Adverse outcomes in SARS-CoV-2–infected pregnant mice are gestational age–dependent and resolve with antiviral treatment
Patrick S. Creisher, … , Andrew Pekosz, Sabra L. Klein
Patrick S. Creisher, … , Andrew Pekosz, Sabra L. Klein
Published August 15, 2023
Citation Information: J Clin Invest. 2023;133(20):e170687. https://doi.org/10.1172/JCI170687.
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Research Article Reproductive biology

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.

Authors

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

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Figure 1

maSCV2 infection of pregnant dams results in gestation-dependent morbidity.

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maSCV2 infection of pregnant dams results in gestation-dependent morbidi...
Nonpregnant adult females (A) or dams at E6 (B), E10 (C), and E16 (D) were intranasally inoculated with 1 × 105 TCID50 of a mouse adapted SARS-CoV-2 (maSCV2) or mock inoculated with media. Following infection, mice were monitored for change in body mass and clinical signs of disease over 14 days (A–D). AUC of body mass change curves for infected and uninfected animals were calculated, and then the AUC of infected animals was subtracted from the average AUC of mock animals of the same reproductive status and gestational age (E). Clinical scores given to animals included dyspnea, piloerection, hunched posture, and absence of an escape response and are quantified on a score of 0–4. The cumulative clinical score over the 14-day monitoring period is reported for each animal (F). Individual shapes (A–D) or bars (E and F) represent the mean (A–E) or median (F) ± SEM (A–E) from 2 independent replications (n = 7–13/group) with individual mice indicated by shapes (E and F). Statistical significance was determined by 2-way repeated measures ANOVA with Bonferroni posthoc test (A–F, to compare individual time points), 2 tailed unpaired t test of AUCs (A–F, to compare across all time points), 1-way ANOVA with Bonferroni posthoc test (E), or Kruskal-Wallis test (F). *P < 0.05.