four studies. Folic acid supplementation during pregnancy did not show any impact on reducing mean pre-delivery red cell folate levels (SMD 1.59, 95% CI -0.07 to 3.26; four studies, 427 participants; random-effects, T² = 2.79, I² = 97% ( Analysis 1.12)). All the studies pooled for this outcome compared folic acid + iron versus iron alone.

 

Megaloblastic anaemia

Folic acid supplementation during pregnancy significantly reduced the incidence of megaloblastic anaemia by 79% (RR 0.21, 95% CI 0.11 to 0.38; four studies, 3839 women ( Analysis 1.13)).

 

Outcomes not reported in the included studies

The included studies did not report on the impact of folic acid supplementation on hyperhomocysteinaemia, respiratory disease and allergic disease in the child.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms
 

Summary of main results

From our meta-analysis of randomised controlled trials on folic acid supplementation, we found no evidence of an effect of supplements on preterm birth, stillbirth/neonatal death, mean birthweight/low birthweight, low pre-delivery haemoglobin and serum red cell folate. However, we found a risk reduction on low pre-delivery serum folate and megaloblastic anaemia.

 

Quality of the evidence

First, all the included studies were conducted over 30 to 45 years ago, and we found poor subjective and objective compliance with random allocation, adequate concealment and blinding. Bias and confounding thus seem to be the likely explanation for our findings.

Second, for combining studies, it is important that the outcome measures are comparable. Of note, trials included in this analysis reported outcomes quite differently from each other. This could have resulted in higher risk of bias due to selective reporting in these trials. However, we pooled them separately, wherever possible, to minimise this bias.

 

Potential biases in the review process

We undertook a systematic, thorough search of the literature to identify all studies meeting the inclusion criteria and we are confident that the included trials met the set criteria. Study selection and data extraction were carried out in duplicate and independently and we reached consensus by discussing any discrepancies. A protocol was published for this review. All the analyses were specified a priori, with the exception of a post hoc analysis of the different cut-off values for biochemistry markers.

 

Agreements and disagreements with other studies or reviews

Previous observational studies have suggested that higher folate status in pregnancy is associated with higher birthweight, higher placental weight, and prolonged gestation (Goldenberg 1992; Neggers 1997; Tamura 1992). Preconception folic acid supplementation has also shown effects on decreasing preterm births (Bukowski 2009). However, the findings from this review are inconclusive.

A review on folic acid supplementation during pregnancy by Charles et al (Charles 2005b) that included results from large randomised controlled trials found no conclusive evidence of benefit for folic acid supplementation in pregnant women. An earlier version of this Cochrane review also reached the same conclusion (Mahomed 1997).

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms

 

Implications for practice

Our meta-analysis of folic acid supplementation in pregnancy included 31 studies and provided non-conclusive evidence of folic acid supplementation for pregnant women on pregnancy outcomes except for improvement in mean birthweight. A reduction in the risk of megaloblastic anaemia and improvement in folate levels, however, has been noted with folic acid supplementation against supplementation with placebo but the limitation to this finding is the few number of studies reporting the outcome.

 
Implications for research

More well-designed, large scale randomised controlled trials are needed to establish the benefit of folic acid supplementation during pregnancy. Researchers of future trials should also make efforts to describe the participants in more detail before enrolment and should undertake long-term follow-up of the participants and their children in order to study the long-term effects of folic acid supplementation. Bias should also be reduced by adequate randomisation and allocation concealment of the assignment of intervention by achieving blinding of the participants, providers and the outcome assessors and by minimising loss to follow-up of the participants, in order to produce trials of adequate methodological quality.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms

We thank Kate Barton and Rebecca Gainey as translators of Lira 1989; Elena Intra as translator of Polatti 1992; Alison Ledward as translator of Weil 1977, Austin Anderson Leirvik as translator of Tchernia 1982 and Caroline Summers as translator of Balmelli 1974 and Roth 1980.

