Pathogenesis and Outcomes of SARS-CoV-2 In Utero Transmission - Immunologic and Virologic Evaluations

Importance: Despite effective vaccines, SARS-CoV-2 infection remains a major public health problem for pregnant women and their newborns as they have increased morbidity and mortality. Studies on estimated rates of in utero transmission are conflicting and reported on small numbers mostly limited to PCR testing at birth. Critical Gaps include limited diagnostics to identify in utero infection and lack of understanding of factors that impact MTCT and the pathogenesis of disease. From October 2021 through February 2023, we studied 1294 infant cord bloods for presence and level of SARS-CoV-2 antibodies. Overall, 89.9% had anti-RBD IgG, indicating maternal vaccination and/or previous infection and 55.1% had both anti-N and anti-RBD IgG, indicative of past infection. Fetal IgA and/or IgM antibodies to SARS-CoV-2 were found in 21.8% of 176/808 samples with anti-N, indicative of in utero transmission. The overall goal of this study is to identify newborns with in utero SARS-CoV-2 and prospectively follow infants to identify clinical and neurodevelopment outcomes. Aim 1: Identify newborns with in utero SARS-CoV-2 infection using a multi-faceted approach and assess relationship with inflammation, placental infection and pathology, and immunity. Hypothesis 1: In utero infection will be associated with elevated soluble markers of inflammation in newborn cord blood and evidence of placental infection and dysfunction. Using cord blood we will screen 3,600 newborns for anti-N, S, and RBD IgG antibodies (Abs) and if anti-N+ we will assess for SARS-CoV-2 specific anti-IgM and anti-IgA abs. Maternal SARS-CoV-2 qPCR testing will be done at delivery, and if qPCR+, newborn qPCR will be performed at 24/48 hours. Variant type will be determined by ddPCR. Newborn meconium/stool samples will have qPCR testing. Soluble biomarkers of inflammation and immune activation will be determined. Finally, placentas will be evaluated for pathology and SARS-CoV-2 infection. Aim 2. Longitudinally assess for immune activation, dysregulation, and function among a subset of infants with in utero infection and matched controls. Hypothesis 2: In utero infected infants will have abnormal markers of inflammation, immune activation, and dysregulation that if sustained will be associated with adverse clinical outcomes. In a subset of 100 infants with in utero SARS-CoV-2 and 50 uninfected controls we will determine levels of CD4 and CD8 T-cell activation and dysregulation and assess for SARS-CoV-2 specific antibodies and T cell response in mother-infant dyads at birth and longitudinally. We will then correlate with clinical and neurodevelopmental outcomes. At the end of this project, we will have developed a comprehensive algorithm to screen and follow newborns with in-utero SARS-CoV-2 and will have determined if there are immunologic dysfunctions impacting clinical, developmental, neurologic, and other abnormalities that may require long-term follow-up, treatments and/or interventions.