Higher incidence of Neuropsychiatric disorders linked to spectrum of preterm births: JAMA

It is recognized that children born very preterm (<32 weeks) and preterm (<37 weeks) are especially vulnerable to neuropsychiatric diseases, less is known about potential risk patterns among the term births.

Using data from Danish national registers, Xia et al aimed to evaluate the associations between 6 gestational age groups, considering the full range of gestational duration, from very preterm to postterm birth, and rates of 9 major types and 8 subtypes of childhood-onset and adult-onset neuropsychiatric disorders. They also investigated whether comorbidity of multiple neuropsychiatric disorders was associated with gestational ages at birth.

This cohort study evaluated data from a nationwide register of singleton births in Denmark from January 1, 1978, to December 31, 2016. Data analyses were conducted from October 1, 2019, through November 15, 2020.

Gestational age subgroups were classified according to data from the Danish Medical Birth Register: very preterm (20-31 completed weeks), moderately preterm (32-33 completed weeks), late preterm (34-36 completed weeks), early term (37-38 completed weeks), term (39-40 completed weeks, reference), and late or postterm (41-45 completed weeks).

Neuropsychiatric diagnostic records (International Statistical Classification of Diseases and Related Health Problems) were ascertained from the Danish Psychiatric Central Register up to August 10, 2017.

The major neuropsychiatric diseases disorders included (1) mental and behavioral disorders due to psychoactive substance abuse (2) schizophrenia and related disorders (3) mood disorders (4) neurotic, stress-related, and somatoform disorders (5) eating disorders (6) specific personality disorders (7) intellectual disability (8) pervasive developmental disorders and (9) behavioral and emotional disorders with onset usually occurring in childhood and adolescence.

Of all 23,27,639 singleton births studied (11,94,925 male newborns [51.3%]), 22,647 (1.0%) were born very preterm, 19,801 (0.9%) were born moderately preterm, 99,488 (4.3%) were born late preterm, 3,88,416 (16.7%) were born early term, 11,98,605 (51.5%) were born at term, and 5,98,682 (25.7%) were born late or postterm).

A gradient of decreasing IRRs was found from very preterm to late preterm for having any or each of the 9 neuropsychiatric disorders (eg, very preterm: IRR, 1.49 [95% CI, 1.43-1.55]; moderately preterm: IRR, 1.23 [95% CI, 1.18-1.28]; late preterm: IRR, 1.17 [95% CI, 1.14-1.19] for any disorders) compared with term births.

Individuals born early term had 7% higher rates (IRR, 1.07) for any neuropsychiatric diagnosis and a 31% higher rate for intellectual disability (IRR, 1.31) compared with those born at term. The late or postterm group had lower IRRs for most disorders, except pervasive developmental disorders, for which the rate was higher for postterm births compared with term births (IRR, 1.06).

This study provides a detailed assessment of the association between finer categorizations of gestational age groups and the incidence rates for major childhood and adult neuropsychiatric disorders in Denmark.

The authors found that diagnosis of both child-onset and adult-onset neuropsychiatric diseases was associated with preterm birth, with a gradient of risk observed from very preterm (20-31 weeks) to late preterm (34-36 weeks) birth. This study also provides evidence of heterogeneity in long-term neuropsychiatric risk by gestational age within the term spectrum. Early term births (37-38 weeks), usually considered as a low-risk group in previous studies, had a slightly elevated rate for multiple neuropsychiatric disorders. Late or postterm births (41-45 weeks) had the lowest rates for most of the major and subtypes of neuropsychiatric disorders evaluated, except pervasive developmental disorders, specifically childhood autism. In addition, the data illustrated that gestational age at birth was associated with comorbidity of major neuropsychiatric disorders, suggesting possible shared mechanisms for disease cause or susceptibility stemming from impaired brain development early in life.

Mechanisms linking gestational age with later risk of neuropsychiatric disorders are likely to be multifactorial. With regard to preterm birth, placental insufficiency might be associated with both the development of the brain and preterm or early term birth because of fetal growth restriction or preeclampsia. The last trimester of pregnancy is a critical period for brain development and growth, when multiple important neurobiological processes are actively taking place, including substantial increases in cerebral volume, rapid gyrification, and formation of cortical connections. Insufficient development in late gestation could affect extensive structural brain alterations and/or alterations in other developmentally regulated processes that underlie long-term neuropsychiatric deficits.

This cohort study provides a comprehensive assessment of incidence rates for major neuropsychiatric disorders according to finer classifications of gestational age at birth in Denmark. Gestational age, not only across the spectrum of preterm but also beyond the conventional threshold of term, is associated with occurrences of single and multiple neuropsychiatric disorders later in life.

"Our findings suggest that childhood and adult neuropsychiatric disorders might stem from factors related to early development. Intervention strategies targeted at perinatal risk factors and obstetric practices preventing nonoptimal delivery timing and improving postnatal care for those born with nonoptimal gestational duration might reduce long-term neuropsychiatric risk in the population."

Source: Xia et al; JAMA Network Open. 2021;4(6):e2114913. doi:10.1001/jamanetworkopen.2021.14913