As part of the pre-publication editorial process, this review 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.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms
Download statistical data

 
Comparison 1. Folic acid versus no folic acid

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

 1 Preterm birth32959Risk Ratio (Fixed, 95% CI)1.01 [0.73, 1.38]

    1.1 As categorised by: birth between 36-38 weeks of gestation
153Risk Ratio (Fixed, 95% CI)0.75 [0.33, 1.71]

    1.2 As categorised by: birth before 38 weeks of gestation
1109Risk Ratio (Fixed, 95% CI)0.14 [0.01, 2.65]

    1.3 As categorised by: birth before 37 weeks of gestation
12797Risk Ratio (Fixed, 95% CI)1.09 [0.77, 1.54]

 2 Stillbirths/neonatal deaths33110Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.96, 1.85]

 3 Low birthweight43113Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.66, 1.04]

    3.1 Less than 2500 g
33089Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.63, 1.02]

    3.2 Less than 2400 g
124Risk Ratio (M-H, Fixed, 95% CI)1.3 [0.79, 2.15]

 4 Mean birthweight (g)5774Mean Difference (IV, Random, 95% CI)104.96 [-25.50, 235.41]

    4.1 Folate + Iron
5774Mean Difference (IV, Random, 95% CI)104.96 [-25.50, 235.41]

 5 Mean birth weight (sensitivity analysis-after removing Trigg 1976)4625Mean Difference (IV, Random, 95% CI)135.76 [47.85, 223.68]

    5.1 Folate + Iron
4625Mean Difference (IV, Random, 95% CI)135.76 [47.85, 223.68]

 6 Pre-delivery anaemia84149Risk Ratio (M-H, Random, 95% CI)0.62 [0.35, 1.10]

    6.1 Anaemia: as categorized by haemoglobin < 11 g/dL
135Risk Ratio (M-H, Random, 95% CI)2.8 [0.39, 19.93]

    6.2 Anaemia: as categorized by haemoglobin < 10.5 g/dL
2407Risk Ratio (M-H, Random, 95% CI)0.70 [0.31, 1.61]

    6.3 Anaemia: as categorized by haemoglobin < 10 g/dL
22448Risk Ratio (M-H, Random, 95% CI)0.35 [0.05, 2.42]

    6.4 Anaemia: did not mention their cut-off
31259Risk Ratio (M-H, Random, 95% CI)0.71 [0.25, 2.02]

 7 Mean pre-delivery haemoglobin level121806Mean Difference (IV, Random, 95% CI)-0.03 [-0.25, 0.19]

    7.1 Folate + Iron
121806Mean Difference (IV, Random, 95% CI)-0.03 [-0.25, 0.19]

 8 Mean pre-delivery haemoglobin level121806Mean Difference (IV, Random, 95% CI)-0.03 [-0.25, 0.19]

    8.1 Folic acid < 400 µg
7582Mean Difference (IV, Random, 95% CI)0.06 [-0.09, 0.20]

    8.2 Folic acid >400 µg
51224Mean Difference (IV, Random, 95% CI)-0.17 [-0.54, 0.21]

 9 Mean pre-delivery serum folate81250Std. Mean Difference (IV, Random, 95% CI)2.03 [0.80, 3.27]

    9.1 Folate + Iron
81250Std. Mean Difference (IV, Random, 95% CI)2.03 [0.80, 3.27]

 10 Mean pre-delivery serum folate81250Std. Mean Difference (IV, Random, 95% CI)2.03 [0.80, 3.27]

    10.1 Folic acid < 400 µg
4253Std. Mean Difference (IV, Random, 95% CI)3.70 [0.28, 7.11]

    10.2 Folic acid > 400 µg
4997Std. Mean Difference (IV, Random, 95% CI)0.68 [-0.75, 2.10]

 11 Low pre-delivery serum folate2696Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.25, 0.59]

    11.1 Pre-delivery serum folate: as categorised by < 2.5 ng/mL
1643Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.16, 0.63]

    11.2 Pre-delivery serum folate: did not report the cut-off value
153Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.30, 0.78]

 12 Mean red cell folate4427Std. Mean Difference (IV, Random, 95% CI)1.59 [-0.07, 3.26]

    12.1 Folate + Iron
4427Std. Mean Difference (IV, Random, 95% CI)1.59 [-0.07, 3.26]

 13 Megaloblastic anaemia43839Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.11, 0.38]

 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms

Protocol first published: Issue 1, 2008
Review first published: Issue 3, 2013


DateEventDescription

16 February 2010AmendedAuthor contact details edited.

20 September 2008AmendedConverted to new review format.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms

Zohra Lassi entered the data, created the comparisons, conducted the analyses and wrote the text of the review under the guidance of Dr Zulfiqar Bhutta. The draft protocol was written by Dr Batool Haider (BAH) who also designed the eligibility and data extraction forms. Rehana Salam (RAS) took part in assisting with data analysis.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms
 

Internal sources

  • The Aga Khan University, Pakistan.

