Periventricular/IntraventricularHemorrhage and NeurodevelopmentalOutcomes: A Meta-analysisAmit Mukerji, MDa, Vibhuti Shah, MDb, Prakesh S. Shah, MDb

abstract CONTEXT:Periventricular/intraventricular hemorrhage (PIVH) is a common short-term morbidityin preterm infants, but its long-term neurodevelopmental impact, particularly with mild PIVH,remains unclear.

OBJECTIVE: To systematically review and meta-analyze the neurodevelopmental outcomes ofpreterm infants #34 weeks’ gestation with mild and severe PIVH, compared with no PIVH.

DATA SOURCES: Medline, Embase, CINAHL, and PsychINFO databases from January 2000 throughJune 2014.

STUDY SELECTION: Studies reporting long-term neurodevelopmental outcomes based on severity ofPIVH were included.

DATA EXTRACTION: Study characteristics, inclusion/exclusion criteria, exposures, and outcomeassessment data extracted independently by 2 coauthors.

RESULTS: The pooled unadjusted odds ratios of the primary outcome of death or moderate-severeneurodevelopmental impairment (NDI) were higher with both mild (1.48, 95% CI 1.26–1.73; 2studies) and severe PIVH (4.72, 4.21–5.31; 3 studies); no studies reported adjusted odds ratios.Among survivors, odds of moderate-severe NDI were higher with mild and severe PIVH in bothunadjusted (1.75, 1.40–2.20; 3 studies; 3.36, 3.06–3.68; 5 studies) and adjusted (1.39, 1.09–1.77;3 studies; 2.44, 1.73–3.42; 2 studies) pooled analyses. Adjusted odds of cerebral palsy andcognitive delay were higher with severe but not mild PIVH.

LIMITATIONS: Only observational studies were included. Fifteen of 21 included studies had amoderate-high risk of bias.

CONCLUSIONS:Mild and severe PIVH are associatedwith progressively higher odds of death or moderate-severe NDI compared with no PIVH, but no studies adjusted for confounders. Among survivors, mildPIVH was associated with higher odds of moderate-severe NDI compared with no PIVH.

aDepartment of Paediatrics, McMaster Children’s Hospital, McMaster University, Hamilton, Canada; and bDepartment of Paediatrics, Mount Sinai Hospital, University of Toronto, Toronto, Canada

Dr Mukerji conceptualized and designed the study, conducted the literature search, performed the initial screening of articles, performed initial analyses, and draftedthe manuscript; Dr V Shah screened shortlisted articles to ensure no missing articles for selection, verified the risk of biases for included studies, double-checked allnumbers included in meta-analyses and results, and helped revise the manuscript; Dr PS Shah provided statistical supervision, design and methodology supervision,oversaw the analyses, and critically reviewed the manuscript; and all authors approved the final version.

This trial has been registered at PROSPERO (International Database of Prospectively Registered Systematic Reviews; registration number CRD42015017105).

www.pediatrics.org/cgi/doi/10.1542/peds.2015-0944

DOI: 10.1542/peds.2015-0944

Accepted for publication Sep 23, 2015

Address correspondence to Amit Mukerji, MD, 1280 Main St West, Room 4F-1E, Hamilton, Ontario, Canada, L8S 4K1. E-mail: mukerji@mcmaster.ca

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2015 by the American Academy of Pediatrics

REVIEW ARTICLE PEDIATRICS Volume 136, number 6, December 2015 by guest on September 9, 2020www.aappublications.org/newsDownloaded from

Periventricular/intraventricularhemorrhage (PIVH) is a frequentcomplication of prematurity, resultingin brain injury. Its incidence hasdeclined since the 1980s, but becauseof improvements in neonatal careresulting in increased survival ofextremely preterm infants, theabsolute number of cases remainshigh.1,2 It occurs in 25% to 30% of allvery low birth weight preterm infants,1500 g,3 and the reported incidencein extremely low birth weight infants,1000 g is as high as 45%.4,5

In preterm infants, PIVH results frombleeding in the germinal matrix, ahighly cellular and vascularized layerlocated between the caudate nucleusand the thalamus at the level of theforamen of Monro, from whereneurons and glial cells arise duringfetal development.6 The germinalmatrix starts to involute by 28 weeksand is generally absent in terminfants.7 Extreme friability ofcapillaries in the germinal matrixcombined with their inability toautoregulate cerebral blood flowmakes preterm infants susceptible toPIVH.8

Severity of PIVH is commonlydescribed according to the modifiedPapile classification6,9 as follows:grade 1 PIVH refers to bleedingconfined to the germinal matrix;grade 2 denotes PIVH occupying#50% of the lateral ventricle volume;grade 3 PIVH occupies .50% oflateral ventricle volume, usuallyleading to distension and dilatation ofventricles; and grade 4 PIVH indicatespresence of an infarction and/orhemorrhage in the periventricularwhite matter ipsilateral to a largePIVH. Even though the classificationwas based on computed tomographyimages, cranial ultrasonography(CUS) is most commonly used in theclinical setting to report PIVH.Despite suggestions in recent years toreplace this classification system witha more precise and descriptivenomenclature,10,11 the Papile criteriaremains widely used12 in clinical

settings, and decisions regardingmanagement and counseling aremostly based on these findings.

