A large proportion of pregnant women worldwide (21% in our CDC-funded Generation C cohort, current n=2,545) has been recently exposed to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and women of reproductive age continue to be infected despite widespread vaccination. However, the acute and subacute effects of SARS-CoV-2 infection during the vulnerable period of pregnancy and postpartum are not yet clear. Pregnancy and the postpartum are high-risk periods for coronavirus disease 19 (COVID-19) and for developing neuropsychiatric symptoms. Infections and dysregulation of inflammatory processes in the periphery and central nervous system (CNS) are thought to play a role in this vulnerability. We now know that SARS-CoV-2 causes high rates of subacute and long-term psychiatric and cognitive sequelae in the general population. There is a need to also understand the long-term effects of SARS-CoV-2 infection on mental health and cognition in the vulnerable population of pregnant and postpartum women, especially because they often are excluded from large cohort studies. We propose to study the long-term effects of prior SARS-CoV-2 infection on psychiatric and cognitive sequelae postpartum, with a mediating role of central and peripheral inflammation. We will leverage a well-powered pregnancy cohort (Generation C cohort, target n>3,000) established in April 2020 in New York, with 21% of the cohort previously exposed to SARS-CoV-2 infection to date. In a subset of this cohort (n=500), we propose to collect paired blood and cerebrospinal fluid (CSF) samples, which will provide the unique opportunity to investigate the subacute and long-term impacts of SARS-CoV-2 infection on inflammatory processes in the central nervous system (CNS). We hypothesize that prior SARS-CoV-2 infection can lead to dysregulation of peripheral and central inflammatory processes during pregnancy, and that this contributes to causing psychiatric symptoms and cognitive dysfunction in the vulnerable post-partum period. Aim 1 will characterize the subacute and long-term impact of prior exposure to SARS-CoV-2 on central and peripheral inflammation in pregnant women, including measuring SARS-CoV-2 IgG antibodies, characterizing inflammatory profiles using a high-sensitivity multiplex immunoassay for 11 inflammatory markers in CSF and blood, and examining the presence of neuronal autoantibodies. Aim 2 will examine the association between prior SARS-CoV-2 exposure, central and peripheral inflammation during pregnancy, and psychiatric symptoms postpartum. Aim 3 will examine the association between prior SARS-CoV-2 exposure, central and peripheral inflammation during pregnancy, and cognitive deficits in attention, memory and executive functioning postpartum.

The results of the proposed study will begin to elucidate the link between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) exposure, central and peripheral inflammation in pregnancy, and psychiatric and cognitive sequelae postpartum. We will identify central and peripheral markers of subacute and long-term neuropsychiatric sequelae of SARS- CoV-2. The results of this study will have important implications for mental health in the vulnerable periods of pregnancy and postpartum, and will identify targets for personalized treatment to ameliorate long-term neuropsychiatric sequelae of Coronavirus Disease-19 (COVID-19) and other infections.