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms

Outcome measures have been separated into 'Primary' and 'Secondary' outcomes.

We have added two additional outcomes: respiratory disease in the child; allergic disease in the child.

 

Notes

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Notes
  16. Index terms

This review has been developed to update the previously published review, 'Folate supplementation in pregnancy' , which was withdrawn from publication in Issue 3, 2006, of The Cochrane Library because it was out of date. See Other published versions of this review.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé scientifiqueアブストラクト
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Balmelli 1974 {published data only}
  • Balmelli GP, Huser HJ. Folic acid deficiency in pregnant women in Switzerland [Zur Frage des Folsäuremangels bei Schwangeren in der Schweiz]. Schweizerische Medizinische Wochenschrift 1974;104(10):351-6.
Batu 1976 {published data only}
  • Batu AT, Toe T, Pe H, Nyunt KK. A prophylactic trial of iron and folic acid supplements in pregnant Burmese women. Israel Journal of Medical Sciences 1976;12:1410-7.
Baumslag 1970 {published data only}
Blot 1981 {published data only}
  • Blot I, Papiernik E, Kaltwasser JP, Werner E, Tchernia G. Influence of routine administration of folic acid and iron during pregnancy. Gynecologic and Obstetric Investigation 1981;12:294-304.
Castren 1968 {published data only}
  • Castren O, Levanto A, Rauramo L, Ruponen S. Preventive iron and folic acid therapy in pregnancy. Annales Chirurgiae et Gynaecologiae Fenniae 1968;57:382-6.
Chanarin 1965 {published data only}
Chanarin 1968 {published data only}
Charles 2005 {published data only}
Chisholm 1966 {published data only}
  • Chisholm M. A controlled clinical trial of prophylactic folic acid and iron in pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth 1966;73:191-6.
Christian 2003 {published data only}
  • Christian P, Darmstadt GL, Wu L, Khatry SK, Leclerq SC, Katz J, et al. The effect of maternal micronutrient supplementation on early neonatal morbidity in rural Nepal: a randomised, controlled, community trial. Archives of Disease in Childhood. Fetal and Neonatal Edition 2008;93(8):660-4.
  • Christian P, Jiang T, Khatry SK, LeClerq SC, Shrestha SR, West Jr KP. Antenatal supplementation with micronutrients and biochemical indicators of status and subclinical infection in rural Nepal. American Journal of Clinical Nutrition 2006;83:788-94.
  • Christian P, Khatry SK, Katz J, Pradhan EK, LeClerq SC, Shrestha SR, et al. Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: double blind randomised community trial. BMJ 2003;326(7389):571.
  • Christian P, Khatry SK, LeClerq SC, Dali SM. Effects of prenatal micronutrient supplementation on complications of labor and delivery and puerperal morbidity in rural Nepal. International Journal of Gynecology & Obstetrics 2009;106(1):3-7.
  • Christian P, Murray-Kolb LE, Khatry SK, Katz J, Schaefer BA, Cole PM, et al. Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal. JAMA 2010;304(24):2716-23.
  • Christian P, Shrestha J, LeClerq SC, Khatry SK, Jiang T, Wagner T, et al. Supplementation with micronutrients in addition to iron and folic acid does not further improve the hematologic status of pregnant women in rural Nepal. Journal of Nutrition 2003;133(11):3492-8.
  • Christian P, Stewart CP, LeClerq SC, Wu L, Katz J, West KPJ, et al. Antenatal and postnatal iron supplementation and childhood mortality in rural Nepal: a prospective follow-up in a randomized, controlled community trial. American Journal of Epidemiology 2009;170(9):1127-36.
  • Christian P, West KP, Khatry SK, Leclerq SC, Pradhan EK, Katz J, et al. Effects of maternal micronutrient supplementation on fetal loss and infant mortality: a cluster-randomized trial in Nepal. American Journal of Clinical Nutrition 2003;78(6):1194-202.
