An analysis of data from Israel’s National Birth Registry found that congenital malformations are more common in children diagnosed with autism spectrum disorder (ASD) than in typically developing children. The most common physical abnormalities were malformations of the circulatory and genitourinary systems. Interestingly, this study suggests clear biological sex differences. Reproductive malformations were more common in boys with ASD, whereas nongenitourinary malformations (primarily cardiovascular) were more common in girls with ASD than in typically developing girls. The paper is molecular psychiatry.
Autism spectrum disorders are neurological and developmental conditions that affect 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 manifests itself very differently and exhibits a wide range of strengths, challenges, and support needs.
Common features include difficulty with social communication and interaction, and restricted or repetitive behaviors, interests, or activities. Some people with autism speak fluently, while others use few words or are nonverbal. Many people with autism also experience differences in learning, attention, sensory processing, or behavior. Scientists suggest that the cause of autism is multifactorial, heavily influenced by genetic and environmental factors, but the exact underlying mechanisms are not fully understood.
Study author Ronnie Kleper and colleagues set out to investigate whether certain physical deformities present at birth are associated with an increased likelihood of a later ASD diagnosis. A robust body of evidence indicates that early intervention tends to improve outcomes and functioning for individuals with ASD. Therefore, identifying whether certain congenital malformations act as developmental “red flags” may help direct at-risk newborns to early diagnostic screening.
To investigate this, researchers analyzed data from the Israeli National Birth Registry, which records all births in the country and detects congenital malformations, alongside the Israeli Ministry of Social Affairs’ Autism Registry.
The analysis used data on 4,302 singleton pregnancies that resulted in live births from 1993 to early 2006, excluding twin and triplet pregnancies. This cohort included all enrolled children (2,099) diagnosed with ASD during this period and were paired with an equal number of age- and gender-matched neurotypical children.
The results provided evidence that congenital malformations occur more frequently in the ASD group. Overall, children who were later diagnosed with ASD were 75% more likely to have congenital malformations. This association remained mathematically robust even after researchers adjusted the model for confounders such as birth weight, parental age, ethnicity, and maternal immigration.
The highest differences in the frequency of congenital malformations were seen in the circulatory system (2.1% of children with ASD and 1.2% of neurotypical children) and genitourinary tract (1.8% of children with ASD and 0.8% of neurotypical children).
Importantly, when the researchers stratified the data by gender, a clear pattern emerged. Genital malformations were associated with ASD diagnosis, especially in boys. Conversely, girls with ASD were more likely to suffer from non-genitourinary malformations (primarily cardiovascular) compared to girls without ASD.
The researchers suggest that this sex-specific split illustrates the complex ways in which sex hormones, especially androgens like testosterone, can differentially impact fetal and neurological development. For example, male genitourinary malformations are often associated with defects in prenatal androgen signaling. On the contrary, fetal androgen excess is known to adversely affect the development of the circulatory system, which is consistent with the abnormalities observed in the female ASD group.
“In conclusion, CM (congenital malformations) are most prominent in the genitourinary system, primarily in men, while other malformations seen in women (mainly in the circulatory system) are more prevalent in neonates later diagnosed with ASD compared to age- and sex-matched controls,” the study authors concluded. “These sex-specific CMs may represent useful prenatal and postnatal markers of ASD, and the presence of these CMs in neonates at risk for ASD may indicate earlier and more frequent neurodevelopmental evaluation.”
While this study provides valuable population-level evidence for scientific understanding of ASD, the authors note several limitations. Diagnostic criteria for ASD changed during and after the study period, resulting in higher reporting rates of ASD in recent years.
Furthermore, the modern widespread use of prenatal ultrasound allows early diagnosis of significant structural malformations, leading to an increase in abortions in severe cases. This may introduce survival bias that limits the ability to fully analyze the association between ASD and the most severe birth defects. Finally, this study lacked available data on family genetic history, a highly relevant factor for both ASD and fetal development.
The paper, “The Association between Autism Spectrum Disorders and Congenital Malformations: A Population-Based Nested Case-Control Study,” was authored by Rony Cleper, Ori Kapra, Nadav Goldental, and Raz Gross.