Because of the nature of the injury,prognostication of long-termneurodevelopmental outcomes inpreterm infants with PIVH has beenan active area of research. Low-grade(mild) PIVH, consisting of grades 1and 2, were previously believed notto increase the risk ofneurodevelopmental impairment(NDI) beyond the risk associated withprematurity alone.13 However, somerecent studies have challenged thisnotion,14,15 whereas others16

continue to support the benign natureof mild PIVH. On the other hand,severe grades of PIVH (grade 3 and 4)are well known to be associated withNDI, but there are significantvariations in the reportedoutcomes,17–20 which may lead tovariability in counseling of long-termoutcomes between practitioners.None of the previous reviews havesystematically summarizedneurodevelopmental outcomes ofdifferent grades of PIVH afteradjusting for confounders and effectmodifiers.13 Because of thewidespread use of this system, thereis a need for a systematic review ofthis literature with a meta-analysisthat will aid neonatologists whenproviding counseling to parents ofpreterm infants with PIVH.

METHODS

This meta-analysis was conductedand reported as per the guidelinesfrom PRISMA (Preferred ReportingItems for Systematic Reviews andMeta-Analyses).21 The protocol forthe review was registered withPROSPERO (registration numberCRD42015017105), the internationalprospective register for systematicreviews (http://www.crd.york.ac.uk/NIHR_PROSPERO).

Types of Studies

Observational studies includingcohort and case-control studies were

included if published in peer-reviewed journals and published after2000. Studies that followed a cohortof patients enrolled in a previouslyconducted randomized controlledtrial were deemed eligible forinclusion. Only those studies thatreported on long-term outcomesbased on PIVH severity and did nothave a prespecified primary predictorother than PIVH were considered forinclusion. Narrative reviews, letters/editorials, case reports, cross-sectional studies, case series, anddissertations were excluded.

Types of Participants

Studies reporting on long-termoutcomes in preterm infants (,34weeks’ completed gestational age[GA]) were included. Studies thatincluded a mix of preterm and late-preterm infants (34–36 weeks’completed GA) or preterm and terminfants ($37 weeks’ completed GA)were excluded.

Exposure and Comparison

To be considered eligible forinclusion, studies must have reported(or provided adequate information togenerate) childhoodneurodevelopmental outcome dataadequate for at least 1 of thefollowing comparison groups:

• Comparison 1: mild PIVH versus noPIVH

• Comparison 2: severe PIVH versusno PIVH

• Comparison 3: severe PIVH versusmild PIVH

Specifically, studies that did notdistinguish between mild and severePIVH were excluded. Furthermore,studies that reported outcome ofsevere PIVH versus a combination ofno PIVH and nonsevere PIVH wereexcluded. The highest grade of PIVHreported (on either left or right side)for an individual patient was used forclassification purposes.

The determination of mild and severePIVH was based on the aforementioned

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modified Papile criteria.9 As such, onlystudies that classified PIVH basedon the modified Papile criteria (orprovided adequate information to doso) were included. Mild PIVH consistedof grade 1 and/or 2 PIVH, whereassevere PIVH consisted of grade 3and/or grade 4 PIVH. Presence ofadditional CUS anomalies such asintraparenchymal echodensity/echolucency, porencephalic cysts,and/or periventricular leukomalaciawere not a cause for exclusion butwere noted.

Outcomes

Studies were included if theyprovided outcome data for $1 of thefollowing aforementionedcomparison groups.

Primary Outcome

1. Composite of death or moderate-severe NDI at 18 to 24 months.

Moderate-severe NDI was defined as$1 of moderate to severe cerebralpalsy (CP; as determined by using theGross Motor Functional ClassificationScale22 for CP or a comparable,validated assessment tool); moderateto severe cognitive delay (assessedper the Bayley Scales of InfantDevelopment [second or thirdedition]23,24 Mental DevelopmentalIndex or a comparable validatedscale); severe visual impairment,defined as visual acuity ,6/60(metric scale) in the better eye; orsevere hearing impairment, definedas requirement of unilateral/bilateralhearing aids or cochlear implants.

Secondary Outcomes

2. Death before 18- to 24-month fol-low-up.

3. Moderate to severe NDI at 18 to24 months, as defined above.

4. CP, as defined above.

5. Cognitive impairment, as definedabove.

6. Neurodevelopmental outcomes at3 to 18 years, as assessed by astandardized, validated tool.

Planned sensitivity analyses includedstudies with and without .30% lossto follow-up and meta-analysis ofprimary outcome with and withoutstudies with a high risk of bias.Planned subgroup analyses for theprimary outcome included analyses ofGA #28 weeks and .28 weeks, as

well as infants ,1000 g and 1000 to1500 g at birth.

