Autism and Preterm Birth: Clarifying Risk and Exploring Mechanisms

In the current issue of Pediatrics, the thoughtful work of Crump et al, entitled “Preterm or Early Term Birth and Risk of Autism” has added an important contribution to our understanding of associations between autism and prematurity.¹  Building on the strengths of population-based registries, the authors were able to assess 4 061 795 singleton infants born in Sweden between 1973 and 2013 using the Swedish Medical Birth Register (which contains prenatal and birth information) and link clinical diagnoses of autism spectrum disorder (ASD) from hospital, outpatient, and primary care registries. Prevalence rates of ASD were inversely proportional to gestational age: 6.1% for extremely preterm (EPT) (22–27 weeks), 2.6% for very preterm to moderate preterm (28–33 weeks), 1.9% for late preterm (LPT) (34–36 weeks), 1.6% for early term (ET) (37–38 weeks), and 1.4% term (39–41 weeks). After adjusting for covariates and stratifying by sex, prevalence ratios revealed similar trends, ranging from 3.7 to 1.11 among EPT- to ET-born male infants and 4.19 to 1.16 among EPT- to ET-born female infants. In an attempt to assess influences of genetic and/or environmental factors, cosibling analysis was performed, with only modest mitigation of risk.

As allowed with large cohort studies, the robust sample size and stratification by gestational age grouping allowed for the important finding that there is increased risk for ASD across the range of prematurity. The findings by Crump et al are consistent with previous work, also from Sweden, suggesting a dose response–type relationship between degree of prematurity and ASD risk.²  The elevated risk even in LPT infants is not completely surprising because a number of investigators have shown higher incidences of early cognitive, language motor and impairment, and school problems, social-emotional problems, and psychiatric disorders, some of which may extend to adulthood.³  Indeed, it was the Helsinki Birth Cohort study in which researchers yielded results of late adulthood cognitive impairment among those born LPT.⁴  In their works, Raju et al have clearly pointed out that infants born even a few weeks before term are at increased risk of respiratory, gastrointestinal, immunologic, and hormonal disturbances⁵  and that developmental maturation is a continuous process and not always linear. Thus, careful attention should be paid to biological vulnerabilities at later gestational ages. For example, between 34 and 40 weeks, brain weight increases nearly one-third, cortical volume increases nearly 50%, and absolute myelinated white matter volume increases fivefold.^6,7 

Emerging evidence linking behavior and alterations in brain structure, function, and connectivity furthers our understanding of biological and environmental risks. Brain regions predominantly affected by preterm birth are also involved in sensory and social interactions, including white and gray matter.⁸  In a cohort of very preterm–born infants, Brown et al demonstrated that associations between atypical behavior and degree of white matter injury may be evident as early as term equivalent.⁹  Using quantitative MRI techniques, Rogers et al reported that disruptions in regional brain circuits at term-equivalent ages in preterm infants predicted social-emotional disturbances at age 5 years.¹⁰  As Crump et al point out in their discussion, neuroinflammation, which occurs in response to stress and infection, activate microglia, which results in a cascade of neuronal injury and alterations, pointing to potential mechanisms linking preterm birth to increased risk for ASD. Indeed, there are reports of associations between elevated cytokine levels at birth and subsequent diagnoses of ASD,^11,12  and there is contemporary interest in the relationship more generally between immunologic factors and ASD risk.¹³  It is noted that the vulnerability of the preterm brain structure and function that is exposed to the inflammatory environment of prematurity is present until term gestation.

The report by Crump et al is in many ways a definitive accounting of the elevated rates of ASD in preterm infants. And although the impact of prematurity on brain development may be part of the causal chain resulting in ASD (or other neurodevelopmental outcomes), these factors are operating in a complex biological landscape, with pathways to ASD outcomes that can be expected to be heterogeneous. In previous work, researchers suggest that suboptimal obstetric outcomes and perinatal complications may, in some cases, result from underlying ASD etiologies.¹⁴  Moreover, even when assuming that prematurity is part of the causal chain leading to ASD outcomes, it will be important to investigate the interactions between the underlying genetics of ASD and the impact of prematurity. In time, increased implementation of next-generation genetic testing in ASD¹⁵  will offer opportunities to understand such pathways, and studies of premature infants may yield unique opportunities for investigating the developmental emergence of ASD.

ASD

autism spectrum disorder

EPT

extremely preterm

ET

early term

LPT

late preterm