  • Katz J, Christian P, Dominici F, Zeger SL. Treatment effects of maternal micronutrient supplementation vary by percentiles of the birth weight distribution in rural Nepal. Journal of Nutrition 2006;136(5):1389-94.
  • Nanayakkara-Bind A, Schulze K, Wu L, Le SC, Khatry SK, Christian P. Effects of antenatal micronutrient supplementation on cortisol and erythropoietin in pregnant Nepalese women. FASEB Journal 2011;25:779.15.
  • Stewart CP, Christian P, LeClerq SC, West KPJ, Khatry SK. Antenatal supplementation with folic acid + iron + zinc improves linear growth and reduces peripheral adiposity in school-age children in rural Nepal. American Journal of Clinical Nutrition 2009;90(1):132-40.
  • Stewart CP, Christian P, Schulze KJ, Arguello M, Leclerq SC, Khatry SK, et al. Low maternal vitamin B-12 status is associated with offspring insulin resistance regardless of antenatal micronutrient supplementation in rural Nepal. Journal of Nutrition 2011;141(10):1912-7.
  • Stewart CP, Christian P, Schulze KJ, Leclerq SC, West KPJ, Khatry SK. Antenatal micronutrient supplementation reduces metabolic syndrome in 6- to 8-year-old children in rural Nepal. Journal of Nutrition 2009;139(8):1575-81.
Dawson 1962 {published data only}
Decsi 2005 {published data only}
  • Broekaert I, Campoy C, Iznaola C, Hoffman B, Mueller-Felber W, Koletzko BV. Visual evoked potentials in infants after dietary supply of docosahexaenoic acid and 5-methyl-tetrahydrofolate during pregnancy. Journal of Pediatric Gastroenterology and Nutrition 2004;39(Suppl 1):S33.
  • Campoy C, Escolano-Margarit MV, Ramos R, Parrilla-Roure M, Csabi G, Beyer J, et al. Effects of prenatal fish-oil and 5-methyltetrahydrofolate supplementation on cognitive development of children at 6.5 y of age. American Journal of Clinical Nutrition 2011;94(6 Suppl):1880S-8S.
  • Campoy C, Marchal G, Decsi T, Cruz M, Szabo E, Demmelmair H, et al. Spanish pregnant women's plasma phospholipids LC-PUFAs concentrations and its influence on their newborns. Journal of Pediatric Gastroenterology and Nutrition 2004;39(Suppl 1):S11.
  • Decsi T, Campoy C, Koletzko B. Effect of n-3 polyunsaturated fatty acid supplementation in pregnancy: the nuheal trial. Advances in Experimental Medicine & Biology 2005;569:109-13.
  • Demmelmair H, Klingler M, Campoy C, Decsi T, Koletzko B. Low eicosapentaenoic acid concentrations in fish oil supplements do not influence the arachidonic acid contents in placental lipids. Journal of Pediatric Gastroenterology and Nutrition 2004;39(Suppl 1):S11.
  • Demmelmair H, Klingler M, Campoy C, Diaz J, Decsi T, Veszpremi B, et al. The influence of habitual diet and increased docosahexaenoic acid intake during pregnancy on the fatty acid composition of individual placental lipids [abstract]. Journal of Pediatric Gastroenterology & Nutrition 2005;40(5):622-3.
  • Dolz V, Campoy C, Molloy A, Scott J, Marchal G, Decsi T, et al. Homocysteine, folate & methylenetetrahydrofolate reductase (MTHFR) 677 - T poly-morphism in Spanish pregnant woman and in their offspring [abstract]. Journal of Pediatric Gastroenterology & Nutrition 2005;40(5):623-4.
  • Franke C, Demmelmair H, Decsi T, Campoy C, Cruz M, Molina-Font JA, et al. Influence of fish oil or folate supplementation on the time course of plasma redox markers during pregnancy. British Journal of Nutrition 2010;103(11):1648-56.
  • Krauss-Etschmann S, Shadid R, Campoy C, Hoster E, Demmelmair H, iménez M, et al. Nutrition and Health Lifestyle (NUHEAL) Study Group. Effects of fish-oil and folate supplementation of pregnant women on maternal and fetal plasma concentrations of docosahexaenoic acid and eicosapentaenioc acid: a European randomised multicenter trial. American Journal of Clinical Nutrition 2007;85(5):1392-400.
