AccScience Publishing / AN / Volume 2 / Issue 4 / DOI: 10.36922/an.1719
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Worsening of cerebral palsy following neonatal encephalopathy: A meta-analysis

Meng Yang1 Sarah Eide1 Emily W.Y. Tam2 Vann Chau2 S.R. Wayne Chen3 Steven P. Miller4 Hong-Shuo Sun1,5 Zhong-Ping Feng1*
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1 Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
2 Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
3 Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
4 Department of Pediatrics, Faculty of Medicine, University of British Columbia and BC Children’s Hospital, Vancouver, British Columbia, Canada
5 Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Advanced Neurology 2023, 2(4), 1719
Submitted: 30 August 2023 | Accepted: 28 November 2023 | Published: 15 December 2023
© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( )

Cerebral palsy (CP), the most common motor disorder in early childhood, arises from neonatal brain injury. The potential role of neonatal encephalopathy (NE) as a risk factor for cerebral palsy has been postulated, yet a systematic examination of its clinical impact on cerebral palsy patients remains absent. This meta-analysis aims to delineate the incidence of commonly reported complications associated with cerebral palsy following NE compared to those without a history of NE. A systematic search of PubMed and Google Scholar yielded 424 studies, with 7 meeting the inclusion criteria. These studies reported at least one comparison of cerebral palsy symptoms between patients with or without NE and provided the corresponding case numbers for each group. Utilizing RevMan 5.4, we analyzed the data and assessed potential publication bias. Among the 7 studies included, we compared the characteristics of 117 patients with cerebral palsy with preceding NE to 287 without such antecedents. Significantly, the incidence of the spastic quadriplegic subtype of cerebral palsy was higher in patients with NE (odds ratio [OR]: 4.34, 95% confidence interval [CI]: 2.69 – 7.00, P < 0.00001). CP patients following NE exhibited a significantly increased incidence of severe communication difficulties (OR: 2.33, 95% CI: 1.32 – 4.10, P = 0.003), difficulty swallowing (OR: 2.50, 95% CI: 1.31 – 4.77, P = 0.005), and cognitive impairment (OR: 2.73, 95% CI: 1.45 – 5.13, P = 0.002). Children with cerebral palsy born following NE were more predisposed to the most severe spastic quadriplegic subtype and encountered significant comorbidities. It is essential to acknowledge the limitations of this study, primarily the small number of studies that separately reported cerebral palsy cases with or without NE. Nevertheless, these findings contribute valuable insights for a more accurate clinical prognosis and the prospective development of targeted treatments for specific complications associated with cerebral palsy in patients with NE.

Neonatal encephalopathy
Cerebral palsy
Hypoxic-ischemic brain injury
Natural Sciences and Engineering Research Council of Canada
Canadian Institutes of Health Research
Ontario Graduate Scholarship
  1. Walstab JE, Bell RJ, Reddihough DS, et al., 2004, Factors identified during the neonatal period associated with risk of cerebral palsy. Australian and New Zealand Journal of Obstetrics and Gynaecology, 44: 342–346.


  1. Wimalasundera N, Stevenson VL, 2016, Cerebral palsy. BMJ J, 16: 184–194.


  1. Oskoui M, Coutinho F, Dykeman J, et al., 2013, An update on the prevalence of cerebral palsy: A systematic review and meta-analysis. Dev Med Child Neurol, 55: 509–519.


  1. Garfinkle J, Wintermark P, Shevell MI, et al., 2016, Cerebral palsy after neonatal encephalopathy: Do neonates with suspected asphyxia have worse outcomes? Dev Med Child Neurol, 58: 189–194.


  1. Zhang S, Li B, Zhang X, et al., 2020, Birth asphyxia is associated with increased risk of cerebral palsy: A meta-analysis. Front Neurol, 11: 704.


  1. Bax M, Goldstein M, Rosenbaum P, et al., 2005, Proposed definition and classification of cerebral palsy, April 2005. Dev Med Child Neurol, 47: 571–576.


  1. Rosenbaum P, Paneth N, Leviton A, et al., 2007, A report: The definition and classification of cerebral palsy April 2006. Dev Med Child Neurol, Supplement, 109: 8–14.


  1. Gorter JW, Rosenbaum PL, Hanna SE, et al., 2004, Limb distribution, motor impairment, and functional classification of cerebral palsy. Dev Med Child Neurol, 46: 461–467.


