Integrase inhibitor drugs during pregnancy and congenital anomalies: A case/non‐case study from the global pharmacovigilance database VigiBase®

Abstract

Abstract In 2018, a significant neural tube defects (NTD) signal was reported after pre‐conceptional exposure to dolutegravir, but was not confirmed in further analysis. Since 2019, dolutegravir‐based regimen, an integrase inhibitor (INI), is recommended by WHO as the most‐effective first‐line therapy in all patients living with HIV. To explore the potential INI‐related teratogenic effect, we searched disproportionate signals between exposure to INI‐class drugs and congenital anomalies, compared to non‐INI drugs, using the international pharmacovigilance database, VigiBase®. We selected all the reports registered in VigiBase® between 01/01/2007 and 30/03/2021 on any antiretroviral drug‐related fetal or neonatal adverse drug reactions, declared either in children (<2 years) exposed in utero or in pregnant women (12–50 years). A case/non‐case study was conducted to detected signals between congenital anomalies and prenatal exposure to any INI‐class drug, compared to non‐INI drugs, by estimating adjusted reporting odds ratios (aROR) with 95% confidence intervals (95%CI). We identified 2521 unique reports, among which 664 (26.3%) were related to INI‐class use. Overall, 520 congenital anomalies were cited from 327 unique reports, of whom 31.0% were INI‐related. Compared to non‐INI drugs, no significant disproportionate reporting signal between prenatal exposure to INI‐class drugs and congenital anomalies was found (aROR 1.13; 95% CI:0.85–1.51). However, specific significant signals were reported for raltegravir/elvitegravir/dolutegravir drug exposure and urinary malformations (aROR 2.43; 95%CI:1.08–5.43), digestive malformations (aROR 3.09; 95%CI:1.22–7.84), and NTDs (aROR 3.02; 95%CI:1.09–8.37). Although specific congenital anomalies signals associated with raltegravir/elvitegravir/dolutegravir exposure were notified, causal relationship needs to be further investigated in prospective studies.

Keywords

• antiretroviral drugs
• case/non‐case study
• congenital anomalies
• HIV
• integrase inhibitors
• pregnancy