Edelstein 1968 {published data only}
  • Edelstein T, Stevens K, Baumslag N, Metz J. Folic acid and vitamin B12 supplementation during pregnancy in a population subsisting on a sub-optimal diet. Journal of Obstetrics and Gynaecology of the British Commonwealth 1968;75:133-7.
Fleming 1968 {published data only}
  • Fleming AF, Hendrickse JP, Allan NC. The prevention of megaloblastic anaemia in pregnancy in Nigeria. Journal of Obstetrics and Gynaecology of the British Commonwealth 1968;75(4):425-32.
Fletcher 1971 {published data only}
Giles 1971 {published data only}
  • Giles PF, Harcourt AG, Whiteside MG. The effect of prescribing folic acid during pregnancy on birthweight and duration of pregnancy. A double blind trial. Medical Journal of Australia 1971;2:17-21.
Harrison 1985 {published data only}
  • Fleming AF, Ghatoura GBS, Harrison KA, Briggs ND, Dunn DT. The prevention of anaemia in pregnancy in primigravidae in the guinea savanna of Nigeria. Annals of Tropical Medicine and Parasitology 1986;80:211-33.
  • Fleming AF, Ludwig H, Thomsen K. Anaemia in pregnancy in the Guinea Savanna of Nigeria. Gynecology and Obstetrics. Berlin: Springer-Verlag, 1986:122-4.
  • Harrison KA, Fleming AF, Briggs ND, Rossiter CE. Child-bearing, health and social priorities: a survey of 22,774 consecutive hospital births in Zaria, Northern Nigeria. 5. Growth during pregnancy in Nigerian teenage primigravidae. British Journal of Obstetrics and Gynaecology 1985;92(5):32-9.
Hibbard 1969a {published data only}
Iyengar 1975 {published data only}
Lira 1989 {published data only}
  • Lira P, Barrena N, Foradori A, Gormaz G, Grebe G. Folate deficiency in pregnancy: effect of supplementary folic acid [Deficienca de folatos en el embarazo: efecto de una suplementacion con acido folico]. Sangre 1989;34(1):24-7.
Menon 1962 {published data only}
  • Menon MKK, Rajan L. Prophylaxis of anaemia in pregnancy. Journal of Obstetrics and Gynaecology of India 1962;12:382-9.
Metz 1965 {published data only}
  • Metz J, Festenstein H, Welch P. Effect of folic acid and vitamin B12 supplementation on test of folate and Vitamin B12 nutrition in pregnancy. American Journal of Clinical Nutrition 1965;16:472-9.
Pack 1980 {published data only}
  • Pack ARC, Thomson ME. Effects of folic acid (FA) supplementation on gingivitis in pregnancy. Journal of Dental Research 1980;59(D1):1777.
  • Pack ARC, Thomson ME. Effects of topical and systemic folic acid supplementation on gingivitis in pregnancy. Journal of Clinical Periodontology 1980;7:402-14.
Rae 1970 {published data only}
  • Rae PG, Robb PM. Megaloblastic anaemia of pregnancy: a clinical and  laboratory study with particular reference to the total and  labile serum folate levels. Journal of Clinical Pathology 1970;23:379-91.
Rolschau 1979 {published data only}
Roth 1980 {published data only}
Srisupandit 1983 {published data only}
  • Srisupandit S, Pootrakul P, Areekul S, Neungton S, Mokkaves J, Kiriwat O, et al. A prophylactic supplementation of iron and folate in pregnancy. Southeast Asian Journal of Tropical Medicine and Public Health 1983;14:317-23.
Tchernia 1982 {published and unpublished data}
  • Tchernia G, Blot I, Rey A, Kaltwasser JP, Zittoun J, Papiernik E. Maternal folate status, birthweight and gestational age. Developmental Pharmacology Therapeutics 1982;4:58-65.
Trigg 1976 {published data only}
  • Trigg KH, Rendall EJC, Johnson A, Fellingham FR, Prankerd TAJ. Folate supplements during pregnancy. Journal of the Royal College of General Practitioners 1976;26:228-30.
Weil 1977 {published data only}
  • Weil A, Mauracher E. Folic acid and pregnancy, a real problem? [Acide folique et gravidité, problème réel?]. Schweizer Medizinische Wochenschrift 1977;107:1943-7.
Willoughby 1967 {published data only}

