Early-Onset Neonatal Infection and Attention Deficit Hyperactivity and Autism Spectrum Disorder: A Nationwide Cohort Study.

Background: Early-onset neonatal infections are among the most common neonatal diseases. However, the long-term outcomes of the infections are not well understood.

Objective: To study the association between early-onset neonatal infection and attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).

Methods: A nationwide register-based cohort study was conducted, including near-term and term children born between 1997 and 2013 with follow-up until 2021. An early-onset infection was defined as an invasive bacterial infection occurring within the first week of life, including both physician-assigned diagnoses and positive bacterial cultures. ADHD and ASD were defined by diagnoses or prescriptions of relevant medication. Associations between sepsis and the neurodevelopmental disorders were investigated using multivariable Cox regression to estimate adjusted hazard ratios (HR), whereas associations with meningitis were examined using person-time incidence rate ratios (IRR). Sibling-matched analyses were also conducted for associations with sepsis.

Results: A total of 981,869 children were included, with 8154 defined as having sepsis and 152 defined as having meningitis. Among these, only 257 children had culture-positive sepsis, whereas 32 had culture-positive meningitis. The incidence rate of ADHD and ASD for children with sepsis was 4.5 per 1000 and 3.3 per 1000 person-years, respectively. Sepsis was associated with an increased adjusted likelihood of both ADHD (HR 1.28, 95% CI 1.17, 1.39) and ASD (HR 1.43, 95% CI 1.30, 1.58). However, sibling-matched analyses especially attenuated the association with ADHD (HR 1.12, 95% CI 0.93, 1.34). Point estimates suggested that children with meningitis also had an increased likelihood of both ADHD (IRR 1.77, 95% CI 0.88, 3.17) and ASD (IRR 2.05, 95% CI 0.89, 4.04).

Conclusions: Early-onset sepsis was associated with an increased likelihood of ASD, whereas the majority of the association with ADHD could be explained by unmeasured shared familial confounding.