Review Methods

Search Strategy

The search strategy was designed inconjunction with an informationspecialist at Mount Sinai Hospital,

FIGURE 1Study selection log of systematic review by using 4 databases (Embase, Medline, PsychINFO, andCINAHL).

TABLE 1 Risk of Bias for Included Studies as per Modified Newcastle-Ottawa Scale

Authors, Year Selection(Total 4)

Comparability(Total 2)

Outcome(Total 3)

Overall Score(Total 9)

Riskof Bias

Adams-Chapman, 2008 4 2 2 8 LowAmbalavanan, 2000 3 2 2 7 ModerateAncel, 2006 4 0 2 6 ModerateBeaino, 2010 4 2 2 8 LowBolisetty, 2014 4 2 2 8 LowBroitman, 2007 4 0 2 6 ModerateDoyle, 2000 3 0 3 6 ModerateGoldstein, 2013 4 1 3 8 LowHoekstra, 2004 3 0 2 5 HighKeichl-Kohlendorfer, 2013 4 0 2 6 ModerateKlebermass-Schrehof, 2012 3 0 1 4 HighMerhar, 2012 4 1 2 7 ModerateNeubauer, 2008 3 2 2 7 ModerateO’Keefe, 2001 3 0 1 4 HighPatra, 2006 4 1 2 7 ModeratePayne, 2014 4 2 2 8 LowSchmidhauser, 2006 4 2 3 9 LowSherlock, 2005 3 0 3 6 ModerateVan de Bor, 2004 3 0 3 6 ModerateVollmer, 2003 3 0 3 6 ModerateVollmer, 2006 3 0 3 6 Moderate

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University of Toronto. The followingdatabases were searched (in English):Embase, Medline, CINAHL, andPsychINFO (all from January 1, 2000through June 9, 2014). The details ofsearch terms used are available inSupplemental Information 1.

Data Extraction

One author (A.M.) conducted theliterature search in conjunction withreference librarians at Mount SinaiHospital, University of Toronto. Afteramalgamation of results from the 4databases, titles and abstracts wereused to screen studies by A.M. Of theremaining studies, a standardizedscreening form was used by 2 authors(A.M. and V.S.) to identify eligiblestudies based on aforementionedcriteria. In addition, studies identifiedfrom references were similarlyscreened and assessed for eligibility.Any discrepancies were resolved byinvolving the third author (P.S.). Data

extraction for included studiesregarding study design, patientcharacteristics, inclusion andexclusion criteria, exposures andcomparisons, and outcomeassessments were performed by A.M.and double checked by V.S.

Assessment of Risk of Bias

The risk of bias for each includedstudy was assessed by using amodified Newcastle-Ottawa Scale25

and the following domains wereevaluated: selection, comparability,and outcome. A priori, a score of 8 or9 of 9 was deemed low risk; 6 or 7 of9, moderate risk; and #5 of 9, highrisk of bias. Of all included studies inthe systematic review, only thosewith low or moderate risk of biaswere deemed eligible for inclusion inmeta-analyses. Studies with a highrisk of bias would be eligible forresults but not meta-analysis. Inaddition, follow-up loss of .30%,

regardless of score on modifiedNewcastle-Ottawa Scale, wasconsidered a high risk of bias.Assessment of risk of bias wasperformed by 2 authors (A.M., V.S.),independently and any conflictswere resolved with involvement ofthe third author (P.S.).

Data Synthesis and Statistical Analysis

Studies deemed not comparable dueto clinical or methodologicalheterogeneity as assessed by theauthors were not considered eligiblefor meta-analysis. Unadjusted andadjusted data from studies eligiblefor meta-analysis were combinedusing a fixed effects model for allcomparisons of interest. Unadjustedand adjusted odds ratios (ORs) werecalculated, reflecting the ratio ofodds of the outcome of interestbetween comparison groups. Allanalyses were performed usingReview Manager 5.2 (Cochrane

FIGURE 2Unadjusted pooled ORs for the primary outcome of death or moderate-severe NDI for all 3 comparisons.

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Collaboration, Nordic CochraneCentre, Copenhagen, Denmark).26

Heterogeneity and Publication BiasAssessment

Variability in the study design,participants, exposures, outcomesassessed, and biases were evaluatedqualitatively to determine clinical andmethodological heterogeneity and toassess the appropriateness of poolingstudies together by 2 authors (A.M. andV.S.) independently, and discrepancieswere resolved by involving the thirdauthor (P.S.). Furthermore, Forrestplots were assessed for heterogeneity.Statistical heterogeneity wasdetermined for studies groupedtogether using I2 values (derived fromthe x2 Q statistic). It was determined apriori that if any comparison for anyoutcome were to have .10 studieseligible for pooled analysis, a funnel

plot was to be generated to assess forpublication bias.