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé scientifiqueアブストラクト
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Bjerre 1967 {published data only}
  • Bjerre B. Study of the haematological effect of prophylactic folic acid medicamentation in pregnancy. Acta Obstetricia et Gynecologica Scandinavica 1967;46(4):71-85.
Colman 1974 {published data only}
Colman 1975 {published data only}
  • Colman N, Larsen JV, Barker M, Barker EA, Green R, Metz J. Prevention of folate deficiency by food fortification. III. Effect in pregnant subjects of varying amounts of added folic acid. American Journal of Clinical Nutrition 1975;28:465-70.
Ellison 2004 {published data only}
Giles 1960 {published data only}
Gregory 2001 {published data only}
  • Gregory JF 3rd, Caudill MA, Opalko FJ, Bailey LB. Kinetics of folate turnover in pregnant women (second trimester) and nonpregnant controls during folic acid supplementation: stable-isotopic labeling of plasma folate, urinary folate and folate catabolites shows subtle effects of pregnancy on turnover of folate pools. Journal of Nutrition 2001;131(7):1928-37.
Hague 1998 {published data only}
  • Hague B, Crowther C, Robinson J, Dekker G, Odendaal H. Prevention of recurrent pre-eclampsia by folic acid supplementation in women with hyperhomocysteinaemia: proposal for a randomized trial. Netherlands Journal of Medicine 1998;52:S24.
  • Hague B, Dekker G, Crowther C, Robinson J, Odendaal H. The HOPE (hyperhomocysteinaemia in pre-eclampsia) trial: prevention of recurrent pre-eclampsia by folic acid supplementation in women with hyperhomocysteinemia. Hypertension in Pregnancy 2000;19(Suppl 1):Abstract no P10.
Hamilton 1973 {published data only}
  • Hamilton PJS, Gebbie DAM. Antenatal clinics as trial units in evaluating treatment of anaemia in pregnancy. The use and abuse of drugs and chemicals in Tropical Africa. Proceedings of the 1973 Annual Scientific Conference of the East African Medical Research Council. Nairobi, Kenya.: Nairobi: East African Literature Bureau, 1973:463-6.
Hekmatdoost 2011 {published data only}
  • Hekmatdoost A. Comparison of the effect of folic acid and 5-methyltetrahydrofolate (5MTHF) on serum folate and homocysteine levels, and abortion rates in women suffering from recurrent abortion. IRCT Iranian Registry of Clinical Trials (www.irct.ir) (accessed 8 July 2011).
Hibbard 1969 {published data only}
Khanna 1977 {published data only}
Klinger 2006 {published data only}
  • Klingler M, Blaschitz A, Campoy C, Cano A, Molloy AM, Scott JM, et al. The effect of docosahexaenoic avid and folic acid supplementation on placental apoptosis and proliferation. British Journal of Nutrition 2006;96(1):182-90.
Kristoffersen 1979 {published data only}
  • Kristoffersen K, Rolschau J, Date JV, Honore E. The influence of folic acid supplement on intrauterine growth [abstract]. 9th World Congress of Gynecology and Obstetrics;Tokyo, Japan; 1979 October 26-31. 1979:242.
Ma 2008 {published data only}
  • Ma AG, Schouten EG, Zhang FZ, Kok FJ, Yang F, Jiang DC, et al. Retinol and riboflavin supplementation decreases the prevalence of anaemia in Chinese pregnant women taking iron and folic acid supplements. Journal of Nutrition 2008;138(10):1946-50.
Manizheh 2009 {published data only}
  • Manizheh SM, Mandana S, Hassan A, Amir GH, Mahlisha KS, Morteza G. Comparison study on the effect of prenatal administration of high dose and low dose folic acid. Saudi Medical Journal 2009;30(1):88-97.
Melli 2008 {published data only}
  • Melli MS, Shojaiee M, Sheshvan MK. Prenatal administration of high dose and low dose of folic acid on maternal plasma homocysteine concentration and its relationship to the development of preeclampsia. Journal of Maternal-Fetal and Neonatal Medicine 2008;21(Suppl 1):82.
Ouma 2006 {published data only}
  • Ouma P, Parise ME, Hamel MJ, ter Kuile FO, Otieno K, Ayisi JG, et al. A randomised controlled trial of folate supplementation when treating malaria in pregnancy with sulfadoxine-pyrimethamine. PLoS Clinical Trials 2006;1(6):e28.
  • van Eijk AM, Ouma PO, Williamson J, ter Kuile FO, Parise M, Otieno K, et al. Plasma folate level and high-dose folate supplementation predict sulfadoxine-primethamine treatment failure in pregnant women in Western Kenya who have uncomplicated malaria. Journal of Infectious Diseases 2008;198(10):1550-3.
Polatti 1992 {published data only}
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Taylor 1979 {published data only}
Taylor 1981 {published data only}
Tchernia 1982a {published data only}
Thomson 1982 {published data only}
Ulrich 1999 {published data only}
  • Ulrich M, Kristoffersen K, Rolschau J, Grinsted P, Schaumburg E, Foged N. The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part II. Congenital anomalies. A randomised study. European Journal of Obstetrics & Gynecology and Reproductive Biology 1999;87(2):111-3.
Wang 2012 {published data only}
  • Wang W, Yan H, Zeng L, Cheng Y, Wang D, Li Q. No effect of maternal micronutrient supplementation on early childhood growth in rural western China: 30 month follow-up evaluation of a double blind, cluster randomized controlled trial. European Journal of Clinical Nutrition 2012;66(2):261-8.
Zeng 2008 {published data only}
  • Zeng L, Dibley MJ, Cheng Y, Dang S, Chang S, Kong L, et al. Impact of micronutrient supplementation during pregnancy on birth weight, duration of gestation, and perinatal mortality in rural western China: double blind cluster randomised controlled trial. BMJ 2008;337:a2001.
  • Zeng L, Yan H, Cheng Y, Dang S, Dibley MJ. Adherence and costs of micronutrient supplementation in pregnancy in a double-blind, randomized, controlled trial in rural western China. Food and Nutrition Bulletin 2009;30(4):S480-7.

