Up to one half of the 30,000 infants born in the United States at extremely low gestational age (ELGANs) have moderate or severe neurodevelopmental disabilities. This study builds on the ELGAN-1 prospective study of nearly a thousand ELGANs who were evaluated following birth and again at two years of age. 11% had cerebral palsy, 40% had a developmental quotient below 70, and 11% had microcephaly. Placenta organisms and histologic characteristics, as well as proteins measured in the blood of these infants in the very first weeks of life predicted 2-year cognitive and motor impairments, and diminished brain growth. Additionally, among children without motor, visual, or hearing deficits, 16% screened positive for autism spectrum disorders at two years. The primary hypothesis of the proposed Elgan-2 study is that ELGANs with elevated blood concentrations of inflammation-associated biomarkers in the first two postnatal weeks are more likely than other ELGANs at nine years to have neurocognitive disorders (low scores on standardized measures of IQ, language, executive function, and academic achievement), neurobehavioral disorders (autism spectrum disorders, attention deficit hyperactivity disorders), and brain structural abnormalities (diminished white and gray matter volumes and diminished fractional anisotropy in white matter tracts on MRI). In Elgan-2, we will evaluate at age 9 the participants of ELGAN-1, assessing neuropsychological and neurocognitive function, measuring head circumference, and quantifying motor impairment. Additionally, sub- samples of children representing high, intermediate and low risks for adverse outcomes, based on blood protein profiles in the first two postnatal weeks, will have brain volumes and white matter fractional anisotropy measured by MRI. Study participants who are deemed to be at risk for ASD on the Social Communication Questionnaire (SCQ) will undergo gold-standard autism diagnostic assessments, first with the Autism Diagnostic Interview - Revised (ADI-R), and if indicated, with the Autism Diagnostic Observation Schedule (ADOS). Elgan-2 will evaluate the relationship between early biomarkers (placental characteristics and blood proteins) and neurological, neurocognitive and neurobehavioral dysfunction and brain structural abnormalities at nine years.
Achieving Elgan-2 specific aims has the potential to provide convincing evidence that the risk for long-lasting neurological and neurocognitive impairments in ELGANs can be identified by the presence of circulating biomarkers in the first weeks of life. Such evidence likely will broaden and redirect the rationale for preventive and therapeutic interventions intended to reduce the risk and severity of neurodevelopmental disorders in ELGANs. It will also establish a method for identifying infants at high risk for subsequent neurodevelopmental disorders as targets for clinical trials of prophylactic and therapeutic interventions while minimizing the risk for children who are unlikely to have later impairments.
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