Pediatrics 2014 Weisz e1024 46

PDA Ligation and Health Outcomes: A Meta-analysis

abstractBACKGROUND AND OBJECTIVE: Patent ductus arteriosus (PDA) liga-tion has been variably associated with neonatal morbidities andneurodevelopmental impairment (NDI). The objective was to system-atically review and meta-analyze the impact of PDA ligation in preterminfants at ,32 weeks gestation on the risk of mortality, severeneonatal morbidities, and NDI in early childhood.

METHODS: Medline, Embase, Cochrane Central Register of ControlledTrials, Education Resources Information Centre (ERIC), Cumulative In-dex to Nursing and Allied Health (CINAHL), PsycINFO, and the Disserta-tion database were searched (1947 through August 2013). Risk of biaswas assessed by using the Newcastle-Ottawa Scale and the CochraneRisk of Bias tool. Meta-analyses were performed by using a random-effects model. Unadjusted and adjusted odds ratios (aORs) with 95%condence intervals (CIs) were pooled when appropriate.

RESULTS: Thirty-nine cohort studies and 1 randomized controlled trialwere included. Nearly all cohort studies had at least moderate risk ofbias mainly due to failure to adjust for survival bias and importantpostnatal preligation confounders such as ventilator dependence,intraventricular hemorrhage, and sepsis. Compared with medicaltreatment, surgical ligation was associated with increases in NDI(aOR: 1.54; 95% CI: 1.012.33), chronic lung disease (aOR: 2.51; 95%CI: 1.983.18), and severe retinopathy of prematurity (aOR: 2.23; 95%CI: 1.623.08) but with a reduction in mortality (aOR: 0.54; 95% CI:0.380.77). There was no difference in the composite outcome ofdeath or NDI in early childhood (aOR: 0.95; 95% CI: 0.581.57).

CONCLUSIONS: Surgical ligation of PDA is associated with reducedmortality, but surviving infants are at increased risk of NDI. However,there is a lack of studies addressing survival bias and confounding byindication. Pediatrics 2014;133:e1024e1046

AUTHORS: Dany E. Weisz, MD,a,b Kiran More, MD,b Patrick J.McNamara, MD, MSc,b,c,d and Prakesh S. Shah, MD, MSce,f

aDepartment of Newborn and Developmental Pediatrics,Sunnybrook Health Sciences Center, Toronto, Canada;bDepartment of Pediatrics, Hospital for Sick Children, Toronto,Canada; cDepartment of Physiology and fInstitute of Health Policy,Management and Evaluation, University of Toronto, Toronto,Canada; dPhysiology and Experimental Medicine Program,Hospital for Sick Children Research Institute, Toronto, Canada;and eDepartment of Pediatrics, Mt Sinai Hospital, Toronto,Canada

KEY WORDSpatent ductus arteriosus, neurodevelopmental impairment,death, chronic lung disease, retinopathy of prematurity, cerebralpalsy, cognitive impairment, mortality

ABBREVIATIONSaORadjusted odds ratioCIcondence intervalCLDchronic lung diseaseGAgestational ageIVHintraventricular hemorrhageNDIneurodevelopmental impairmentNECnecrotizing enterocolitisNSAIDnonsteroidal antiinammatory drugPDApatent ductus arteriosusRCTrandomized controlled trialROPretinopathy of prematurityVCPvocal cord paresis

Dr Weisz conceptualized and designed the study, acquired andinterpreted the data, drafted the initial manuscript, and revisedthe manuscript; Dr More revised the protocol, acquired andinterpreted the data, and revised the manuscript; Dr McNamararevised the protocol, interpreted the data, and revised themanuscript; Dr Shah conceptualized and designed the study,revised the protocol, interpreted the data, and revised themanuscript; and all authors approved the nal manuscript.

