Health Professionals:

Research on Folic Acid

In 1965, Hibbard and Smithells suggested that nutritional factors, particularly folic acid, could be related to the occurrence of congenital malformations, including NTDs. This and the observation that NTDs occur more frequently in areas with low socioeconomic levels and, presumably, poor diets, led Smithells and other investigators to use periconceptional multivitamin supplementation to prevent the recurrence of NTDs (Laurence et al. 1981, Smithells et al. 1983, Smithells et al. 1981). Their findings, however, were not universally accepted because of the lack of adequate randomization.

In 1991, the Medical Research Council (MRC) reported the results of a multicenter, prospective, randomized study of folic acid supplementation for the prevention of NTDs in 1817 women who had a previous child with a NTD (MRC Vitamin Study Research Group, 1991). The data conclusively demonstrated a 71% reduction in the recurrence of NTDs in the group that took daily 4-milligram doses of folic acid with or without other vitamins before and during early pregnancy. Use of multivitamins without folic acid did not result in a reduction of NTDs.

In a nonrandomized study conducted in Cuba, a 5-milligram daily dose of folic acid given periconceptionally to 101 women who had a previous NTD birth resulted in no recurrences. In contrast, four recurrences were noted among 118 women who received no supplementation (Vergel et al. 1990).
In 1989, Milunsky et al. reported the results of an observational study of first-occurrence of NTD in a cohort of women undergoing maternal serum alpha-fetoprotein screening or amniocentesis around 16 weeks of gestation. The prevalence of NTDs was 3.5 per 1000 among non-supplemented subjects (women who never used multivitamins before or after conception or who used multivitamins before conception only) vs. 0.9 per 1000 among women who took a multivitamin containing folic acid during the first six weeks of pregnancy. For women who used multivitamins without folic acid during the first 6 weeks of pregnancy and women who used multivitamins containing folic acid beginning after 7 or more weeks of pregnancy, the prevalences were similar to that of the non-supplemented group.

Three other observational case-control studies also identified a reduced risk for NTDs among women who reported taking adequate amounts of folic acid periconceptionally (Mulinare et al. 1988, Werler et al. 1993, Bower & Stanley 1989). Only one study failed to demonstrate this protective effect (Mills et al. 1989).

To assess the effect of folic acid on first occurrence of NTDs in Hungary, Czeizel and Dudas, studied a large number of women planning a pregnancy (Czeizel & Dudas 1992). The investigators randomized the women to receive either a multivitamin supplement containing 0.8 milligrams of folic acid or a trace element supplement daily for at least one month before conception and until the date of the second missed menstrual period or later. Pregnancy was confirmed in 4753 women. The outcome of pregnancy was known in 2104 women who received the vitamin supplement and in 2052 who received the trace-element supplement. There were no cases of NTDs among the offspring of women who received periconceptional multivitamin supplements compared to 6 cases of NTDs among women supplemented with the trace-mineral supplement (P =0.029).
The preventive effect of folic acid has been further corroborated by the published results of an intervention study conducted by the Centers for Disease Control and Prevention (CDC) in two areas of China, one with high prevalence and the other with low prevalence of NTDs (Berry et al. 1999). The investigators found that among women who took 400 micrograms of folic acid from the time of their premarital examination until the end of the first trimester of pregnancy, the risk of NTDs was reduced by 85 percent in the region with high risk for NTDs and by 40 percent in the low risk region. The results of this study were important because it established that the observed reduction in NTD-affected births could be attributed solely to consumption of folic acid and also substantiated that a daily intake amount of 400 micrograms was effective for occurrence prevention. The study in China is the last folic acid supplement intervention study reported as it has now been firmly established that periconceptional folic acid intake plays a critical role in NTD risk reduction.

Preliminary data from a large population-based cohort study that included over 1.5 million Chinese women reported that compared to women who did not take folic acid supplements before and during pregnancy, women who took folic acid supplements had 55% lower odds for having a baby with a neural tube defect and 12% lower odds for having a baby with any birth defect (He et al. 2016). In this study, folic acid supplement use that began 3 months before the last menstrual period was associated with even higher reduced odds for birth defects compared to no use of folic acid.

The benefits of folic acid fortification of foods on reducing NTD rates have been reported in studies conducted with populations in the US (Williams et al. 2015), China (Wang et al. 2016), Canada (Mills & Signore 2004), Chile (Nazer and Cifuentes 2013), and California (Yang et al. 2016). A systematic review of studies examining the relationship between folic acid fortification and NTD rates in the US, Canada, Chile, Argentina, Brazil, Costa Rica, Iran, Jordan, and South Africa concluded that folic acid fortification of flour was associated with a significant reduction in the number of NTDs reported in countries where folic acid fortification is mandated (Castillo-Lancellotti et al. 2013). In this analysis, NTD reduction rates ranged from 15.5% in California to 58% in Costa Rica when comparing pre- to post-fortification time periods.

Mothers who gave birth to babies with an NTD had significantly higher plasma homocysteine concentrations compared to mothers with normal babies (Yang et al. 2016). However, no such association was seen in countries with mandatory folic acid fortification.