RESULTS

Description of Studies

The results of the search, the studyselection log, and the number ofstudies are as shown in Fig 1. Of the3347 studies resulting from thedatabase searches, 85 full-text studieswere evaluated for eligibility, andauthors were contacted wherenecessary to provide clarification ormissing data. This process resulted in20 studies deemed eligible forinclusion.14–16,19,27–42 Additionally, 1study43 was identified and deemedeligible through searching referencesof included studies, bringing the finaltotal to 21. Baseline characteristics ofthe 21 included studies are as shownin Supplemental Information 2.

References for all excluded studies,including causes for exclusion, areavailable in SupplementalInformation 3.

Risk of Bias Among Included Studies

The risk of bias, as determined by themodified Newcastle-Ottawa Scale forincluded studies, is as shown inTable 1. Eighteen studies had a low ormoderate risk of bias, and 3 studieswith a high risk of bias all lost pointson the comparability subscale due tothe lack of any adjusted analyses.None of the included studies had aloss to follow-up of .30% among theknown survivors at time of discharge.

Primary Outcome: Death orModerate to Severe NDI at 18 to 24Months

There were 3 studies that provideddata on the primary outcome for at

FIGURE 3A, Unadjusted pooled ORs for moderate-severe NDI among survivors for all 3 comparisons. B, Adjusted pooled ORs for moderate-severe NDI amongsurvivors for all 3 comparisons.

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least 1 of the 3 comparisons.15,29,30

The results from the unadjustedmeta-analyses for the 3 comparisonsare shown in Fig 2. Mild PIVH (2studies, 3508 subjects, unadjusted OR1.48, 95% confidence interval [CI]1.26–1.73, I2 = 79%) and severe PIVH(3 studies, 8830 subjects, unadjustedOR 4.72, 95% CI 4.21–5.31, I2 = 97%)were both associated with higher oddsof death or moderate-severe NDIcompared with no PIVH. Severe PIVHwas associated with a higher odds ofdeath or moderate-severe NDI at 18 to24 months (2 studies, 1584 subjects,unadjusted OR 3.35, 95% CI2.69–4.16, I2 = 97%) compared withmild PIVH. None of the studiesprovided adjusted analyses for deathor moderate NDI. In all 3 studies,mortality rates were provided by PIVHseverity, and adjusted outcomeanalyses were only performed amongthose known to have survived at leastuntil discharge. Furthermore, allstudies included infants #28 weeks’GA and/or a birth weight #1000 g,

and thus subgroup and sensitivityanalyses planned a priori could not beperformed. All studies had a low ormoderate risk of bias.

Secondary Outcome: Moderate toSevere NDI at 18 to 24 Months

Seven studies reported unadjustedand adjusted ORs for at least 1 of the3 comparison groups.14–16,27,30,31,43

The results from the unadjustedmeta-analyses are shown in Fig 3A,and the adjusted meta-analyses are asdepicted in Fig 3B. Mild PIVH wasassociated with higher odds ofmoderate-severe NDI compared withno PIVH among those who survived todischarge (3 studies, 3032 subjects,unadjusted OR 1.75, 95% CI 1.40–2.20,I2 = 76%%; adjusted OR 1.39, 95% CI1.09–1.77, I2 = 70%). Severe PIVH wasalso associated with higher odds of theoutcome compared with no PIVH (5studies, 13 691 subjects, unadjusted OR3.36, 95% CI 3.06–3.68, I2 = 39%; 2studies, 2670 subjects, adjusted OR2.44, 95% CI 1.73–3.42, I2 = 82%).

Finally, severe PIVH was associatedwith higher odds of moderate-severeNDI when compared with mild PIVHamong survivors (2 studies, 880subjects, unadjusted OR 2.62, 95% CI1.83–3.74, I2 = 0%; 2 studies, 1686subjects, adjusted OR 2.16, 95% CI1.36–3.43, I2 = 0%).

Other Secondary Outcomes: Death,CP, and Cognitive Delay

Results from meta-analysis ofunadjusted and adjusted ORs (whereavailable) for death, CP, and cognitivedelay are reported in Table 2.

Other Secondary Outcomes:Neurodevelopmental Outcome at 3 to18 Years

Because of the variability in theexposures and reported outcomes(both outcome measure as well astiming of outcome assessment), therewas deemed to be significant clinicaland methodological heterogeneity,and hence, no meta-analyses wereperformed. Table 3 depicts studies

FIGURE 3Continued.

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that report variousneurodevelopmental outcomesbetween 3 and 18 years and theirprimary results. CP was evaluated in4 of these studies and showedgenerally incrementally higher rateswith worsening grades ofPIVH.19,32,34,37 Doyle et al reported alower rate of CP in cases of grade 4PIVH (20%) compared with grade 3PIVH (31.2%).32 In contrast,Klebermass-Schrehof et al reportedrates of CP as high as 90.9% amonggrade 4 PIVH in their cohort at 5years of age.34 The only study thatprovided adjusted ORs for CP at 5years found no difference in CP withgrade 1 PIVH (adjusted OR 1.78, 95%CI 0.94–3.40) but a significantlyincreased adjusted OR of 29.66 (95%CI 16.71–52.62) when comparinggrade 4 with no PIVH.19 Although notassessing CP directly, Schmidhauseret al evaluated motor outcomes at 6years by using the Zurich neuromotorscale and found worsening of puremotor, adaptive fine and gross motor,and static balance with each grade ofIVH in a regression model (with onlyadaptive gross motor decline reachingstatistical significance).42