References to ongoing studies

  1. Top of page
  2. AbstractRésumé scientifiqueアブストラクト
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Wen 2012 {published data only}
  • Wen SW. Effect of folic acid supplementation in pregnancy on pre-eclampsia - folic acid clinical trial (FACT). Current Controlled Trials (http://www.current-trials.com) (accessed 8 July 2011).
  • Wen SW, Champagne J, Rennicks R, Walker M. Effect of folic acid supplementation in pregnancy on preeclampsia - Folic acid clinical trial (FACT). Pregnancy Hypertension 2012;2(3):180.
  • Wen SW, Walker M. Effect of folic acid supplementation in pregnancy on preeclampsia. Pregnancy Hypertension 2010;1(Suppl 1):S28.

Additional references

  1. Top of page
  2. AbstractRésumé scientifiqueアブストラクト
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Açkurt 1995
  • Açkurt F, Wetherilt H, Löker M, Hacibekiro M. Biochemical assessment of nutritional status in pre- and post-natal Turkish women and outcome of pregnancy. European Journal of Clinical Nutrition 1995;49:613-22.
Bailey 1995
  • Bailey LB. Folate requirements and dietary recommendations. In: Bailey LB editor(s). Folate in Health and Disease. New York: Marcel Dekker, 1995:123-52.
Bates 1986
  • Bates CJ, Fuller NJ, Prentice AM. Folate status during pregnancy and lactation in a West African rural community. Human Nutrition. Clinical Nutrition 1986;40:3-13.
Botto 1996
  • Botto LD, Khoury MJ, Mulinare J, Erickson JD. Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population based, case-control study. Pediatrics 1996;98(5):911-7.
Bruinse 1995
Bukowski 2009
  • Bukowski R, Malone FD, Porter FT, Nyberg DA, Comstock CH, Hankins GDV, et al. Preconception folate supplementation and the risk of spontaneous preterm birth: prospective cohort study. PLoS Medicine 2009;6(5):e1000061.
Caudill 1998
  • Caudill MA, Gregory JF III, Hutson AD, Bailey LB. Folate catabolism in pregnant and nonpregnant women with controlled folate intakes. Journal of Nutrition 1998;128(2):204-8.
Chanarin 1969
  • Chanarin I. The Megaloblastic Anemias. London, United Kingdom: Blackwell Scientific, 1969:786-829.
Charles 2005b
Czeizel 1992
Czeizel 1993
Czeizel 1996
De Benoist 2008
  • De Benoist B. Conclusions of a WHO Technical Consultation on folate and vitamin B12 deficiencies. Food Nutrition Bulletin 2008;29(Suppl 2):S238-S244.
De-Regil 2010
Dietary Ref 1998
  • Anonymous. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic acid, Biotin and Choline. Institute of Medicine, 1998.
Fleming 1972
Food and Nutrition Board 1970
  • Food, Nutrition Board. National Research Council. Maternal Nutrition and the Course of Pregnancy. Washington, DC: National Academy of Sciences, 1970.
Food and Nutrition Board 1998
  • Food, Nutrition Board. Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline. Washington, DC: National Academy Press, 1998.
Goldenberg 1992
  • Goldenberg RL, Tamura T, Cliver SP, Cutter GR, Hoffman HJ, Copper RL. Serum folate and fetal growth retardation: a matter of compliance?. Obstetrics and Gynecology 1992;79:719-22.
Green 1995
  • Green R, Jacobsen DW. Clinical implications of hyperhomocysteinemia. In: Bailey LB editor(s). Folate in Health and Disease. Newyork (NY): Marcel Dekker, 1995:75-122.
