What Is the Risk of Birth Defects From HIV Drugs?

What animal studies and statistical research tell us

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Lunar Caustic

There have long been concerns that women who take certain antiretroviral drugs during pregnancy may run an increased risk of birth defects. The research is often conflicting and concerns about the potential risks can sometimes skew our perceptions about the drugs' actual safety.

The drug Sustiva (efavirenz) has long been a focus of concern with earlier guidelines suggesting that it be avoided, at least during the first trimester, due to a possible risk of teratogenicity (birth defects).

The recommendations have since changed and now allow for the use of efavirenz in the first trimester should the mother have an undetectable viral load.

With that being said, the same guidelines suggest that non-pregnant women of childbearing years avoid any and all drug therapies containing efavirenz.

So what does this actually means? Is the U.S. health panel simply hedging their bets about a drug that may or may not be harmful, or should we be concerned about this and other drugs?

Animal Studies Show Potential Risk

In assessing the risk of HIV drugs and birth defects, most of the current research has not come from human studies but from animal research (clearly because you can’t ethically expose a human fetus to potentially dangerous medications).

With regards to Sustiva, concerns about teratogenicity were first raised when three of 20 cynomolgus monkeys exposed to the drug had babies with cleft palates and central nervous system malformations Moreover, the drug concentration was only 1.3 times higher than that used in humans.

Meanwhile, rats exposed to Sustiva experienced fetal resorption, a phenomenon in which fetuses that died during gestation were reabsorbed by the remaining siblings.

There were no birth defects seen in rabbits.

Statistical Studies in Human

Statistics taken from the Antiretroviral Pregnancy Registry (APR) have painted a somewhat different picture.

While the APR identified birth defects in 18 of 766 children exposed to Sustiva during the first trimester, the low number of neural tube defects—the types seen in animal studies—cast doubts as whether the effect in humans would be the same as in monkeys and rats.

A subsequent analysis of 19 different studies, including the APR, has since identified 39 birth defects out of 1,437 children exposed to Sustiva. Based on those figures, the rate is seen to be no difference than that seen in the general U.S. population.

Despite the relatively low number of confirmed defects, health officials remained reluctant to give Sustiva the thumbs-up.

Birth Defect Risk in Other HIV Drugs

In 2014, researchers from the French Perinatal Cohort published a study that looked at the number of birth defects seen in children exposed to a variety of antiretroviral drugs during pregnancy. The multinational study involved a total of 13,124 children born to women with HIV from 1986.

The results were interesting: while an increase in birth defects was associated with certain antiretroviral drugs, such as Crixivan (indinavir), the rate was still no different than that of seen in the general population. Moreover, no specific pattern in the type or severity of birth defects can be found.

Meanwhile, of 372 babies exposed to Sustiva in the first trimester, no association could be found between the drug and birth defects.

That's not to say that the drugs carry no risk. The French researchers did note a two-fold increase in heart defects in babies exposed to AZT (zidovudine). Most involved a ventricular septal defect, a common congenital defect in which a hole develops between the two lower chambers of the heart.

Research from the Harvard School of Public Health, published in 2014, confirmed many of the French findings. The study, which involved 2,580 American children exposed to antiretroviral drugs during the first trimester, found that few individual drugs and no class of class 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 exposed to ritonavir-boosted Reyataz (atazanavir) during the first trimester. While the researchers suggested that further research may be needed to assess the risk of Reyataz in pregnancy, they still concluded that the overall risk remains low.

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."

Sources:

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.

Antiretroviral Pregnancy Registry Steering Committee. "Antiretroviral Pregnancy Registry international interim report for 1 January 1989-31 January 2017." Wilmington, North Carolina; updated January 2017.

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.

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