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Suzan L. Carmichael, PhD; Gary M. Shaw, DrPH; Cecile Laurent, MS; Mary S. Croughan, PhD; Richard S. Olney, MD; Edward J. Lammer, MD; for the National Birth Defects Prevention Study

Arch Pediatr Adolesc Med. 2005;159:957-962.

Background  Previous studies have suggested that maternal intake of progestins during early pregnancy may be associated with an increased risk of hypospadias. Progesterone and its derivatives are commonly prescribed during early pregnancy, for example, in cases of luteal phase dysfunction and in conjunction with ovulation stimulation drugs.

Objective  To examine whether risk of hypospadias was associated with periconceptional progestin intake.

Design and Setting  The National Birth Defects Prevention Study, a population-based, multistate, case-control study including deliveries that had estimated due dates from October, 1997 to December, 2000.

Participants  Participation in the study was 71% among case mothers and 68% among control mothers. This analysis included 502 subjects diagnosed with second- or third-degree hypospadias (ie, the urethra opened at the penile shaft, scrotum, or perineum) and 1286 male, live-born, nonmalformed control subjects.

Results  Forty-two case mothers (8.4%) and 31 control mothers (2.4%) reported any pregnancy-related progestin intake from 4 weeks before through 14 weeks after conception, resulting in an odds ratio of 3.7 (95% confidence interval [CI], 2.3-6.0). Analyses stratified by several potential covariates also suggested elevated risks. For example, among the 10 cases and 13 controls who did not report any fertility-related procedures or treatments other than progestins, the odds ratio was 2.2 (95% CI, 1.0-5.0). Progestin intake for the purpose of contraception was not associated with increased risk.

Conclusion  This study found that pregnancy-related intake of progestins was associated with increased hypospadias risk.

Author Affiliations: March of Dimes Birth Defect Foundation/California Department of Health Services, California Birth Defects Monitoring Program, Berkeley (Drs Carmichael and Shaw, and Ms Laurent); Departments of Obstetrics, Gynecology and Reproductive Sciences, and Epidemiology and Biostatistics, University of California, San Francisco (Dr Croughan); National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Ga (Dr Olney); Children's Hospital Oakland Research Institute, Oakland, Calif (Dr Lammer).

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