Impact of peri-intraventricular haemorrhage and periventricular leukomalacia in the neurodevelopment of preterms: A systematic review and meta-analysis

Autoři: Juliana Wendling Gotardo aff001;  Nathalia de Freitas Valle Volkmer aff002;  Guilherme Pucci Stangler aff003;  Alícia Dorneles Dornelles aff002;  Betânia Barreto de Athayde Bohrer aff002;  Clarissa Gutierrez Carvalho aff002
Působiště autorů: Department of Pediatrics, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil aff001;  Faculty of Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil aff002;  Department of Radiology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223427



Whether all degrees of periventricular leukomalacia (PVL) and peri-intraventricular haemorrhage (PIVH) have a negative impact on neurodevelopment.


To determine the impact of PVL and PIVH in the incidence of cerebral palsy, sensorineural impairment and development scores in preterm neonates. Registered in PROSPERO (CRD42017073113).

Data sources

PubMed, Embase, SciELO, LILACS, and Cochrane databases.

Study selection

Prospective cohort studies evaluating neurodevelopment in children born preterm which performed brain imaging in the neonatal period.

Data extraction

Two independent researchers extracted data using a predesigned data extraction sheet.

Statistical methods

A random-effects model was used, with Mantel-Haenszel approach and a Sidik-Jonkman method for the estimation of variances, combined with Hartung-Knapp-Sidik-Jonkman correction. Heterogeneity was assessed through the I2 statistic and sensitivity analysis were performed when possible. No funnel plots were generated but publication bias was discussed as a possible limitation.


Our analysis concluded premature children with any degree of PIVH are at increased risk for cerebral palsy (CP) when compared to children with no PIVH (3.4, 95% CI 1.60–7.22; 9 studies), a finding that persisted on subgroup analysis for studies with mean birth weight of less than 1000 grams. Similarly, PVL was associated with CP, both in its cystic (19.12, 95% CI 4.57–79.90; 2 studies) and non-cystic form (9.27, 95% CI 5.93–14.50; 2 studies). We also found children with cystic PVL may be at risk for visual and hearing impairment compared to normal children, but evidence is weak.


Major limitations were the lack of data for PVL in general, especially for the outcome of neurodevelopment, the high heterogeneity among methods used to assess neurodevelopment and the small number of studies, which led to meta-analysis with high heterogeneity and wide confidence intervals.


There was no evidence supporting the hypothesis that PIVH causes impairment in neuropsychomotor development in our meta-analysis, but review of newer studies show an increased risk for lower intelligence scores in children with severe lesions, both PIVH and PVL. There is evidence to support the hypothesis that children with any degree of PIVH, especially those born below 1000 grams and those with severe haemorrhage, are at increased risk of developing CP, as well as children with PVL, both cystic and non-cystic.

Klíčová slova:

Deafness – Hemorrhage – Infants – Metaanalysis – Neurodevelopment – Systematic reviews – Visual impairments – Cerebral palsy


1. Purisch SE, Gyamfi-Bannerman C. Epidemiology of preterm birth. Semin Perinatol. 2017;41(7):387–391. doi: 10.1053/j.semperi.2017.07.009 28865982

2. Victora CG, Aquino EML, Leal MC, Monteiro CA, Barros FC, Szwarcwald CL. Maternal and child health in Brazil: progress and challenges. Lancet 2011; 377:1863–1876. doi: 10.1016/S0140-6736(11)60138-4 21561656

3. Theme-Filha MM, Baldisserotto ML, Fraga ACSA, Ayers S, Gama SGN, Leal MC. Factors associated with unintended pregnancy in Brazil: cross-sectional results from the Birth in Brazil National Survey, 2011/2012. Reprod Health. 2016;13:118. doi: 10.1186/s12978-016-0227-8 27766945

4. NVSS: Vital Statistics rapid release. Births: Provisional data for 2017. Accessed September 2, 2018.

5. Chevallier M, Debillon T, Pierrat V, Delorme P, Kayem G, Durox M, et al. Leading causes of preterm delivery as risk factors for intraventricular hemorrhage in very preterm infants: results of the EPIPAGE 2 cohort study. Am J Obstet Gynecol. 2017;216(5):518.e1–518.e12.

