Association of Clomiphene and Assisted Reproductive Technologies With the Risk of Neural Tube Defects

Clomiphene and assisted reproductive technologies (ART) are methods used to help subfertile couples become pregnant. ART has been reported to be associated with neural tube defects (NTDs) in offspring. To evaluate these associations, we studied mothers of 219 cases and 4,262 controls from the Slone Epidemiology Center Birth Defects Study (1993-2012) who were interviewed within 6 months after delivery about pregnancy events, including use of fertility treatments. We considered exposures to clomiphene (without ART) and ART during the periconceptional period. Logistic regression models were used to calculate adjusted odds ratios and 95% confidence intervals, controlling for education and study center. We observed elevated adjusted odds ratios of 2.1 (95% confidence interval: 0.9, 4.8) and 2.0 (95% confidence interval: 1.1, 3.6) for clomiphene and ART exposure, respectively. We performed a mediation analysis to assess whether the observed elevated NTD risk was mediated through multiple births. For clomiphene exposure without ART use, the direct effect estimate of the adjusted odds ratio (aOR(DE)) was 1.7 and the indirect effect estimate (aOR(IE)) was 1.4. Conversely, for ART exposure, the aOR(DE) was 0.9 and the aOR(IE) was 2.5. Our findings suggest that relatively little of the clomiphene-NTD association is mediated through the pathway of multiple births, while the ART-NTD association was explained by the multiple-births pathway.