Neurocognitive Impairment in Extremely Premature

New results from the large Extremely Low Gestational Age Newborns Study (ELGANs) suggest that at age 10 boys born before 28 weeks’ gestation suffer from neurocognitive impairments, including autism spectrum disorders (ASD), to a higher degree than girls. However, extremely premature girls and boys have similar rates of seizures and epilepsy, according to study results.¹

The findings were published online in Journal of Pediatrics. They confirm past evidence suggesting a neurodevelopmental disadvantage among extremely premature boys compared to girls, and contrast to a recent metanalysis of studies published through 2014 suggesting that the difference in neurocognitive outcome between girls and boys narrows by age five. Few large, epidemiological studies, though, have evaluated long-term neurocognitive outcomes in extremely premature children born after the use of surfactant and antenatal steroids became routine in the early 1990s. 

“Our data confirm the few other recent large, epidemiologic studies that children born EP have an excessive burden of cognitive deficits in later childhood (7-12 years old) … We confirm that the excessive burden of cognitive deficits reported in boys in early childhood also is evident in later childhood,” wrote first author Karl CK Kuban, MD, SNEpi, of Boston Medical Center, and colleagues. 

The study included 889 children (428 girls, 446 boys) before 28 weeks and enrolled in the Extremely Low Gestational Age Newborns Study (ELGANs) from 2002-2004. ELGANs is a multicenter, observational study that is assessing structural and functional neurological disorders in children born extremely premature. At age 10, participants received a battery of neuropsychological tests that evaluated a wide range of neurocognitive and behavioral factors, including IQ, executive functioning, language ability, epilepsy/seizures, motor impairment, microcephaly, and ASD. Parents also self-reported children’s behavior, development, and seizures. 

Key Results:

• Summary measurement of cognitive abilities: After adjusting for socioeconomic factors, gestational age, and birth weight, boys were twice as likely to be severely impaired (OR 2.1, 95% CI 1.2-3.8) and 1.8 times as likely to be moderately impaired (OR 1.8, 95% CI 1.1-2.7), compared to girls

♦ Boys were more impaired than girls on almost all measures of cognition, including verbal and nonverbal IQ, language, working memory, executive function, verbal reasoning ability, and oral and written language tests measuring listening comprehension

♦ Microcephaly: Twice as likely in boys compared to girls (OR 2.4, 95% CI 1.5-4.0)

♦ Motor impairment: Boys were twice as likely as girls to need assistive devices to ambulate (OR 2.1, 95% CI 1.1-4.0)

♦ Gross motor function: 50% higher risk of mild impairment compared to girls (OR 1.6, 95% CI 1.2, 2.3), even after adjusting for cerebral palsy

• ASD: Twice as likely in boys vs girls (OR 2.0, 95% CI 1.1, 3.6)

♦ Lower boy-to-girl ratio than the overall US population where risk of autism is four times higher in boys vs girls

♦ 20 times higher risk in girls and 9 times higher risk in boys compared to the US general population

• History of seizure: Similar risk for girls and boys (OR 1.1, 95% CI 0.7-1.7)

• Epilepsy: Similar risk for girls and boys (OR 1.3, 95% CI 0.7-2.2)

The authors offered explanations for the differences between girls and boys found in this study. Hormonal disruption related to extremely premature birth could interfere with conversion of testosterone to estradiol, and higher circulating levels of testosterone in boys may affect brain development. Or, extremely premature girls and boys may have different rates of brain maturation and different vulnerabilities and resilience to extremely premature birth.

They also pointed out the “surprising” similarities in seizure and epilepsy rates between girls and boys.

“Although boys may be at greater risk of structural brain injury, the cellular mechanisms that underlie seizures or epilepsy may be less sex-specific, and may involve inflammatory, genetic, and epigenetic mechanisms,” they hypothesized. “The similar male/female prevalence rates of seizures and epilepsy in our ELGAN cohort, though unexpected, afford an opportunity to explore the relationship between prematurity and neuronal excitability.”

Take-home Points

• Results from the large, observational ELGAN trial of children born before 28 weeks suggest that boys are twice as likely as girls to be severely cognitively impaired and 1.8 times as likely to be moderately cognitively impaired at age 10.

• Boys were more impaired than girls on almost all measures of cognition, including verbal and nonverbal IQ, language, working memory, executive function, verbal reasoning ability, and oral and written language tests measuring listening comprehension.

• Boys were twice as likely as girls to suffer from microcephaly and motor impairment requiring assistive devices for ambulation.

• ASD was twice as likely in boys vs girls, though ASD risk was 20 times higher in girls and 9 times higher in boys compared to the US general population.

• Girls and boys had similar risk for seizures and epilepsy.

References:

1. Kuban KC, et al. Girls and boys born before 28 weeks gestation: risks of cognitive, behavioral, and neurologic outcomes at age 10 years. J Pediatr. 2016 Mar 19.

2. Linsell L, et al. Prognostic factors for poor cognitive development in children born very preterm or with very low birth weight: a systematic review. JAMA Pediatr. 2015 Dec;169(12):1162-1172.