Birth Defects among Children Born to Human Immunodeficiency Virus-infected Women: Pediatric AIDS Clinical Trials Protocols 219 and 219C

Susan B. Brogly, PhD; Mark J. Abzug, MD; D. Heather Watts, MD; Coleen K. Cunningham, MD; Paige L. Williams, PhD; James Oleske, MD; Daniel Conway, MD; Rhoda S. Sperling, MD; Hans Spiegel, MD; Russell B. Van Dyke, MD


Pediatr Infect Dis J. 2010;28(8):721-727. 

In This Article

Abstract and Introduction


Background: Some studies have detected associations between in utero antiretroviral therapy (ARV) exposure and birth defects but evidence is inconclusive.
Methods: A total of 2202 human immunodeficiency virus (HIV)-exposed children enrolled in the Pediatric AIDS Clinical Trials Group 219 and 219 C protocols before 1 year of age were included. Birth defects were classified using the Metropolitan Atlanta Congenital Defects Program coding. Logistic regression models were used to evaluate associations between first trimester in utero ARV exposure and birth defects.
Results: A total of 117 live-born children had birth defects for a prevalence of 5.3% (95% confidence interval [CI]: 4.4, 6.3). Prevalence did not differ by HIV infection status or overall ARV exposure; rates were 4.8% (95% CI: 3.7, 6.1) and 5.8% (95% CI: 4.2, 7.8) in children without and with first trimester ARV exposure, respectively. The defect rate was higher among children with first trimester efavirenz exposure (5/32, 15.6%) versus children without first trimester efavirenz exposure (adjusted odds ratio [aOR] = 4.31 [95% CI: 1.56, 11.86]). Protective effects of first trimester zidovudine exposure on musculoskeletal defects were detected (aOR = 0.24 [95% CI: 0.08, 0.69]), while a higher risk of heart defects was found (aOR = 2.04 [95% CI: 1.03, 4.05]).
Conclusions: The prevalence of birth defects was higher in this cohort of HIV-exposed children than in other pediatric cohorts. There was no association with overall ARV exposure, but there were some associations with specific agents, including efavirenz. Additional studies are needed to rule out confounding and to evaluate newer ARV agents.


Since 1998, the US Public Health Service has recommended the use of combination antiretroviral therapy (ARV) to prevent mother-to-child human immunodeficiency virus (HIV) transmission.[1] Because zidovudine and other nucleoside analogues can affect nuclear and mitochondrial deoxyribonucleic acid replication, the safety of in utero exposure to these drugs is of concern.[2] In addition, there is inadequate fetal and neonatal safety data for non-nucleoside analogues and protease inhibitors. Efavirenz, a non-nucleoside analogue, is considered a potential teratogen on the basis of animal data and case reports.[1,3–6]

While existing data on in utero ARV exposure and birth defects have been mostly reassuring,[7–9] some studies have reported elevated risks with specific exposures;[10,11] others have been limited by small sample size or possible confounding. The US Woman and Infants Transmission Study documented a birth defect rate of 3.56 per 100 live births in 2527 infants born to HIV-infected women from 1990 through 2000,[12] which was not significantly different than the rate major of defects of 2.76 per 100 live births in the general pediatric population estimated by the Metropolitan Atlanta Congenital Defects Program (MACDP).[11] However, first trimester zidovudine exposure was significantly associated with an increased risk of hypospadias among male infants. The US Antiretroviral Pregnancy Registry (APR) estimated an overall prevalence of defects of 2.9% (95% confidence interval [CI]: 2.4, 3.5) among greater than 4300 first trimester ARV exposed children, which did not differ from the rate among children exposed in later trimesters.[13] The Pediatric AIDS Clinical Trials Group (PACTG) protocols 219 and 219C provided an opportunity to further estimate the independent association between in utero ARV exposure, including newer agents, and birth defects.


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