The ELGAN study of the brain and related disorders in extremely low gestational age newborns
Introduction
In 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.
We 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], [2], [3]. These processes, which are likely inflammatory, involve the fetus [4], are complex [5], [6], [7], [8], [9], [10], probably persist for days if not weeks [11], and need not be initiated by microorganisms [12]. Originally our focus was on inflammatory exposures associated with preterm labor and pre-labor premature rupture of membranes, but has since been expanded to the processes that impair fetal growth as well.
Second, the developmental processes during the 23rd through 27th 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 facilitate 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], [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 is what we think makes the developing brain so vulnerable.
Biomarkers are objectively measured cellular or molecular characteristics that may be useful for studies of risk and causation. The ELGAN Study biomarkers include organisms recovered from the placenta parenchyma, placenta histologic characteristics, and blood proteins in maternal blood, umbilical cord blood, and postnatal blood obtained 1, 3, 5, 7, 14, 21, and 28 days after birth.
The risk of cerebral palsy and developmental dysfunctions increases with decreasing gestational age [19]. Thus, the study was limited to infants deemed to be at highest risk (<28 weeks).
Birth weight-defined eligibility for a study results in an overrepresentation of infants who are growth restricted but gestationally older [20]. This distortion hinders drawing inferences about maturational processes. We chose the name ELGAN to emphasize the gestational-age-defined sample.
Because of our interest in inflammatory exposures associated with preterm labor and pre-labor premature rupture of membranes, maternal blood and placenta were important sources of biomarker data. Antenatal enrollment allowed us to request permission for placentas and pre-delivery maternal blood, which otherwise could not have been available to us. Consequently, at most institutions, mothers were enrolled shortly after they were admitted to the hospital and before delivery. To these women we said “We hope you deliver well past the 28th week and do not become a participant. If you do deliver early, however, we want you to be part of our study.”
Some institutions did not approve of enrolling mothers prior to delivery. One of them came up with a compromise that several other institutions implemented, including those that enrolled gravida antenatally. These institutions informed all women that placentas of babies born prematurely are routinely saved for several days, so that should she enroll in a study of placentas, a piece would be used, but otherwise the placenta would be discarded.
Because of the large number of biomarkers to be studied, the range of outcomes, and the multiple potential (and interactive) risk factors, a large sample was needed for sufficient statistical power. Having many centers participate would also increase the generalizability of results. By enrolling newborns at 14 institutions, the ELGAN Study achieved large numbers (close to 1500) and generalizability.
A long-standing assumption is that all cerebral palsy is the same. The epidemiologic literature, however, suggests that the three most common clinical forms of cerebral palsy in preterm newborns, diplegia, quadriplegia, and hemiplegia, are not equivalent etiologically [21], [22]. Rather than aggregating possibly heterogenous outcomes in an effort to increase statistical power, we have chosen to define homogenous entities in order to increase validity [23], [24].
As the design for the ELGAN Study became more complex, the need grew for expertise in diverse disciplines. We had experience in epidemiology, statistics, neonatology, and neurology. Neonatologists were the site principal investigators and perinatologists were also involved. Moreover, important scientific questions required the expertise of sonologist/radiologists, pathologists, ophthalmologists, developmentalists, and lab directors with expertise in immunology, bacteriology, endocrinology, and molecular biology.
We created data collection instruments based on forms of proven value from a prior study [25], [26], [27], [28], [29], [30], [31], [32], [33] and instituted data quality control procedures that were also of proven value (http://www.fstrf.org/intro.html). Colleagues who provided subjective data (sonologists/radiologists, pathologists, ophthalmologists, and those who assessed motor and developmental functions at age two years) participated in exercises to minimize inter-observer variability.
To assure frequent communication at multiple levels, the study personnel were connected through a hub and spoke arrangement. The principal investigator communicated frequently with three hub directors who, in turn, communicated frequently with principal investigators at 3 to 5 study sites. These site principal investigators then communicated frequently with study coordinators, sonologist/radiologists, pathologists, ophthalmologists, and developmentalists. On several occasions each year, a steering committee comprised of the principal investigator, the National Institutes of Health project officer, the three hub directors, a neonatologist representing each hub, and the study coordinators, met. Each year the site principal investigators met with the principal investigators and hub directors. To reduce costs, these meetings took place at the Pediatric Academic Societies meetings, which many of the investigators ordinarily attend.
Inclusiveness is one of the core values of the study leadership. When data collection was complete, we encouraged all investigators to participate in data analyses and manuscript preparation related to topics in which they are interested. At this writing, more than 100 individuals have co-authored published manuscripts arising from the ELGAN Study; and five junior faculty members, who had not directly participated in the ELGAN study, were provided the opportunity to be lead authors [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56].
