Association of maternal antiretroviral use with microcephaly in children who are HIV-exposed but uninfected (SMARTT): a prospective cohort study

Abstract

Background: Perinatal HIV transmission has substantially decreased with combination antiretroviral regimens, but complications in children who are HIV-exposed but uninfected, such as microcephaly, warrant ongoing surveillance. We aimed to evaluate whether individual in utero antiretroviral exposures were associated with increased risk of microcephaly based on long-term follow-up of infants and children who are HIV-exposed but uninfected.

Methods: We evaluated children aged younger than 18 years who were HIV-exposed but uninfected with at least one head circumference measurement while enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study at 22 clinical sites in the USA, including Puerto Rico. This prospective cohort study was done by the Pediatric HIV/AIDS Cohort Study network. Microcephaly was defined as having a head circumference Z score <-2 according to the 2000 US Centers for Disease Control and Prevention growth charts for children 6-36 months old and according to Nellhaus standards (head circumference <2nd percentile) after 36 months (SMARTT criteria); an alternate definition for microcephaly was based on applying Nellhaus standards across all ages (Nellhaus criteria). Modified Poisson regression models were fit to obtain relative risks (RRs) for associations between in utero antiretroviral exposure and microcephaly status, adjusted for potential confounders. Neurodevelopmental functioning was compared in children who are HIV-exposed but uninfected with or without microcephaly.

Findings: Between March 21, 2007, and Aug 1, 2017, 3055 participants enrolled in SMARTT had at least one head circumference measurement. The cumulative incidence of microcephaly over a median of 5·1 years of follow-up (IQR 3·0-7·2) was 159 (5·2%, 95% CI 4·4-6·1) by Nellhaus criteria and 70 (2·3%, 1·8-2·9) by SMARTT criteria. In adjusted models, in utero exposure to efavirenz (4·7% exposed) was associated with increased risk of microcephaly by both Nellhaus standards (adjusted RR 2·02, 95% CI 1·16-3·51) and SMARTT criteria (2·56, 1·22-5·37). These associations were more pronounced in children exposed to combination regimens of efavirenz that included zidovudine plus lamivudine than those including tenofovir plus emtricitabine. Protective associations were observed for darunavir exposure (adjusted RR 0·50, 95% CI 0·24-1·00). Children who are HIV-exposed but uninfected with microcephaly had lower mean scores on neurodevelopmental assessments at age 1 and 5 years and a higher prevalence of neurodevelopmental impairment than those without microcephaly.

Interpretation: These findings support consideration of alternatives to efavirenz as part of first-line antiretroviral therapy for pregnant women.

Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Figure 1.. Associations of in utero ARV Exposures with Microcephaly by Nellhaus criteria

Numbers in brackets after each drug name indicate number of microcephaly cases among those exposed to the specific ARV drug during pregnancy, and number of cases among those exposed to that ARV drug during the first trimester. Adjusted relative risks (aRRs) are based on modified Poisson regression models adjusting for low education, low household income, alcohol use during pregnancy, and birth cohort (2007–2010, 2011–2014 and 2015–2017 vs <2007). Models based on 1976 children born after 2007 for darunavir, raltegravir, fosamprenavir, and IIs (as drug class), 927 children born after 2011 for rilpivirine, and 506 children born after 2013 for dolutegravir and elvitegravir; all other ARV drugs are evaluated in the full SMARTT cohort (N=2983).

Figure 2.

Percent of HEU Infants with Microcephaly by efavirenz (EFV)-containing Maternal ARV Regimen, with Adjusted Risk Ratios (aRRs) and 95% Confidence Intervals

Figure 3.. Sensitivity Analyses for Associations of efavirenz and darunavir with Microcephaly in HEU Infants and Children

Numbers in brackets indicate the number of microcephaly cases among those exposed to efavirenz (panel (a)) or darunavir (panel (b)), by the Nellhaus and SMARTT criteria, respectively; the total sample size for each sensitivity analysis is also provided. Adjusted relative risks (aRRs) and adjusted incidence rate ratios (aIRRs) are based on modified Poisson regression models adjusting for low education, low household income, alcohol use during pregnancy, and birth cohort (2007–2010, 2011–2014 and 2015–2017 vs <2007) for microcephaly by Nellhaus criteria, and adjusting for low education, 1^st trimester tobacco, and birth cohorts (2007–2010, 2011–2014 and 2015–2017 vs <2007) for microcephaly by SMARTT criteria. Models accounting for clustering within site or within the same mother/family are fit using generalized estimating equation models with an assumed exchangeable correlation structure. Incidence rates are estimated based on person-time from birth or study entry to the first date of documented microcephaly or latest study visit without microcephaly. FUP=follow-up, cART= combination ARV regimen.