The ELGAN study of the brain and related disorders in extremely low gestational age newborns

Abstract

IntroductionIn the late 1990's, we designed and laid the foundations for a study intended to advance our understanding of what contributes to brain damage in extremely low gestational age newborns (ELGANs). Our planning considered the following: A model of brain damage in the preterm newbornWe postulate that the preterm newborn is at very high risk of brain damage, for at least three reasons.First, the very processes that lead to preterm delivery can contribute to brain damage.(1-3) These processes, which are likely inflammatory, involve the fetus,(4) are complex,(5-10) probably persist for days if not weeks,(11) and need not be initiated by microorganisms. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interests:The authors declare that they have no conflicts of interests. NIH Public Access Author ManuscriptEarly Hum Dev. Author manuscript; available in PMC 2010 November 1. Published in final edited form as:Early Hum Dev. 2009 November ; 85(11): 719-725. doi:10.1016/j.earlhumdev.2009.060. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOriginally our focus was on inflammatory exposures associated with preterm labor and prelabor premature rupture of membranes, but has since been expanded to the processes that impair fetal growth as well.Second, the developmental processes during the 23 rd through 27 th weeks of gestation might be among the most vulnerable. The transformation of oligodendrocyte precursor to oligodendrocyte is one maturational process that appears particularly vulnerable. (13) Another is the migration of neuron precursors from the germinal plate to their final destination. (14,15) In addition, excitatory neurotransmitter pathways are up-regulated in the immature brain, apparently to faciliate neuronal migration, division, and organization, and the development of synapses and synaptic networks.(16) This heightened excitatory state enhances the vulnerability of the brain to excitotoxic injury from inflammatory or metabolic disorders.Third, ELGANs are born before they can synthesize adequate amounts of proteins normally provided by the placenta/mother. These proteins, many of which satisfy criteria for being called neurotrophins because they promote the differentiation/maturation of neurons and oligodendroglia, have the capacity to protect these cells against perturbation/adversity. (17,17,18) The combination of a potentially damaging exposure, easily disturbed developmental processes, and the lack of protection against the disturbances provoked by the damaging exposure are what we think make the developing brain so vulner...

Neurocognitive and Academic Outcomes at Age 10 Years of Extremely Preterm Newborns

“…Newborn characteristics (GA, birth weight, and growth restriction), neonatal brain injuries (echolucent lesions of cerebral white matter, ventriculomegaly), and neonatal medical characteristics (necrotizing enterocolitis requiring surgery, prethreshold retinopathy of prematurity, and bronchopulmonary dysplasia) were defined according to standard procedures. 26 …”

“…Although some view the 2 as equivalent, very low birth weight samples have an overrepresentation of growth-restricted infants whose GA might be older than most others in the cohort. [26][27][28] Consequently, birth weight-defined samples cannot adequately assess the contribution to immaturity/vulnerability that is specifically determined by GA. Other strengths of this study include the relatively large number of children who were born at an extremely low GA and followed until age10 years and the broad assessment of neurocognitive and academic function. The main limitation is our lack of a term control group, which required us to estimate neurocognitive and academic outcomes in relation to the respective test norms.…”

Score for Neonatal Acute Physiology–II and Neonatal Pain Predict Corticospinal Tract Development in Premature Newborns

“…Pregnancy-induced hypertension was defined as the development of new arterial hypertension (blood pressure over 140/90 mmHg) during pregnancy, after 20 weeks gestation and without proteinuria. Given the association of PROM with poor motor outcome [8][9][10], we examined the role of chorioamnionitis as measured by placental histopathology, a more sensitive measure of intrauterine infection [25]. To measure early illness severity, we used SNAP-II during the first 24 hours of life; SNAP-II quantifies six physiological variables (blood pressure, temperature, PO 2 /fraction of inspired oxygen, serum pH, seizures, and urine output), with higher scores reflecting more disturbances in neonatal physiology [14].…”

“…Our aim was to explore in a prospective cohort of premature newborns serially studied with diffusion tensor imaging, the associations of established risk factors for motor impairment with development of the major motor pathway measured with diffusion tensor tractography. These risk factors include antenatal exposures, such as pregnancy-induced hypertension [6], gestational diabetes [7], and intrauterine inflammation [8][9][10], as well as male sex [11][12][13]. Putative perinatal and post-natal risk factors include early illness severity as measured by the Score of Neonatal Acute Physiology-Version II (SNAP-II) [14,15], infection [9,16,17], necrotizing enterocolitis [16,17], patent ductus arteriosus [18], chronic lung disease [18][19][20][21], and neonatal procedural pain [22].…”

‘Does ________ predict neurodevelopmental impairment in former preterm infants?’ Is this the right question to be asked?

“…1 The ELGAN study represents a prospective multicenter group of infants born at o28 weeks between the years 2002 to 2004, with prospectively planned neurodevelopmental assessments at multiple time points. 2 With the original sample size of 1506, the investigators were able to assess nearly 900 children at 10 years of age. 1 This remarkable cohort has helped to inform some of our understanding of the pathophysiology associated with brain injury in ELGANs, as well as provide insight into the long-term outcomes, which are often lacking in clinical trials.…”