Neurodevelopmental delay in children exposed to maternal SARS-CoV-2 in-utero

Abstract

It is unclear if SARS CoV-2 infection during pregnancy is associated with adverse neurodevelopmental repercussions to infants. We assessed pediatric neurodevelopmental outcomes in children born to mothers with laboratory-confirmed SARS CoV-2 infection during pregnancy. Neurodevelopmental outcomes of in-utero exposed children were compared to that of pre-pandemic control children in Los Angeles (LA), CA, USA and Rio de Janeiro, Brazil. Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), the gold standard tool for evaluating neurodevelopment until 36 months of age and Ages and Stages Questionnaires (ASQ-3), a frequently used screening instrument for evaluating neurodevelopment in this same age group were the assessment tools used. Developmental delay (DD) was defined as having a score < - 2 SD below the norm (< 70) in at least one of three Bayley-III domains, (cognitive, motor or language) or a score below the cut-off (dark zone) in at least one of five ASQ-3 domains (communication, gross motor, fine motor, problem solving, personal-social). Exposed children were born between April 2020 and December 2022 while control children were born between January 2016 to December 2019. Neurodevelopmental testing was performed in 300 children total: 172 COVID-19 exposed children between 5-30 months of age and 128 control children between 6-38 months of age. Bayley-III results demonstrated that 12 of 128 exposed children (9.4%) had DD versus 2 of 128 controls (1.6%), p = 0.0007. Eight of 44 additional exposed children had DD on ASQ-3 testing. Fully, 20 of 172 exposed children (11.6%) and 2 of 128 control children (1.6%), p = 0.0006 had DD. In Rio, 12% of exposed children versus 2.6% of controls, p = 0.02 had DD. In LA, 5.7% of exposed children versus 0 controls, p = 0.12 had DD. Severe/critical maternal COVID-19 predicted below average neurodevelopment in the exposed cohort (OR 2.6, 95% CI 1.1-6.4). Children exposed to antenatal COVID-19 have a tenfold higher frequency of DD as compared to controls and should be offered neurodevelopmental follow-up.

Figure 1

Bayley-III assessments for children exposed to maternal COVID-19 in Rio de Janeiro, RJ, Brazil (n = 75) and Los Angeles (n = 53), CA, USA [n = 128] compared to pre-pandemic control children from Rio de Janeiro (n = 78) and Los Angeles (n = 50), [n = 128]. Total = 256. Distribution of Bayley-III scores for cognitive, motor and language domains among 128 case and 128 control children in Rio de Janeiro, Brazil and Los Angeles, CA. Scores < 85 to 70 are between − 1 and − 2 SD and reflect risk of developmental delay. Scores < 70 are less than − 2 SD and reflect developmental delay.

Figure 2

Distribution of Bayley-III results in children exposed to maternal COVID-19 in pregnancy and pre-pandemic healthy control children in Rio de Janeiro and Los Angeles.

Figure 3

ASQ-3 assessments for 80 children exposed to maternal COVID-19 in utero (age 4–28 months), Los Angeles, CA. Distribution of ASQ-3 results for children born to mothers with COVID-19 in Los Angeles, CA for communication, gross motor, fine motor, problem solving and personal-social domains.

Figure 4

Predictors of below average neurodevelopment (developmental delay and risk of delay) in COVID-19 exposed infants. Graphic representation of logistic regression analysis of potential variables associated with developmental delay (DD) on Bayley-III testing (< − 2 SD or score < 70 in any of the 3 functional domains) or an ASQ-3 assessment below the cut-off (if Bayley-III was not done) for children exposed to maternal COVID-19 in Rio de Janeiro (A), Los Angeles (B) and both sites combined (C). (D–F) include children at risk for DD and children with DD on Bayley 3 testing (< − 1 SD/scores < 85) or an ASQ-3 below the cut-off. Children in Rio de Janeiro are depicted in (D), children from LA in (E) and both sites are shown in (F). LBW: low birth weight; SGA: small for gestational age; Vacc: maternal vaccination in pregnancy; Ces: C-section delivery; Fever: maternal fever due to COVID-19 in pregnancy; Severe/Crit: severe or critical COVID-19 in pregnancy; Maternal Infec 2/3 Tri: maternal COVID-19 in the 2nd or 3rd trimester of pregnancy; Mental: mental co-morbidities; Comorb: comorbidities as defined in Table 2. Individual details for the panels and numerical variables are provided in the Supplemental Tables.