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

Disclosures

AIDS. 2020;34(9):1377-1387. 

In This Article

Abstract and Introduction

Abstract

Objective: To evaluate whether there is an increased risk of neurologic diagnoses in children who are HIV-exposed but uninfected (CHEU) exposed in utero to specific antiretroviral medications.

Design: Prospective cohort study of CHEU enrolled from 2007 to 2017.

Methods: We evaluated children for neurologic case status, including microcephaly, febrile seizures, seizure disorders, ophthalmologic disorders, and other neurologic disorders. Adjusted relative risks (aRRs) were estimated for the association between in-utero antiretroviral exposure and neurologic case using log-binomial regression, accounting for potential confounders. Sensitivity analyses were conducted to evaluate robustness of findings.

Results: Among 3747 eligible CHEU, 231 (6.2%) met neurologic case criteria (95% CI 5.4–7%). Most eligible children (86%) were exposed in utero to combination antiretroviral regimens. In adjusted models, children exposed to efavirenz at any time during pregnancy had higher risk of neurologic case status (aRR = 1.53, 95% CI 0.94–2.51). This association was stronger when comparing efavirenz exposure at conception to no exposure during pregnancy (aRR = 1.92, 95% CI 1.09–3.36) and considering follow-up and case diagnosis only through age 2 (aRR = 2.14, 95% CI 1.11–4.12). Children exposed to didanosine at conception and during the first trimester had increased risk of neurologic case status (aRR = 2.28, 95% CI 1.07–4.87 and aRR = 2.02, 95% CI 1.01–4.04, respectively), compared with didanosine-unexposed children. Children with dolutegravir exposure had some suggestion of increased risk of neurologic case (aRR = 2.43, 95% CI 0.75–7.84), which was observed consistently across several sensitivity analyses.

Conclusion: Efavirenz and didanosine exposure during pregnancy were associated with higher risk of neurologic abnormalities in CHEU, and dolutegravir exposure showed some suggestive associations, which warrant further monitoring.

Introduction

With an estimated 1.3 million women living with HIV giving birth annually, it is critical to assess the safety of in-utero antiretroviral exposure to the fetus.[1–3] There have long been concerns regarding the potential teratogenicity of antiretroviral medications, in particular, efavirenz (EFV).[4–7] Multiple studies have now shown that in-utero EFV exposure is not associated with an increased risk of central nervous system congenital anomalies;[8,9] however, data on newer antiretrovirals are limited. Indeed, the recent experience with periconception dolutegravir (DTG) exposure and neural tube defects has highlighted the importance of continued surveillance for potential adverse effects from in-utero antiretroviral exposure.[10–12]

Most studies of antiretroviral safety in pregnancy have focused on outcomes at or soon after birth; however, not all adverse effects are evident at birth and data on the risk of more subtle neurologic diagnoses are limited.[13–16] Studies with follow-up beyond 1 month of life have not demonstrated an increased risk of neurologic diagnoses in children who are HIV-exposed but uninfected (CHEU), but have limited follow-up to the first few years of life or less.[8,9,17,18] As new antiretrovirals are introduced in pregnancy, the safety of in-utero exposure remains a critical public health issue.

The Surveillance Monitoring for ART Toxicities (SMARTT) Study is a prospective observational study established by the Pediatric HIV/AIDS Cohort Study (PHACS) network to identify potential adverse effects of in-utero antiretroviral exposure to CHEU.[19] The aim of this analysis was to determine the prevalence of neurologic diagnoses among CHEU and to evaluate whether there is an increased risk of neurologic diagnoses associated with in-utero exposure to specific antiretrovirals.

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