Etiology and pathogenesis of neonatal encephalopathy
- Sidhartha Tan, MD
Sidhartha Tan, MD
- Professor of Pediatrics
- Wayne State University School of Medicine
- Yvonne Wu, MD, MPH
Yvonne Wu, MD, MPH
- Professor of Neurology and Pediatrics
- University of California, San Francisco
- Section Editors
- Douglas R Nordli, Jr, MD
Douglas R Nordli, Jr, MD
- Section Editor — Pediatric Neurology
- Chief of Neurology
- Children’s Hospital Los Angeles
- Vice Chair of Neurology
- USC Keck School of Medicine
- Leonard E Weisman, MD
Leonard E Weisman, MD
- Section Editor — Neonatology
- Professor of Pediatrics
- Baylor College of Medicine
Neonatal encephalopathy is a heterogeneous syndrome characterized by signs of central nervous system dysfunction in newborn infants. Clinical suspicion of neonatal encephalopathy should be considered in any infant exhibiting an abnormal level of consciousness, seizures, tone and reflex abnormalities, apnea, aspiration, feeding difficulties [1,2], and an abnormal hearing screen.
This topic will review the etiology and pathogenesis of neonatal encephalopathy. Other clinical aspects of this syndrome are discussed separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)
"Neonatal encephalopathy" has emerged as the preferred term to describe central nervous system dysfunction in the newborn period [2,3]. The American College of Obstetricians and Gynecologists (ACOG) describes neonatal encephalopathy as a clinically defined syndrome of disturbed neurologic function in the earliest days of life in an infant born at or beyond 35 weeks of gestation, manifested by a subnormal level of consciousness or seizures, and often accompanied by difficulty with initiating and maintaining respiration and depression of tone and reflexes .
The terminology does not imply a specific underlying pathophysiology, which is appropriate since the nature of brain injury causing neurologic impairment in a newborn is poorly understood. While neonatal encephalopathy was once automatically ascribed to hypoxia-ischemia , it is now known that hypoxia-ischemia is only one of many possible contributors to neonatal encephalopathy. Whether a particular newborn's encephalopathy can be attributed to hypoxic-ischemic brain injury is often unclear.
Some investigators require stringent criteria for using the term neonatal encephalopathy, such as two or more symptoms of encephalopathy lasting over 24 hours , while others require no more than a low five minute Apgar score . However, the use of Apgar scores alone is problematic, as Apgar scores may be low due to maternal analgesia or prematurity, or can be normal in the presence of acute hypoxia-ischemic injury.
- Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976; 33:696.
- Ferriero DM. Neonatal brain injury. N Engl J Med 2004; 351:1985.
- Dammann O, Ferriero D, Gressens P. Neonatal encephalopathy or hypoxic-ischemic encephalopathy? Appropriate terminology matters. Pediatr Res 2011; 70:1.
- Executive summary: Neonatal encephalopathy and neurologic outcome, second edition. Report of the American College of Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy. Obstet Gynecol 2014; 123:896.
- Sartwelle TP. Defending a neurologic birth injury. Asphyxia neonatorum redux. J Leg Med 2009; 30:181.
- Badawi N, Kurinczuk JJ, Keogh JM, et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ 1998; 317:1549.
- Bartha AI, Foster-Barber A, Miller SP, et al. Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome. Pediatr Res 2004; 56:960.
- Wu Y. Brain injury in newborn babies: we can't afford to get it wrong. Ann Neurol 2012; 72:151.
- Volpe JJ. Neonatal encephalopathy: an inadequate term for hypoxic-ischemic encephalopathy. Ann Neurol 2012; 72:156.
- Bax M, Nelson KB. Birth asphyxia: a statement. World Federation of Neurology Group. Dev Med Child Neurol 1993; 35:1022.
- Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. ACOG Committee Opinion. Number 326, December 2005. Inappropriate use of the terms fetal distress and birth asphyxia. Obstet Gynecol 2005; 106:1469.
