Safety of In-Utero Antiretroviral Exposure

Neurologic Outcomes in Children Who Are HIV-Exposed But Uninfected

Claudia S. Crowell; Paige L. Williams; Cenk Yildirim; Russell B. Van Dyke; Renee Smith; Ellen G. Chadwick; George R. Seage III; Alexandria Diperna; Rohan Hazra


AIDS. 2020;34(9):1377-1387. 

In This Article


Study Population

The PHACS SMARTT study includes two cohorts of CHEU: the Static cohort (children enrolled from 2007–2009 ages 1–12 years who had participated in prior studies with available pregnancy and birth data) and the Dynamic cohort (enrolled during gestation or within 1 week after birth).[19] The SMARTT study is conducted at 22 clinical research sites in the United States including Puerto Rico and enrollment and follow-up are ongoing, with youth followed to age 18 years. The protocol was approved by Institutional Review Boards at each site and at the Harvard T.H. Chan School of Public Health. Written informed consent was obtained from the parent or legal guardian of each enrolled child.

Maternal and child clinical diagnoses and dates of prenatal antiretroviral use were obtained from medical records and participant interview at study entry; retrospectively for the Static cohort. Birth characteristics (gestational age, birth weight, and delivery mode) were abstracted and maternal HIV disease characteristics during pregnancy were collected, including plasma HIV viral load, absolute CD4+ lymphocyte (CD4+) cell counts, and CD4%. Information on substance use during pregnancy was obtained by self-reported questionnaire, including alcohol, tobacco, marijuana, opiates, and other substances.[20] After enrollment, children and their mothers or caregivers were followed at annual study visits. A complete physical examination was conducted on the child including anthropometric assessments [height, weight, head circumference], and any new diagnoses or illnesses that occurred since the prior study visit were abstracted from the medical chart or interview. Caregivers completed questionnaires on household composition, education and income levels, history of psychiatric diagnoses or substance use, and other information related to family environment at all study visits.

A study 'trigger' for potential neurologic diagnoses was defined as a febrile or afebrile seizure, microcephaly, or other neurologic or ophthalmologic disorders, as previously described.[19] Children meeting any of these triggers either at enrollment (retrospectively for the Static cohort) or at an annual study visit were referred to an appropriate specialist (neurologist or ophthalmologist) for clinical evaluation. The results of the triggered evaluations were reviewed and children classified as cases or noncases by the SMARTT Review Panel (SRP), a group of clinical and epidemiological experts, using a predefined 'neurologic case' definition and blinded to the specific antiretroviral regimens mothers used during pregnancy. The following diagnoses did not require a follow-up assessment by a specialist for confirmation: microcephaly, febrile seizures and diagnoses that were recorded at two or more consecutive study visits (e.g. persisted for ≥2 years). Neurologic diagnoses determined to be secondary to events occurring after birth (e.g. postnatal meningitis, trauma) were not included as cases. A small percentage of participants met a trigger but did not have follow-up assessments needed to determine case status and were considered unevaluable for case determination (Figure 1). Children were deemed eligible for inclusion in this analysis if they enrolled by 1 April 2017 and had a study visit for neurologic trigger assessment by 1 August 2017.

Figure 1.

Derivation of study population for evaluating incidence of neurologic diagnoses and associations with in-utero antiretroviral exposures.

Outcome Measures

As the purpose of this study was to identify any potential signal of a neurological adverse event associated with in-utero antiretroviral exposure, the primary outcome of neurologic case was broadly defined and included all of the diagnoses chosen a priori to be included in the definition of a neurologic trigger. Microcephaly was determined based on head circumference measurements obtained after 6 months of age and was defined as a head circumference z-score less than −2 for children up to age 3 years based on the Centers for Disease Control and Prevention (CDC) growth curves, and less than the second percentile according to annual thresholds based on criteria published by Nellhaus for children over 3 years.[21] We accounted for prematurity for children up to age 2 years by subtracting the gestational age in weeks from 40, and adjusting the age at head circumference measurement by this difference. Children were classified as a neurologic case if they met the criteria at any time during follow-up, while those never having any of the diagnoses of interest were considered to not have the outcome.

Exposure Measures

The primary exposure of interest was in-utero antiretroviral exposure. Children were classified according to exposure to individual antiretroviral agents, by trimester of maternal antiretroviral initiation, and by preconception exposure versus never exposed during gestation. The reference group was children unexposed to the specific antiretroviral agent of interest, either overall or within the time period (trimester or preconception) of interest. For example, for first trimester exposure, the exposed groups were defined as children of mothers who initiated the antiretroviral agent of interest during the first trimester whereas the unexposed (reference) group were children who were not exposed to the antiretroviral agent during gestation. Individual antiretroviral agents were evaluated among a targeted at-risk subset of participants, based on the calendar year in which the antiretroviral had been approved. Specifically, models were restricted to children born after 2007 for darunavir and raltegravir, after 2011 for rilpivirine, and after 2013 for DTG and elvitegravir. These restrictions allowed a more appropriate comparison to contemporaneous regimens in use at the time each child was born. All other antiretroviral drugs were evaluated in the full SMARTT cohort.

Potential Confounders

We identified potential confounders using directed acyclic graphs (DAGs) based on previous literature and our own study findings. These potential confounders included maternal factors (age, race, ethnicity, chronic health conditions, obstetrical complications, and substance use), birth cohort (<2011, 2011–2014, 2015–2017), and family/household factors (socioeconomic status, household income level, and caregiver education level). As maternal antiretroviral use has been demonstrated to be associated with adverse birth outcomes and maternal health measures in pregnancy, preterm birth, low birthweight, cesarean section, maternal HIV viral load and CD4+ cell count were not considered as potential confounders (e.g. not considered for inclusion in adjusted models) as they may be on the causal pathway between in-utero antiretroviral exposure and adverse neurologic outcomes. However, descriptive summaries of neurologic case status by these measures were provided.

Statistical Analysis

The percentage classified as neurologic cases and the corresponding exact 95% confidence intervals (CIs) were estimated under the binomial distribution. Demographic and maternal characteristics were compared between cases and noncases using Fisher's exact test for binary characteristics and chi-square tests for categorical characteristics. Log-binomial regression analysis was used to obtain relative risks (RRs) for associations with in-utero antiretroviral exposure. Due to the large number of antiretroviral exposures evaluated, covariates included in the final adjusted models for case status were selected based on their association with neurologic case and potential role as a confounder based on the DAGs described above. Missing indicator approaches were used to account for missing information on covariates. A significance level of P = 0.05 was employed, but conclusions were based on consistency across primary and multiple sensitivity analyses.

Sensitivity Analyses. A number of sensitivity analyses were conducted to assess the robustness of findings. As follow-up of the cohort is currently ongoing, children born in earlier years generally had more follow-up time during which a neurologic case could occur. We conducted analyses to account for this possible bias: by restricting analysis to children enrolled in the dynamic cohort; by restricting follow-up to the first two years of life (i.e. excluding events after age 2 and children enrolled after age 2); and by fitting Poisson regression models for the incidence rate ratios (IRRs) accounting for person-time of follow-up by each participant. For the first two sensitivity analyses noted above, we utilized modified Poisson regression to obtain estimated RRs and their corresponding 95% CIs.[22] A sensitivity analysis adjusting for preterm birth was also conducted to confirm that associations between antiretroviral exposure and neurologic case were not solely because of prematurity. Sensitivity analyses were also conducted to account for clustering of children within clinical research sites and to account for clustering of children within families (e.g. the same mother or caregiver). Finally, we conducted a sensitivity analysis excluding children with major congenital anomalies based on review by the SRP and outside experts.