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Individual and Combined Associations of Maternal Fever, Placental Inflammation, and Prematurity With Autism and ADHD

Alexandra Starr1, Xueqi Qu1, Xiumei Hong1

  • 1Department of Population, Family and Reproductive HealthCenter on Early Life Origins of Disease, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, E4132, Baltimore, MD, 21205-2179, USA.

Journal of Autism and Developmental Disorders
|March 10, 2026
PubMed

Insights

Maternal immune activation (MIA) and preterm birth (PTB) increase neurodevelopmental disorder (NDD) risks. Placental inflammation is a key MIA factor, and PTB partially explains the MIA-NDD link, especially for ADHD.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Public Health

Background:

  • Prenatal maternal immune activation (MIA) and preterm birth (PTB) are independently linked to increased risks of neurodevelopmental disorders (NDDs) like autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).
  • Previous research has shown inconsistent findings due to varying definitions of MIA, highlighting the need for standardized approaches.
  • The combined effects of MIA and PTB on NDD risk require further investigation.

Purpose of the Study:

  • To assess the relationship between maternal immune activation (MIA) and neurodevelopmental disorders (NDDs) using distinct MIA definitions.
  • To examine the joint associations of MIA and preterm birth (PTB) with NDDs, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).
  • To investigate the mediating role of PTB in the association between MIA and NDDs.

Main Methods:

  • Utilized data from 2,975 mother-child dyads.
  • Employed adjusted logistic regressions to estimate associations between MIA and NDDs.
  • Assessed additive interactions between MIA and PTB using Relative Excess Risk due to Interaction (RERI) and conducted mediation-moderation analyses.

Main Results:

  • Binary MIA was associated with increased odds of NDDs (aOR=1.33) and ADHD (aOR=1.71).
  • The four-level MIA subtype definition revealed the highest risk for NDDs (aOR=3.25) and ADHD (aOR=3.16) in children exposed to both maternal fever and placental inflammation.
  • Joint associations of MIA and PTB showed greater-than-additive effects for ADHD (RERI=0.88 for binary MIA; RERI=2.14 for MIA subtype), with PTB partially mediating the MIA-NDD and MIA-ADHD associations.

Conclusions:

  • Placental inflammation is a significant risk factor for NDDs and ADHD, underscoring the utility of MIA subtype classification.
  • MIA and PTB exhibit synergistic effects on ADHD risk, exceeding simple additive impacts.
  • Preterm birth partially mediates the pathway through which MIA influences the risk of NDDs and ADHD.
Abstract

Keywords:
Attention-deficit/hyperactivity disorder (ADHD)Autism spectrum disorder (ASD)Boston birth cohort (BBC)Maternal immune activation (MIA)Neurodevelopmental disorders (NDDs)Placental inflammationPreterm birth (PTB)

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