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


We observed a high percentage of children who developed one or more neurologic diagnoses in our cohort compared with previous studies (6.2 vs. 0.3–2%).[13,14,16,23] This may be in part as our study was designed to detect a broad range of adverse neurologic events, including microcephaly and eye-related abnormalities, which previous studies have not included, and as our study included longer follow-up of infants and children.

Our findings demonstrate that infants with in-utero EFV exposure had over 50% increased risk of having a neurologic diagnosis. This association persisted in multiple sensitivity analyses. In-utero DTG exposure was associated with an increased risk of having a neurologic diagnosis but the associations were not statistically stable except in specific sensitivity analyses because of the small number of exposed cases. The data on the association between in-utero antiretroviral exposure and neurologic diagnoses in CHEU have been conflicting; however, studies to date have been limited by their duration of follow-up, sample size, and ability to adjust for confounders. The French Perinatal Cohort Study (FPCS) found that CHEU exposed to a nonnucleoside reverse transcriptase inhibitor combination, most commonly zidovudine with lamivudine, were more likely to be classified as having mitochondrial dysfunction compared with CHEU exposed to zidovudine monotherapy (RR = 2.5; 95% CI 1.0–6.5) with the majority of cases characterized by neurologic symptoms (86%); however, this analysis did not adjust for potential confounders.[14] A follow-up study of the FPCS found that CHEU exposed to EFV in utero had a higher risk of neurologic congenital anomalies but this was only statistically significant in a secondary analysis when applying a broader classification of neurologic congenital anomalies.[5] The IMPAACT 219/219C study demonstrated an increased risk of mitochondrial dysfunction associated with third trimester initiation of lamivudine alone and in combination with zidovudine.[16] In addition, ddI exposure during the peri-conception period and during the first trimester was found to be associated with an increased risk of having a neurologic diagnosis.

Subsequent studies in other cohorts have failed to confirm this potential increased risk of neurologic diagnoses associated with in-utero antiretroviral exposure; however, most of these studies have been limited by either their duration of follow-up, restricted outcome definition to only cases that resulted in death, or limited ability to compare various antiretroviral regimens.[17,18,23–28] Experience with other medications has demonstrated the importance of long-term follow-up when evaluating the safety of medications administered in pregnancy.[29] Indeed, results from the FPCS have shown that symptoms of mitochondrial dysfunction are usually not present in the first few months of life. We followed children in our cohort for a median of 4 years allowing us to detect potential safety signals later in childhood. The median age of first confirmation of neurologic case status was 2.1 years, suggesting that a large proportion of cases would be missed if follow-up were restricted to the first few months of life.

Additionally, when conducting analyses of drug safety in pregnancy, it is crucial to have the correct comparator groups. Comparing antiretroviral-exposed to antiretroviral-unexposed CHEU raises issues of confounding by indication (e.g. worse maternal HIV disease status leading to antiretroviral initiation in the antiretroviral-exposed group in earlier years of SMARTT). Comparing one antiretroviral-exposed group to another can raise issues of confounding by historical bias if the years of exposure differ greatly between the two groups. Given our large sample size and the high proportion of in-utero antiretroviral-exposure in our cohort, we were able to address these issues by restricting our analyses to the specific time-period when the antiretroviral of interest was approved for use.

Febrile seizures was one of the most commonly encountered neurologic diagnosis in our study (17.6%) with an overall prevalence of 1.3%. The prevalence in our cohort is lower than that found in the general U.S. population (2–5%); however, this does not necessarily negate an association with specific antiretroviral exposures. Indeed, the FPCS observed a higher cumulative risk of febrile seizures by 18 months in CHEU with in utero and/or postnatal antiretroviral exposure compared with CHEU without antiretroviral exposure (11.0 vs. 4.1 per 1000, P = 0.02).[15] Their study observed no association with specific antiretroviral exposures, but was conducted early in the epidemic when the number of antiretrovirals available was limited.

Our study had several limitations. First, as mentioned above, in an observational study, both known and unknown confounders could be present. We adjusted for several confounders and restricted the analyses to the time-period when the antiretroviral of interest was approved for use. Additionally, we systematically identified and confirmed our neurological cases blinded to antiretroviral exposure. As many participants enrolled after birth, we may have missed some major neurologic congenital anomalies that were detected on prenatal ultrasound and subsequently resulted in either spontaneous or therapeutic abortion. Missing cases because of pregnancy termination would have biased our findings towards the null and excluding children with major congenital anomalies did not change the magnitude of the associations seen in our study. Our analysis was implemented as a screening study rather than a test of any single hypothesis, with a goal of identifying potential signals of toxicity. We recognize that this approach involves multiple comparisons and may increase the risk of false-positive findings. At the same time, we did not want to fail to detect true associations. Key to this screening strategy is an emphasis on consistency and robustness of findings across multiple sensitivity analyses, along with the need to confirm any potential associations in further more focused studies. We also acknowledge that sensitivity analyses conducted to examine different exposure periods do not reflect independent analyses, given the overlap in antiretroviral-exposed cases between time periods of interest; these time-specific risk estimates must be interpreted cautiously but can help inform whether the effect of antiretroviral exposure differs by timing. Another limitation was that smaller numbers of children were exposed to newer antiretroviral agents, which limited our ability to detect statistically significant signals for these agents; our data suggest a potential association between DTG and neurologic case status emphasizing the importance of continued surveillance of CHEU exposed to DTG and other new antiretroviral agents. Finally, in an attempt to be inclusive and not miss any potential safety signals our definition of neurologic case included all potential neurologic and ophthalmologic diagnoses, which precludes us from making any conclusions about causal effects and potential long-term consequences. Despite the broad outcome measure, we feel that our results are important as they demonstrate potential safety concerns associated with specific in-utero antiretroviral exposures. Given the fact that our outcome measure represents different causes with potentially different causal mechanisms and severity of presentation, it is important that our findings be confirmed with larger sample sizes within specific exposure groups of interest.

In conclusion, we found that in-utero EFV and ddI exposure were associated with higher risks of neurologic abnormalities in infancy and childhood. There was a suggestion of an association between in-utero DTG exposure and higher risk of neurologic abnormalities in infancy and childhood but this association was not statistically stable because of the recent introduction of DTG and the small numbers of cases to date. The recommended antiretroviral therapy (ART) in pregnancy has recently been called into question by reports of increased risk of neural tube defects in CHEU exposed to DTG.[10] Statistical modelling suggests that despite this increased risk of neural tube defects, DTG-based ART in pregnancy would avert more maternal deaths than EFV-based ART.[30] Our findings highlight the importance of continuing to proactively evaluate the safety of ART in pregnancy and the need for long-term follow-up of CHEU.[31] Further study is needed to confirm our findings in other cohorts, as well as to determine the clinical implications of the neurologic diagnoses and investigate the underlying mechanisms of the associations seen in our study.[32,33]