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Maternal Hypertension, Medication Use, and Hypospadias in the National Birth Defects Prevention Study

Van Zutphen, Alissa R. PhD; Werler, Martha M. ScD; Browne, Marilyn M. PhD; Romitti, Paul A. PhD; Bell, Erin M. PhD; McNutt, Louise-Anne PhD; Druschel, Charlotte M. MD, MPH; Mitchell, Allen A. MD

doi: 10.1097/AOG.0000000000000103
Contents: Original Research

OBJECTIVE: To investigate whether antihypertensive classes and specific medications in early pregnancy increase the risk of severe hypospadias and to assess prior associations detected for late-treated and untreated hypertension in the National Birth Defects Prevention Study.

METHODS: Using telephone interviews from mothers of 2,131 children with severe hypospadias and 5,129 nonmalformed male control children for 1997–2009 births in a population-based case–control study, we estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) with multivariable logistic regression. We adjusted P values to account for multiple testing.

RESULTS: Forty-eight (2.3%) case and 70 (1.4%) control mothers reported early pregnancy antihypertensive treatment, 45 (2.1%) case and 31 (0.6%) control mothers reported late treatment, and 315 (14.8%) case and 394 (7.7%) control mothers reported untreated hypertension. Selective β-blockers, centrally acting agents, renin–angiotensin system-acting agents, diuretics, and specific medications, methyldopa and atenolol, were not associated with hypospadias. Nonselective β-blockers (adjusted OR 3.22, 95% CI 1.47–7.05) were associated with hypospadias; however, P values adjusted for multiple testing were not statistically significant. We confirmed prior findings for associations between hypospadias and untreated hypertension (adjusted OR 2.09, 95% CI 1.76–2.48) and late initiation of treatment (adjusted OR 3.98, 95% CI 2.41–6.55). The increased risks would translate to severe hypospadias prevalences of 11.5, 17.7, and 21.9 per 10,000 births for women with untreated hypertension, nonselective β-blocker use, and late initiation of treatment, respectively.

CONCLUSION: Our study suggests a relationship between hypospadias and the severity of hypertension.


Hypospadias is associated with early pregnancy nonselective β-blocker use, late-treated hypertension, and untreated hypertension, suggesting a relationship with the severity of maternal hypertension.

Congenital Malformations Registry, New York State Department of Health, Albany, and the Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, New York; the Slone Epidemiology Center at Boston University, Boston, Massachusetts; and the Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa.

Corresponding author: Alissa R. Van Zutphen, PhD, Congenital Malformations Registry, New York State Department of Health, Empire State Plaza, Corning Tower, Room 1203, Albany, NY 12237; e-mail:

Supported by a cooperative agreement from the Centers for Disease Control and Prevention (Cooperative Agreement U01DD000487). The Slone Drug Dictionary under license from the Slone Epidemiology Center at Boston University, Boston, Massachusetts, was used to classify medications.

We thank the participants, staff, and scientists of the National Birth Defects Prevention Study from Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. We thank Adrian Michalski for replicating the analyses.

Presented in a poster at the Society for Epidemiologic Research 43rd Annual Meeting, June 23–26, 2010, Seattle, Washington.

The findings and conclusions in this report have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy.

Financial Disclosure Dr. Mitchell receives research support from Novartis Vaccines and Diagnostics for research related to a meningitis vaccine and serves on Biogen-Idec pregnancy registry advisory committees for agents used to treat multiple sclerosis. During the period of study and until August 2012, he owned stock (value less than $20,000) in Johnson & Johnson. Dr. Werler serves on the advisory boards of studies supported by manufacturers of medications used to treat rheumatoid arthritis. These manufacturers may include antihypertensive medications in their product lines. The other authors did not report any potential conflicts of interest.

© 2014 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.