Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants

JAMA Pediatr. 2015 Jan;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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Drug-Induced / epidemiology
  • Abnormalities, Drug-Induced / etiology*
  • Anti-Retroviral Agents / adverse effects*
  • Female
  • Georgia / epidemiology
  • HIV Infections / drug therapy*
  • HIV Infections / transmission
  • Humans
  • Infant, Newborn
  • Infectious Disease Transmission, Vertical / prevention & control*
  • Pregnancy
  • Pregnancy Complications, Infectious / drug therapy*
  • Pregnancy Trimester, First
  • Prenatal Exposure Delayed Effects / chemically induced*
  • Prenatal Exposure Delayed Effects / epidemiology
  • Prevalence
  • Prospective Studies
  • Risk Factors
  • Treatment Outcome


  • Anti-Retroviral Agents