Impact of respiratory viral infections during pregnancy on the neurological outcomes of the newborn: current knowledge

Abstract

Brain development is a complex process that begins during pregnancy, and the events occurring during this sensitive period can affect the offspring's neurodevelopmental outcomes. Respiratory viral infections are frequently reported in pregnant women, and, in the last few decades, they have been related to numerous neuropsychiatric sequelae. Respiratory viruses can disrupt brain development by directly invading the fetal circulation through vertical transmission or inducing neuroinflammation through the maternal immune activation and production of inflammatory cytokines. Influenza virus gestational infection has been consistently associated with psychotic disorders, such as schizophrenia and autism spectrum disorder, while the recent pandemic raised some concerns regarding the effects of severe acute respiratory syndrome coronavirus 2 on neurodevelopmental outcomes of children born to affected mothers. In addition, emerging evidence supports the possible role of respiratory syncytial virus infection as a risk factor for adverse neuropsychiatric consequences. Understanding the mechanisms underlying developmental dysfunction allows for improving preventive strategies, early diagnosis, and prompt interventions.

Keywords: influenza virus; maternal infection; neurodevelopmental outcome; respiratory syncytial virus; respiratory viral infections; severe acute respiratory syndrome coronavirus 2.

Figure 1

Mechanisms affecting the brain development during maternal respiratory viral infections. During pregnancy, physiological changes in the maternal immune system increase the susceptibility to respiratory viral infections. (A) The reduction in the Th1/Th2 phenotype ratio and natural killer cell activation impair the immune response, while the intravascular inflammation enhances the virulence, increasing the risk of vertical transmission. (B) Cytokines and inflammatory mediators produced by the mother during infections can cross the placental barrier and interfere with the fetal brain development. (C) Both the vertical transmission and maternal immune activation induce neuroinflammation, further sustained by fetal production of inflammatory products. All these mechanisms disrupt the development of the fetal central nervous system.

Figure 2

Mechanisms and effects of Maternal Immune Activation on fetal brain. The maternal immune response to respiratory infections induces the release of pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, and IFN-γ. In turn, IL-6 leads to the activation of Th17 cells and the production of IL-17a. In the placenta, TNF-α contributes to the activation of the immune resident cells, resulting in further production of pro-inflammatory cytokines that cross the placental-fetal barrier and participate in the neuroinflammatory processes in the fetal brain. Neuroinflammation may alter normal brain development, resulting in adverse neuropsychiatric outcomes during childhood and adulthood, such as developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), cerebral palsy (CP), attention-deficit/hyperactivity disorder (ADHD), schizophrenia, depression, anxiety, and bipolar disorder.

Figure 3

Immunopathological mechanisms of maternal respiratory infections. Maternal respiratory infections caused by Influenza virus, SARS-CoV-2, and RSV trigger the host’s immune response, leading to the production of several pro-inflammatory cytokines. This Maternal Immune Activation (MIA) is deemed responsible for adverse neuropsychiatric outcomes in offspring. Passing the viruses in the maternal blood may result in placental infection, potentially leading to vertical transmission to the fetus. In turn, the invasion of placental cells can provoke further production of pro-inflammatory cytokines, contributing to MIA.