Newborn IgG and IgM antibodies to maternal SARS-CoV-2 infection in pregnancy and child neurodevelopmental outcomes

Maternal immune activation is a hypothesized mechanism by which prenatal exposure to infection adversely impacts fetal brain development. SARS-CoV-2 IgG class antibodies generated to viral proteins in pregnancy are transferred across the placenta to the newborn. This study aimed to investigate the association between neonatal levels of IgG antibodies to SARS-CoV-2 nucleocapsid and spike proteins and risk of neurodevelopmental disorders (ND) among children with gestational SARS-CoV-2 exposure. Using a longitudinal prospective cohort design within an integrated healthcare system with a diverse patient population in Northern California, the study looked at 399 children born to mothers who had SARS-CoV-2 infection during pregnancy and had not received the COVID-19 vaccination. Exposure was IgG and IgM class antibodies to SARS-CoV-2 nucleocapsid, IgG directed against the full-length spike protein, the s1-receptor binding domain (RBD) and s1 N-terminal domain (NTD) of the spike protein, and IgM to the full length and RBD spike proteins. The main outcome and measure were all ND, including autism spectrum disorder (ASD), speech/language delay, and motor delay. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% confidence intervals (CIs), with adjustment for maternal sociodemographic and clinical characteristics, and child sex. Among the 399 study children (208 females,191 males) followed up to 64 months, 95% had gestational age ≥ 37 weeks and birthweight ≥ 2500 g. The mean maternal age was 31 +- 5 years; 12% were Asian, 5% Black, 45% Hispanic, 33% White, and 5% other/unknown race/ethnicity; 80% had more than a High School education; 86% had commercial insurance; 37% were primiparous; and 35% had pre-pregnancy obesity. A total of 73 children were diagnosed with ND in follow-up (22 ASD, 67 speech/language disorder, 11 motor delay). Associations between SARS-CoV-2 nucleocapsid IgG antibody level and risk of ND differed significantly by child sex, with increased risk observed only among males (ND: aHR = 1.25 1.01-1.56; ASD: aHR = 1.38 0.93-2.06; speech/language delay: aHR = 1.33 1.06-1.67). Risk also differed by trimester of maternal SARS-CoV-2 infection, with over 2-fold increased risks observed with exposure in the first trimester (ND: aHR = 2.12 1.08-4.15; speech/language delay: aHR = 2.16 1.06-4.47) and second trimester (speech/language delay: aHR = 2.22 1.23-4.00). Results were similar for the SARS-CoV-2 spike, RBD and NTD proteins. Few of the neonates had detectable levels of IgM antibodies to the SARS-CoV-2 proteins. In conclusion, higher levels of neonatal IgG antibodies to SARS-CoV-2 proteins following infection in pregnancy may indicate increased risk for ND. If replicated, these findings suggest that newborn antibody testing of infants with prenatal SARS-CoV-2 exposure may provide a novel avenue for early identification of infants at risk for ND and opportunities for early intervention and prevention of adverse child outcomes.