Background: We previously reported a preliminary safety signal associating dolutegravir exposure from conception and neural tube defects (NTDs), impacting antiretroviral choices for women of reproductive potential. Planned analysis of NTDs with data collected through March 2019 in the Tsepamo Study is now reported
Methods: We conducted birth outcomes surveillance at 8 government hospitals throughout Botswana from 2014-2018, expanding to 18 hospitals in 2018-2019. Trained midwives performed surface examinations of all live births and stillbirths and described abnormalities. Research assistants photographed major abnormalities after maternal consent, which were reviewed by a birth defects expert blinded to exposures. Prevalence of NTDs and major structural defects detectable by surface exam were determined by maternal HIV and antiretroviral exposure status (95%CI by Wilson method). The primary analysis evaluated prevalence differences by exposure status (95%CI by Newcombe method).
Results: From August 2014 through March 2019, 119,477 deliveries were captured in surveillance; 119,033 (99.6%) had an evaluable infant surface exam, with 98 (0.08%, 95%CI 0.07%, 0.10%) NTDs identified (60 with photo, 38 by description only). Among women on dolutegravir from conception, 5/1684 NTDs occurred (0.30%; 95%CI 0.13%, 0.69%): 2 myelomeningoceles, 1 anencephaly, 1 encephalocele, and 1 iniencephaly. In comparison, NTDs occurred in 15/14,792 (0.10%; 95%CI 0.06%, 0.17%) women delivering on any non-dolutegravir antiretrovirals from conception, 3/7959 (0.04%; 95%CI 0.01%, 0.11%) on efavirenz from conception, 1/3,839 (0.03%; 95%CI 0%, 0.15%) on dolutegravir started in pregnancy, 70/89,372 (0.08%; 95%CI 0.06, 0.10%) HIV-uninfected women. NTD prevalence differed significantly between dolutegravir and any non-dolutegravir antiretrovirals from conception (0.20% difference; 95%CI 0.01%, 0.59%), and for all other comparisons with dolutegravir (Table). Major structural defects were observed in 0.95% (95%CI 0.59, 1.54) of DTG-conception exposures and 0.68% (95%CI 0.56, 0.83) of non-dolutegravir exposures from conception (0.27% difference; 95%CI -0.13, 0.87).
Conclusions: NTDs occurred in 3 per 1000 deliveries among women on dolutegravir from conception, a small but significant increase compared with all other antiretroviral exposures. Ongoing NTD surveillance in the Tsepamo Study is planned.

Exposure Group Comparisons% Prevalence Difference (95% CI)
DTG at conception vs. Non-DTG at conception0.20% (0.01%,0.59%)
DTG at conception vs. EFV at conception0.26% (0.07%,0.66%)
DTG at conception vs. DTG started in pregnancy0.27% (0.06%,0.67%)
DTG at conception vs. non-DTG started in pregnancy0.25% (0.05%,0.64%)
DTG at conception vs. HIV-uninfected0.22% (0.05%,0.61%)
[Table. Differences in Neural Tube Defect Prevalence by HIV- and ART-exposure status]