Autism spectrum disorder is associated with specific congenital malformations

An analysis of data from the Israel National Birth Registry found that congenital malformations were more common in children diagnosed with autism spectrum disorder (ASD) than in neurotypical children. The most prevalent physical anomalies were circulatory and urogenital system malformations. Interestingly, the study suggests a distinct biological sex divide: genital system malformations were more frequent exclusively in boys with ASD, while non-genitourinary malformations (primarily circulatory) were more common in girls with ASD when compared to neurotypical girls. The paper was published in Molecular Psychiatry.

Autism spectrum disorder is a neurological and developmental condition that affects how a person interacts, communicates, learns, and behaves. Symptoms usually begin in early childhood, often within the first two years of life. Autism is characterized as a spectrum because it can manifest very differently from one person to another, presenting a wide range of strengths, challenges, and support needs.

Common features include difficulties with social communication and interaction, as well as restricted or repetitive behaviors, interests, or activities. Some autistic individuals speak fluently, while others may use few words or be nonverbal. Many autistic people also experience differences in learning, attention, sensory processing, or movement. Scientists suggest that autism has a multifactorial origin heavily influenced by genetic and environmental factors, though the exact underlying mechanisms are not fully understood.

Study author Rony Cleper and his colleagues set out to investigate whether certain physical malformations present at birth are associated with an increased likelihood of a later ASD diagnosis. A robust body of evidence shows that early intervention tends to improve outcomes and functioning for individuals with ASD. Because of this, identifying whether specific congenital malformations could serve as developmental “red flags” might help direct at-risk newborns toward earlier diagnostic screening.

To explore this, the researchers analyzed data from the Israel National Birth Registry, which records all live births and detected congenital malformations in the country, alongside the Autism Registry of the Israeli Ministry of Social Affairs.

The analyses utilized data from 4,302 singleton pregnancies resulting in live births between 1993 and early 2006, excluding twin and triplet pregnancies. This cohort included all registered children diagnosed with ASD during this period (2,099 individuals) paired with an equal number of age- and sex-matched neurotypical children.

The results provided evidence that congenital malformations were more frequent in the ASD group. Overall, children later diagnosed with ASD had 75% higher odds of having a congenital malformation. This association remained mathematically robust even after researchers adjusted the models for confounding factors like birth weight, parental age, ethnicity, and maternal immigration.

The highest differences in congenital malformation frequencies were found in the circulatory system (2.1% of children with ASD vs. 1.2% of neurotypical children) and urogenital organs (1.8% of children with ASD vs. 0.8% of neurotypical children).

Crucially, when the researchers stratified the data by sex, distinct patterns emerged. Genital malformations were specifically associated with an ASD diagnosis in boys. Conversely, girls with ASD were more likely to have non-genitourinary malformations (primarily circulatory) compared to girls without the disorder.

The researchers suggest that this sex-specific split points to the complex ways sex hormones—specifically androgens like testosterone—may differently influence embryonal and neurological development. For instance, urogenital malformations in males are often linked to a deficiency in prenatal androgen signaling. On the flip side, an excess of embryonic androgens is known to negatively impact the development of the circulatory system, which aligns with the anomalies observed in the female ASD group.

“In conclusion, CM [congenital malformations], most notably genitourinary in males exclusively, and others (mostly circulatory) in females, are more prevalent in newborns later diagnosed with ASD, as compared with age- and sex-matched controls,” the study authors concluded. “These sex-specific CM might represent useful pre- and postnatal markers of ASD, and their presence in newborns at-risk of ASD might indicate earlier and more frequent neurodevelopmental assessments.”

While the study contributes valuable population-level evidence to the scientific understanding of ASD, the authors note several limitations. Diagnostic criteria for ASD changed during and after the study period, resulting in higher reported rates of ASD in more recent times.

Additionally, the widespread modern use of prenatal ultrasounds allows for the early diagnosis of major structural malformations, triggering a rise in pregnancy terminations in severe cases. This could create a survival bias that limits the ability to fully analyze the link between ASD and the most severe birth defects. Finally, the study lacked available data regarding family genetic histories, which is a highly relevant factor in both ASD and embryonal development.

The paper “The association between autism spectrum disorder and congenital malformations: a population-based nested case-control study” was authored by Rony Cleper, Ori Kapra, Nadav Goldental, and Raz Gross.