What Is the Risk of Birth Defects From HIV Drugs?

New Research Shows Low Overall Risk but Highlights Potential Concerns

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It has long been suggested that women who take certain antiretroviral medications (ARVs) during pregnancy may run an increased risk of birth defects in their children. The data is often confusing, and concerns about the potential for such defects sometimes skew our perceptions about the drugs' actual safety.

Sustiva (efavirenz, Stocrin), for example, has long been a focus of concern, with earlier clinical recommendations suggesting that it be avoided during pregnancy, or at least during the first trimester, due to a possible risk of fetal teratogenicity (birth defect).

Guidelines have since changed, which now allow for the use of efavirenz in first trimester should virologic suppression—in the way of an undetectable viral load—be achieved.

That said, the same recommendations suggest that non-pregnant women of childbearing years be advised about the potential risks, as well as the "desirability of avoiding pregnancy while on efavirenz-containing (drug) regimens."

So what does this actually means? Is the U.S. health panel simply hedging their bets about a drug that has minimum potential for birth defects? And might there be other ARVs we should be concerned about, which carry similar risk, minimal or not?

Early Research Identifies Potential Risk

In ascertaining risk, it's important to note that most data concerning ARV-induced birth defects have been based mostly on animal studies.

In regards to Sustiva, for example, concerns about teratogenicity were founded on research which identified central nervous system malformations and cleft palates in three of 20 cynomolgus monkeys receiving Sustiva during pregnancy (at plasma concentrations 1.3 higher than seen in humans).

No such defects were seen in rabbits, while rats exposed to Sustiva ran an increased risk of an entirely different concern: namely fetal resorption (wherein some of the multiple rat fetuses died during gestation and were either partially or fully reabsorbed by the surviving fetuses).

Human analyses, in the form of a review of the Antiretroviral Pregnancy Registry (APR), have painted a somewhat different picture.

While birth defects were identified in 18 of 766 children exposed to Sustiva during the first trimester of pregnancy, the low number of neural tube defects—the types seen in animal studies—put some doubt as to whether Sustiva was the sole culprit for these outcomes.

A subsequent meta-analysis of 19 different studies, including the APR, has since identified 39 birth defects out of 1,437 children exposed to Sustiva in the first trimester, but concluded that the rate was actually no different to that of the general U.S. population. Still, the low number of confirmed first-trimester exposures remained insufficient to make any definitive judgment, one way or the other.

Newer Analyses Sheds Light on Birth Defect Risks

In April 2014, researchers from the French Perinatal Cohort published a study that assessed the potential for birth defects in children exposed to a range of ARVs during pregnancy. The multi-national cohort, started in 1986, enrolled pregnant, HIV-positive women in 90 centers and compared the prevalence of birth defects in their children to those of the general population.

The results were interesting: while an increase in birth defects were seen in some of the ARVS—such as Crixivan (indinavir), where 350 birth defects were noted of the 13,124 children included in the cohort—no specific pattern was identified.

Meanwhile, of 372 babies exposed to Sustiva during the first trimester, no association between overall birth defects and the drug was noted.

That's not to say that the drugs carry no risk. In assessing their data, the French researchers did note a greater than two-fold increase in heart defects were seen in babies exposed to Retrovir (zidovudine, AZT)—primarily ventricular septal defects, common congenital defects that present with a hole between the two lower chambers of the heart.  The findings led the investigators to suggest further research to better pinpoint the potential causes for this anomaly.

Research from the Harvard School of Public Health, published shortly after in November 2014, confirmed many of the French findings. In looking at 2,580 American children exposed to ARVs during the first trimester—between the years 2007 and 2012—few individual ARVs and no classes of drug were associated with an increased risk of birth defects.

However, the Harvard researchers did note an elevated risk for skin and musculoskeletal disorders in children with first-trimester exposure to ritonavir-boosted Reyataz (atazanavir) and concluded that, while further research is warranted into Reyataz use during pregnancy, "given the low absolute (congenital anomaly) risk, the benefits of recommended ARV therapy use during pregnancy still outweigh such risks."


U.S. Department of Health and Human Services (DHHS). "Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States."  Washington, D.C.; updated March 28, 2014; accessed November 23, 2014.

Antiretroviral Pregnancy Registry Steering Committee. "Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989-31 July 2013." Wilmington, North Carolina; accessed November 23, 2014.

Sibiude, J.; et al. "Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11)." PLoS|Medicine. April 29, 2014; DOI: 10.1371/journal.pmed.1001635.

Williams, P.; Crain, M.; Yildirim, C.; et al. "Congenital Anomalies and In Utero Antiretroviral Exposure in Human Immunodeficiency Virus–Exposed Uninfected Infants." JAMA Pediatrics. 2014; DOI: 10.1001/jamapediatrics.2014.1889.

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