6. Romero-Guzman GJ, Lopez-Munoz F. Prevalence and risk factor for periventricular leukomalacia in preterm infants. A systematic review. Rev Neurol. 2017;65(2):57–62. 28675256

7. Mukerji A, Shah V, Shah PS. Periventricular/Intraventricular Hemorrhage and Neurodevelopmental Outcomes: a Meta-Analysis. Pediatrics 2015;136(6):1132–1143. doi: 10.1542/peds.2015-0944 26598455

8. Hielkema T, Hadders-Algra M. Motor and cognitive outcome after specific early lesions of the brain: a systematic review. Dev Med Child Neurol. 2016;58(4):46–52.

9. Linsell L, Malouf R, Morris J, Kurinczuk JJ, Marlow N. Prognostic factors for cerebral palsy and motor impairment in children born very preterm or very low birthweight: a systematic review. Dev Med Child Neurol. 2016;58(6):554–569. doi: 10.1111/dmcn.12972 26862030

10. Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Medi 2009;6:e1000097.

11. Cheng J, Pullenayegum E, Marshall JK, Iorio A, Thabane L. Impact of including or excluding both-armed zero-event studies on using standard meta-analysis methods for rare event outcome: a simulation study. BMJOpen 2016; 6:e010983. doi: 10.1136/bmjopen-2015-010983 27531725

12. Catto-Smith AG, Yu VYH, Bajuk B, Orgill AA, Astbury J. Effect of neonatal periventricular haemorrhage on neurodevelopmental outcome. Arch Dis Child. 1985;60:8–11. doi: 10.1136/adc.60.1.8 2578773

13. Ment LR, Scott DT, Ehrenkranz RA, Duncan CC. Neurodevelopmental assessment of very low birth weight neonates: Effect of germinal matrix and intraventricular hemorrhage. Pediatr Neurol. 1985;1:164–168. doi: 10.1016/0887-8994(85)90058-x 3880401

14. Szymonowick W, Yu VYH, Bajuk B, Astbury J. Neurodevelopmental outcome of periventricular haemorrhage and leukomalacia in infants 1250 g or less at birth. Early Hum Dev. 1986;14:1–7. doi: 10.1016/0378-3782(86)90164-7 3525094

15. Graham M, Levene MI, Trounce JQ, Rutter N. Prediction of cerebral palsy in very low birthweight infants: prospective ultrasound study. Lancet 1987;2:593–596. doi: 10.1016/s0140-6736(87)92986-2 2887887

16. Salomon WL, Benitz WE, Enzmann DR, Bravo RH, Murphy-Irwin K, Stevenson DK. Correlation of echoencephalographic findings and neurodevelopmental outcome: intracranial hemorrhage and ventriculomegaly in infants of birth weight 1,000 grams or less. J Clin Monit. 1987;3:178–186. 3612216

17. Nwaesei CG, Allen AC, Vincer MJ, Brown SJ, Stinson DA, Evans JR, et al. Effect of timing of cerebral ultrasonography on the prediction of later neurodevelopmental outcome in high-risk preterm infants. J Pediatr. 1988;112:970–975. doi: 10.1016/s0022-3476(88)80228-2 3286856

18. Bennett FC, Silver G, Leung EJ, Mack LA. Periventricular echodensities detected by cranial ultrasonography: usefulness in predicting neurodevelopmental outcome in low-birth-weight, preterm infants. Pediatrics 1990;85:400–404. 2406694

19. Beverley DW, Smith IS, Beesley P, Jones J, Rhodes N. Relationship of cranial ultrasonography, visual and auditory evoked responses with neurodevelopmental outcome. Dev Med Child Neurol. 1990;32:210–222. doi: 10.1111/j.1469-8749.1990.tb16927.x 2179002

20. Van de Bor M, Den Ouden L, Guit GL. Value of cranial ultrasound and magnetic resonance imaging in predicting neurodevelopmental outcome in preterm infants. Pediatrics 1992; 90:196–199. 1641282

21. Fazzi E, Lanzi G, Gerardo A, Ometto A, Orcesi S, Rondini G. Neurodevelopmental outcome in very-low-birth-weight infants with or without periventricular haemorrhage and/or leucomalacia. Acta Paediatr. 1992;81:808–811. doi: 10.1111/j.1651-2227.1992.tb12108.x 1384827

