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Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects

RHL Commentary by Bhutta ZA and Hasan B

1. EVIDENCE SUMMARY

The primary objective of this review was to determine the beneficial effect, if any, of the administration of folate and/or multivitamins (FMV) during the periconceptional period primarily on the incidence of neural tube defects (NTDs) but also on other congenital abnormalities and fetal survival.

Four trials were included in the meta-analysis. The analysis demonstrated a beneficial effect of folate supplementation on the incidence of NTDs. The odds ratio (OR) of delivering a neonate with NTD in the group that received supplementation was 0.28 (95% CI 0.15-0.53). This beneficial effect was equally beneficial in reducing recurrence (OR: 0.13; 95% CI: 0.03-0.65) and first-time occurrence of the defect (OR: 0.32; 95% CI: 0.16-0.64). The analysis also showed a statistically significant association between folate supplementation specifically and reduction in the prevalence of NTDs, whereas the administration of multivitamins without folate was of little benefit in this regard. A direct comparison of folate versus multivitamin groups indicated a statistically significant reduction in the incidence of NTDs in the folate group (OR 0.28; 95% CI: 0.09 to 0.92).

There was no statistically significant increase in adverse effects of folate supplementation such as incidence rates of spontaneous abortion or ectopic pregnancy. However, the primary reviewer highlighted one potential area of concern. Three of the four trials included in the meta-analysis demonstrated an increase in multiple pregnancies, although the results did not reach statistical significance (OR: 1.4; 95% CI: 0.93-2.11). The reviewers concede that even a small increase in multiple pregnancies at a population level could alter markedly the risk-benefit ratio of folate supplementation.

The quality of the four trials included varied. All evaluated trials had relatively low power to identify any impact of FMV supplementation on the prevalence of major congenital defects other than NTDs. Overall, however, all trials were consistent in showing a strong beneficial effect of folate supplementation on the incidence of NTDs.

A new large-scale trial conducted in China (1), corroborated the above findings. In this quasi-experimental trial conducted in areas with both low and high prevalence of NTDs, women who were planning to marry and thus underwent a premarital examination, were asked to take 400 mcg of folic acid daily until the end of the first trimester of pregnancy. Women who took folate in the periconceptional period and who had a high compliance rate (defined as at least 80% use rate of the supplement) showed an 85% reduction in risk in the area with high rates of NTDs and a 40% decrease in risk in the area with lower NTD rates.

Overall, the review strongly supports the use of periconceptional folate supplementation for the prevention of NTDs.

Overall, the search strategy was adequate, although the trial from China (1), and India (2), were not included. The review does not adequately address the need to evaluate the most effective means of delivering folate supplementation.

Although the principle outcomes measured were NTDs and other congenital malformations, the effect of folate supplementation on other adverse pregnancy outcomes should have been mentioned. The reviewer does not refer to the related Cochrane Review by Mahomed (3), which evaluated the effect of folate supplementation during pregnancy on various pregnancy outcomes.

2. RELEVANCE TO UNDER-RESOURCED SETTINGS

2.1. Magnitude of the problem

Recent data describing the prevalence of this problem in developing countries are both conflicting and sparse. However, as there have been few public health interventions involving folate supplementation, it is likely that the prevalence rates mentioned in previous studies (cited below) would not have altered to a significant degree. As reported in several epidemiological surveys (4, 5), the prevalence of NTDs was fairly high and varied in different parts of India (ranging from as low as 1.1/1000 live births in Kolkata to as high as 18/1000 live births in the state of Rajasthan). Another study (6), indicated that the prevalence of NTDs was 11.4/1000 births in one of the areas of India. A study from China(7), showed that in the northern province of Hebei the rates of NTDs ranged from 5-6/1000 live births, whereas the rates were much lower (1/1000 births) in the southern provinces of Zhejiang and Jiangsu. The magnitude of the problem can be judged from the prevalence rates in the USA, which according to a survey(8), done between 1985 and1994 were 1/1000 live births. A report from the WHO in 1992 (9, 10), indicated that the percentage of pregnant women with a serum folic acid level less than 3 ng/ml was highest among pregnant women in Sri Lanka (57%), followed by India (41.6%), Myanmar (13%) and Thailand (15%).

