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 4

Third trimester-equivalent maSCV2 infection causes intrauterine growth restriction.

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Third trimester-equivalent maSCV2 infection causes intrauterine growth r...
At E6, E10, or E16, pregnant dams were intranasally inoculated with 1 × 105 TCID50 of maSCV2 or mock inoculated with media. At 3 DPI, a subset of dams were euthanized, and fetal viability was determined as the percentage of fetuses within the uterus (A, n = total number of fetuses from 8–12 dams per group from 2 independent replicates). Fetuses were counted as nonviable if they were smaller or discolored compared with gestational age-matched live fetuses or if a fetus was absent at an implantation site. A subset of dams were followed into the postnatal period to characterize adverse birth outcomes. At postnatal day 0 (PND0) overall litter size (B), pup mass (C), pup body length (D), and pup head diameter (E) were measured. Average measurements of each independent litter were graphed (B–E). Bars represent the mean ± SEM from 2 independent replicates (n = 7–14/group) with the average of individual litters indicated by shapes. Statistical significance was determined by χ2 (A) or 2-way ANOVA with Bonferroni posthoc test (B–E). *P < 0.05.