This systematic review has been registered with PROSPERO(international database of prospectively registered systematicreviews) (identier CRD42013005390).

www.pediatrics.org/cgi/doi/10.1542/peds.2013-3431

doi:10.1542/peds.2013-3431

Accepted for publication Dec 19, 2013

Address correspondence to Dany E. Weisz, MD, Department ofNewborn and Developmental Paediatrics, Sunnybrook HealthSciences Centre, 2075 Bayview Ave, Toronto, ON, Canada M4N 3M5.E-mail: [email protected]

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

Copyright 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno nancial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicatedthey have no potential conicts of interest to disclose.

e1024 WEISZ et al at Indonesia:AAP Sponsored on June 7, 2015pediatrics.aappublications.orgDownloaded from

Patent ductus arteriosus (PDA) occurs innearly 50% of preterm infants born at,32 weeks gestation.1 The PDA shuntsblood away from the descending aortainto the pulmonary artery, resulting insystemic hypoperfusion and pulmonaryovercirculation.2,3 It is considered a sig-nicant precursor to mortality andmorbidity in extremely preterm neo-nates, including congestive heart failure,intraventricular hemorrhage (IVH), nec-rotizing enterocolitis (NEC), prolongedventilator dependency, and chronic lungdisease (CLD).1,4 Methods to close orminimize the effects of a clinically sig-nicant PDA include conservative man-agement (eg, uid restriction, diuretics,ventilation strategies), cyclooxygenaseinhibitors (eg, indomethacin or ibupro-fen), acetaminophen, or surgical liga-tion.5,6 Surgical ligation is usually onlyconsidered whenmedical treatment haseither failed or was contraindicated.7

Several investigators have studied PDAligation and its association with neo-natal mortality, short-term morbidity,and neurodevelopmental impairment(NDI) in early childhood.Mireaetal8 andClyman et al9 found increased reti-nopathy of prematurity (ROP) and CLDin infants treated with ligation com-pared with nonsurgically treatedinfants. Two large studies found thatextremely preterm infants who weretreated with surgical ligation had sig-nicantly higher odds of NDI at 2-yearfollow-up,10,11 although a third studyshowed no increased risk.12

In light of these concerns and some-what conicting results, themerits andsafety of ligation have been questioned,with increasing uncertainty about ap-propriate patient selection and theoptimal timing for surgery to minimizemorbidity.1316 This uncertainty hasbeen associated with a secular trendtoward a permissive approach to thePDA.1719 However, few of the studiesperformed to date have controlled forconfounding by indication, that infants

referred for surgical ligation mayrepresent a more ill cohort and maybe at higher risk of NDI. As a result,there is a paucity of relevant, reliablestudies to guide the PDA ligation de-cision.

Our objective was to systematicallyreview and meta-analyze the impact ofPDA ligation in preterm infants at,32weeks gestation on the risk of mor-tality, severe neonatal morbidities, andNDI.

METHODS

We conducted and reported this reviewfollowing the Preferred Reporting Itemsfor Systematic Reviews and Meta-analyses guidelines.20 The protocol forthis review was registered with PROS-PERO, the international prospectiveregister of systematic reviews (http://www.crd.york.ac.uk/NIHR_PROSPERO,identier CRD42013005390).

Types of Studies

Randomized controlled trials (RCTs)and case-control or cohort studieswitha comparator group were included ifpublished in the form of an originalresearch manuscript in a peer-reviewed journal, an abstract in con-ference proceedings, or a dissertation.Narrative reviews, letters, editorials,and commentaries were excluded butread to identify potential studies. Du-plicate reports not providing additionalinformation were excluded. Cross-sectional studies, case reports andseries, qualitative studies, review arti-cles, and studies that did not reportmethods were excluded but read toidentify potential studies. Studies ininfantswith a PDA that did not report onoutcomes in infants who underwentsurgical ligation were excluded.

Types of Participants

Preterm infants born at a gestationalage (GA),32weekswith a clinical and/or

echocardiographic diagnosis of PDAwere included. Studies in which someinfants were born$32 weeks GA wereincluded if.80% of infants in the studypopulation had a GA ,32 weeks. Thediagnosis of PDA was made on the ba-sis of clinical suspicion and/or echo-cardiography. Echocardiography diagnosiswas preferable but not mandatory forinclusion in this review.