Gregory 2001b
  • Gregory JF III, Caudill MA, Opalko J, Bailey LB. Kinetics of folate turnover in pregnant women (second trimester) and nonpregnant controls during folic acid supplementation: stable-isotopic labelling of plasma folate, urinary folate and folate catabolites shows subtle effects of pregnancy on turnover of folate pools. Journal of Nutrition 2001;131:1928-37.
Haider 2006
Herbert 1997
  • Herbert V, Bigaoutte J. Call for endorsement of a petition to the Food and Drug Administration to always add vitamin B-12 to any folate fortification or supplement. American Journal of Clinical Nutrition 1997;65(2):572-3.
Higgins 2000
Higgins 2011
  • Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Institute of Medicine 2000
  • Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline. Washington, DC: National Academy Press, 2000:196-305.
Krishnaswamy 2001
Landon 1971
Lawson 1988
  • Lawson JB. Anaemia in pregnancy. In: Lawson JB, Stewart DB editor(s). Obstetrics and Gynaecology in the Tropics and Developing Countries. London: Edward Arnold, 1988:76-8.
Li 1995
Makedos 2007
  • Makedos G, Papanicolaou A, Hitoglou A, Kalogiannidis I, Makedos A, Vrazioti V, et al. Homocysteine, folic acid and B12 serum levels in pregnancy complicated with preeclampsia. Archives of Gynecology and Obstetrics 2007;275(2):121–4.
McPartlin 1993
Morrison 1998
MRC 1991
Neggers 1997
  • Neggers YH, Goldenberg RL, Tamura T, Cliver SP, Hoffman HJ. The relationship between maternal dietary intake and infant birthweight. Acta Obstetricia et Gynecologica Scandinavica 1997;165:71-5.
NICE 2008
  • National Institute for Health and Clinical Excellence. NICE public health guidance 11: Improving the nutrition of pregnant and breastfeeding mothers and children in low-income households. London: NICE, 2011 July.
Patrick 2004
  • Patrick TE, Powers RW, Daftary AR, Ness RB, Roberts JM. Homocysteine and folic acid are inversely related in black women with preeclampsia. Hypertension 2004;43(6):1279–82.
Pena-Rosas 2006
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RevMan 2011
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
Rush 1994
Scholl 2000
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Selhub 1993
Shaw 1995
  • Shaw GM, Lammer EJ, Wasserman CR, O'Malley CD, Tolarova MM. Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet 1995;346(8972):393-6.
Smith 1983
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Smits 2001
Tamura 1992
  • Tamura T, Goldenberg RL, Freeberg LE, Cliver SP, Cutter GR, Hoffman HJ. Maternal serum folate and zinc concentrations and their relationships to pregnancy outcome. American Journal of Clinical Nutrition 1992;56:365-70.
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References to other published versions of this review

  1. Top of page
  2. AbstractRésumé scientifiqueアブストラクト
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Mahomed 1995
  • Mahomed K. Routine folate supplementation in pregnancy. [revised 28 April 1993]. In: Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, Crowther C (eds.) Pregnancy and Childbirth Module. In: The Cochrane Pregnancy and Childbirth Database [database on disk and CDROM]. The Cochrane Collaboration; Issue 2, Oxford: Update Software; 1995.
Mahomed 1997