Brazil provides more evidence on link between dolutegravir and birth defects

22 January 2021

Review initially finds dolutegravir has no links to birth defects then revises its findings to report a ‘slightly higher’ – but minimal – incidence after two cases emerge.

child touching mother's pregnant tummy

The question of whether the antiretroviral dolutegravir (DTG) causes neural tube defects (NTDs) in newborns if women are taking the drug at the time of conception, has received new insight after Brazil released findings from a national investigation.

In May 2018 the World Health Organization (WHO) issued a warning on the use of DTG following alarming early results from a Botswana study that found a link between birth defects and DTG-use among pregnant women. Immediate changes were made to WHO treatment recommendations for women of childbearing age (15 to 49 years). This development caused grave concern around the world.

Since then, further evidence has clarified the initial evidence, including updated results from the Botswana study itself. The study reported a lower NTD prevalence than its earlier results, although at 0.3% this rate was still higher than the NTD rate in the general population of pregnant women. The WHO now recommends all adults, including women of childbearing potential, be offered DTG, and that women should be provided with all the information around benefits and risks to make their own decisions.

To add to the evidence, Brazil – an early adopter of DTG – conducted a national investigation on whether women who were on DTG when they conceived were more likely to experience NTDs, stillbirth or miscarriage than other women.

The study, published in The Lancet, involves the largest group of women since the Botswana study.

Using Brazil’s national ART database, researchers reviewed data from pregnant women who had been taking DTG within 8 weeks of conception between January 2017 and May 2018 (380). For comparison, they also reviewed pregnant women taking efavirenz between January 2015 and May 2018 (1,045). No NTDs were found in either group.

Among women on DTG, 6% had stillbirths or miscarriages, compared to 3% in the efavirenz group. But further analysis did not find a significant association between DTG and stillbirth or miscarriage, suggesting this higher level was down to other factors during pregnancy.

After May 2018, when WHO’s guidelines had been revised and the study period had closed, two confirmed NTDs cases among babies born to women who had been on DTG when they conceived were reported. This, along with data up to February 2019, took the NTD incidence rate to 0.18%. Although this is still less than 1%, it is slightly higher than NTD incidence among the general population of pregnant women, which stands at 0.06%.

Writing in The Lancet, Elaine Abrams of Columbia University and Landon Myer of the University of Cape Town describe the study as “impressive in its scope but not without limitations, particularly as a retrospective review with a relatively small sample.”

They add that the association between DTG and NTDs found by the study “is small in absolute terms and highly likely to be outweighed by the benefits of dolutegravir as an agent to treat HIV infection in women”.

They also discuss the issue of folic supplements, which prevent birth defects. Around half (48%) of the DTG group and 44% of the efavirenz group in the Brazil study received folic supplements, and the study’s findings are in line with those from settings with similar folic fortification programmes. If DTG was to increase NTD risk through a mechanism related to folic deficiency, detecting an association might be difficult in such settings. Botswana, by comparison, does not offer routine folic supplements for pregnant women.

The Brazil study revealed an unexpectedly high number of women on DTG during conception after May 2018, despite national guidance that it should only be given to women on reliable birth control. This highlights the need for better monitoring of birth outcomes among pregnant women living with HIV.

Written by Hester Phillips

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