Maternal Efavirenz Use Linked to Microcephaly in Children

By Will Boggs MD

December 05, 2019

NEW YORK (Reuters Health) - Maternal use of the antiretroviral efavirenz is associated with an increased risk of microcephaly in children who are HIV-exposed but uninfected, according to findings from the SMARTT study.

"Women of reproductive age may want to consider alternatives to efavirenz," Dr. Paige L. Williams of Harvard T. H. Chan School of Public Health, in Boston, told Reuters Health by email. "However, these findings also need to be confirmed in other populations in which efavirenz is widely used, such as sub-Saharan Africa where the HIV prevalence among pregnant women is particularly high."

Some studies have found significantly lower head circumference among children who are HIV-exposed but uninfected, compared with children born to women without HIV infection.

Dr. Williams and colleagues in the Pediatric HIV/AIDS Cohort Study network evaluated the association of antiretroviral therapy (ART) exposure with microcephaly based on long-term follow-up of more than 3,000 infants and children who were HIV-exposed but uninfected and enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study.

Over a median follow-up of 5.1 years, 5.2% of these children had microcephaly identified by Nellhaus criteria (lower than the second percentile of head circumference for age); 2.3% had microcephaly by the SMARTT criteria (head circumference Z score less than -2 based on U.S. Centers for Disease Control and Prevention (CDC) growth standards for children up to age 3 years and below Nellhaus criteria for older children); and 2.2% had microcephaly using World Health Organization (WHO) criteria.

Most mothers (93.5%) had received combination ART during pregnancy, and all but 2.1% received at least two ART drugs.

After adjustment for other factors, efavirenz exposure was associated with a two-fold higher risk of microcephaly by Nellhaus standards, a 2.56-fold higher risk of microcephaly by SMARTT criteria and a 3.69-fold higher risk of microcephaly by WHO criteria, both significant risk increases compared with children unexposed to efavirenz, the researchers report in The Lancet HIV, online November 15.

Fosamprenavir was associated with a higher risk of microcephaly by Nellhaus criteria but not by SMARTT standards, whereas darunavir showed a protective association with microcephaly based on Nellhaus criteria but not by SMARTT standards.

In adjusted models including all antiretroviral exposures simultaneously, efavirenz was the only antiretroviral drug associated with a significantly increased risk of microcephaly by SMARTT criteria, even after accounting for all other antiretroviral drugs used in the same regimen.

Among the children who had complete neurodevelopmental assessment, scores for cognitive, motor and language domains were significantly lower in those with than without microcephaly, as were intelligence scores for most subscales.

In the more than 2,089 children with any neurodevelopmental assessment, the percentage impaired was 14.8% with microcephaly by Nellhaus criteria (versus 4.6% without) and 25.0% with microcephaly by SMARTT criteria (versus 4.7% without).

"Clinicians routinely monitor newborns for adverse outcomes such as microcephaly," Dr. Williams said. "However, microcephaly may also be apparent in young children, and our findings suggest that children born to women with HIV should be closely monitored for this condition."

"The association of in utero exposure to efavirenz with microcephaly was stronger when it was used together with certain other antiretroviral medications, specifically zidovudine and lamivudine, as compared to using efavirenz together with tenofovir and emtricitabine," she said. "Future studies should investigate these types of combination regimens to identify the safest possible regimen to use in pregnancy."

Dr. Stanzi Maria le Roux of the University of Cape Town, in South Africa, who co-authored a linked editorial, told Reuters Health by email, "Although the article's main focus is naturally the potential adverse effects of efavirenz on fetal head growth, what I found most interesting is the very low numbers of efavirenz-using women in the cohort, many of whom seemed to have vulnerabilities on more than one health domain, including higher antenatal alcohol abuse. Additionally, I found it very reassuring that the average head size in the cohort was within normal range. This is great news for HIV-positive mothers and their children."

"All effective medicines have potential adverse effects, and it is up to the individual patient and her health care provider to discuss and consider the many factors at play," she said. "For me, the most critical factors are to ensure continued maternal HIV viral control (lack of which has substantially worse fetal effects than efavirenz) and dealing with the other areas critical to optimize maternal-fetal health. These include ensuring a healthy pregnancy without concurrent use of alcohol or other substances, optimal nutrition, and early identification and treatment of other co-infections, including cytomegalovirus and hepatitis B."

"These findings are but one set of data from an observational study in the U.S., while other observational studies from resource-limited settings have found no discernible adverse effects of efavirenz use in pregnancy," Dr. le Roux said. "Vertical HIV acquisition is a substantially higher potential risk, and for this, efavirenz remains a highly effective medication to maintain maternal viral control. Personally, I would not change a patient over from efavirenz to another regimen on the basis of this study alone."

Dr. Lynne M. Mofenson, HIV Senior Technical Advisor at Elizabeth Glaser Pediatric AIDS Foundation, in Washington, D.C., told Reuters Health by email, "Given the small number of exposures, I would view this study as hypothesis-generating and needing confirmation by additional studies, rather than definitive proof of an association of microcephaly with efavirenz use."

"The preferred agents for ART in pregnancy in the United States include dolutegravir, raltegravir or darunavir/ritonavir or atazanavir/ritonavir; efavirenz is listed as an alternative agent," said Dr. Mofenson, who was not involved in the new research. "Similarly in the recent WHO guidelines, dolutegravir is the preferred agent for use in pregnancy, as the overall benefits are felt to outweigh the risks. I don't think these data change these recommendations, but rather indicate the need for further study."

The study had no commercial funding and the researchers report no conflicts of interest.


Lancet HIV 2019.