- Gunn AJ, Bennet L. Timing of injury in the fetus and neonate. Curr Opin Obstet Gynecol 2008; 20:175.
- Cowan F, Rutherford M, Groenendaal F, et al. Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet 2003; 361:736.
- Badawi N, Kurinczuk JJ, Keogh JM, et al. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ 1998; 317:1554.
- American Collge of Obstetricians and Gynecologists (ACOG). Neonatal encephalopathy and cerebral palsy: executive summary. Obstet Gynecol 2004; 103:780.
- Nelson KB, Bingham P, Edwards EM, et al. Antecedents of neonatal encephalopathy in the Vermont Oxford Network Encephalopathy Registry. Pediatrics 2012; 130:878.
- Martinez-Biarge M, Diez-Sebastian J, Wusthoff CJ, et al. Antepartum and intrapartum factors preceding neonatal hypoxic-ischemic encephalopathy. Pediatrics 2013; 132:e952.
- Locatelli A, Incerti M, Paterlini G, et al. Antepartum and intrapartum risk factors for neonatal encephalopathy at term. Am J Perinatol 2010; 27:649.
- Hayes BC, McGarvey C, Mulvany S, et al. A case-control study of hypoxic-ischemic encephalopathy in newborn infants at >36 weeks gestation. Am J Obstet Gynecol 2013; 209:29.e1.
- Bukowski R, Burgett AD, Gei A, et al. Impairment of fetal growth potential and neonatal encephalopathy. Am J Obstet Gynecol 2003; 188:1011.
- McDonald DG, Kelehan P, McMenamin JB, et al. Placental fetal thrombotic vasculopathy is associated with neonatal encephalopathy. Hum Pathol 2004; 35:875.
- Redline RW. Severe fetal placental vascular lesions in term infants with neurologic impairment. Am J Obstet Gynecol 2005; 192:452.
- Chang T, Reyes C, Teng J, et al. Neonatal encephalopathy, sentinel events, and the placenta. J Neonatal Perinatal Med 2012; 5:41.
- Barger MK, Nannini A, Weiss J, et al. Severe maternal and perinatal outcomes from uterine rupture among women at term with a trial of labor. J Perinatol 2012; 32:837.
- Landon MB, Hauth JC, Leveno KJ, et al. Maternal and perinatal outcomes associated with a trial of labor after prior cesarean delivery. N Engl J Med 2004; 351:2581.
- Redline RW. Cerebral palsy in term infants: a clinicopathologic analysis of 158 medicolegal case reviews. Pediatr Dev Pathol 2008; 11:456.
- Okereafor A, Allsop J, Counsell SJ, et al. Patterns of brain injury in neonates exposed to perinatal sentinel events. Pediatrics 2008; 121:906.
- Garfinkle J, Wintermark P, Shevell MI, et al. Cerebral palsy after neonatal encephalopathy: do neonates with suspected asphyxia have worse outcomes? Dev Med Child Neurol 2016; 58:189.
- Lieberman E, Lang J, Richardson DK, et al. Intrapartum maternal fever and neonatal outcome. Pediatrics 2000; 105:8.
- Blume HK, Li CI, Loch CM, Koepsell TD. Intrapartum fever and chorioamnionitis as risks for encephalopathy in term newborns: a case-control study. Dev Med Child Neurol 2008; 50:19.
- Impey LW, Greenwood CE, Black RS, et al. The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy. Am J Obstet Gynecol 2008; 198:49.e1.
- Shalak LF, Perlman JM, Jackson GL, Laptook AR. Depression at birth in term infants exposed to maternal chorioamnionitis: does neonatal fever play a role? J Perinatol 2005; 25:447.
- Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 1997; 278:207.
- Wu YW, Colford JM Jr. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA 2000; 284:1417.
- Wu YW, Escobar GJ, Grether JK, et al. Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 2003; 290:2677.
