J Autism Dev Disord. 2026 Mar 10. doi: 10.1007/s10803-026-07245-z. Online ahead of print.
ABSTRACT
PURPOSE: Prenatal maternal immune activation (MIA) and preterm birth (PTB) have each been linked to increased risk for neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, MIA definitions varied across studies and few investigations have examined their combined effects. This study assessed the relationship between MIA and NDDs using two MIA definitions: binary (fever and/or placental inflammation) and a four-level subtype (fever only, inflammation only, both, or neither); and examined the joint associations of MIA and PTB with NDDs.
METHODS: This report includes 2,975 mother-child dyads. Adjusted logistic regressions estimated associations between MIA and NDDs. Additive interactions between MIA and PTB were assessed using the Relative Excess Risk due to Interaction (RERI). Mediation-moderation analyses examined the extent to which the association between MIA and ADHD was statistically explained by PTB.
RESULTS: Binary MIA was associated with elevated odds of NDD (adjusted odds ratio [aOR] = 1.33, 1.08-1.64) and ADHD (aOR = 1.71, 1.30-2.25). Using the four-level definition, the highest risk was among children exposed to both maternal fever and placental inflammation (NDD: aOR = 3.25, 1.87-5.66; ADHD: aOR = 3.16, 1.50-6.65). Co-occurrence of binary MIA and PTB yielded a RERI of 0.88 (0.28-1.48) for ADHD, while both (Fever + IUI) MIA subtype and PTB yielded RERI of 2.14 (0.66-3.62), indicating greater-than-additive joint associations. In mediation analyses, we found that the positive associations of MIA with NDD and ADHD were partly explained by PTB.
CONCLUSION: Placental inflammation, more so than fever, is associated with NDDs and ADHD risk, supporting the value of MIA subtype measure. MIA and PTB are jointly associated with increased ADHD risk beyond additivity, and PTB partially mediated the association between MIA and ADHD.
PMID:41806249 | DOI:10.1007/s10803-026-07245-z
