Genes and environment in neonatal intraventricular hemorrhage
Introduction
Preterm birth affects an estimated 13 million newborns worldwide annually,1, 2 and sophisticated advances in perinatal care have improved survival for the prematurely born.3 In contrast, the incidence of neurodevelopmental handicap in the prematurely born has changed little during the last 2 decades,4, 5, 6 mandating a more complete assessment of injury to the developing preterm brain. Intraventricular hemorrhage (IVH), or hemorrhage into the germinal matrix tissues of the developing brain with ventricular enlargement and parenchymal involvement, is one of the major causes of morbidity in the prematurely born, often resulting in cerebral palsy and cognitive handicap.7, 8 Notably, there are over 2800 new cases of mental retardation attributable to IVH in the US each year, and the lifetime care costs for these children exceed $4 billion (2010) annually.9, 10 Emerging data suggest that IVH is a complex developmental disorder with contributions from both the environment and the genome.11
IVH occurs during the critical period of time before 32–33 weeks gestation and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature.12 Inflammation, coagulation, and vascular factors may also play a role.8, 12 Severe IVH is characterized by the acute hemorrhagic distension of the cerebral ventricular system (grade 3) and parenchymal venous infarction (grade 4). The cascade of adverse events following IVH includes destructive, inflammatory, and maturational disturbances and is characterized by white matter injury, delayed oligodendroglial maturation, loss of gamma-aminobutyric acid (GABA) interneurons, and impaired thalamo-cortical connectivity.8 All may contribute to developmental disability.
The purpose of this report is to review both environmental and genetic data supporting the hypothesis that IVH is a complex disorder. Candidate genes, gene-by-environment interaction studies reviewed, and a recent genome-wide association study (GWAS) will be reported.
Section snippets
The etiology of IVH is multifactorial
Multiple sources of data support the hypothesis that, similar to most other morbidities in preterm neonates,13, 14 the etiology of IVH is multifactorial. Maternal transport and antenatal steroid (ANS) administration for fetal lung maturation and improved resuscitation techniques have become standard of care for women in preterm labor and premature infants worldwide,15, 16, 17, 18 but the incidence of severe IVH has remained 12–15% for the past 10–15 years.15, 19, 20, 21, 22, 23 In addition,
Environmental factors and health care disparities are permissive for hemorrhage
IVH occurs against the backdrop of preterm birth in which both risk and protective factors have been well described.15 Lower GA and birth weight (BW), male gender, white race, chorioamnionitis, Apgar <3 at 5 min, delivery room resuscitation, surfactant administration, neonatal transport, illness severity, assisted ventilation, disturbances of partial pressure of CO2, respiratory distress syndrome, and high frequency ventilation have all been reported to increase risk for IVH, while a complete
Preclinical studies: Mutations in microvascular proteins confer vulnerability to IVH
The germinal matrix is a region of active angiogenesis, and IVH begins in this region. The microvessels of the germinal matrix lack the traditional components of the blood brain barrier, endothelial tight junctions, basement membrane proteins, glial endfeet and perivascular pericytes.12 IVH is thought to be a critical period disorder, and previous work has suggested that it is the developmental stage of the germinal matrix microvessels that are permissive to hemorrhage.35
Preclinical data
Clinical studies suggest coagulation, inflammation, and vascular pathways
IVH has been attributed to alterations in cerebral blood flow to the immature germinal matrix microvasculature, and risk factor studies across the past 2 decades have suggested the role of genes contributing to coagulation and vascular pathways. Similarly, the risk for injury is higher in preterm neonates exposed to prenatal inflammation, and candidate genes subserving infection and inflammation have also been interrogated.
Numerous variants in the coagulation pathway have been investigated, but
Genome-wide association study for IVH: An unbiased discovery strategy
Although environmental risk factors have been identified and candidate genes investigated, IVH remains a significant problem for the prematurely born. To investigate potential genetic etiologies of severe IVH in preterm infants, employing a cohort of 458 inborn appropriate for gestational age neonates with severe IVH and 866 infants without IVH, we conducted a GWAS among cases and controls across the US and Scandinavia to identify disease susceptibility or protection genes and generate
Methods
Inborn infants with BW 500–1250 g and either severe (grades 3–4) IVH or normal cranial ultrasounds were enrolled prospectively at 24 universities; additional samples were provided from the extremely low gestational age newborns (ELGAN),55 Iowa Prematurity,27 and Oulu University56 studies. The protocol was approved by institutional review boards at each institution and all subjects have appropriate informed consent.
Patient characteristics
Neonates with Gr 3–4 IVH had lower BWs and GAs than controls (p < 0.001 for both; Table 1). Mothers of cases were less likely to have at least one prenatal visit (p = 0.044), preeclampsia (p < 0.001), or a complete course of ANS (p < 0.001) than control mothers. In contrast, they more often had chorioamnionitis (p < 0.001).
Cases were less likely than controls to have Cesarean section delivery (p < 0.001), and more often had low 5-min Apgar scores (Apgar5 <3; p < 0.001), intubation for
Moving forward: Gene-by-environment interactions for the prevention of IVH
Severe IVH of the prematurely born is a high-prevalence, high-impact disorder, but the genetic investigations of IVH have thus far been largely disappointing. Future studies supporting the rationale design of multicenter randomized clinical trials must therefore include not only large-scale GWAS, but also whole exome sequencing data and, ultimately, whole genome sequencing. Transcriptomics and epigenomics also merit examination, as IVH is a critical period disorder. Finally, causal relations of
Sources of funding
The Gene Targets for IVH Study Group was supported by NIH NS053865. Dr. Zhang was partially supported by NIH R01 DA016750-09.
The National Institutes of Health, United States (General Clinical Research Center grants M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587, UL1 RR24979) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States (Grants U01 HD36790, U10 HD21364,
Gene targets for IVH study group
The following investigators participated in this study: Cindy Bryant, BSN, CCRN, CCRP; Christopher Cassady, MD; Carmen Garcia, RN, BSN; Yvette R. Johnson, MD, MPH; Heidi E. Karpen, MD; Martha M. Munden, MD; Geneva Shores, RNC-LRN (Baylor College of Medicine, Texas Childrenʼs Hospital and Ben Taub General Hospital); John Cassese, MD; Angelita M. Hensman, RN, BSN; Elisa Vieira, BS, RN; Betty Vohr, MD; Michael Wallach, MD (Brown University and Women & Infants Hospital); James J. Cummings, MD;
Neonatal research network genomics study group
NRN Steering Committee Chair: Alan H. Jobe, MD PhD, University of Cincinnati.
Case Western Reserve University, Rainbow Babies & Childrenʼs Hospital (U10 HD21364, M01 RR80)—Michele C. Walsh, MD, MS; Avroy A. Fanaroff, MD; Nancy S. Newman, RN; Bonnie S. Siner, RN.
Cincinnati Childrenʼs Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084)—Kurt Schibler, MD; Edward F. Donovan, MD; Vivek Narendran, MD, MRCP; Barbara Alexander, RN; Cathy Grisby, BSN CCRC;
Acknowledgments
We are indebted to our medical, nursing, and research colleagues and the infants and their parents who agreed to take part in this study. The authors are grateful to Deborah Hirtz, MD, Alan Leviton, MD, Richard Ehrenkranz, MD, Murim Choi, PhD, Xiaoyi Min, PhD, Zhifa Liu, MS, and Carol Nelson-Williams, PhD, for scientific expertise, Jill Maller-Kesselman, MA, and Rebecca Linsky, BA, for study management, Walter Allan, MD, T. Robin Goodman, MB, Daniel Young, MD, and Stuart Royal, MD, for
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