- Aly H, Khashaba MT, El-Ayouty M, et al. IL-1beta, IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy. Brain Dev 2006; 28:178.
- Odd DE, Lewis G, Whitelaw A, Gunnell D. Resuscitation at birth and cognition at 8 years of age: a cohort study. Lancet 2009; 373:1615.
- Goldaber KG, Gilstrap LC 3rd, Leveno KJ, et al. Pathologic fetal acidemia. Obstet Gynecol 1991; 78:1103.
- Locatelli A, Incerti M, Ghidini A, et al. Factors associated with umbilical artery acidemia in term infants with low Apgar scores at 5 min. Eur J Obstet Gynecol Reprod Biol 2008; 139:146.
- Becher JC, Bell JE, Keeling JW, et al. The Scottish perinatal neuropathology study: clinicopathological correlation in early neonatal deaths. Arch Dis Child Fetal Neonatal Ed 2004; 89:F399.
- Bejar R, Vigliocco G, Gramajo H, et al. Antenatal origin of neurologic damage in newborn infants. II. Multiple gestations. Am J Obstet Gynecol 1990; 162:1230.
- Logitharajah P, Rutherford MA, Cowan FM. Hypoxic-ischemic encephalopathy in preterm infants: antecedent factors, brain imaging, and outcome. Pediatr Res 2009; 66:222.
- Reddy K, Mallard C, Guan J, et al. Maturational change in the cortical response to hypoperfusion injury in the fetal sheep. Pediatr Res 1998; 43:674.
- Keunen H, Blanco CE, van Reempts JL, Hasaart TH. Absence of neuronal damage after umbilical cord occlusion of 10, 15, and 20 minutes in midgestation fetal sheep. Am J Obstet Gynecol 1997; 176:515.
- Windle WF. Brain damage at birth. Functional and structural modifications with time. JAMA 1968; 206:1967.
- Juul SE, Aylward E, Richards T, et al. Prenatal cord clamping in newborn Macaca nemestrina: a model of perinatal asphyxia. Dev Neurosci 2007; 29:311.
- Usta IM, Mercer BM, Sibai BM. Current obstetrical practice and umbilical cord prolapse. Am J Perinatol 1999; 16:479.
- Poetker DM, Rijhsinghani A. Fetal survival after umbilical cord prolapse for more than three days. A case report. J Reprod Med 2001; 46:776.
- Derrick M, Luo NL, Bregman JC, et al. Preterm fetal hypoxia-ischemia causes hypertonia and motor deficits in the neonatal rabbit: a model for human cerebral palsy? J Neurosci 2004; 24:24.
- Drobyshevsky A, Luo K, Derrick M, et al. Motor deficits are triggered by reperfusion-reoxygenation injury as diagnosed by MRI and by a mechanism involving oxidants. J Neurosci 2012; 32:5500.
- Schober ME, McKnight RA, Yu X, et al. Intrauterine growth restriction due to uteroplacental insufficiency decreased white matter and altered NMDAR subunit composition in juvenile rat hippocampi. Am J Physiol Regul Integr Comp Physiol 2009; 296:R681.
- Morrison JL. Sheep models of intrauterine growth restriction: fetal adaptations and consequences. Clin Exp Pharmacol Physiol 2008; 35:730.
- Murphy DJ, Sellers S, MacKenzie IZ, et al. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995; 346:1449.
- Back SA, Luo NL, Borenstein NS, et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci 2001; 21:1302.
- Volpe JJ. Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev 2001; 7:56.
- Tan S, Zhou F, Nielsen VG, et al. Sustained hypoxia-ischemia results in reactive nitrogen and oxygen species production and injury in the premature fetal rabbit brain. J Neuropathol Exp Neurol 1998; 57:544.
- Tan S, Parks DA. Preserving brain function during neonatal asphyxia. Clin Perinatol 1999; 26:733.
