The impact of COVID-19 during pregnancy on fetal brain development

The development of the brain as the most complex structure of the human body is a long process that begins in the third week of pregnancy and continues until adulthood and even until the end of life (1). Human brain myelination begins one to two months before birth in the visual system and eventually lasts until the age of two in other sensory systems and then the motor systems (4). Processes associated with normal brain development involve a wide range of molecular events, including the expression of genes and environmental events (1). If the brain is exposed to some environmental factors, its normal development will be disrupted (2) because the fetus is very sensitive to physical and chemical disruptive factors in different stages (5). Generally, factors that upon exposure during pregnancy lead to changes in the growth or structure of the developing fetus and ultimately cause defects in the physical structure or abnormalities in fetal behavior are called teratogens (6). Some viral infections have devastating impacts on the developing fetal brain. Viruses like Zika and cytomegalovirus can pass directly through the placenta to the fetal brain. These viruses cross the blood-brain barrier of the developing fetus, infecting and damaging brain tissue (9,10). Other infections including the influenza virus that do not cross the placental barrier have been associated with adverse effects on neural growth in offspring, mainly through mechanisms involved in activating the immune system of the mother, placenta, and subsequently the fetus (11,12). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new type of coronavirus that emerged in late 2019 and its related disease is known as coronavirus disease 19 (COVID-19). Nowadays, great attention is paid to COVID-19 infection in pregnant women and possible damage to their offspring. Although studies on COVID-19 are progressing rapidly, the effects of SARS-CoV-2 on fetal growth are unclear (16). In this review, we discussed evidence on the impact of SARS-CoV-2 infection during pregnancy on neurodevelopmental outcomes. Moreover, potential mechanisms by which prenatal SARS-CoV-2 exposure might impact the developing fetal brain were explored. These mechanisms are as follows: (1) direct fetal infection of neurologic tissues via transplacental transmission of the virus (2) impaired placental function resulting in adverse pregnancy outcomes associated with an increased risk of neurologic harm (e.g. fetal growth restriction and preterm birth) (3) via MIA (maternal immune activation) during neurodevelopment in pregnancy (16,17,18). A growing body of evidence suggests that SARS-CoV-2 infection can cause acute and chronic neurological complications in adults and children (19,20,21). There is no definite link between prenatal SARS-CoV-2 exposure and developmental neurological disorders in offspring, which may be partly due to the fact that most children born to infected mothers, are still very young for diagnosis of many developmental neurological conditions. However, epidemiological and clinical data indicate the potential of SARS-CoV-2 exposure during pregnancy to influence early neurodevelopmental outcomes. Preliminary data on the immune and inflammatory response to SARS-CoV-2 in pregnancy showed proinflammatory cytokines in pregnant women with SARS-CoV-2 that IFN-γ and IL-6 play the most important role (33,34). Significant infiltration of maternal immune cells into the placenta has been observed in cases of severe maternal COVID-19 and high SARS-CoV-2 viral load in the placenta (38). In placental specimens without evidence of direct SARS-CoV-2 infection, upregulation of the inflammatory pathways of natural killer cells (NK cells), T cells in mothers infected with SARS-CoV-2, and interferon-stimulated genes (ISGs) in villi tissue of placenta were shown (35,36). The placenta is the primary source of serotonin for the developing fetal brain. Studies show that activation and inflammation of the maternal and placental immune systems alter placental serotonin signaling, which in turn affects fetal brain development through impaired synaptogenesis, neuronal migration, and axonal targeting (40,41). Activation of the maternal and placental immune systems is also associated with other changes in fetal brain neurotransmitter signaling, including dopaminergic, cholinergic, GABA, and glutamatergic systems, which affect fetal brain development conditions (42,43). Activation of the maternal and placental immune system is associated with mitochondrial dysfunction of the placenta and fetus, oxidative stress, and impaired protein homeostasis (44,45). Maternal and infant gut microbiome may also be important modulators of the effect of MIA on the developing brain. Given the extent of synapse formation in the fetus and infant, the microglial function is a critical goal for research to better understand the effect of SARS-CoV-2-induced immune activation on the developing fetal brain (46). Transmission of the virus through the placenta, which can infect neural tissue, can have lasting and devastating consequences for the developing fetus's brain. A key factor in understanding the risk of possible fetal infection is whether maternally acquired SARS-CoV-2 can be transmitted from the placenta (a primary physiological and immune barrier that prevents the virus from being transmitted from mother to fetus) (48). Most of the evidence to date shows that the negative effects of neurodevelopment of SARS-CoV-2 infection occur mostly through activation of the mother and placenta's immunity rather than direct fetal infection with SARS-CoV-2 in utero. The data showed that the rate of SARS-CoV-2 positivity in infants in pregnancies exposed to SARS-CoV-2 is between 1% and 3%, and placental infection is a relatively rare event. A meta-analysis of case reports and case series estimated the placental infection rate at 7% (49). Mechanisms of protection against placental infection include low maternal SARS-CoV-2 viremia, maintenance of immune defense at the syncytophoblast border, and failure to express the molecules required (ACE2 and TMPRSS2) to bind and enter SARS-CoV-2 into the syncytrophoblast (36,37). Due to the small number of cases of placental infection and vertical transmission, data on completed pregnancies exposed to SARS-CoV-2 are now available throughout the developmental period (first to third trimesters). To date, no specific congenital syndrome has emerged following prenatal SARS-CoV-2 exposure indicating direct fetal infection (50,51). All of these data point to the activation of the maternal and placental immune systems and the subsequent activation of the fetal nervous system as the primary stimuli of neurodevelopmental complications in children exposed to SARS-CoV-2. Instead, direct infection of the placenta and fetal brain with Zika virus or cytomegalovirus infection has been observed. The data presented demonstrated the potential for maternal SARS-CoV-2 infection to stimulate maternal, placental, and fetal immune activation. Future studies will need to evaluate whether the fetoplacental immune responses in maternal SARS-CoV-2 infection are associated with neurodevelopmental morbidity in offspring. Effect of infection time, different strains of the virus, fetal gender, and prenatal status (eg, maternal cardiac metabolic status, substance use, stress, drug use) on offspring's neurodevelopment is important in the next generation for a comprehensive understanding of the potentially lasting impact of the COVID-19.