The Risk of Birth Defects From HIV Drugs

There have long been concerns that women with HIV 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 a drug's actual safety.

Nurses monitoring baby in incubator
Morsa Images / Getty Images


The antiretroviral drug Sustiva (efavirenz) has long been a focus of concern, with earlier treatment guidelines advising against its use, 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 Sustiva, albeit as an alternative to preferred agents such as Descovy (emtricitabine + tenofovir AF), Prezista (darunavir), and Isentress (raltegravir).

The same alarms were sounded in 2018 and 2019 about Tivicay (dolutegravir), an antiretroviral drug believed to be linked to 11 cases of neural tube defects in Rwanda and Botswana.

In response to these early reports, the U.S. Department of Health and Human Services (DHHS) moved Tivicay to "alternative status," a decision that has since been rescinded. In February 2021, after an extensive investigation, Tivicay was once again granted "preferred status" for people trying to conceive.

These warnings have left many people confused as to whether these antiretrovirals pose any real risks to an unborn child and, if so, how much?


In assessing the actual risk of antiretroviral-associated birth defects, most of the current evidence has come from animal studies and antiretroviral pregnancy records.

In most cases, animal studies have been responsible for sounding the alarms, leading the DHHS and others to take proactive measures to investigate the claims (sometimes over the course of years) and "put the brakes" on a drug until then.

Such has been the case with Sustiva.

Animal Studies

Concerns about Sustiva-induced teratogenicity were first raised in 1998 when three of 20 cynomolgus monkeys exposed to the drug had babies with cleft palates and neural tube defects. What made the findings concerning was that the relative drug concentration was only 1.3 times higher than that used in humans.

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

Despite the validity of these studies, the findings overall were not consistent, with some investigations finding no link between Sustiva and birth defects in mice and rabbits.

Epidemiologic Research

As striking as the findings were, they were not confirmed in humans. Although an early review of the Antiretroviral Pregnancy Registry (APR) identified birth defects in 27 of 1,142 children exposed to Sustiva during the first trimester, the low incidence of neural tube defects—the predominant type of defect seen in animal studies—cast doubts as to whether the drug actually posed risks to human fetuses.

According to the APR data from 1989 to 2020, the rate of birth defects in children exposed to Sustiva during pregnancy was no different than that of children in the general U.S. population.

A subsequent analysis in low- to medium-income countries rendered similar results, wherein 44 birth defects were noted among 2,026 children exposed to Sustiva during pregnancy.

Similar research from France punctuated the findings with only 372 birth defects out of 13,124 live births, none of which involved the neural tube defects seen in animals.

Even so, the Food and Drug Administration (FDA) continues to advise women to avoid pregnancy while taking Sustiva and to advise their health providers to avoid prescribing the drug during the first trimester.


Unlike Sustiva, most of the concerns surrounding Tivicay and the risk of birth defects were triggered by isolated reports of teratogenicity in Africa.

In Botswana, alarm bells were sounded when a 2019 study funded by the National Institutes of Health revealed that the rate of neural tube defects was higher among women who took Tivicay compared to any other antiretroviral drug (0.3% to 0.1%).

However, when the scope of the investigation was expanded, the same team of researchers found that 0.19% of children exposed to Tivicay during pregnancy had neural tube defects compared to 0.2% with all other antiretrovirals—a statistically insignificant difference.

It was surmised that the primary factor driving the incidence of neural tube defects among this population of African children was not antiretrovirals but widespread folate deficiency.

In the United States and other developed countries, folate supplementation is recommended to reduce the risk of neural tube defects like spina bifida and anencephaly. The same is lacking in African countries like Botswana.

Based on updated data from the APR (in which the rate of birth defects from prenatal exposure to Tivicay was no different than the general population), the DHHS reinstated Tivicay as a preferred agent during pregnancy.

Other Antiretrovirals

In 2014, researchers from the French Perinatal Cohort published a study that examined 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 1994 to 2010.

While an increase in birth defects was associated with certain antiretroviral drugs, such as Crixivan (indinavir)—a drug no longer in use in the United States—the rate was still no different than that of the general population. Moreover, no specific pattern in the type or severity of birth defects was found.

That is not to say that the drugs carry no risks. The French researchers noted a two-fold increase in heart defects in babies exposed to zidovudine (AZT). 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. However, among 2,580 children exposed to antiretrovirals during the first trimester, no class of drug was associated with an increased risk of birth defects compared to what was seen in the general public.

The Harvard researchers noted an increased risk for skin and musculoskeletal disorders in children exposed to ritonavir-boosted Reyataz (atazanavir) during the first trimester. While further research was recommended, the scientists still concluded that the overall risk was low.

A Word From Verywell

If you are pregnant or planning to get pregnant, it is important to speak with your healthcare provider about the benefits and risks of any antiretroviral drug to make an informed choice.

This is especially important because a slew of new drugs have been approved since 2018, including Biktarvy (bictegravir + emtricitabine + tenofovir AF), Cabenuva (cabotegravir + rilpivirine injectable), Pifeltro (doravirine), Rukobia (fostemsavir), and Trogarzo (ibalizumab-uiyk). For these agents, there remains insufficient data to assess their safety during pregnancy.

It is important to note that breastfeeding is not recommended for any mother with HIV irrespective of antiretroviral use. Given the availability of highly nutritious baby formulas, health authorities in the United States advise breastfeeding to further reduce the risk of mother-to-children transmission of HIV.

11 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States.

  2. Phillips AN, Bansi-Mathara L, Venter F, et al. Updated assessment of risks and benefits of dolutegravir versus efavirenz in new antiretroviral treatment initiators in sub-Saharan Africa: modelling to inform treatment guidelines. Lancet HIV. 2020 Mar;7(3):e193-e200. doi:10.1016/S2352-3018(19)30400-X

  3. Nightingale SL. From the Food and Drug Administration. JAMA. 1998 Nov 4;280(17):1472.

  4. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report.

  5. Ford N, Mofenson L, Shubber Z, et al. Safety of efavirenz in the first trimester of pregnancy: An updated systematic review and meta-analysis. AIDS. 2014;28 Suppl 2:S123-31. doi:10.1097/QAD.0000000000000231

  6. Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: An analysis of the French Perinatal Cohort Study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635. doi:10.1371/journal.pmed.1001635

  7. Bristol-Myers Squibb. Product insert - Sustiva.

  8. Zash R, Holmes L, Diseko M, et al. Neural-tube defects and antiretroviral treatment regimens in Botswana. N Engl J Med. 2019;381(9):827-40. doi:10.1056/NEJMoa1905230

  9. Zash R, Beth Israel Deaconess Medical Center. Update on neural tube defects with antiretroviral exposure in the Tsepamo study, Botswana. International AIDS Conference.

  10. Adams E, Myer L. Lessons from dolutegravir and neural tube defects. Lancet HIV. 2021 Jan 1;8(1):E3-4. doi:10.1016/S2352-3018(20)30280-0

  11. 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;169(1):48-55. doi:10.1001/jamapediatrics.2014.1889

By James Myhre & Dennis Sifris, MD
Dennis Sifris, MD, is an HIV specialist and Medical Director of LifeSense Disease Management. James Myhre is an American journalist and HIV educator.