  1. Paul S, Nahar A, Bhagawati M, et al., 2022, A review on recent advances of cerebral palsy. Oxid Med Cell Longev, 2022: 2622310.


  1. Abd Elmagid DS, Magdy H, 2021, Evaluation of risk factors for cerebral palsy. Egypt J Neurol Psychiat Neurosurg, 57: 13.


  1. Grunt S, Mazenauer L, Buerki SE, et al., 2015, Incidence and outcomes of symptomatic neonatal arterial ischemic stroke. Pediatrics, 135: e1220–e1228.


  1. Tann CJ, Nakakeeto M, Willey BA, et al., 2018, Perinatal risk factors for neonatal encephalopathy: An unmatched case-control study. Arch Dis Child Fetal Neonatal Ed, 103: F250–F256.


  1. Gupta SN, Kechli AM, Kanamalla US, 2009, Intracranial hemorrhage in term newborns: Management and outcomes. Pediatr Neurol, 40: 1–12.


  1. Alkalay AL, Sarnat HB, Flores-Sarnat L, et al., 2005, Neurologic aspects of neonatal hypoglycemia. Isr Med Assoc J, 7: 188–192.


  1. Diringer M, 2017, Neurologic manifestations of major electrolyte abnormalities. Handb Clin Neurol, 141: 705–713.


  1. Glass HC, Shellhaas RA, Wusthoff CJ, et al., 2016, Contemporary profile of seizures in neonates: A prospective cohort study. J Pediatr, 174: 98–103.e1.


  1. Saudubray JM, Garcia-Cazorla À, 2018, Inborn errors of metabolism overview: Pathophysiology, manifestations, evaluation, and management. Pediatr Clin North Am, 65: 179–208.


  1. Felix JF, Badawi N, Kurinczuk JJ, et al., 2007, Birth defects in children with newborn encephalopathy. Dev Med Child Neurol, 42: 803–808.


  1. Ryan KS, Prewitt KC, Hayer S, et al., 2023, Opioid use in pregnancy: A review. Obstet Gynecol Surv, 78: 35–49.


  1. Badawi N, Pemberton PJ, Kurinczuk JJ, et al., 1998, Antepartum risk factors for newborn encephalopathy. Pediatr Res, 44: 434.


  1. Ferriero DM, 2004, Neonatal brain injury. N Engl J Med, 351: 1985–1895.


  1. Douglas-Escobar M, Weiss MD, 2015, Hypoxic-ischemic encephalopathy: A review for the clinician. JAMA Pediatr, 169: 397–403.


  1. Dirnagl U, Iadecola C, Moskowitz MA, 1999, Pathobiology of ischaemic stroke: An integrated view. Trends Neurosci, 22: 391–397.


  1. Kurinczuk JJ, White-Koning M, Badawi N, 2010, Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev, 86: 329–338.


  1. Allen KA, Brandon DH, 2011, Hypoxic ischemic encephalopathy: Pathophysiology and experimental treatments. Newborn Infant Nurs Rev, 11: 125–133.


  1. Drury PP, Bennet L, Gunn AJ, 2010, Mechanisms of hypothermic neuroprotection. Semin Fetal Neonatal Med, 15: 287–292.


  1. Wassink G, Lear CA, Gunn KC, et al., 2015, Analgesics, sedatives, anticonvulsant drugs, and the cooled brain. Semin Fetal Neonatal Med, 20: 109–114.


  1. Chen W, Xu B, Xiao A, et al., 2015, TRPM7 inhibitor carvacrol protects brain from neonatal hypoxic-ischemic injury. Mol Brain, 8: 11.


  1. Turlova, E, Wong R, Xu B, et al., 2021, TRPM7 mediates neuronal cell death upstream of calcium/calmodulin-dependent protein kinase II and calcineurin mechanism in neonatal hypoxic-ischemic brain injury. Transl Stroke Res, 12: 164–184.


  1. Ovcjak A, Xiao A, Kim JS, et al., 2022, Ryanodine receptor inhibitor dantrolene reduces hypoxic-ischemic brain injury in neonatal mice. Exp Neurol, 351: 113985.


  1. Fatemi A, Wilson MA, Johnston MV, 2009, Hypoxic-ischemic encephalopathy in the term infant. Clin Perinatol, 36: 835–858, vii.


  1. Felix JF, Badawi N, Kurinczuk JJ, et al., 2000, Birth defects in children with newborn encephalopathy. Dev Med Child Neurol, 42: 803–808.


