Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana

Abstract

Background: A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)-infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies.

Methods: We conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals.

Results: From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, -0.13 to 0.87).

Conclusions: The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.).

Figure 1.. Deliveries at the Surveillance Sites According to Maternal ART and HIV Infection Status, August 2014–March 2019.

In the case of 72 (4%) of the 1683 deliveries in which the mother had been taking dolutegravir (DTG) at conception, the mother switched to a different regimen during pregnancy, and in 6 (0.4%) the mother switched during the first 6 weeks of pregnancy (no neural-tube defects or major malformations were identified in the infants in these 6 deliveries). Tenofovir–emtricitabine or tenofovir–lamivudine was the nucleoside reverse-transcriptase inhibitor backbone in the regimen taken by 1653 (98.2%) of the mothers who took DTG-based antiretroviral treatment (ART) and by 7792 (97.9%) of the mothers who took efavirenz (EFV)–based ART. In addition to 7959 deliveries in which the infants were exposed to EFV at the time of conception, deliveries in which the infants had non-EFV ART exposure from conception included 1848 with exposure to nevirapine–tenofovir plus either emtricitabine or lamivudine, 2966 to nevirapine–zidovudine–lamivudine, 579 to lopinavir–ritonavir–tenofovir plus either emtricitabine or lamivudine, 385 to lopinavir–ritonavir–zidovudine–lamivudine, 884 to unspecificied (non-DTG) regimens, and 171 to other regimens.

Figure 2.. Neural-Tube Defects According to Maternal ART and HIV Infection Status, August 2014–March 2019.

There were 7 additional infants with neural-tube defects in the full cohort: 3 born to women who started non-DTG ART during pregnancy, 3 born to HIV-infected women who did not receive ART during pregnancy, and 1 born to a woman of unknown HIV infection status who did not receive ART. Photographs for confirmation of the neural-tube defect were available for 4 of the 5 infants exposed to DTG from conception, 8 of 15 of those exposed to non-DTG ART from conception, 2 of 3 of those exposed to EFV from conception, 1 of 1 exposed to DTG treatment that was started in pregnancy, and 42 of 70 born to HIV-negative mothers. Among the infants exposed to DTG that was initiated during pregnancy, the median gestational age at the time of treatment initiation was 19 weeks (interquartile range, 13 to 25).