2.2. Feasibility of the intervention

Folate supplementation would be of great benefit in developing country settings for several reasons. First, the prevalence of NTDs in developing countries is very high compared to the developed world. Folic acid supplements are readily available and affordable. Since iron supplementation is almost universally recommended in pregnancy, especially in developing country reproductive health programmes, it would be convenient to combine the two interventions. However, the key is to administer the folic acid supplement periconceptionally, which may not be easy in public health programmes geared principally towards pregnant women.

An economic analysis of folic acid fortification of grain from the USA (11), demonstrated clearly that the food fortification was a cost-effective method of folate supplementation. The ratio of benefit to cost is estimated at 4.3:1 for low-level and 6.1:1 for high-level fortification, respectively. Such methods of food fortification are potentially cost-effective options for large-scale folate supplementation programmes at a population level.

2.3. Applicability of the results of the Cochrane Review

The applicability of the result of the trials reviewed in this analysis is obvious for developing country settings. In a multicentre randomized placebo-controlled trial in India (2), a similar beneficial effect of supplementation of multivitamin (consisting of 5 mg folate) was observed, with a recurrence rate in the vitamin group of 2.9% compared to 7.0% in the placebo group (p=0.06). However, a criticism of this trial was the extremely high, although similar, rate of dropouts in both the intervention (40.7%) and the placebo groups (39.6%), which could effect the interpretation of the data.

2.4. Implementation of the intervention

The Cochrane Review argues strongly in favour of rapid implementation of this intervention. While this can be accomplished quickly and easily in developed countries (most of which have well established programmes), the same may not be easy in developing countries. In particular, where reproductive health programmes are principally geared towards interventions in pregnancy and antenatal care typically starts after the first trimester, periconceptional interventions may be difficult to implement. It may be feasible instead to focus on the administration of iron-folate tablets to newly weds in high-risk populations and those with previous births with NTDs.

2.5. Research

Although the benefit of periconceptional folate supplementation on the prevention of NTDs seems well established, there are several issues that still merit further research. These include determination of the most feasible and cost-effective method of supplementing large at-risk populations, determination of the most appropriate dose and other potential beneficial effects on outcomes of pregnancy. The following may merit further consideration:

• Since a placebo-controlled trial will no longer be ethical, a trial looking at different doses of folate supplementation and its effect in decreasing the prevalence of NTD would be helpful to determine not only the minimum effective dose (which is presently regarded as 0.4 mg/day) for decreasing the incidence of occurrence of NTDs but also the minimum dose required to decrease the prevalence of recurrent NTD (which presently is 4 mg/day).
• A community-based effectiveness trial should be conducted to look at the most cost-effective and sustainable method of providing folate supplementation during the periconceptional period. This may involve comparisons of approaches like food fortification, dietary counseling, folate supplementation in primary health clinics or a combination of methods. A recent study (12), of the relationship between red blood cell folate and consumption of different sources of folate demonstrated that those receiving folic acid had higher mean red blood cell folate levels than those consuming cereals fortified with folic acid. Red blood cell folate levels higher than 400 mcg /ml (a level considered to be optimal for the prevention of NTDs) were found nearly exclusively among folic acid supplement users.
• Several studies have also revealed highly variable rates of folate consumption by both pregnant and non-pregnant women. A study to determine the knowledge, attitudes and practices of mothers regarding folic acid intake during the periconceptional period (13), showed that only 76 % of the women were cognizant of its importance and of these only 44 % had taken the supplements. Thus, further research is needed on strategies to improve compliance with folic acid intake.
• Although the evidence linking folate deficiency to increased risk of NTDs is pervasive, the contributory effect of other micronutrient deficiencies cannot be excluded. Further research should be conducted to determine the associations between the prevalence of deficiencies of other vitamins and micronutrients and risk of NTDs. Such studies could then be followed up with randomized controlled trials to evaluate at any beneficial effect of administering additional supplements along with folate.
• The reportedly increased incidence of multiple pregnancies among women administered folate supplements, merits further evaluation.

References

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• Multicentric study of efficacy of periconceptional folic acid containing vitamin supplementation in prevention of open neural tube defects from India. Indian journal of medical research 2000;112:206-211.
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This document should be cited as: Bhutta ZA and Hasan B. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects: RHL commentary (last revised: 7 January 2002). The WHO Reproductive Health Library; Geneva: World Health Organization.