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.

Keywords: Coronavirus disease 2019; Maternal-fetal interface; Neurodevelopment; Neuroimmune interactions; Pregnancy; Severe acute respiratory syndrome-related coronavirus 2.

Fig. 1

Hypothetical neuroimmune-endocrine mechanisms by which SARS-CoV-2 infection may lead to damages in fetal brain development. Under normal conditions, the maternal, fetal, and placental HPA axes work in an integrated manner to avoid damages to fetal neurodevelopment. During pregnancy, the levels of placental 11β-HSD2 (glucocorticoid-inactivating enzyme) rise throughout gestation, ensuring proper fetus exposure to glucocorticoids. Steroid hormones (e.g., progesterone) also increase during gestation progress, shifting the cytokine balance toward an anti-inflammatory profile at the maternal-fetal interface. During a viral infection (e.g., SARS-CoV-2 infection), such regulatory mechanisms could be impaired. In these circumstances, SARS-CoV-2 (1) may lead to a disruption in the suitable regulation of the HPA axis; (2) glucocorticoids controlling mechanisms, as placental 11β-HSD2 expression, may be disrupted and rise fetal exposure to these hormones, which could lead to neuropsychiatric disturbances in childhood or adulthood; (3) a dysregulation of progesterone production by the placenta can contribute to an unbalanced inflammatory environment for the fetus; and (4) the exacerbated maternal inflammation may break proper immune-endocrine interactions and impair the offspring's neurodevelopment (e.g., ASD-related cortical and behavioral abnormalities). SARS-CoV-2, severe acute respiratory syndrome-related coronavirus 2; HPA, hypothalamic-pituitary-adrenal; CRH, corticotrophin-releasing hormone; 11β-HSD2, 11β-hydroxysteroid dehydrogenase type 2; ASD, autism spectrum disorders.

Fig. 2

Major pathways for neurodevelopmental and neuropsychiatric outcomes in the offspring of mothers infected by SARS-CoV-2. SARS-CoV-2 infection during pregnancy could lead to devastating outcomes in the offspring's brain, and in this case, there are 2 major pathways that can be responsible for affecting brain health and its proper development. a First, the virus could supposedly cross placental tissues (vertical transmission) and reach the fetus' brain, leading to harmful effects. b Second, despite the SARS-CoV-2 vertical transmission possibility, the virus can trigger an exacerbated inflammatory response in the infected pregnant mother (upper panel). The inflammatory mediators produced by the mother can effectively cross all placental barriers and the fetus' BBB, which can trigger neurodevelopmental and/or neuropsychiatric damages in the offspring (e.g., neuroanatomical changes, cognitive impairments, schizophrenia spectrum disorders, ASD, and ADHD manifestations) (bottom panel). SARS-CoV-2, severe acute respiratory syndrome-related coronavirus 2; BBB, blood-brain barrier; ASD, autism spectrum disorders; ADHD, attention-deficit/hyperactivity disorder.

Fig. 3

Possible pathways for SARS-CoV-2 vertical transmission at the maternal-fetal interface. Similar to other pathogens, SARS-CoV-2 infection during pregnancy could reach the placenta and impair the fetal development through different pathways. This schematic picture shows the fetus inside the intrauterine cavity (left panel), along with a magnification of the maternal-fetal interface with its main components such as placenta, decidua, spiral artery, fetal blood vessels, trophoblast cells (e.g., cytotrophoblast and syncytiotrophoblast), immune cells (e.g., NK cells and macrophages), and migrating microglia (middle panel). There are some possible pathways for SARS-CoV-2 vertical transmission crossing the maternal-fetal interface and were indicated by the numbers throughout the picture (dashed red square) and in the right panel: (1) through maternal endothelial microvasculature to endovascular extravillous trophoblasts; (2) spread through infected maternal immune cells; (3) transcytosis of virions via immune-mediated receptors; (4) transvaginal ascending infection; and (5) release of inflammatory mediators, leading to increased permeability of placental barriers. SARS-CoV-2, severe acute respiratory syndrome-related coronavirus 2; NK, natural killer.