Section snippets
Overview
Of the mothers approached, 85% gave consent for participation in our study. The ELGAN cohort is described in Table 1. Of the 1506 newborns enrolled, 1222 (81%) survived until discharge and 1201 (80%) survived to 2 years corrected age. Of the 1506 infants enrolled, 1445 had had at least one set of protocol ultrasound scans. All ultrasound scans were ordered by clinicians for clinical purposes. The protocol specified procedures for obtaining and reading the scans. For study purposes, the only
Summary and future directions
The ELGAN Study's primary goal has been to identify the antecedents of brain damage, as detected with ultrasound, as well as with clinical examinations, among the most vulnerable preterm infants, those born before 28 weeks of gestation. We are seeking to identify not only initiators and damage promoters that increase the risk of brain damage, but also damage modulators, growth factors, and other molecules and processes that decrease the risk. With this information, clinical trials can be
Acknowledgments
This study was supported by a cooperative agreement with The National Institute of Neurological Disorders and Stroke (NINDS) (5U01NS040069-05). The authors gratefully acknowledge the contributions of our subjects and their families, as well as those of our colleagues.
References (79)
- et al.
Cytokines and perinatal brain damage
Clin Perinatol
(2008) - et al.
Inflammatory brain damage in preterm newborns - dry numbers, wet lab, and causal inferences
Early Hum Dev
(2004) - et al.
Preconditioning and the developing brain
Semin Perinatol
(2004) Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances
Lancet Neurology
(2009)- et al.
Neuronal damage accompanies perinatal white-matter damage
Trends Neurosci
(2007) - et al.
Plasticity and injury in the developing brain
Brain & Develop
(2009) - et al.
Antenatal corticosteroids and cranial ultrasonographic abnormalities
Am J Obstet Gynecol
(1999) - et al.
Hypothyroxinemia of prematurity and the risk of cerebral white matter damage
J Pediatr
(1999) - et al.
Histological characteristics of singleton placentas delivered before the 28th week of gestation
Pathology
(2008) - et al.
Reference weights for placentas delivered before the 28th week of gestation
Placenta
(2007)
The wealth of information conveyed by gestational age
J Pediatr
SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores
J Pediatr
The antenatal identification of funisitis (fetal inflammation) with a rapid MMP-8 bedside test
Am J Obstet Gynecol
Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant
Semin Pediatr Neurol
Do white cells matter in white matter damage?
Trends Neurosci
Inflammation, brain damage and visual dysfunction in preterm infants
Seminars in Fetal & Neonatal Medicine
Bias in analytic research
J Chron Dis
The role of inflammation and infection in preterm birth
Seminars in Reproductive Medicine
Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn
Pediatr Res
The role of the fetus in perinatal infection and neonatal brain injury
Curr Opin Pediatr
Coagulation, inflammation, and the risk of neonatal white matter damage
Pediatr Res
The adaptive immune response in neonatal cerebral white matter damage
Ann Neurol
Lung and brain damage in preterm newborns, and their association with gestational age, prematurity subgroup, infection/inflammation and long term outcome
Bjog-An International Journal of Obstetrics and Gynaecology
Perinatal brain damage causation
Dev Neurosci
Persistent neuro-inflammation in cerebral palsy: a therapeutic window of opportunity?
Acta Paediatr
Endoplasmic reticulum stress, inflammation, and perinatal brain damage
Pediatr Res
Maturation-dependent vulnerability of perinatal white matter in premature birth
Stroke
Neuregulin-1: a potential endogenous protector in perinatal brain white matter damage
Neonatology
Brain damage in preterm newborns: might enhancement of developmentally-regulated endogenous protection open a door for prevention?
Pediatrics
Analysis by gestational age of cerebral palsy in singleton births in north-east England 1970–94
Paediatr Perinat Epidemiol
Very low birth weight: a problematic cohort for epidemiologic studies of very small or immature neonates
Am J Epidemiol
Prenatal events and the risk of cerebral palsy in very low birth weight infants
Am J Epidemiol
Maternal infection and cerebral palsy in infants of normal birth weight
JAMA
Interpreting epidemiologic evidence
Definition and classification of cerebral palsy — an epidemiologist perspective
Dev Med Child Neurol
Bronchopulmonary dysplasia is not associated with ultrasound-defined cerebral white matter damage in preterm newborns
Pediatr Res
Very low birthweight infant's placenta and its relation to pregnancy and fetal characteristics
Pediatr Dev Pathol
Topography of cerebral white matter disease of prematurity studied prospectively in 1607 very-low-birthweight infants
J Child Neurol
Maternal receipt of magnesium sulfate does not seem to reduce the risk of neonatal white matter damage
Pediatrics
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