Exposure and Comparison

Studies must have included and com-pared, at aminimum,a surgically versusmedically treated group or subgroup.Surgical subgroups included thoseinfants treated with pharmacotherapyfollowed by surgical ligation (pharma-cotherapy and ligation subgroup, in-dicating treatment with a nonsteroidalantiinammatory drug [NSAID] or acet-aminophen, followed by surgery) orthose infants who underwent primaryligation (primary ligation subgroup,indicating surgical ligation withoutpreceding pharmacotherapy). Medicalsubgroups included infants who re-ceived pharmacotherapy only (phar-macotherapy only subgroup, indicatingtreatment with NSAIDs or acetamino-phen but not surgery) and those treatedwithout surgery or pharmacotherapy(conservative subgroup). Conservativemanagement referred only to watchfulobservation and the use of uid re-striction, diuretics, digoxin, and/ormechanical ventilation adjustment tomanage the PDA shunt but excludedNSAID/acetaminophen and surgicaltreatments. Infants in the surgical orpharmacotherapy groups may havebeen treated with conservative mea-sures initially before their respectivedenitive treatment.

Surgical ligation must have been per-formed before 40 weeks corrected GA,either at the bedside or in the operat-ing room, via a left lateral thoracotomyusing a clip or ligature and not inconjunction with another surgery.

REVIEW ARTICLE

PEDIATRICS Volume 133, Number 4, April 2014 e1025 at Indonesia:AAP Sponsored on June 7, 2015pediatrics.aappublications.orgDownloaded from

Outcomes

Studies were included if they reportedat least 1 of the following outcomes forany treatment groups or subgroups:

1. death before discharge;

2. CLD, dened as the need for anyform of respiratory support (oxygenor positive-pressure support) at 36weeks corrected GA or at the timeof transfer to a step-down unit21;

3. severe ROP, dened as stage $3according to the international clas-sication,22 or stage 2 with plusdisease requiring treatment with la-ser therapy or vascular endothelialgrowth factor inhibitor;

4. NDI in early childhood (1548months corrected GA), dened as acomposite of at least 1 of cognitive/language impairment, cerebral palsy,severe hearing impairment, or se-vere visual impairment (cognitiveimpairment was dened as a BayleyScales of Infant Development II men-tal development index or BayleyScales of Infant Development III cog-nitive or language score [or similarstandardized examination] .2 SDsbelow the mean23,24; cerebral palsywas dened as a nonprogressivemotor impairment characterizedby abnormal muscle tone and de-creased range or control of move-ments [diagnosed on or before 24months of age]25);

5. composite outcome of death or NDIin early childhood;

6. cognitive impairment as denedabove; and

7. cerebral palsy as dened above.

Studies were included if neonatal orneurodevelopmental outcomes werecomplete for $90% and $75% of thecohort, respectively. A lower neuro-developmental follow-up rate ($70%)was accepted if infants lost to follow-upwere described in detail and compara-ble to the cohort with known outcomes.

Review Methods

Search Strategy

The search strategy was designed withthe assistance of an information scien-tist. We searched the following data-bases without language restriction:Medline (1948 through August 21, 2013),Embase Classic and Embase (1947through August 21, 2013), CochraneCentral Register of Controlled Trials(through August 21, 2013), CINAHL(through August 21, 2013), ERIC (throughAugust 21, 2013), PsycINFO (throughAugust 21, 2013), Pediatric AcademicSocieties Conference E-abstracts (20022013), and Canadian Pediatric SocietyConference E-abstracts (20102013).Detailed search terms are provided inSupplemental Information 1.