Similarly, studies that evaluatedschool performance found generallyworsening scores despite utilizing avariety of assessment tools.33,38

Kiechl-Kohlendorfer et al recentlyreported that almost 46% and 75% ofinfants with mild and severe PIVHhave delayed numerical skills,respectively.33 Van deBor reportedthat .20% of children with mildand/or severe PIVH were in specialeducation programs, compared with

8.7% of preterm infants with normalCUS.38 Studies reporting compositeNDIs at various school ages showsimilar trends, with infants with bothmild and severe PIVH havinggenerally worse impairment thaninfants with no CUSabnormality.35,39–41 One study(O’Keefe et al) reported on visualoutcomes alone in patients only withPIVH and found impairment rates of6.6% and 13.2% with mild and severePIVH, respectively.36 However, noneof these studies on schoolperformance or compositeneurodevelopmental outcomesreported adjusted outcomes.

DISCUSSION

In this systematic review and meta-analysis of long-term outcomes inpreterm infants with PIVH, weidentified that both mild and severePIVH were associated with adverselong-term outcomes compared withneonates who did not have PIVH. Inparticular, mild PIVH was shown tobe associated with higher odds ofdeath or moderate-severe NDI,although all studies reporting thisprimary outcome only providedunadjusted data. There were higherodds of moderate-severe NDI alone inpreterm survivors with mild PIVHbased on both unadjusted andadjusted data, but no increase in CPor cognitive delay individually at 18to 24 months. On the other hand,severe PIVH was associated withadverse outcomes in all domainsassessed when compared with bothno PIVH as well as mild PIVH, with

the exception of cognitive delay afteradjustment. This suggests thatincreasing grades of PIVH may haveincreasing impact on long-termoutcomes, and mild PIVH may not bebenign as previously suggested.13

However, many of the reportedoutcomes are based on unadjusteddata and must be interpreted withcaution.

Our results confirm that severe PIVHleads to worse neurodevelopmentaloutcomes than mild PIVH or no PIVHand yields specific unadjusted andadjusted ORs that may be valuableduring counseling parents of affectedinfants. Data from the meta-analysesalso point to the need for closersurveillance for NDI in those withmild PIVH, and the importance ofpostnatal interventions and follow-upprograms. Although the progressivelyworse outcomes from none to mild tosevere PIVH may suggest acontinuum, it must be rememberedthat the various grades of PIVHrepresent often distinct pathology.10

The question as to why mild PIVH(limited to the subependymal liningof the germinal matrix [grade 1 PIVH]and/or within the ventricle [grade 2])without any apparent injury to thebrain parenchyma would causeneurologic impairment is important.There are limited human studiesevaluating the mechanism of suchinjury on outcomes, but in vitrostudies have demonstrated thatvarious blood components have toxiceffects in subventricular zone cellsand may impair proliferation,differentiation, and migration ofoligodendrocyte precursors.44,45

TABLE 2 Secondary Outcomes

Mild Versus No PIVH Severe Versus No PIVH Severe Versus Mild PIVH

UaOR, CI or (n) aOR, CI or (n) UaOR, CI or (n) aOR, CI or (n) UaOR, CI or (n) aOR, CI or (n)

Death 1.50,a 1.13–2.00 N/A 6.02,a 5.34–6.79 N/A 8.81,a 6.32–12.27 N/ANo. studies (subject n) 1 (2110) N/A 2 (7355) N/A 1 (819) N/ACP 1.47,a 1.16–1.87 1.00, 0.61–1.64 5.64,a 4.91–6.46 3.43,a 2.24–5.25 4.06,a 2.92–5.63 3.44,a 1.96–6.04No studies (subject n) 4 (4898) 1 (1291) 4 (9989) 1 (1202) 3 (1340) 1 (451)Cognitive delay 1.95,a 1.50–2.53 1.41, 0.97–2.06 2.76,a 2.42–3.16 1.37, 0.79–2.38 2.40,a 1.50–3.84 1.46, 0.74–2.88No. studies (subject n) 4 (3266) 2 (1653) 3 (7922) 1 (1202) 2 (828) 1 (451)

aOR, adjusted OR; N/A, not applicable; UaOR, unadjusted OR.a OR with statistical significance (95% CI does not cross 1).

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TABLE3

MainResults

andCharacteristicsof

StudiesReportingOutcom

esat

3to

18Years

Study,Year

Patient

Population

Outcom

esAnalyzed

andTimingof

Follow-up

MainResult(s)

Beaino,201019

Allbirths

between22

and32

wkGA

in9regions

ofFrance

in1997

who

survived

todischarge

andcompleted

follow-upat

5yage(n

=1812)

Outcom

e:CP.M

ethod/tool:standardizedquestionnaire

with

expert

review

ofquestionnaireswith

abnorm

alneurologic

exam

ination.Timing:5y.

