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


Characteristics of Study Population

A total of 3758 SMARTT participants had enrolled as of 1 April 2017 and had at least one study visit by 1 August 2017. Among these, 11 had an indeterminate neurologic case status and were excluded from analyses, yielding 3747 evaluable participants; their characteristics are shown in Table 1. Just under half were girls (48%), 68% black, and 31% Hispanic. Self-reported tobacco and alcohol use during pregnancy were relatively common (17 and 8%, respectively), and 8% of mothers reported marijuana use during pregnancy; however, reported cocaine/opiates use was relatively rare (3%).

Case status and Neurologic Diagnoses

Of the 3747 participants included, 231 (6.2%; exact 95% CI 5.4%, 7.0%) met criteria for being a neurologic case over a median follow-up of 4.3 years [interquartile range (IQR): 1.4–7.0). The most common neurologic diagnoses were microcephaly (25.1%), febrile seizure (17.6%), eye-related abnormalities including esotropia, exotropia, strabismus, ptosis, nystagmus, ambylopia, and optic nerve abnormalities (16.5%) and nonfebrile seizure (13.5%). A full list of the neurologic diagnoses is provided in Supplemental Table 1, The median age of first neurologic diagnosis was 2.1 years (IQR 1.1–5.0).

Demographic and Maternal Characteristics by Neurologic Case Status

Children were more likely to be a neurologic case if they were born in earlier years (≤2010), of white race or Hispanic ethnicity, with low caregiver education, and if their mother reported use of tobacco, alcohol, marijuana, or cocaine/opiates during pregnancy (Table 1). In multivariable models, tobacco use during pregnancy emerged as the substance most strongly associated with neurologic case status and, because of high rates of concurrent tobacco use, other substances (alcohol, marijuana, cocaine/opiates) were no longer related to case status after accounting for tobacco use. Low caregiver education was also no longer associated with case status in multivariable models after adjusting for the other demographic characteristics and sociodemographic measures. The final adjusted model included Hispanic ethnicity, tobacco use during pregnancy, and birth cohort (2011–2014 and 2015–2017 vs. pre-2011).

Association of In-utero Antiretroviral Exposures With Neurologic Case Status

In adjusted models, exposure to EFV was associated with a 53% increased risk of neurologic case [adjusted RR (aRR) = 1.53, 95% CI 0.94–2.51] (Table 2 and Figure 2). There was a stronger association for EFV exposure at conception (aRR = 1.92, 95% CI 1.09–3.36) (Supplemental Table 2, In addition, didanosine (ddI) exposure at conception (aRR = 2.28, 95% CI 1.07–4.87) was associated with an increased risk of being a neurologic case. DTG exposure was associated with over two-fold increased risk of being a neurologic case (aRR = 2.43, 95% CI 0.75–7.84). The magnitude of association for DTG was stronger for exposure during the first trimester (aRR = 2.95, 95% CI 0.79–11.01) and at conception (aRR = 3.47, 95% CI 0.74–16.36).

Figure 2.

Adjusted relative risks for associations of in-utero antiretroviral exposures with neurologic case, based on any exposure during pregnancy and first trimester exposures. Adjusted relative risks (aRRs) and their confidence intervals (CIs) were estimated by log-binomial regression for full SMARTT cohort and by modified Poisson regression for other subgroups. Adjusted models include Hispanic ethnicity, tobacco use during pregnancy, and birth cohorts (2011–2014 and 2015–2017 vs. <2011. Models restricted to children born after 2007 for darunavir and raltegravir, after 2011 for rilpivirine, and after 2013 for dolutegravir and elvitegravir; all other antiretroviral drugs were evaluated in the full SMARTT cohort.

Sensitivity Analyses

Analyses restricting to those enrolled at birth, accounting for clustering within research site and within the same family (same mother or caregiver), considering only the first 2 years of life, excluding children with major congenital anomalies, accounting for person-years of follow-up and adjusting for prematurity for associations between EFV, ddI, or DTG exposure (any exposure in pregnancy and first trimester exposure only) with neurologic case status are shown in Figure 3. Results of the unadjusted analyses and sensitivity analyses for all antiretrovirals are provided in Supplemental Tables 3–10, Of note, the magnitude of association between in-utero EFV exposure and neurologic case status was similar to that seen in the primary analyses across all sensitivity analyses and was statistically significant when restricting to the first 2 years of life for any EFV exposure or first trimester exposure. The magnitude of association between in-utero DTG exposure and neurologic case status also remained similar across all sensitivity analyses to that seen in the primary analyses and was statistically significant for first trimester DTG exposure after accounting for person-years of follow-up and after accounting for clustering within site.

Figure 3.

Sensitivity analyses for associations of efavirenz, dolutegravir, and didanosine with neurologic case status. Adjusted relative risks (aRRs) are based on modified Poisson regression models and adjusted incidence rate ratios (aIRRs) are based on standard Poisson regression models accounting for person time; both types of models adjust for Hispanic ethnicity, tobacco use during pregnancy, and birth cohort (2011–2014 and 2015–2017 vs. <2011). 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. FUP, follow-up.