Possible preventive effect of high doses of folic acid for isolated hypospadias: a national population-based case-control study.

Hypospadias is a common structural birth defect (congenital abnormality) of the male genital organ. The objective of this study was to test the hypothesis regarding the possible preventive effect of folic acid for isolated hypospadias (IH). Folic acid use was compared in 3,038 cases with IH and 24,814 male controls without any defects in the national population-based Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. In Hungary only one kind of folic acid tablet, containing 3 mg/tablet was available during the study period. Hungarian obstetricians recommended daily use of 1-3 tablets, that is, 3-9 mg of folic acid during pregnancy; the estimated daily dose was 5.7 or 5.6 mg in the mothers of cases with IH and controls, respectively. Of 3,038 mothers of cases 1,474 (48.5%) were supplemented with high doses of folic acid during pregnancy and 13,509/24,814 mothers of controls (54.9%) as reference were supplemented at this level as well (OR 95% CI: 0.79, 0.73-0.85). If only medically recorded folic acid use in the critical period of IH was evaluated, the preventive effect was more apparent (OR 95% CI: 0.36, 0.32-0.41). The intake of folic acid among mothers of infants with severe IH was lower than among mothers of infants with mild IH, suggesting a dose-response relationship. In conclusion, this study suggests that high doses of folic acid are associated with a reduced risk of IH. However, this analysis was based on observational data; therefore, confirmation in a well-controlled study is needed.