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Publications

Journal Article Research Support, N.I.H., Extramural Epublish 14 citations

PubMed: 37581940 DOI: 10.1172/JCI170687

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

J Clin Invest 133(20)

Authors: Patrick S Creisher, Jamie L Perry, Weizhi Zhong, Jun Lei, Kathleen R Mulka, W Hurley Ryan, Ruifeng Zhou, Elgin H Akin, Anguo Liu, Wayne Mitzner, Irina Burd, Andrew Pekosz, Sabra L Klein

Affiliations

  • W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
  • Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
  • Department of Environmental Health and Engineering, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

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.

MeSH

Pregnancy, Sars-Cov-2, Growth, Ritonavir, Gestational Age, Covid-19, Viruses, Morbidity, Therapeutics, Severe Acute Respiratory Syndrome-Related Coronavirus, Antiviral Agents, Infections, Neurodevelopment

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