Maternal immune activation during pregnancy is associated with more difficulties in socio-adaptive behaviors in autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) are neurodevelopmental conditions characterised by deficits in social communication and interaction and repetitive behaviours. Maternal immune activation (MIA) during the mid-pregnancy is a known risk factor for ASD. Although reported in 15% of affected individuals, little is known about the specificity of their clinical profiles. Adaptive skills represent a holistic approach to a person's competencies and reflect specifically in ASD, their strengths and difficulties. In this study, we hypothesised that ASD individual with a history of MIA (MIA⁺) could be more severely socio-adaptively impaired than those without MIA during pregnancy (MIA^-). To answer this question, we considered two independent cohorts of individuals with ASD (PARIS study and FACE ASD) screened for pregnancy history, and used supervised and unsupervised machine learning algorithms. We included 295 mother-child dyads with 14% of them with MIA⁺. We found that ASD-MIA⁺ individuals displayed more severe maladaptive behaviors, specifically in their socialization abilities. MIA⁺ directly influenced individual's socio-adaptive skills, independent of other covariates, including ASD severity. Interestingly, MIA⁺ affect persistently the socio-adaptive behavioral trajectories of individuals with ASD. The current study has a retrospective design with possible recall bias regarding the MIA event and, even if pooled from two cohorts, has a relatively small population. In addition, we were limited by the number of covariables available potentially impacted socio-adaptive behaviors. Larger prospective study with additional dimensions related to ASD is needed to confirm our results. Specific pathophysiological pathways may explain these clinical peculiarities of ASD- MIA⁺ individuals, and may open the way to new perspectives in deciphering the phenotypic complexity of ASD and for the development of specific immunomodulatory strategies.

Figure 1

More severe impact on adaptative behaviors related to socialization is associated with maternal immune activation during pregnancy. (A) Correlogram of the different subdomain of the Vineland II with clinical parameters. (B) Classification decision tree of the risk of maternal immune activation during pregnancy depending on Vineland II—Socialisation sub-score and ADOS total score on the autistic offspring. (C) Feature importance for the logistic analysis. Feature importance computes the importance of features by calculating the increase in the model prediction error after permuting the feature. (D) Feature importance for the linear discriminant analysis. (E) Classification decision tree of the risk of maternal immune activation during pregnancy depending on Vineland II—Communication sub-score and ADOS total score on the autistic offspring. MIA: Maternal immune activation, SRS: Social Responsiveness Scale 2nd edition; ADOS Autism Diagnostic Observation Schedule 2nd edition, VABS: Vineland Adaptive Behavior Scales 2nd edition.

Figure 2

Maternal immune activation may directly affected the socio-maladaptive behaviors in autism children. (A) Predictions of the linear model on socialization sub scores compared to measured scores. (B) Feature Iimportance of the linear regression model. (C) Path analysis on the influence of MIA on socialization sub-score. MIA: Maternal immune activation, SRS: Social Responsiveness Scale 2nd edition; ADOS Autism Diagnostic Observation Schedule 2nd edition, VABS: Vineland Adaptive Behavior Scales 2nd edition, PROM: Premature rupture of membranes; MFI: Materno-fetal infection; TLI: Tucker-Lewis index; CFI comparative fit index; RMSEA root mean square error of approximation; SRMR: standardized root mean squared residual.