Editorial

Gender Bias, Female Resilience, and the Sex Ratio in Autism

Dysbiosis of the maternal gut microbiome during pregnancy is associated with adverse neurodevelopmental outcomes. We previously showed that maternal high-fat diet (MHFD) in mice induces gut dysbiosis, social dysfunction, and underlying synaptic plasticity deficits in male offspring (F₁). Here, we reason that, if HFD-mediated changes in maternal gut microbiota drive offspring social deficits, then MHFD-induced dysbiosis in F₁ female MHFD offspring would likewise impair F₂ social behavior. Metataxonomic sequencing reveals reduced microbial richness among female F₁ MHFD offspring. Despite recovery of microbial richness among MHFD-descendant F₂ mice, they display social dysfunction. Post-weaning Limosilactobacillus reuteri treatment increases the abundance of short-chain fatty acid-producing taxa and rescues MHFD-descendant F₂ social deficits. L. reuteri exerts a sexually dimorphic impact on gut microbiota configuration, increasing discriminant taxa between female cohorts. Collectively, these results show multigenerational impacts of HFD-induced dysbiosis in the maternal lineage and highlight the potential of maternal microbiome-targeted interventions for neurodevelopmental disorders.

La littérature scientifique suggère que le Trouble du spectre autistique (TSA), chez les femmes, peut se manifester, de façon différente, en raison de nombreux facteurs, impactant, de ce fait, l’obtention de ce diagnostic, en particulier à l’âge adulte. D’après des données récentes, la prévalence du diagnostic de TSA évoluerait vers un rapport de trois hommes pour une femme. Plusieurs auteurs ont tenté d’expliquer ce ratio en évoquant, notamment, de possibles ressources subjectives amenant les femmes à ne pas présenter les manifestations autistiques attendues par les outils standards. En particulier, certaines « stratégies de camouflage » ne seraient pas détectées lors des évaluations habituelles. Or, ces stratégies comportent certains désavantages, notamment sur le registre de la construction identitaire.

Nous avons procédé à une revue de littérature sur les caractéristiques et expressions du phénotype de l’autisme féminin et sur les stratégies dites de « camouflage ». Dans ce cadre, nous avons traduit en français le Camouflaging Autistic Traits Questionnaire (CAT-Q), développé et validé par Hull et ses collègues (2019), afin d’encourager son évaluation scientifique dans le cadre de recherches sur le diagnostic de TSA pour des femmes.

Nous avons alors repéré plusieurs raisons aux origines des problématiques diagnostiques rencontrées par des femmes autistes : l’aspect androcentrique de la recherche sur l’autisme ; les biais sexuels ; la complexité diagnostique en lien avec les nombreuses comorbidités ; ainsi que l’inadéquation des instruments et dispositifs diagnostiques. L’évolution de l’autisme au féminin suppose aussi que la construction de la personnalité vient moduler l’expression de ces troubles.

Ce travail ouvre, à la fois, à une réflexion pour l’amélioration des procédures et outils diagnostiques pour tous les sujets autistes et à un intérêt clinique pour leurs ressources psychiques. Nous suggérons aussi que l’emploi d’une épreuve projective pourrait permettre de contourner certains des biais ainsi manifestés par les instruments usuels.

Ces discussions sont à poursuivre pour accompagner la prise de conscience des rapports entre l’autisme et le genre et avancer sur la modélisation des « stratégies de camouflage », cela afin de proposer des adaptations dans les pratiques cliniques et diagnostiques, répondre aux enjeux importants autour de la population de femmes autistes, et peut-être plus globalement participer à repenser l’hétérogénéité et les définitions de l’autisme.

The scientific literature shows that Autism Spectrum Disorder (ASD) in women may be differentiated by a number of factors, thus impacting how many women are diagnosed with ASD, particularly in adulthood. According to recent data, the prevalence of ASD diagnosis is 3 males to 1 female. Several authors have attempted to explain this ratio by pointing to possible subjective resources that allow women to avoid the autistic manifestations measured by standard tools. In particular, certain “camouflage strategies” would not be detected during the usual assessments. However, these strategies have certain disadvantages, particularly in terms of identity construction.