- Drobyshevsky A, Derrick M, Prasad PV, et al. Fetal brain magnetic resonance imaging response acutely to hypoxia-ischemia predicts postnatal outcome. Ann Neurol 2007; 61:307.
- Monaghan DT, Holets VR, Toy DW, Cotman CW. Anatomical distributions of four pharmacologically distinct 3H-L-glutamate binding sites. Nature 1983; 306:176.
- Mayer ML, Westbrook GL, Guthrie PB. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 1984; 309:261.
- Ankarcrona M, Dypbukt JM, Bonfoco E, et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995; 15:961.
- Jensen FE. Role of glutamate receptors in periventricular leukomalacia. J Child Neurol 2005; 20:950.
- Leuchtmann EA, Ratner AE, Vijitruth R, et al. AMPA receptors are the major mediators of excitotoxic death in mature oligodendrocytes. Neurobiol Dis 2003; 14:336.
- Rosenberg PA, Dai W, Gan XD, et al. Mature myelin basic protein-expressing oligodendrocytes are insensitive to kainate toxicity. J Neurosci Res 2003; 71:237.
- Beckman JS. The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Dev Physiol 1991; 15:53.
- Ferriero DM, Holtzman DM, Black SM, Sheldon RA. Neonatal mice lacking neuronal nitric oxide synthase are less vulnerable to hypoxic-ischemic injury. Neurobiol Dis 1996; 3:64.
- Iadecola C, Zhang F, Casey R, et al. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci 1997; 17:9157.
- Huang Z, Huang PL, Ma J, et al. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab 1996; 16:981.
- Wu YW, March WM, Croen LA, et al. Perinatal stroke in children with motor impairment: a population-based study. Pediatrics 2004; 114:612.
- Wu YW, Lynch JK, Nelson KB. Perinatal arterial stroke: understanding mechanisms and outcomes. Semin Neurol 2005; 25:424.
- Stromme P, Kanavin OJ, Abdelnoor M, et al. Incidence rates of progressive childhood encephalopathy in Oslo, Norway: a population based study. BMC Pediatr 2007; 7:25.
- Strømme P, Magnus P, Kanavin ØJ, et al. Mortality in childhood progressive encephalopathy from 1985 to 2004 in Oslo, Norway: a population-based study. Acta Paediatr 2008; 97:35.
- Strømme P, Suren P, Kanavin OJ, et al. Parental consanguinity is associated with a seven-fold increased risk of progressive encephalopathy: a cohort study from Oslo, Norway. Eur J Paediatr Neurol 2010; 14:138.
- Westerlinck H, Meylaerts L, Van Hoestenberghe MR, Rossi A. Sulfite oxidase deficiency in a newborn. JBR-BTR 2014; 97:113.
- Bayram E, Topcu Y, Karakaya P, et al. Molybdenum cofactor deficiency: review of 12 cases (MoCD and review). Eur J Paediatr Neurol 2013; 17:1.
- Edwards M, Roeper J, Allgood C, et al. Investigation of molybdenum cofactor deficiency due to MOCS2 deficiency in a newborn baby. Meta Gene 2015; 3:43.
- Johnston MV, Fatemi A, Wilson MA, Northington F. Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 2011; 10:372.
- Wu YW, Hamrick SE, Miller SP, et al. Intraventricular hemorrhage in term neonates caused by sinovenous thrombosis. Ann Neurol 2003; 54:123.
- Sanz EJ, De-las-Cuevas C, Kiuru A, et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005; 365:482.
- Timing of insult
- RISK FACTORS
- HYPOXIC-ISCHEMIC INJURY
- Antecedent events and risk factors
- Acute events
- Level and duration of hypoxia-ischemia
- Vulnerable regions of developing brain
- Mechanisms of neuronal injury
- - Excitotoxic injury
- - Nitric oxide and oxygen-free radicals
- PERINATAL STROKE
- PROGRESSIVE ENCEPHALOPATHY
- Metabolic abnormalities
- OTHER CAUSES