SARS-CoV-2 Infection in Pregnant Women: Neuroimmune-Endocrine Changes at the Maternal-Fetal Interface

Abstract

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has devastating effects on the population worldwide. Given this scenario, the extent of the impact of the disease on more vulnerable individuals, such as pregnant women, is of great concern. Although pregnancy may be a risk factor in respiratory virus infections, there are no considerable differences regarding COVID-19 severity observed between pregnant and nonpregnant women. In these circumstances, an emergent concern is the possibility of neurodevelopmental and neuropsychiatric harm for the offspring of infected mothers. Currently, there is no stronger evidence indicating vertical transmission of SARS-CoV-2; however, the exacerbated inflammatory response observed in the disease could lead to several impairments in the offspring’s brain. Furthermore, in the face of historical knowledge on possible long-term consequences for the progeny’s brain after infection by viruses, we must consider that this might be another deleterious facet of COVID-19. In light of neuroimmune interactions at the maternal-fetal interface, we review here the possible harmful outcomes to the offspring brains of mothers infected by SARS-CoV-2.

COVID-19 in pregnancy: implications for fetal brain development

“…There are multiple potential pathways by which a maternal infection with SARS-CoV-2 could impact the developing fetal brain [13,[26][27][28]: (i) via MIA (see Glossary) during key neurodevelopmental windows in pregnancy; (ii) via direct fetal infection of neurologic tissues via transplacental transmission of virus; or (iii) via compromised placental function resulting in adverse pregnancy outcomes associated with an increased risk of neurologic injury (e.g., fetal growth restriction, preterm birth, abruption). In this review, we present emerging evidence regarding the impact of SARS-CoV-2 infection during pregnancy on offspring neurodevelopmental outcomes, explore potential mechanisms by which prenatal SARS-CoV-2 exposure might impact the developing fetal brain, and discuss virus and host factors that might influence risk.…”

“…A key factor in understanding potential fetal infection risk is whether maternally acquired SARS-CoV-2 can transmit across the placenta, the primary physiological and immunological barrier preventing viral transmission from the maternal to fetal circulation [116][117][118]. The preponderance of evidence to date suggests that adverse neurodevelopmental effects of SARS-CoV-2 infection, at least with the ancestral strain and strains preceding the B.1.617.2 (Delta) variant, are more likely to occur via maternal and placental immune activation and downstream impact on the developing fetal brain, rather than via direct fetal infection with SARS-CoV-2 in utero [28,119]. Population-level data suggest that rates of SARS-CoV-2 positivity among newborns in SARS-CoV-2-exposed pregnancies range from 1% to 3% [83,[120][121][122][123][124], with placental infection being a relatively rare event.…”

Decidual immune response following COVID-19 during pregnancy varies by timing of maternal SARS-CoV-2 infection

“…Of central importance are intrauterine immune responses, governed by maternal decidual leukocytes adjacent to the villous placenta. Among these, decidual T cells, NK cells, and macrophages are known to respond to viral infection at the maternal-fetal interface, either through cellular or cytokine-mediated responses ( Crespo et al, 2016 , Yockey and Iwasaki, 2018 , Jabrane-Ferrat, 2019 , Crespo et al, 2020 , Parker et al, 2020 , Granja et al, 2021 ).…”

Virus-Induced Maternal Immune Activation as an Environmental Factor in the Etiology of Autism and Schizophrenia

“…Since the virus has only been identified recently (end of 2019) there are yet no studies that have been able to investigate neurodevelopmental consequences in the offspring of affected mothers. Based on its clinical manifestation and past “similar” infections, theories have been proposed that suggest potential effects on the offspring ( Granja et al, 2021 ). Following infection with SARS-CoV-2, there is an uncontrolled release of inflammatory cytokines and chemokines that have been involved in brain development [e.g., interleukins (IL-1β,−2,−4,−6,−8,−10), tumor necrosis factor alpha, interferons (IFN-α, IFN-γ)] ( Reyes-Lagos et al, 2021 ).…”