We conducted a literature review on the characteristics and expressions of the female autism phenotype and on so-called “camouflage” strategies. In this context, we translated into French the Camouflaging Autistic Traits Questionnaire (CAT-Q), developed and validated by Hull and colleagues (2019), in order to encourage its scientific evaluation in the context of research on the diagnosis of ASD for women.

We have identified several reasons for the diagnostic issues encountered by women with autism: the androcentric nature of autism research; gender bias; diagnostic complexity because of the many co-morbidities; and inadequate diagnostic instruments and settings. The evolution of autism in women also implies that personality construction modulates the expression of these disorders.

This work opens up both a reflection on the need for improvement of diagnostic procedures and tools for all autistic subjects, as well as a clinical interest in their psychic resources. We also suggest that the use of a projective test could help to circumvent some of the biases present in the habitual tools.

These discussions should be pursued to raise awareness of the relationship between autism and gender. Advancing the modelling of camouflage strategies would make it possible to propose adaptations in clinical and diagnostic practices and to respond to the important issues surrounding the population of women with autism, perhaps more globally to participate in rethinking the heterogeneity and definitions of autism.

Fetal exposure to testosterone may contribute to vulnerability for autism spectrum disorder (ASD). It is hypothesized that placental aromatase prevents fetal exposure to maternal testosterone, however, this pathway and the implications for child neurodevelopment have not been fully explored. We examined the relationships between prenatal maternal testosterone and estradiol at 19.2 ± 1.3 weeks, cord blood testosterone and estradiol at birth, placental aromatase mRNA expression, and neurodevelopment using the Social Communication Questionnaire (SCQ), the Behavioral Assessment System for Children, 3rd Edition (BASC-3), and the Empathizing Quotient for Children (EQ-C) at 4.5–6.5 years of age in a sample of 270 Nulliparous-Mothers-to-be (nuMoM2b) study participants. Maternal testosterone levels were positively associated with SCQ scores, but the association was not significant after adjusting for maternal age at delivery, nor was there a significant interaction with sex. Maternal estradiol levels were negatively associated with BASC-3 Clinical Probability scores among males (n = 139). We report a significant interaction effect of cord blood testosterone and fetal sex on both total SCQ scores and t-scores on the Developmental Social Disorders subscale. Placental aromatase was not associated with any neurodevelopmental or hormone measure, but under conditions of low placental aromatase expression, high maternal testosterone was positively associated with SCQ scores in males (n = 46). No other associations between hormone levels and neurodevelopment were significant. Our findings provide a foundation for further investigation of the mechanisms through which maternal sex hormones and placental steroidogenesis may affect fetal hormone production and neurobehavior.

Sex differences in the prevalence of neurodevelopmental disorders are particularly evident in autism spectrum disorder (ASD). Heterogeneous symptom presentation and the potential of measurement bias hinder early ASD detection in females and may contribute to discrepant prevalence estimates. We examined trajectories of social communication (SC) and restricted and repetitive behaviors (RRBs) in a sample of infant siblings of children with ASD, adjusting for age- and sex-based measurement bias. We hypothesized that leveraging a prospective elevated familial likelihood sample, deriving data-driven behavioral constructs, and accounting for measurement bias would reveal less discrepant sex ratios than are typically seen in ASD.

We conducted direct assessments of ASD symptoms at 6 to 9, 12 to 15, 24, and 36 to 60 months of age (total n_observations = 1254) with infant siblings of children with ASD (n = 377) and a lower ASD-familial-likelihood comparison group (n = 168; n_observations = 527). We established measurement invariance across age and sex for separate models of SC and RRB. We then conducted latent class growth mixture modeling with the longitudinal data and evaluated for sex differences in trajectory membership.

We identified 2 latent classes in the SC and RRB models with equal sex ratios in the high-concern cluster for both SC and RRB. Sex differences were also observed in the SC high-concern cluster, indicating that girls classified as having elevated social concerns demonstrated milder symptoms than boys in this group.

This novel approach for characterizing ASD symptom progression highlights the utility of assessing and adjusting for sex-related measurement bias and identifying sex-specific patterns of symptom emergence.