Risk of Birth Defects and Perinatal Outcomes in HIV-Infected Women Exposed to Integrase Strand Inhibitors During Pregnancy

Jeanne Sibiude; Jérôme Le Chenadec; Laurent Mandelbrot; Catherine Dollfus; Sophie Matheron; Nathalie Lelong; Véronique Avettand-Fenoel; Maud Brossard; Pierre Frange; Véronique Reliquet; Josiane Warszawski; Roland Tubiana


AIDS. 2021;35(2):219-226. 

In This Article

Abstract and Introduction


Objectives: Following an alert on neural tube defects and dolutegravir, we sought to evaluate if the exposure integrase strand transfer inhibitors (INSTIs) at conception was associated with birth defects or other adverse pregnancy outcomes.

Methods: In the prospective national French Perinatal Cohort (EPF), we studied birth defects and other perinatal outcomes by matching each pregnant woman exposed to INSTIs with a pregnant woman exposed to darunavir/ritonavir receiving the same backbone of nucleoside reverse transcriptase inhibitors and matched for other characteristics such as age, geographic origin, centre and year of delivery.

Results: Among 808 women exposed to INSTIs during pregnancy (raltegravir = 703, dolutegravir = 57 and elvitegravir = 48), we reported a slightly higher rate of birth defects in infants exposed at conception to raltegravir (6.7%) vs. infants exposed to raltegravir later in pregnancy: 2.9% if initiated during pregnancy as first-line, and 2.5% as second-line treatment, P =0.04. When compared with matched controls, raltegravir exposure at conception was not significantly associated with birth defects: 6.4 vs. 2.3%, P = 0.08. There was no cluster of birth defect type and no neural tube defects were observed. Other perinatal outcomes, such as preterm birth and stillbirths, did not differ significantly between raltegravir-exposed women and matched counterparts. No difference in any outcome was observed for elvitegravir/cobicistat or dolutegravir.

Conclusion: We found a nonsignificant trend for an association between exposure to raltegravir at conception and birth defects, which needs to be evaluated by larger prospective surveillance data, as these drugs are increasingly prescribed in women living with HIV.


In women living with HIV, the wide use of antiretroviral therapy (ART) has led to a spectacular decrease in the rate of mother-to-child transmission, from about 20% to less than 1% currently in high-income countries and less than 5% in low to middle-income countries.[1–3] Many women are now taking ART before the occurrence of pregnancy and are thus exposed to ART from conception. Concern has been raised about the potential toxicity of these drugs on foetal development, and the risk of birth defects associated with ART has been regularly evaluated in cohorts and registries.[4,5]

An association between dolutegravir, an integrase strand transfer inhibitor (INSTI), administered from the time of conception and neural tube defects[6,7] was observed in a prospective cohort in Botswana. Nonetheless, INSTIs are widely used because of their high antiretroviral potency, low resistance and good tolerance profile. Dolutegravir is now recommended by the WHO as first-line treatment in countries implementing option B+ (lifelong treatment for all pregnant women diagnosed with HIV infection). WHO concluded that the benefit/risk was favourable in comparison with the previous standard efavirenz-based treatment, while stating that reproductive-age women prescribed dolutegravir should receive information on the malformation risk and also be informed about efficient contraception.[8] In contrast, guidelines in most high-resource countries are to consider other options for women wishing to be pregnant.[9]

Raltegravir-based regimens are among these options and are progressively replacing nonnucleoside reverse transcriptase inhibitors (NNRTIs)-based regimens and protease inhibitors based regimens in high-resource countries. In France, the use of INSTIs has regularly increased since 2008, with raltegravir being the most used of the drugs in this class during pregnancy. No signal for birth defects or adverse pregnancy outcomes have been reported in humans yet, but the data are scarce and an increase in supernumerary ribs had been described in rats.[10–12] Thus, following the alert on dolutegravir, questions have been raised on a potential class effect for INSTIs.

We sought to evaluate if the exposure to raltegravir and other INSTIs at conception was associated with birth defects or other adverse pregnancy outcomes.