  1. Badawi N, Felix JF, Kurinczuk JJ, et al., 2005, Cerebral palsy following term newborn encephalopathy: A population-based study. Dev Med Child Neurol, 47: 293–298.


  1. Nelson KB, 2008, Causative factors in cerebral palsy. Clin Obstet Gynecol, 51: 749–762.


  1. Hesse S, Werner C, 2003, Poststroke motor dysfunction and spasticity: Novel pharmacological and physical treatment strategies. CNS Drugs, 17: 1093–1107.


  1. Booth AT, Buizer AI, Meyns P, et al., 2018, The efficacy of functional gait training in children and young adults with cerebral palsy: A systematic review and meta-analysis. Dev Med Child Neurol, 60: 866–883.


  1. Deeks JJ, Higgins JP, 2010, Statistical Algorithms in Review Manager 5 on Behalf of the Statistical Methods Group of The Cochrane Collaboration Data structure Individual Study Estimates: Dichotomous Outcomes, p1–11. Available from: lookup?title=Statistical%20algorithms%20in%20review%20 manager%205&author=J.%20Deeks&publication_ year=2007


  1. Yamada T, Akaishi R, Yamada T, et al., 2014, Risk of cerebral palsy associated with neonatal encephalopathy in macrosomic neonates. J Obstet Gynaecol Res, 40: 1611–1617.


  1. Ellis M, Manandhar N, Shrestha PS, et al., 1999, Outcome at 1 year of neonatal encephalopathy in Kathmandu, Nepal. Dev Med Child Neurol, 41: 689–695.


  1. Evans K, Rigby AS, Hamilton P, et al., 2001, The relationships between neonatal encephalopathy and cerebral palsy: A cohort study. J Obstet Gynaecol, 21: 114–120.


  1. Gaffney G, Flavell V, Johnson A, et al., 1994, Cerebral palsy and neonatal encephalopathy. BMJ, 308: 1507.


  1. Kyriakopoulos P, Oskoui M, Dagenais L, et al., 2013, Term neonatal encephalopathy antecedent cerebral palsy: A retrospective population-based study. Eur J Paediatr Neurol, 17: 269–273.


  1. Freire G, Shevell M, Oskoui M, 2015, Cerebral palsy: Phenotypes and risk factors in term singletons born small for gestational age. Eur J Paediatr Neurol, 19: 218–225.


  1. Gurbuz A, Karateke A, Yilmaz U, et al., 2006, The role of perinatal and intrapartum risk factors in the etiology of cerebral palsy in term deliveries in a Turkish population. J Matern Fetal Neonatal Med, 19: 147–155.


  1. Stelmach T, Pisarev H, Talvik T, 2005, Ante-and perinatal factors for cerebral palsy: Case-control study in Estonia. J Child Neurol, 20: 654–661.


  1. Sandoval Karamian, AG, Mercimek-Andrews S, Mohammad K, et al., 2021, Neonatal encephalopathy: Etiologies other than hypoxic-ischemic encephalopathy. Semin Fetal Neonatal Med, 26: 101272.


  1. Russ JB, Simmons R, Glass HC, 2021, Neonatal encephalopathy: Beyond hypoxic-ischemic encephalopathy. Neoreviews, 22: e148–e162.


  1. Sadowska M, Sarecka-Hujar B, Kopyta I, 2020, Cerebral palsy: Current opinions on definition, epidemiology, risk factors, classification and treatment options. Neuropsychiatr Dis Treat, 16: 1505–1518.


  1. Johnson A, Surveillance of Cerebral Palsy in Europe (SCPE), 2007, Prevalence and characteristics of children with cerebral palsy in Europe. Dev Med Child Neurol, 44: 633– 640.


  1. Himpens E, Van Den Broeck C, Oostra A, et al., 2008, Prevalence, type, distribution, and severity of cerebral palsy in relation to gestational age: A meta-analytic review. Dev Med Child Neurol, 50: 334–340.


  1. Novak I, Morgan C, Adde L, et al., 2017, Early, accurate diagnosis and early intervention in cerebral palsy: Advances in diagnosis and treatment. JAMA Pediatr, 171: 897–907.


  1. Al Mamun A, Yu H, Romana S, et al., 2018, Inflammatory responses are sex specific in chronic hypoxic-ischemic encephalopathy. Cell Transplant, 27: 1328–1339.


