Maternal nutritional factors seem to contribute substantially to the complex aetiologies of NTDs. Foremost among these factors is the periconceptional use of supplements containing folic acid, which is associated with a reduction in the risk of women having NTD-affected pregnancies. More than 30 years ago, seminal work by Smithells et al.6
showed that the diets and postpartum blood of women who had given birth to a foetus with an NTD were deficient in several micronutrients, particularly folate. Subsequent small non-randomized trials in women who had previously had NTD-affected pregnancies showed that taking folic acid or multivitamins containing folate during the periconceptional period resulted in a ~fourfold reduction in the risk of recurrence7–12
. A rigorous double-blind, placebo-controlled, randomized trial, conducted by the UK Medical Research Council13
, showed that supplementation with 4 mg folic acid per day resulted in a threefold reduction in NTD recurrence risk. Taken together, these trials indicate that supplementation of folic acid in the dose range of ~0.4–5 mg per day prevents NTD births among most women who have previously had NTD-affected pregnancies.
There is also substantial evidence that folate supplementation reduces not only the recurrence but also the occurrence of NTDs. For example, several epide-miological studies have reported reductions in NTD risks associated with maternal intake of folic acid supplements or folate-rich diets14–20
. Additional support for the importance of folate in NTD risk reduction was provided by Hernandez-Diaz et al.21
Their study showed that periconceptional intake of medications that act as folic acid antagonists, such as carbamazepine or tri-methoprim, could double the risk of NTD-affected pregnancies. Moreover, these investigators observed that the increased NTD risks associated with folate antagonists were attenuated by folic acid supplementation.
Evidence has emerged to suggest that maternal immunological responses that influence folate transport could affect embryonic development. Recently, Rothenberg et al.22
reported the presence of auto-antibodies to the folate receptor in 75% of mothers who had given birth to NTD-affected infants, but in only 10% of mothers of non-malformed infants. This discrepancy in frequency correlated with a greater than 25-fold increase in the risk of NTDs in the infants of mothers that carried these antibodies. This small study suggests that maternal auto-antibodies that bind to the folate receptor, and so block the intracellular uptake of folate by target epithelial cells, might cause NTDs, which could explain the beneficial effect of periconceptional folate supplementation. In support of this, the lack of folate available to the developing embryo secondary to a defective or blocked folate receptor has been shown to increase the risk of folate-responsive congenital anomalies in experimental animal model systems23–27
Another body of evidence that suggests that altered folate metabolism contributes to abnormal neural tube development derives from analyses of postpartum serum. Several clinical studies indicate that folate concentrations in postpartum serum and red blood cells are lower among women who have previously had a child with an NTD28–30
; however, there have been conflicting results, with some studies failing to find such an association31–35
. Whether it is a low maternal intake or altered absorption/metabolism of folate that is responsible for the observed association with NTD risk has yet to be established36
Finally, a natural population experiment provides further support for the involvement of folate in preventing NTDs. In the United States, fortification of flour and other enriched grain products with folic acid has been compulsory since 1998 (REF. 37
). This has been effective in increasing folate concentration in both serum and red blood cells among women of childbearing age38
: these increased concentrations have been attributed mainly to fortification of food, rather than to increased use of vitamin supplements among these women38
. This supplementation has coincided with a 19% decrease in the prevalence of NTDs39
, which incorporates decreases of 31% and 16% for spina bifida40,41
The preventive effects of folic acid on human NTD risk have therefore been well established. As noted above, the epidemiological evidence is robust, including consistent results from various study designs conducted in different populations: investigations showing elevated NTD risks associated with exposure to folate antagonist medications; the observation of higher auto-antibody titre to folate receptors in women who had previously had NTD-affected pregnancies; clinical studies that have reported lower postpartum folate concentration in red blood cells and serum among women who had previously had a child with an NTD; and a decline in the prevalence of NTDs since 1998, when the US food supply was fortified with folic acid.