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Original Investigation
January 2015

Congenital Anomalies and In Utero Antiretroviral Exposure in Human Immunodeficiency Virus–Exposed Uninfected Infants

Author Affiliations
  • 1Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts
  • 2Departments of Biostatistics and Epidemiology, Harvard School of Public Health, Boston, Massachusetts
  • 3Departments of Pediatrics and Microbiology, University of Alabama at Birmingham
  • 4Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
  • 5Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana
  • 6Department of Pediatrics, University of Illinois at Chicago
  • 7Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
  • 8Department of Pediatric Infectious Disease, Bronx-Lebanon Hospital, Bronx, New York
  • 9University of Florida Center for HIV/AIDS Research, Education and Service, Jacksonville
  • 10State University of New York Downstate Medical Center, Brooklyn
  • 11Office of the US Global AIDS Coordinator, US Department of State, Washington, DC
JAMA Pediatr. 2015;169(1):48-55. doi:10.1001/jamapediatrics.2014.1889

Importance  Most studies examining the association of prenatal antiretroviral (ARV) exposures with congenital anomalies (CAs) in children born to human immunodeficiency virus (HIV)–infected women have been reassuring, but some evidence suggests an increased risk with specific ARV agents.

Objective  To evaluate the association of in utero ARV exposures with CAs in HIV-exposed uninfected children.

Design, Setting, and Participants  Prospective cohort study design. The Pediatric HIV/AIDS Cohort Study’s Surveillance Monitoring of ART Toxicities (SMARTT) Study was performed at 22 US medical centers among 2580 HIV-exposed uninfected children enrolled in the SMARTT Study between March 23, 2007, and June 18, 2012.

Exposures  First-trimester exposure to any ARV and to specific ARV medications.

Main Outcomes and Measures  The primary end point was a CA based on physician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate the association of CAs with first-trimester ARV exposures, adjusting for demographic and maternal characteristics.

Results  Congenital anomalies occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI, 5.85%-7.82%); 242 major CAs were confirmed, including 72 musculoskeletal and 55 cardiovascular CAs. The prevalence of CAs increased significantly among successive birth cohorts (3.8% for children born before 2002 and up to 8.3% for those born 2008-2010). In adjusted models, no association of first-trimester exposures with CAs was found for any ARV, for combination ARV regimens, or for any drug class. No individual ARV in the reverse transcriptase inhibitor drug classes was associated with an increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir sulfate (adjusted odds ratio [aOR], 1.95; 95% CI, 1.24-3.05) and for ritonavir used as a booster (aOR, 1.56; 95% CI, 1.11-2.20). With first-trimester atazanavir exposure, risks were highest for skin (aOR, 5.23) and musculoskeletal (aOR, 2.55) CAs.

Conclusions and Relevance  Few individual ARVs and no drug classes were associated with an increased risk of CAs in HIV-exposed infants after adjustment for calendar year and maternal characteristics. While the overall risk remained low, a relative increase was observed in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV therapy use during pregnancy still outweigh such risks, although further studies are warranted.