Adverse outcomes in SARS-CoV-2 infected pregnant mice are gestational age-dependent and resolve with antiviral treatment

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.

妊娠期间感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）与重型新型冠状病毒肺炎（COVID-19）及不良胎儿结局密切相关，但其潜在致病机制仍未得到充分阐明。此外，针对妊娠人群开展的新冠治疗药物安全性与有效性评估的临床研究数量有限。
为填补这一研究空白，本研究构建了妊娠期间感染SARS-CoV-2的小鼠模型：将远交系CD1小鼠在胚胎发育第6天（E6）、第10天（E10）或第16天（E16）时，接种小鼠适应性SARS-CoV-2（maSCV2）病毒，以表征整个妊娠期母体感染后的母体及新生子代结局。
妊娠期间感染的结局呈现妊娠胎龄依赖性：相较于在E6（相当于人类妊娠早期）或E10（相当于人类妊娠中期）感染的小鼠，在E16（相当于人类妊娠晚期）感染的小鼠发病率更高、肺功能受损更严重、抗病毒免疫应答减弱、病毒载量更高、胎盘损伤更显著，且不良胎儿结局发生率也更高。
为评估推荐用于新冠感染妊娠人群的利托那韦增强奈玛特韦（ritonavir-boosted nirmatrelvir）的治疗效果，我们在maSCV2感染或模拟感染后的E16孕鼠中，给予小鼠等效剂量的奈玛特韦与利托那韦进行干预。相较于仅接受母体感染的小鼠，接受该联合治疗的maSCV2感染孕鼠肺部病毒载量显著降低（但鼻腔病毒载量无明显变化），母体发病率下降，且子代不良结局得以避免。
本研究结果表明，妊娠期间发生的重型新冠以及不良胎儿结局，与母体肺部无法有效控制病毒复制密切相关。利托那韦增强奈玛特韦不仅可改善SARS-CoV-2感染带来的母体不良结局，同时也能改善胎儿相关不良结局。
上述研究结果提示，在抗病毒感染治疗药物的临床前与临床研究中，应进一步纳入妊娠人群相关考量。