Adjusted

ORs(CIs)forCP

with

noIVHas

reference:gradeI1.78

(0.94–3.40);gradeII2.53

(1.30–4.93);gradeIII3.25

(2.02–5.22);gradeIV29.66(16.71–52.62).

Doyle,200032

Inborn

livebirths

atsinglesite

(Royal

Wom

en’s

Hospital,Melbourne)with

BW500–1499

gover

2eras

(18mofrom

October1980,n

=222;12

mofrom

January1992,n

=202)

Outcom

e:CP.M

ethod/tool:Assessm

entby

developm

ental

pediatrician.Timing:5y.

Percentagesof

survivorswith

CPwithin

each

gradeof

IVH;

none

4.1%

;grade

I12.5%

;grade

II15.8%;grade

III31.2%;

gradeIV20%.

Hoekstra,200441

Infantsborn

atGA

23–26

wkbetweenJanuary

1986

andDecember2000

who

survived

(n=675)

Outcom

e:norm

al,m

ild-moderateimpairmentor

severe

impairmentin

neurologicexam

inationand/or

onassessmenttoolsas

describedbelow.M

ethod/tool:First3y:

BSID-II,p

hysicalandneurologicexam

inations;ages3–6:

Denver

Developm

entalScreeningTest,EarlyLanguage

MilestoneScaleandZimmerman

PreschoolArticulationTest;

Children.6y:Universityof

Verm

ontAchenbachChild

Behavior

Checklist,Teacher’s

Report

form

.Timing:wide

range(m

ean47.5mo).

Percentagesof

survivorswith

norm

al,m

ild-moderately

orseverelyabnorm

alassessments,based

onIVH.

NoIVH

(n=unknow

n):73%

,27%

;grade

3(n

=44):36%,64%

;grade

4(n

=39):21%,79%

.

Kiechl-Kohlendorfer,201333

Allinfantsborn

before

32completed

weeks’

gestationin

western

AustriabetweenJanuary

2003

andAugust

2006

(n=303)

Outcom

e:numerical

skills.Method/tool:TEDI-M

ATH,

amulticom

ponent

dyscalculia

test.Timing:5y.

Percentage

ofsubjects

with

delayednumerical

skills:IVH

(allgrades):11/24=45.8%;IVH

grades

3/4):3/4

=75%.

Klebermass-Schrehof,201234

Preterm

infantswith

GAbelow32

wkadmitted

tosingleNICU

inAustriabetween1994

and2005

(n=471)

Outcom

e:MDI

at5y,CP

at5y,visualandacousticimpairment

at5y.Method/tool:M

DIusingBayley

Scales

ofInfant

Developm

entat

2yandK-ABCat

age5y.Timing:2yand5y.

Percentage

ofsubjectswith

K-ABC,70%andCP

byIVH:no

IVH:

7.6%

,14.3%

;grade

IIVH:6.3%,34.8%

;grade

IIIVH:

12.9%,

55%;grade

IIIIVH:

33.3%,63.6%

;grade

IVIVH:

50%,90.9%

.Neubauer,200835

Infantswith

BWbelow1000

gbetweenJanuary

1993

andDecember1998

who

survived

until

discharge(n

=173)

Outcom

e:norm

al,m

inor

ormajor

impairment.Method/tool:

Exam

inations

byexperiencedpediatricneurologistsby

using

amodified

Touw

entest.Timing:widerange(m

ean8.4y).

Outcom

esin

patientswith

gradeI/IIand

gradeIII/IV/PVL.M

ild:

38%

norm

al,46%

minor

impairment,and15%

major

impairment.Severe:22%

norm

al,11%

minor

impairment,

and67%

major

impairment.

O’Keefe,200136

Preterm

infantsborn

,30

wkand/or

BW,1500

gbetween1987

and1998

with

IVH(n

=68)

Outcom

e:Ocular

morbidity.M

ethod/tool:visualacuity,orthoptic

assessment,cycloplegicrefraction,andfundal

exam

ination.

Timing:Between12

and150mo.

Visual

acuity,6/60

byseverityof

IVH:

lowgrade:2/30

(6.6%);

high

grade:5/38

(13.2%

).

Schm

idhauser,200642

Infantswith

BW,1250

gfrom

singlecenter

inGerm

anyborn

betweenJuly1992

and

June

1994

(n=87)

Outcom

e:motor

performance

andmovem

entquality.M

ethod/

tool:Zurichneurom

otor

assessmenttool.Timing:6y.

bcoefficient(SE)

andPvaluein

regression

model

forIVH

grades

(0–4).Puremotor:–0.08

(0.16),P

=.61.Adaptivefine

motor:–

0.39

(0.27),P

=.16.Adaptivegrossmotor:–

0.53

(0.20),P

=.009.Static

balance:=20.36

(0.19),P

=.07.

Associated

movem

ents:0.07(0.18),P

=.67.

