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Early premature birth may increase the risk of attention-deficit/hyperactivity disorder (ADHD) symptoms in preschoolers and inattention symptoms in school-age children, a prospective sibling-comparison study from Norway suggests.

Gestational age less than 34 weeks at birth was associated with increased risk of ADHD at age 5, especially in girls, and symptoms of inattention at age 8, reported Helga Ask, PhD, of the Norwegian Institute of Public Health in Oslo, and colleagues in .

The researchers said they believed it's the first study to contrast siblings to account for genetic and environmental factors.

Sibling-comparison design is "perhaps the closest you get to an experiment," Ask told 番茄社区app. "We found that the observed association between being born premature and ADHD symptoms in childhood was not explained by genetic or environmental factors shared between siblings. In other words, the association appears to be of a causal nature."

Previous analyses have shown a link between prematurity and ADHD, but most have been population-based reports.

"Clinically, this study's design continues to support previous data showing that preterm birth increases ADHD risk, making it applicable to family practitioners and obstetricians working to reduce premature births, as well as pediatricians, family practitioners, and child psychiatrists caring for children born prematurely to further increase diagnostic vigilance for ADHD in this group," Stephanie Hartselle, MD, of Brown University in Providence, who was not involved in the study, told 番茄社区app.

For this analysis, researchers recruited pregnant women from the Norwegian Mother and Child Cohort Study from 1999 through 2008. They studied a total of 113,227 children (48.7% female; 28.0% born at gestational week 40), including 33,081 siblings (48.4% female; 29.3% born at gestational week 40). Mothers reported ADHD symptoms using items from the Conners' Parent Rating Scale–Revised to evaluate 5-year olds and the Parent/Teacher Rating Scale for Disruptive Behavior Disorders to assess 8-year olds. Both questionnaires reflected ADHD criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).

After adjusting for unmeasured genetic and environmental factors, children born early preterm (gestational age less than 34 weeks) had a mean score that was 0.24 SD higher on ADHD symptom tests, 0.33 SD higher on inattention tests, and 0.23 SD higher on hyperactivity/impulsivity tests than children born at gestational week 40.

Corresponding odds ratios (ORs) were 1.55 for ADHD at age 5, 1.85 for inattention at age 8, and 1.52 for hyperactivity at age 8.

Associations between gestational age and preschool ADHD symptoms appeared strongest among girls; early preterm girls scored a mean of 0.80 SD (P=0.02) higher than their term-born sisters, corresponding to an OR of 4.27.

“Our results suggest that the negative consequences of being born preterm are most pronounced in girls (at 5 years of age), although the power of the sex-stratified analyses is limited,” Ask and co-authors wrote. “A high score on inattention might be a reflection of related constructs, for example, anxiety, which is more prevalent among girls than boys, a possible explanation for the observed sex difference.”

The fact that these associations remained after accounting for genetic and environmental variables "lends more confidence to the hypothesis that there really is something about being born premature that is involved in the development of ADHD symptoms," noted David Rettew, MD, of the University of Vermont College of Medicine in Burlington, who also was not involved in the study.

"The results suggest more of a neurodevelopmental model for ADHD, as we know that a very large portion of brain development occurs in the last several weeks of gestation," Rettew told 番茄社区app.

But "it's important to note the effects are not enormous and being born prematurely certainly does not automatically mean a child will develop ADHD," he added.

And according to this research, these children have more inattentive than hyperactive-impulsive symptoms, Max Wiznitzer, MD, of University Hospitals Rainbow Babies and Children's Hospital in Cleveland, who was not involved in the study, pointed out. "This means that, if they have ADHD, the diagnosis may be missed -- the hyperactive-impulsive children are more obvious due to their behaviors -- or interpreted as due to another reason such as learning disability or cognitive impairment."

The authors listed several limitations to their research: Young women, smokers, and women with low educational levels were underrepresented. Only exposure-discordant siblings contributed to estimated associations. And while the ADHD questionnaires closely mirrored DSM-IV criteria, maternal reports are not the same as psychiatric evaluations. "However, previous research has suggested that ADHD as a disorder is not etiologically different from ADHD as a continuum," they noted.

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