22. Ikonen RS, Janas MO, Koivikko MJ, Laippala P, Kuusinen EJ. Hyperbilirubinemia, hypocarbia and periventricular leukomalacia in preterm infants: relationship to cerebral palsy. Acta Paediatr. 1992;81:802–807. doi: 10.1111/j.1651-2227.1992.tb12107.x 1421887

23. Van de Bor M, Ens-Dokkum M, Schreuder AM, Veen S, Brand R, Verloove-Vanhorick SP. Outcome of periventricular-intraventricular haemorrhage at five years of age. Dev Med Child Neurol. 1993;35:33–41. 7680633

24. Roth SC, Baudin J, McCormick DC, Edwards AD, Townsend J, Stewart AL, et al. Relation between ultrasound appearance of the brain of very preterm infants and neurodevelopmental impairment at eight years. Dev Med Child Neurol. 1993;35:755–768. doi: 10.1111/j.1469-8749.1993.tb11727.x 7689065

25. Aziz K, Vickar DB, Sauve RS, Etches PC, Pain KS, Robertson CMT. Province-based study of neurologic disability of children weighing 500 through 1249 grams at birth in relation to neonatal cerebral ultrasound findings. Pediatrics 1995;95:837–844. 7761206

26. Fawer CL, Besnier S, Forcada M, Buclin T, Calame A. Influence of perinatal, developmental and environmental factors on cognitive abilities of preterm children without major impairments at 5 years. Early Hum Dev. 1995;43:151–164. doi: 10.1016/0378-3782(95)01673-2 8903760

27. Vohr B, Allan WC, Scott DT, Katz KH, Schneider KC, Makuch RW, et al. Early-onset intraventricular hemorrhage in preterm neonates: Incidence of neurodevelopmental handicap. Semin Perinatol. 1999;23:212–217. 10405190

28. Sherlock RL, Anderson PJ, Doyle LW. Neurodevelopmental sequelae of intraventricular haemorrhage at 8 years of age in a regional cohort of ELBW/very preterm infants. Early Hum Dev. 2005;81:909–916. doi: 10.1016/j.earlhumdev.2005.07.007 16126353

29. Dyet LE, Kennea N, Counsell SJ, Maalouf EF, Ajayi-Obe M, Duggan PJ, et al. Natural history of brain lesions in extremely preterm infants studied with serial magnetic resonance imaging from birth and neurodevelopmental assessment. Pediatrics 2006;118:536–548. doi: 10.1542/peds.2005-1866 16882805

30. Vollmer B, Roth S, Riley K, Sellwood MW, Baudin J, Neville BG, et al. Neurodevelopmental outcome of preterm infants with ventricular dilatation with and without associated haemorrhage. Dev Med Child Neurol. 2006;48:348–352. doi: 10.1017/S0012162206000764 16608542

31. Locatelli A, Andreani M, Pizzardi A, Paterlini G, Stoppa P, Ghidini A. Antenatal variables associated with severe adverse neurodevelopmental outcome among neonates born at less than 32 weeks. Eur J Obstet Gynecol Reprod Biol. 2010;152:143–147. doi: 10.1016/j.ejogrb.2010.05.027 20579800

32. Van Wezel-Meijler G, de Brüine F, Steggerda SJ, Van den Ber-Huysmans A, Zeilemaker S, Leijser JM, et al. Ultrasound detection of white matter injury in very preterm neonates: practical implications. Dev Med Child Neurol. 2011;53:29–34.