Sherlock,200537

Infantsborn

,1000

gor

very

preterm

(,28

wk)

inVictoria,Australia

betweenJanuary1991

andDecember1992

who

survived

until

age8(n

=298)

Outcom

e:CP,blindness,deafness,intellectualimpairments

(IQ,

–1SD).Method/tool:Pediatricians

andpsychologists

usingWechslerIntelligenceScaleforChildren.Timing:8y.

RatesofCP;IQscore,

–1SD

bygrades

ofIVH.Grade0:12/180

(6.7%);64/180

(35.6%

).GradeI:3/47

(6.7%);18/47(38.3%

).GradeII:6/25

(24%

);9/25

(36.0%

).GradeIII:2/12(16.7%

);7/

12(58.3%

).GradeIV:6/6

(100%);6/6(100%).

Vande

Bor,200438

Infantsborn

inNetherlandsat

GA,32

wk

and/or

BW,1500

gat

1of

8centers

in1983

(n=278)

Outcom

e:Disabilityor

handicaps,schoolperformance.M

ethod/

tool:H

omevisitby

1of

3specifically

trainedpediatricians.

Timing:5y.

Percentage

ofchildreninspecialeducationby

grades

ofIVH:no

IVH:

17/216

(8.7%);gradeI/IIIVH:

9/45

(22.5%

);gradeIII/IV

IVH:

3/17

(20%

).Vollm

er,200339

Allinfants,33

wkGA

born

between1983

and1988

andadmitted

within

1wk

ofbirthto

NICU

ofUniversityCollege

Hospital,London

(n=505)

Outcom

e:No

NDI,impairmentwithoutdisability,and

impairmentwith

disability.Method/tool:

Neurodevelopmentalassessm

entby

investigatorsblindedto

ultrasound

results.Timing:8y.

Percentage

ofdisablingimpairmentsby

IVHgroups:noIVH:17/

271(6.3%);mild

IVH:6/82

(7.3%);severe

IVH:43/152

(28.2%

).

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Human neuroimaging studies havealso demonstrated quantitativedecrease in cortical thickness afteruncomplicated subependymal andintraventricular hemorrhagewithout parenchymal involvement.46

In addition, the contribution ofunderlying events that lead to mildPIVH and associated fluctuations insystemic and intracranial pressureremains to be elucidated. However,another important consideration isthe accuracy of CUS, with a largebody of evidence now reporting thatCUS may miss parenchymal injurywhen compared with MRI.47–49 Assuch, many infants reported to havemild PIVH may have concomitant,but undetected, parenchymal whitematter injury that may becontributory to long-term outcomes.This remains an important issuewarranting exploration in futurestudies. However, from a practicalstandpoint, routine MRI at repeatedtime points is not feasible, and CUSremains the choice of investigativemodality in most NICUs.

The finding of no increase in odds ofCP with mild versus no PIVH afteradjustment was based only on 1study16 and may reflect a true lack ofor limited effect on the brainparenchyma. More intriguing is thelack of apparent effect on cognitiveoutcomes at 18 to 24 months afteradjustment in both mild and severePIVH compared with no PIVH.However, the data for severe PIVHwere also derived from only 1study,16 whereas only 2 studiesreported on mild PIVH.14,16 Adjustedoutcome data for mild PIVH on CPand cognitive delay were notprovided by one of the large studiesincluded in the composite outcome ofmoderate to severe NDI.15 Wespeculate that this is the reason forthe findings of higher odds ofmoderate to severe NDI with mildPIVH despite no increase in odds ofCP or cognitive delay individually.

Studies on long-term outcomes(3–18 years) that report on school

performance and IQ suggestworsening cognitive performance forboth mild and severePIVH.33,34,37,38,41 The lack of effect ofmild PIVH on cognitive outcomes maytruly be reflective of limited or nodamage to the brain parenchyma.Data on short-term impact of PIVH oncognitive performance may also belimited because of the lack of studiesspecifically addressing it, along withthe possibility of selection bias asdescribed further shortly. In addition,it should be noted that numerousstudies in recent years havedemonstrated the often poorcorrelation between BSID scores at18 to 24 months and school-ageoutcomes.50,51

To our knowledge, this is the firstsystematic review and meta-analysiscomparatively evaluating long-termneurodevelopmental outcomes inmild and severe PIVH, compared withno PIVH. The strengths of the studyinclude the importance and relevanceof the question raised and providingquantitative guidance to clinicianswhen counseling parents of infantswith mild or severe PIVH with regardto early childhood outcomes. Otherstrengths include an extensiveEnglish-language literature search;explicit inclusion and exclusioncriteria; and a 3-way comparison ofmild, severe, and no PIVH. No studieswith high risk of bias were includedin the meta-analysis of earlychildhood outcomes adding to theconfidence in the reported outcomes.Furthermore, we chose not to meta-analyze school age outcomes due tothe clinical heterogeneity ofmethodology and outcomes.

