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

ABSTRACT: 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 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 E6, E10, or E16 with a mouse-adapted SARS-CoV-2 (maSCV2) virus. Outcomes were gestational age-dependent, with greater morbidity, reduced antiviral immunity, greater viral titers, and impaired fetal growth and neurodevelopment occurring with infection at E16 (third trimester equivalent) than with infection at either E6 (first trimester equivalent) or E10 (second trimester equivalent). To assess the efficacy of ritonavir-boosted nirmatrelvir, which is recommended for individuals who are pregnant with COVID-19, we treated E16-infected dams with mouse-equivalent doses of nirmatrelvir and ritonavir. Treatment reduced pulmonary viral titers, decreased maternal morbidity, and prevented offspring growth restriction and neurodevelopmental impairments. Our results highlight that severe COVID-19 during pregnancy and fetal growth restriction is associated with heightened virus replication in maternal lungs. Ritonavir-boosted nirmatrelvir mitigated maternal morbidity along with fetal growth and neurodevelopment restriction after SARS-CoV-2 infection. These findings prompt the need for further consideration of pregnancy in preclinical and clinical studies of therapeutics against viral infections.

SUBMITTER: Creisher PS

PROVIDER: S-EPMC10575736 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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

Creisher Patrick S PS Perry Jamie L JL Zhong Weizhi W Lei Jun J Mulka Kathleen R KR Ryan W Hurley WH Zhou Ruifeng R Akin Elgin H EH Liu Anguo A Mitzner Wayne W Burd Irina I Pekosz Andrew A Klein Sabra L SL

The Journal of clinical investigation 20231016 20

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 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 E6, E10, or E16 with a mouse-adapted SARS-CoV-2 (maSCV2) virus. Outcomes were gestational age-dependent, with greater morb ...[more]

PMID: 37581940

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Project description:BackgroundDespite previous research findings on higher risks of stillbirth among pregnant individuals with SARS-CoV-2 infection, it is unclear whether the gestational timing of viral infection modulates this risk.ObjectiveThis study aimed to examine the association between timing of SARS-CoV-2 infection during pregnancy and risk of stillbirth.Study designThis retrospective cohort study used multilevel logistic regression analyses of nationwide electronic health records in the United States. Data were from 75 healthcare systems and institutes across 50 states. A total of 191,403 pregnancies of 190,738 individuals of reproductive age (15-49 years) who had childbirth between March 1, 2020 and May 31, 2021 were identified and included. The main outcome was stillbirth at ≥20 weeks of gestation. Exposures were the timing of SARS-CoV-2 infection: early pregnancy (<20 weeks), midpregnancy (21-27 weeks), the third trimester (28-43 weeks), any time before delivery, and never infected (reference).ResultsWe identified 2342 (1.3%) pregnancies with COVID-19 in early pregnancy, 2075 (1.2%) in midpregnancy, and 12,697 (6.9%) in the third trimester. After adjusting for maternal and clinical characteristics, increased odds of stillbirth were observed among pregnant individuals with SARS-CoV-2 infection only in early pregnancy (odds ratio, 1.75, 95% confidence interval, 1.25-2.46) and midpregnancy (odds ratio, 2.09; 95% confidence interval, 1.49-2.93), as opposed to pregnant individuals who were never infected. Older age, Black race, hypertension, acute respiratory distress syndrome or acute respiratory failure, and placental abruption were found to be consistently associated with stillbirth across different trimesters.ConclusionIncreased risk of stillbirth was associated with COVID-19 only when pregnant individuals were infected during early and midpregnancy, and not at any time before the delivery or during the third trimester, suggesting the potential vulnerability of the fetus to SARS-CoV-2 infection in early pregnancy. Our findings underscore the importance of proactive COVID-19 prevention and timely medical intervention for individuals infected with SARS-CoV-2 during early and midpregnancy.

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

Publications

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

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