  1. Murden S, Borbélyová V, Laštůvka Z, et al., 2019, Gender differences involved in the pathophysiology of the perinatal hypoxic-ischemic damage. Physiol Res, 68: S207–S217.


  1. Rees P, Callan C, Chadda KR, et al., 2022, Preterm brain injury and neurodevelopmental outcomes: A meta-analysis. Pediatrics, 150: e2022057442.


  1. Andersen G, Mjøen TR, Vik T, 2010, Prevalence of speech problems and the use of augmentative and alternative communication in children with cerebral palsy: A registry-based study in Norway. Perspect Augment Altern Commun, 19: 12–20.


  1. Himmelmann K, Lindh K, Hidecker MJ, 2013, Communication ability in cerebral palsy: A study from the CP register of Western Sweden. Eur J Paediatr Neurol, 17: 568–574.


  1. Smith AL, Hustad KC, 2015, AAC and early intervention for children with cerebral palsy: Parent perceptions and child risk factors. Augment Altern Commun, 31: 336–350.


  1. Mei C, Fern B, Reilly S, et al., 2020, Communication behaviours of children with cerebral palsy who are minimally verbal. Child Care Health Dev, 46: 617–626.


  1. Arvedson JC, 2013, Feeding children with cerebral palsy and swallowing difficulties. Eur J Clin Nutr, 67: S9–S12.


  1. Morgan AT, Dodrill P, Ward EC, 2012, Interventions for oropharyngeal dysphagia in children with neurological impairment. Cochrane Database Syst Rev, 10: CD009456.


  1. Rogers B, 2004, Feeding method and health outcomes of children with cerebral palsy. J Pediatr, 145: S28–S32.


  1. Snider L, Majnemer A, Darsaklis V, 2011, Feeding interventions for children with cerebral palsy: A review of the evidence. Phys Occup Ther Pediatr, 31: 58–77.


  1. Stadskleiv K, 2020, Cognitive functioning in children with cerebral palsy. Dev Med Child Neurol, 62: 283–289.


  1. Novak I, McIntyre S, Morgan C, et al., 2013, A systematic review of interventions for children with cerebral palsy: State of the evidence. Dev Med Child Neurol, 55: 885–910.


  1. Jenks KM, de Moor J, van Lieshout EC, et al., 2007, The effect of cerebral palsy on arithmetic accuracy is mediated by working memory, intelligence, early numeracy, and instruction time. Dev Neuropsychol, 32: 861–879.


  1. Jenks KM, van Lieshout EC, de Moor JM, 2012, Cognitive correlates of mathematical achievement in children with cerebral palsy and typically developing children. Br J Educ Psychol, 82: 120–135.


  1. Wahyuni LK, 2023, Multisystem compensations and consequences in spastic quadriplegic cerebral palsy children. Front Neurol, 13: 1076316.


  1. Edwards AD, Brocklehurst P, Gunn AJ, et al., 2010, Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ, 340: c363.


  1. Drury PP, Gunn ER, Bennet L, et al., 2014, Mechanisms of hypothermic neuroprotection. Clin Perinatol, 41: 161–175.


  1. McLaren J, Holmes GL, Berg MT, 2019, Functional connectivity in term neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia. Pediatr Neurol, 94: 74–79.


  1. Shepherd E, Salam RA, Middleton P, et al., 2018, Neonatal interventions for preventing cerebral palsy: An overview of cochrane systematic reviews. Cochrane Database Syst Rev, 3: 7–15.


  1. Zhou WH, Cheng GQ, Shao XM, et al., 2010, Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: A multicenter randomized controlled trial in China. J Pediatr, 157: 367–372.e3.


  1. Simbruner G, Mittal RA, Rohlmann F, et al., 2010, Systemic hypothermia after neonatal encephalopathy: Outcomes of RCT. Pediatrics, 126: e771–e778.


  1. Shankaran S, Pappas A, McDonald SA, et al., 2012, Childhood outcomes after hypothermia for neonatal encephalopathy. Obstet Gynecol Surv, 67: 617–619.


  1. Ovcjak A, Pontello R, Miller SP, et al., 2023, Hypothermia combined with neuroprotective adjuvants shortens the duration of hospitalization in infants with hypoxic ischemic encephalopathy: Meta-analysis. Front Pharmacol, 13: 1037131.
Conflict of interest
The authors declare that they have no competing interests.
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Advanced Neurology, Electronic ISSN: 2810-9619 Published by AccScience Publishing