Data Extraction

Two authors (D.E.W. and K.M.) indepen-dently conducted the literature search.Information about study inclusion, studydesign, key characteristics, and out-comes was extracted independently bythe 2 reviewers using a standardizeddata collection form. Discrepancieswereresolved by consensus or by involvinga third author (P.S.S.). Authors werecontacted for clarications and/or ad-ditional data.

Assessment of Risk of Bias

For randomized studies, we used theCochrane Handbook Risk of Bias as-sessment tool.26 Studies were includedif they had a low or moderate risk ofbias. For observational studies, the riskof bias was assessed by using the in-formation in the original publications,and included evaluation for selection(representative cohort or selectedpopulation), exposure assessment,outcome assessment, attrition, andconfounding factor biases by usinga modied Newcastle-Ottawa Scale,27

which was altered to reect 2 differentfollow-up periods (neonatal and neuro-developmental follow-up) and a focus

on confounding by indication (Supple-mental Information 2). Studies wereincluded if they scored at least 6 (of 10stars) on this modied Newcastle-Ottawa Scale.

We identied, a priori, that the use ofsurgical ligationasa rescue treatmentafter failure of medical therapy poten-tially imparts 2 important sources ofbias. First, it may result in survival bias,because infants initially treated medi-cally must have survived to be eligiblefor ligation. Second, it may result inconfounding by indication, where li-gated infants may bemore likely to haveincreased pretreatment morbidity. In-fants with higher illness severity afterfailed medical treatment, characterizedby, for example, NEC, hypotension, ordependence on mechanical ventilation,may have been more likely to be re-ferred for ligation. Included studieswere therefore descriptively evaluatedon how they adjusted for postnatalconfounders at the time of the decisionto treat the PDA.

The risk of bias assessment was per-formed independently by 2 authors(D.E.W. and K.M.). Differences of opinionwere resolved by discussion and in-volvement of a third author (P.S.S.).

Data Synthesis and StatisticalAnalysis

Unadjusted and adjusted data wererespectively combined in random-effects model meta-analyses (ReviewManager 5.2; Cochrane Collaboration,Nordic Cochrane Centre, Copenhagen,Denmark).28 Meta-analyses were per-formed comparing all groups andsubgroups based on the data pre-sented in the included studies. Themeta-analyses of adjusted data onlyincluded studies that had, at a mini-mum, controlled for GA. Similar toother meta-analyses, no adjustmentfor multiple analyses was made. Studyweight in the meta-analyses was cal-culated by using the generic inverse


variance method. This method assignsgreater weight to larger studies (whichhave smaller SEs) and minimizes theimprecision of the pooled effect esti-mate. The random-effects model wasselected to account for variability be-tween and within studies because weanticipated a degree of clinical and sta-tistical heterogeneity. Because all out-comeswere binary, odds ratioswith 95%condence intervals (CIs) were used toreport differences between groups. Datafrom studies that reported both ad-justed and unadjusted risks in theirpopulation were used in the respectivemeta-analyses. It was anticipated thatnot all studies would have accounted forsimilar confounders in their adjustment,and we obtained information on thecovariates used. Adjusted odds ratios(aORs) were converted to log odds andthen meta-analyzed.

Heterogeneity and Publication BiasAssessment

Clinical heterogeneitywasassessed andreported in the table of included studies(Table 1) by describing the populationsincluded, treatment groups compared,and confounders adjusted. Statisticalheterogeneity was assessed and re-ported by using the I 2 statistic.29

Sources of heterogeneity were soughtif I2 was .50%.

RESULTS

Description of Studies

The results of the search, the studyselection log, and thenumberof studiesare reported in Fig 1. One hundredtwenty-three articles were reviewed indetail. Primary authors were contactedto obtain additional information, asneeded. Six authors provided addi-tional data or analyses not included intheir original publication.8,3034 Base-line characteristics of the 40 studiesincluded8,10,11,3066 (39 cohort studiesand 1 RCT), encompassing 32 345 pre-term infants, are reported in Table 1.