33. Klebermass- Schrehof K, Czaba C, Olischar M, Fuiko R, Waldhoer T, Rona Z, et al. Impact of low-grade intraventricular hemorrhage on long-term neurodevelopmental outcome in preterm infants. Childs Nerv Syst. 2012;28:2085–2092. doi: 10.1007/s00381-012-1897-3 22914924

34. Payne AH, Hintz SR, Hibbs AM, Walsh MC, Vohr BR, Bann CM, et al. Neurodevelopmental outcomes of extremely low-gestational-age neonates with low-grade periventricular-intraventricular hemorrhage. JAMA Pediatrics 2013;167:451–459. doi: 10.1001/jamapediatrics.2013.866 23460139

35. Hintz SR, Vohr BR, Bann CM, Taylor HG, Das A, Gustafson KE, et al. Preterm neuroimaging and school-age cognitive outcomes. Pediatrics 2018;142:e20174058. doi: 10.1542/peds.2017-4058 29945955

36. Tsai AJ, Lasky RE, John SD, Kennedy KA. Predictors of neurodevelopmental outcomes in preterm infants with intraparenchymal hemorrhage. J Perinatol. 2014;34:399–404. doi: 10.1038/jp.2014.21 24556980

37. Resic B, Tomasovic M, Kuzmanic-Samija R, Losic M, Resic J, Solak M. Neurodevelopmental outcome in children with periventricular leukomalacia. Coll. Antropol. 2008;32:143–147.

38. Pidcock FS, Graziani LJ, Stanley C, Mitchell DG, Merton D. Neurosonographic features of periventricular echodensities associated with cerebral palsy in preterm infants. J Pediatr. 1990;116:417–422. doi: 10.1016/s0022-3476(05)82836-7 2407818

39. Ringelberg J, van de Bor M. Outcome of transient periventricular echodensities in preterm infants. Neuropediatrics 1993;24:269–273. doi: 10.1055/s-2008-1071555 8309516

40. Karagianni P, Rallis D, Kyriakidou M, Tsakalidis C, Paraskevi P, Nicolaidis N. Correlation of brain ultrasonography scans to the neuromotor outcome of very-low-birth-weight infants during the first year of life. J Child Neurol. 2013;00(0) 1–7.

41. Brüine FT, van den Berg-Huysmans AA, Leijser LM, Rijken M, Steggerda SJ, van der Grond J, et al. Clinical implications of MR findings in the white matter in very preterm infants. Radiology 2011;261:899–906. doi: 10.1148/radiol.11110797 22031710

42. Nanba Y, Matsui K, Aida N, Sato Y, Toyoshima K, Kawataki M, et al. Magnetic resonance imaging regional T1 abnormalities at term accurately predict motor outcome in preterm infants. Pediatrics 2007;120:e10–e19. doi: 10.1542/peds.2006-1844 17606537

43. Valkama AM, Pääkkö ELE, Vainionpää LK, Lanning FP, Ilkko EA, Koivisto ME. Magnetic resonance imaging at term and neuromotor outcome in preterm infants. Acta Paediatr. 2000;89:348–355. 10772285

44. van’t Hooft J, van der Lee JH, Opmeer BC, Aarnoudse-Moens CS, Leenders AG, Mol BW, et al. Predicting developmental outcomes in premature infants by term equivalent MRI: a systematic review and meta-analysis. BioMed Central 2015;4:71.

45. Patsopoulos NA, Ioannidis JPA. The use of older studies in meta-analysis of interventions: a survey. Open Med 2009;3(2):e62–e68. 19946395

46. Higgins J, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions. Available at: Accessed July 3,2014.

Článek vyšel v časopise


2019 Číslo 10

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Zvyšte si kvalifikaci online z pohodlí domova

Léčba bolesti v ordinaci praktického lékaře
nový kurz
Autoři: MUDr. PhDr. Zdeňka Nováková, Ph.D.

Revmatoidní artritida: včas a k cíli
Autoři: MUDr. Heřman Mann

Jistoty a nástrahy antikoagulační léčby aneb kardiolog - neurolog - farmakolog - nefrolog - právník diskutují
Autoři: doc. MUDr. Štěpán Havránek, Ph.D., prof. MUDr. Roman Herzig, Ph.D., doc. MUDr. Karel Urbánek, Ph.D., prim. MUDr. Jan Vachek, MUDr. et Mgr. Jolana Těšínová, Ph.D.

Léčba akutní pooperační bolesti
Autoři: doc. MUDr. Jiří Málek, CSc.

Nové antipsychotikum kariprazin v léčbě schizofrenie
Autoři: prof. MUDr. Cyril Höschl, DrSc., FRCPsych.

Všechny kurzy
Kurzy Doporučená témata Časopisy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se