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economic status with incidence of NTD, but this has not been analyzed in recent years.

Nutritional markers, particularly maternal serum vitamin B12 and serum and erythrocyte folate, as well as their metabolic indicators of adequacy, have been assessed in relation to the risk of NTD. The results have been inconsistent, some showing no association with NTD prevalence (Wald, 1994). Others have demonstrated low or low normal levels of both vitamin B12 and erythrocyte folate and suggested that both vitamins represent independent risk factors for NTD (Kirke et al., 1993). Methylmalonic acid is elevated in maternal serum of midterm NTD pregnancies (Adams et al., 1995). Some of the women who gave birth to infants with NTDs had elevated homocysteine values (Mills et al., 1995; Steegers-Theunissen et al., 1994). These studies support the proposition that NTD is associated with altered status of vitamin B12, folate, or both during pregnancy.

Teratology Studies. Drugs identified as causes of NTD in humans include folate antagonists (specifically aminopterin, previously used as an antitumor agent) (Thiersch, 1952); carbamazepine (Rosa, 1991) and valproate (commonly used antiepileptic drugs) (Blaw and Woody, 1983; Gomez, 1981; Stanley and Chambers, 1982); and retinoids, including isotretinoin (used to treat acne) (Dai et al., 1989; Hill, 1984) and etretinate (used to treat psoriasis) (Happle et al., 1984). Clomiphene (an oocyte maturation agent) is also suspected as a teratological cause of human NTDs (Wilson, 1973). These agents account for less than 0.1 percent of all NTDs. In general, the induced malformations are not restricted to NTD, and the precise mechanisms of these teratological effects are not clear. Indeed, as with other teratogens, the pharmacological and teratological mechanisms may differ because the embryo, especially at neurulation stages or earlier, is a qualitatively different organism from other developmental stages and the adult.

Risk of NTD According to Maternal Intake of Folate

The possibility that folate might be involved in NTD was first raised by Hibbard (1964). This was followed by observational studies of the effect of both dietary folate and folate supplements on NTD (Table 8-7), nonrandomized intervention studies of folate supplementation (Table 8-8), and randomized prevention studies, most of which were conducted with women who had prior NTD pregnancies (Table 8-8). The best evidence comes from the four randomized prevention trials (Czeizel and Dudas, 1992; Kirke et al., 1992;



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