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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Mcneil, Dawn E
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Boston Medical Center
United States
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Dammann, Olaf; Leviton, Alan (2014) Intermittent or sustained systemic inflammation and the preterm brain. Pediatr Res 75:376-80
Kuban, Karl C K; O'Shea, T Michael; Allred, Elizabeth N et al. (2014) Systemic inflammation and cerebral palsy risk in extremely preterm infants. J Child Neurol 29:1692-8
O'Shea, T Michael; Joseph, Robert M; Kuban, Karl C K et al. (2014) Elevated blood levels of inflammation-related proteins are associated with an attention problem at age 24 mo in extremely preterm infants. Pediatr Res 75:781-7
Wei, Changshuai; Lu, Qing; Khoo, Sok Kean et al. (2014) Comparison of frozen and unfrozen blood spots for gene expression studies. J Pediatr 164:189-191.e1
Allred, Elizabeth N; Capone Jr, Antonio; Fraioli, Anthony et al. (2014) Retinopathy of prematurity and brain damage in the very preterm newborn. J AAPOS 18:241-7
Logan, J Wells; Allred, Elizabeth N; Fichorova, Raina N et al. (2014) Endogenous erythropoietin varies significantly with inflammation-related proteins in extremely premature newborns. Cytokine 69:22-8
Phadke, Anuradha; Msall, Michael E; Droste, Patrick et al. (2014) Impaired visual fixation at the age of 2 years in children born before the twenty-eighth week of gestation. Antecedents and correlates in the multicenter ELGAN study. Pediatr Neurol 51:36-42
Martin, Camilia R; Bellomy, Melissa; Allred, Elizabeth N et al. (2013) Systemic inflammation associated with severe intestinal injury in extremely low gestational age newborns. Fetal Pediatr Pathol 32:222-34
Lee, Jennifer W; McElrath, Thomas; Chen, Minghua et al. (2013) Pregnancy disorders appear to modify the risk for retinopathy of prematurity associated with neonatal hyperoxemia and bacteremia. J Matern Fetal Neonatal Med 26:811-8
Logan, J Wells; Westra, Sjirk J; Allred, Elizabeth N et al. (2013) Antecedents of perinatal cerebral white matter damage with and without intraventricular hemorrhage in very preterm newborns. Pediatr Neurol 49:88-96

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