Administration of nirmatrelvir and ritonavir reverses maternal and fetal adverse outcomes following SARS-CoV-2 infection during pregnancy in mice

SARS-CoV-2 infection during pregnancy is associated with severe COVID-19 and adverse fetal outcomes, but the underlying mechanisms remain poorly understood. Moreover, clinical studies assessing the safety and efficacy of therapeutics against SARS-CoV-2 in pregnancy are limited. To address these gaps, we developed a mouse model of SARS-CoV-2 infection during pregnancy. Outbred CD1 mice were infected at embryonic day (E) 6, E10, or E16 with a mouse adapted SARS-CoV-2 (maSCV2) virus to characterize maternal and neonatal outcomes of maternal infection across gestation. The outcomes of infection during pregnancy were gestational age-dependent with greater morbidity, reduced pulmonary function, reduced anti-viral immunity, greater viral titers, greater placental damage, and more adverse fetal outcomes occurring with infection at E16 (i.e., 3rd trimester-equivalent) than with infection at either E6 (i.e., 1st trimester-equivalent) or E10 (i.e., 2nd trimester-equivalent). To assess the efficacy of ritonavir-boosted nirmatrelvir, which is recommended for pregnant individuals with COVID-19, we treated E16 dams with mouse equivalent doses of nirmatrelvir and ritonavir after either maSCV2 or mock infection. Treatment of maSCV2-infected dams reduced pulmonary, but not nasal viral titers, decreased maternal morbidity, and prevented adverse offspring outcomes as compared with maternal infection alone. Our results highlight that severe COVID-19 during pregnancy and adverse fetal outcomes are associated with an inability to control virus replication in maternal lungs. Ritonavir-boosted nirmatrelvir not only mitigated adverse maternal, but also fetal, outcomes of SARS-CoV-2 infection. These findings prompt the need for further consideration of pregnancy in preclinical and clinical studies of therapeutics against viral infections.