Sex Differences in the Risk of Autistic-Related Traits in Toddlers Born to Mothers with Perinatal Depression: Evidence From Human Cohort and Mouse Study

Why It Matters

The study uncovers a pronounced sex‑specific vulnerability to autism‑like outcomes driven by maternal depression, highlighting the need for gender‑tailored early screening and potential oxytocin‑based interventions.

Key Takeaways

• Maternal perinatal depression raises toddler autistic traits risk
• Female toddlers face 5–9× higher ART odds
• Mouse CUMS model shows sex‑specific behavioral changes
• Prenatal stress reduces microglial Oxt and female Oxtr expression
• Findings suggest oxytocin‑BDNF pathway as therapeutic target

Pulse Analysis

Maternal mental health has emerged as a critical determinant of early neurodevelopment, with perinatal depression affecting up to one‑in‑five pregnancies worldwide. While autism spectrum disorder (ASD) is traditionally reported as more prevalent in males, growing evidence suggests that female offspring may require greater environmental stressors to manifest comparable traits. This sex disparity underscores the importance of investigating how maternal mood disturbances intersect with hormonal and immune pathways that shape the developing brain.

In the recent Tohoku Medical Megabank cohort, researchers analyzed over 23,000 mother‑toddler dyads, finding that mothers with elevated K6 or EPDS scores produced children with significantly higher Tokyo Autistic Behavior Scale (TABS) scores. Adjusted odds ratios indicated a three‑ to four‑fold increase in ART risk overall, but female toddlers exhibited a striking five‑ to nine‑fold elevation when exposed to maternal depression. These findings suggest that standard ASD screening tools may underdetect risk in girls unless maternal mental health is concurrently assessed, prompting clinicians to adopt more nuanced, sex‑sensitive evaluation protocols.

Complementary mouse experiments using chronic unpredictable mild stress (CUMS) during gestation mirrored the human data, revealing divergent behavioral phenotypes: male juveniles displayed hyper‑locomotion, whereas females showed excessive self‑grooming and reduced social novelty preference. At the molecular level, prenatal stress dampened oxytocin (Oxt) expression in microglia of dams and lowered oxytocin‑receptor (Oxtr) transcripts in female offspring’s prefrontal cortex, alongside decreased Bdnf levels. This convergence on the oxytocin‑BDNF signaling axis points to a plausible mechanistic bridge between maternal depression and sex‑specific neurodevelopmental outcomes, offering a target for future therapeutic trials aimed at mitigating autism risk in vulnerable populations.