Placental transfer of medications to treat COVID-19, molnupiravir, favipiravir and nirmatrelvir/ritonavir, in the ex vivo human cotyledon model

Objectives: There have been few studies in pregnant women of medications that are used to reduce severe complications from COVID-19 Infection. Currently, nirmatrelvir/ritonavir (Paxlovid) is recommended by the National Institutes for Health to treat non-hospitalized pregnant patients with mild-to-moderate COVID-19 illness. The aim of this study was to determine the transplacental passage of molnupiravir, nirmatrelvir/ritonavir and favipiravir utilizing an ex vivo placental perfusion model.

Methods: Human placental cotyledons were continuously perfused in a double open circuit. The study molecules and antipyrine, a marker of placental viability, were dissolved in the maternal solution. The experiment was conducted over 90 minutes, and every 5 minutes, samples of the maternal solution and fetal exchange solutions were collected for analysis. We calculated the concentrations of study molecules, fetal transfer ratios and the clearance indexes to determine placental transfer.

Results: Of 18 placentas analysed, 14 were validated by antipyrine transfer. Nirmatrelvir alone had low placental transfer, with a fetal transfer ratio of 0.025. Its placenta transfer increased in the presence of ritonavir, with a fetal transfer ratio of 0.06. The molnupiravir metabolite, β-D-N-4-hydroxycytidine (EIDD 1931), showed low placental transfer, with an average fetal transfer ratio of 0.04. By contrast, favipiravir crossed the placenta with an average fetal transfer ratio of 0.425.

Conclusions: Placental transfer was high for the nucleoside analogue favipiravir, while it was low for molnupiravir and low for the protease inhibitor nirmatrelvir but increased by ritonavir. Clinical data are required to confirm the placental transfer and determine the safety of COVID antivirals in pregnancy.