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Dolutegravir in Early Pregnancy: Updates on Possible Risk of Neural Tube Defects
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Integrase inhibitors have become primary treatment for most people living with HIV; however, the impact of newer integrase inhibitors on pregnancy outcomes has not been well described. Researchers for the observational Tsepamo study have been examining birth outcomes in Botswanan women treated with various ARV regimens during pregnancy since 2014, and have acquired information on 88,755 births, nearly 22,000 of them to women living with HIV. Unexpectedly, an interim analysis in May 2018 found a higher rate of neural tube defects (NTDs) in infants born to women who were on dolutegravir (DTG) at the time of conception (0.95%; n = 4, of 426) compared with women taking efavirenz at the time of conception (0.05%; n = 3, of 5,787) and women taking any non-DTG-containing ART regimen (0.12%; n = 14, of 11,300). No statistically significant difference in NTD prevalence was found between women who started DTG during pregnancy (ie, after conception) (0%; n = 0, of 2,812) and women who initiated non-DTG-containing regimens during pregnancy (0.05%; n = 3, of 5,624). These results were announced in May 2018, and resulted in safety warnings for use of DTG with women who may become pregnant while taking it.

At the 2018 International AIDS Conference in July, researchers presented the latest data from the Tsepamo study. By July 2018, the study team had documented an additional 170 infants born to women who started DTG before conception, and none had an NTD. There were 328 more births to women who started DTG during pregnancy, and 1 had an NTD. Thus, the updated rate of NTD in infants born to women taking DTG at the time of conception dropped to 0.67% (4 of 596 births) but it remains higher than the rate of infants exposed to other ARVs. The updated rate of NTD in infants of mothers who started DTG during pregnancy (0.05%) remains similar to (in fact, numerically lower than) the rate in infants of mothers on non-DTG regimens. Factors that might influence the occurrence or reporting of NTD do not appear to be different in women exposed to DTG at time of conception: there has been no overall increase in NTD in the population, no observed clustering of birth defects by site, and folate supplementation remains generally an uncommon practice throughout Botswana. Additionally, four different types of NTD were observed in the DTG preconception group, so there is no indication that a specific biological pathway is responsible for the various NTDs.

Clinical Bottom Line

More data on the safety of DTG when given prior to conception or when started during pregnancy will be forthcoming in April 2019, as the Tsepamo study expands from 8 to 18 sites and researchers continue to evaluate birth outcomes. Meanwhile, the U.S. Department of Health and Human Services has recommended that women with HIV who are of childbearing potential and currently taking DTG either be using effective contraception or be switched to a non-DTG-containing regimen.

References
Zash R, Holmes L, Makhema J, et al. Surveillance for neural tube defects following antiretroviral exposure from conception. Presented at the 22nd International AIDS Conference; July 23-27, 2018; Amsterdam.