Folic acid and birth malformations
Authors: C Bille, J C Murray, S F Olsen
Journal: BMJ (2007)

With prevalences of 10-15 per 10 000 and 20 per 10 000 live births, neural tube defects and oral clefts are among the most common congenital malformations. Good evidence shows that periconceptional supplementation with folic acid reduces the risk of neural tube defects.1,2 What is less clear is the effect of folic acid supplementation on other birth defects, such as cleft lip, with or without cleft palate.

In this week's BMJ, Wilcox and colleagues3 report a population based case-control study from Norway, which shows that supplementation with folic acid in the periconceptional period reduces the risk of cleft lip, with or without cleft palate, in newborns. Supplementation with 400µg of folic acid for three months around conception was associated with a 40% reduction in the prevalence of cleft lip, with or without cleft palate, at birth (adjusted odds ratio 0.61, 95% confidence interval 0.39 to 0.96). Exposure data were obtained retrospectively one year after conception, but the reliability of the data was enhanced by evaluating information on pill bottle labels and brands. This was a large, well designed study that used high quality registries; this enabled efficient early case identification and control selection. The study supports findings from other recent studies,4 including a large meta-analysis.5

The evidence that folic acid reduces malformations is robust, but how much is needed and how it should be taken is less clear. Despite these uncertainties, 400 µg folic acid per day has been estimated to prevent a large proportion of neural tube defects.1,2 Three public health strategies for reaching this dose have been suggested. The first is for women to eat a diet rich in natural folates. However, it is difficult to reach this dose with diet alone, and folate in the diet has lower bioavailability than synthetic folic acid. The second is for women to take supplements of folic acid in the periconceptual period. This strategy is compromised by low compliance and high rates of unplanned pregnancy. Studies have shown that although mass media campaigns increased awareness up to nearly 80%, fewer than 50% of women followed the recommendations.6,7 The third strategy is mandatory fortification of staple foods (such as wheat, corn flour, or rice). This would achieve coverage in a large section of the population. Countries differ substantially in their choices of preventive strategy. 

The World Health Organization has recommended supplementation with 400 µg of folic acid in the periconceptual period. Fortification of food is mandatory in an increasing number of countries (Brazil, Canada, Chile, Costa Rica, Jordan, South Africa, and the United States). In general, however, Europe has not followed, despite the finding that even suboptimal fortification (for example, 180 µg/day in the US) greatly reduces neural tube defect rates.7,8 Further support for mandatory fortification of food comes from a cohort study showing that simply recommending women planning pregnancy to take folic acid is not enough to substantially reduce the prevalence of neural tube defects at birth.9 Accumulating evidence of a protective effect of folic acid supplementation on the prevalence of oral cleft defects3,10,11,12 also supports the introduction of mandatory food fortification. However, in many European countries mandatory fortification has been limited by theoretical concerns. These include the potential of masking symptoms of vitamin B12 deficiency, interactions with certain drugs (antifolates),6 and other unrecognised adverse effects such as the risk that some women may have idiosyncratic reactions to folic acid even in small amounts (and others might need far larger doses for a preventive or therapeutic effect). But mandatory folic acid fortification to achieve around 180 µg/day on average and 1000 µg/day at maximum holds little risk of complications.6 Despite this, questions about adverse effects and long term effects of mandatory food fortification remain unanswered, and any change in diet must be closely monitored.

What is Europe waiting for? A common argument is that introducing mandatory fortification to reach a relatively small group (women getting pregnant) is not a good enough reason to intervene at population level. If fortification would also reduce the burden of major disorders such as cardiovascular diseases and dementia the case might be different. The risks of these disorders increase with high plasma concentrations of homocysteine, and folic acid supplementation can reduce these concentrations in humans.13 However, definitive evidence (such as data from randomised controlled trials) of a protective effect of folic acid on these two diseases has yet to be found. In theory, any clinical improvement could have a long latency period, which could make it difficult or impossible to detect even in a large randomised controlled trial.

So, if this is the kind of evidence that Europe is waiting for mandatory fortification with folic acid may never happen. If this is the case, we will lose the chance of decreasing the burden of 4500 neural tube defects that occur each year in the European Union alone, not to mention the effect on cleft lip with or without cleft palate shown by Wilcox and colleagues.