A study of births in women exposed to dolutegravir around the time of conception has confirmed that infants exposed to dolutegravir do not have an increased risk of neural tube defects.
The study authors say that their study suggests that in a setting where food is supplemented with folic acid, infants exposed to dolutegravir around the time of conception of in early pregnancy do not show an increased risk of neural tube defects such as spina bifida.
But the study did find a slightly increased risk of pregnancy loss in all women with HIV who were taking antiretroviral treatment around the time of conception.
Concerns were first raised about an increased risk of neural tube defects associated with dolutegravir in 2018, when a study of women with HIV in Botswana found an increased risk of neural tube defects in infants exposed to dolutegravir around the time of conception. That safety signal led to the temporary suspension of dolutegravir treatment in women of childbearing potential in many countries and slowed the introduction of dolutegravir-based treatment.
Subsequent follow-up of the Botswana cohort has shown that the risk of neural tube defects is only slightly higher when dolutegravir is taken around the time of conception or during the first three months of pregnancy.
Studies in other countries, including Brazil and Canada, have not shown an increased risk of neural tube defects associated with dolutegravir.
World Health Organization and national guidelines in Europe and North America now recommend that dolutegravir can be used in pregnancy or by women of childbearing potential.
Some researchers have suggested that folate fortification of food or folic acid supplementation protects against the risk of neural tube defects when dolutegravir is taken, just as in any other pregnancy.
Researchers from the US Centers for Disease Control and Prevention carried out a study of the outcomes of more than 18 million pregnancies recorded in two large healthcare databases in the United States between January 2008 and December 2020. They used the Medicaid claims database, which covers all claims for medication and treatment for people with Medicaid insurance in the United States, and the MarketScan database, which includes around 20% of people with employer-sponsored health insurance in the US. The investigators looked only at pregnancies that were fully covered by the insurance databases, from conception to delivery.
They identified 14,346,116 pregnancies in the Medicaid database and 4,484,280 pregnancies in the MarketScan database in women without HIV (the comparator group).
Among women with HIV, they identified 59,745 pregnancies in the Medicaid database and 5,035 in the MarketScan database.
They defined periconception exposure to antiretroviral drugs as lasting from the date of a prescription issued at least eight weeks before the last premenstrual period until the end of the first trimester of the pregnancy. A pregnancy could only be counted as a periconception exposure if it fulfilled these criteria.
In the Medicaid database, 11,041 pregnancies included periconception exposure to non-dolutegravir antiretroviral drug regimens, while 1463 pregnancies included periconception exposure to dolutegravir.
In the MarketScan database, 993 pregnancies included periconception exposure to non-dolutegravir antiretroviral drug regimens, while 69 pregnancies included periconception exposure to dolutegravir.
Approximately 60% of the Medicaid population of women with HIV were Black compared to 23% of women without HIV. Women with HIV also tended to be older (24% of women taking dolutegravir around conception were aged 35-44 compared to 11% of women without HIV).
The investigators looked for records of neural tube defects in infants, as well as cases of stillbirths or pregnancy loss (spontaneous or induced), as pregnancies involving severe congenital defects may lead to pregnancy loss.
In the Medicaid cohort they found three cases of neural tube defects in pregnancies with periconceptional exposure to antiretrovirals other than dolutegravir (3.8 per 10,000) and one case in pregnancies with periconceptional exposure to dolutegravir (10.6 cases per 10,000), compared to 639 cases in women without HIV (5.7 cases per 10,000).
They found no cases of neural tube defects in pregnancies of women with HIV exposed to any antiretroviral drugs around conception in the MarketScan cohort. The rate of neural tube defects in women without HIV in this cohort was similar to the Medicaid cohort (4.1 per 10,000).
The investigators carried out a multivariable analysis that controlled for demographic characteristics and maternal comorbidities. They found that the risk of neural tube defects in the Medicaid cohort was not significantly higher in either pregnancies exposed to dolutegravir around conception (adjusted risk ratio 1.81 [95% confidence interval 0.26-12.89]) compared to pregnancies in women without HIV or in pregnancies exposed to other antiretrovirals (aRR 0.66 (95% CI 0.21-2.06]). Nor was there a significant difference between pregnancies exposed to dolutegravir compared to other antiretrovirals (aRR 2.97 [0.31-28.89]).
Looking at pregnancy loss or stillbirth, the study found higher rates of pregnancy loss in women with HIV compared to women without HIV, whether they were exposed to dolutegravir or not. The risk of pregnancy loss was 41% higher in pregnancies with periconception exposure to dolutegravir in the and 11% higher in pregnancies with periconception exposure to other antiretrovirals compared to women without HIV in the Medicaid cohort.
There was no significant difference in the risk of stillbirth in the Medicaid cohort. In the Market-Scan cohort, no stillbirths occurred in the dolutegravir recipients while the risk was twice as high in pregnancies exposed to other antiretrovirals compared to women without HIV.
Studies which have looked at pregnancy loss in women with and without HIV do not show consistent results, so although this study adds to the evidence base, the study authors say that better quality evidence is needed in the form of prospective surveillance to address this issue.
The study authors say that their rigorous methodology for identifying pregnancies with periconceptional exposure to antiretrovirals contributes to the improved surveillance of antiretroviral safety in pregnancy. They say that the public health need for safety surveillance in pregnant women with HIV and in women exposed to antiretrovirals as PrEP will become more pressing as the number of women exposed during pregnancy grows.
Kourtis AP et al. Dolutegravir and pregnancy outcomes including neural tube defects in the USA during 2008-20: a national cohort study. Lancet HIV 10: e588-e596, 2023.
DOI:https://doi.org/10.1016/S2352-3018(23)00108-X