EXCEED THE SPACE PROVIDED. Infants bom very prematurely are at greatly increased risk of cerebral white matter damage (defined as presence of a cranial ultrasound echolucency), which is the best neonatal predictor of cerebral palsy and severe mental retardation, and is also associated with learning and attention disorders, and visual and auditory impairments. Advances in perinatal care have had limited success in reducing the frequency of white matter damage and its developmental consequences. This study aims to provide understanding of the molecular antecedents of white matter damage, and to lay the foundation for clinical trials designed to prevent cerebral white matter damage. To achieve these goals, we will identify and measure four sets of fetal, placenta!, and neonatal biomarkers, which, in animal and in vitro studies, have been associated with an altered risk of cerebral white matter damage: 1.initiators of the fetal inflammatory response (e.g., bacteria), 2. damage promoters (e.g., pro-inflammatory cytokines), 3. modulators of the inflammatory response (e.g., anti-inflammatory cytokines, cytokine binding proteins, cytokine receptor antagonists), and 4. cerebral white matter protectors (e.g., hormones and growth promoters). We propose to enroll 1,600 infants born before 28 weeks of gestation in a multi-center study. We will: a) identify and measure clinical characteristics and experiences of the mother and her newborn; b) identify and measure in the placenta and umbilical cord: cellular morphology, infectious organisms, and receptors for, and expression of endocrine hormones and non-endocrine growth factors and their modulators; c) measure in umbilical cord blood and multiple postnatal blood samples: cytokines, hormones, and growth and survival factors; d) from a, b and c, identify the clinical, morphologic, and biochemical characteristics that predict white matter damage as indicated by an echolucency on cranial ultrasound scan; e) maintain contact with families so that at older ages (after the termination of initial funding) neurologic examinations and neuropsychologic tests can be performed; and 0 maintain a """"""""tissue bank"""""""" of placenta, umbilical cord, and blood that will be available for analyses to be suggested by future research findings. By identifying biomarkers of exposures that influence the risk of cerebral white matter damage, we expect to develop a rational and ethical basis for the design of clinical trials to reduce the occurrence of early brain damage and later developmental disabilities in the most vulnerable newborns.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1-SRB-K (01))
Program Officer
Hirtz, Deborah G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital Boston
United States
Zip Code
Leviton, Alan; Joseph, Robert M; Allred, Elizabeth N et al. (2018) Antenatal and neonatal antecedents of learning limitations in 10-year old children born extremely preterm. Early Hum Dev 118:8-14
Korzeniewski, Steven J; Allred, Elizabeth N; O'Shea, T Michael et al. (2018) Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation. Transl Psychiatry 8:115
Leviton, Alan; Joseph, Robert M; Fichorova, Raina N et al. (2018) Executive Dysfunction Early Postnatal Biomarkers among Children Born Extremely Preterm. J Neuroimmune Pharmacol :
Leviton, Alan; Allred, Elizabeth N; Fichorova, Raina N et al. (2018) Circulating biomarkers in extremely preterm infants associated with ultrasound indicators of brain damage. Eur J Paediatr Neurol 22:440-450
van der Burg, Jelske W; O'Shea, T Michael; Kuban, Karl et al. (2018) Are Extremely Low Gestational Age Newborns Born to Obese Women at Increased Risk of Cerebral Palsy at 2 Years? J Child Neurol 33:216-224
O'Shea, Thomas M; Joseph, Robert M; Allred, Elizabeth N et al. (2018) Accuracy of the Bayley-II mental development index at 2 years as a predictor of cognitive impairment at school age among children born extremely preterm. J Perinatol 38:908-916
Logan, J Wells; Allred, Elizabeth N; Msall, Michael E et al. (2018) Neurocognitive function of 10-year-old multiples born less than 28 weeks of gestational age. J Perinatol :
Leviton, Alan; Allred, Elizabeth N; Joseph, Robert M et al. (2018) Behavioural dysfunctions of 10-year-old children born extremely preterm associated with corticotropin-releasing hormone expression in the placenta. Acta Paediatr 107:1932-1936
Leviton, Alan; Joseph, Robert M; Allred, Elizabeth N et al. (2018) Antenatal and Neonatal Antecedents of Executive Dysfunctions in Extremely Preterm Children. J Child Neurol 33:198-208
Linthavong, Olivia; O'Shea, T Michael; Allred, Elizabeth et al. (2018) Neurocognitive and Health Correlates of Overweight and Obesity among Ten-Year-Old Children Born Extremely Preterm. J Pediatr 200:84-90.e4

Showing the most recent 10 out of 161 publications