Among the weaknesses of the review,one relates to the fact that of the 21included studies, only 5 providedadjusted data for the desiredoutcomes, and only 2 of these studiesincluded postnatal steroids as acovariate. In fact, none of the includedstudies have reported adjustedoutcome measures for death ormoderate-severe NDI as a compositeTA

BLE3

Continued

Study,Year

Patient

Population

Outcom

esAnalyzed

andTimingof

Follow-up

MainResult(s)

Vollm

er,200640

Allinfantsborn

,33

wkGA

betweenJanuary

1979

andDecember1991

admitted

tosingle

NICU

UniversityCollege

Hospital,London

(n=682)

Outcom

e:No

NDI,impairmentwithoutdisability,and

impairmentwith

disability.Method/tool:

Neurodevelopmentaloutcom

ewas

assessed

at8yby

pediatrician

orpsychologist.Timing:8y.

Cognitive

assessmentscores

offull-scaleIQ

byusingWechsler

(SD);TOM

Iscores(SD).NoIVH:10117 ;3.26

(2.5);grade3IVH:

9623;5.98(4.2).

BSID,B

ayleyScales

ofInfant

Developm

ent;BW

,birth

weight;IVH,

intraventricular

hemorrhage;K-ABC,Kaufman

AssessmentBatteryforChildren;MDI:M

entalDevelopm

entIndex;TOMI,Test

ofMotor

Impairment.

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outcome, which limits the validity ofthe primary outcome. The fear withthis is that infants with higher gradesof PIVH may have had othercoexisting pathologies such early-onset sepsis, hemodynamiccompromise, or higher ventilationrequirements, all of which areassociated with PIVH, as well as deathand NDI.1,13 Patients with suchcomorbidities may have had theworst prognosis and may have diedwhile in the NICU or been subject towithdrawal of life-sustaining therapydue to the projected poor outcome. Assuch, the secondary outcome ofmoderate-severe NDI in survivorssuffers from selection bias becausethe survivors do not represent thebreadth of population first diagnosedwith PIVH, and, in turn, the parents ofpatients who the neonatologist isfaced with providing counseling inthe acute phase. The same limitationholds true for studies reporting dataon mild versus no PIVH, for whichnone of the studies reported adjusteddata for the primary outcome.

Another weakness is the fact that fewstudies report outcomes by severityof PIVH as well as in comparison withno PIVH. On the basis of thepredefined inclusion/exclusioncriteria, this unfortunately resulted inthe elimination of many large

population based studies thatreported on long-term outcomes inpreterm infant (SupplementalInformation 3). Few studies and highvariability in reported results fromeach study led to high statisticalheterogeneity. We used a fixed effectsmodel; however, this may call intoquestion our confidence in reportedoutcomes. There was also a widebirth-year span, ranging from 1992 to2005 in studies included in the meta-analyses, which covered eras of rapidchange in clinical practice; this mayhave resulted in some clinicalheterogeneity between studies.Furthermore, significant clinical andmethodological heterogeneity instudies reporting outcomes at 3 to 18years made a meta-analysis of suchstudies unfeasible.19,32–42 Finally,some studies report severe PIVH as acombination of grades 3 and/or 4PIVH along with several otherintracerebral lesions such asperiventricular leukomalacia,porencephalic cysts, andintraparenchymal echodense lesions,often without separating them fromisolated grade 3 and 4 PIVH.19,35,39

This limits our ability to quantify theimpact of grade 3 or 4 IVH alone onoutcomes of interest. However, inclinical practice, grade 3 and 4 PIVHoften coexist with such anomalies.13

CONCLUSIONS

Increasing grades of PIVH may beassociated with adverse long-termneurodevelopmental outcomes, andmild PIVH alone may independentlyhave an impact compared with noPIVH. Severe PIVH is associatedwith a worse outcome comparedwith both mild PIVH and no PIVH.Neonatologists, follow-upclinicians, parents, and teachersmust be cautious in theirassessment of infants and childrenwith a history of mild PIVH becausethese children may need additionalresources to maximize theirpotential. However, furtherresearch is required to furtherelucidate the true effect of mildPIVH on mortality and long-termprognosis of preterm infants.

ABBREVIATIONS

CI: confidence intervalCP: cerebral palsyCUS: cranial ultrasonographyGA: gestational ageNDI: neurodevelopmental

impairmentOR: odds ratioPIVH: periventricular/

intraventricularhemorrhage

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: This study received no specific funding. Dr PS Shah is supported by an Applied Research Chair in Maternal and Child Health Services and Policy Research

Award from the Canadian Institutes of Health Research, Canada. The Canadian Institutes of Health and Research had no role in the design, conduct, analyses, or

interpretation of the results of this study.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

COMPANION PAPER: A companion to this article can be found on page 1185, and online at www.pediatrics.org/cgi/doi/10.1542/peds.2015-3553.

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DOI: 10.1542/peds.2015-0944 originally published online November 23, 2015; 2015;136;1132Pediatrics 

Amit Mukerji, Vibhuti Shah and Prakesh S. ShahOutcomes: A Meta-analysis

Periventricular/Intraventricular Hemorrhage and Neurodevelopmental

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