Eighty-three studies were excluded; 63studies were excluded because theydid not report sufcient data to com-pare outcomes of treatment assign-ment groups or subgroups.9,17,67127

Five studies were excluded becausethey were a review or an editorial.128132

Three studies were excluded becausethey represented cohorts alreadyaccounted for in another includedstudy.133135 Ten studies were excludedbecause.20% of infants in the cohortwere$32 weeks GA.136145 Two studieswere excluded because the cohort andanalysis included all admitted infantsrather than only infants with a PDA.12,146

NSAIDs (ibuprofen or indomethacin)were the only pharmacologic therapiesused.

Twenty-eight of the 39 included cohortstudies performed treatment groupcomparisons without adjustment forcovariates, and these data were pooledonly in the meta-analyses of univariateresults. Eleven cohort studies performedmultivariate analyses. Data from 9 ofthese studies8,10,11,30,33,51,58,63,64 and theRCT35were combined inmeta-analyses ofmultivariate results. Data from 2 cohortstudies32,34 could not be pooled becauseof insufcient information to interpretthe adjusted results. Meta-analyses wereperformed comparing all treatmentgroup and subgroup combinations whendata were provided in the includedstudies (Table 2).

Risk of Bias Among IncludedStudies

The risk of bias among cohort studies isreported in Table 3. The single includedRCT35 had a low to moderate risk of biaswith adequate allocation concealment,complete data collection, and no obvi-ous bias in reporting of outcomes.However, the study did not describe useof random sequence generation ormethods used to blind the assessmentof outcomes. Most cohort studies hada low to moderate risk of bias based onthe modied Newcastle-Ottawa Scale.Studies that performed only univariatecomparisons had a moderate to highrisk of bias because there were impor-tant perinatal differences between theligated and medically treated infants(Table 1). Ligated infants tended to havelower GA and birth weight comparedwith the medically treated infants.Among the 9 cohort studies included inmeta-analyses of multivariate results,6 studies8,10,11,33,51,64 adjusted for peri-natal covariates only. Three cohortstudies30,58,63 adjusted for postnatalPDA-related morbidities. However, 2 ofthese studies30,63 adjusted for morbid-ities that were measured or occurredafter the date of ligation (such as totalduration of mechanical ventilation, CLD,and ROP), which may have introducedbias if these morbidities are on thecausal pathway between ligation andthe outcomes of death or NDI. Only 1

FIGURE 1Study selection log.

REVIEW ARTICLE


TABLE1

Charac

teristicsof

Stud

iesInclud

edin

theAn

alysis

FirstA

utho

r,Year

Type

ofStud

yPo

pulatio

nDenitio

nan

dDiag

nosisof

PDA

Trea

tmen

taOu

tcom

ebCo

variates

Follo

w-upCo

mplete

Cotton

,3519

78RC

TVLBW

preterm

infants,

with

HSPD

Aan

dde

pend

ent

oninvasive

mecha

nica

lven

tilationde

spite

cons

ervativ

eman

agem

ent(

n=25

)

Rand

omly

assign

edto

cons

ervativ

eman

agem

ent

orim

med

iate

surgical

clos

ure.

Days

toextuba

tion,

death,

retrolen

tal

brop

lasia,

CLD

None

100%

neon

atal

outcom

es

Trea

tmen

tgroup

sco

mpa

red:

Cons

ervativ

eman

agem

ent(

n=15

):GA

,28.36

0.3wk;

BW,1

0066

49g

Surgical

clos

ure(n

=10

):GA

,29.06

0.5wk;

BW,1

0886

46g

Merritt,36

1978

Retros

pective

coho

rt19

7419

77Co

mmon

PDAtrea

tmen

tap

proa

chDe

ath

None

100%

neon

atal

outcom

esPreterm

infantswith

anHS

PDA(clin

ical

andecho

diag

nosis)

desp

iteco

nservativ

eman

agem

ent

(n=59

).Co

mpa

riso

n:Indo

only

(n=31

),Indo

+Ligation(n

=4),P

rimaryLiga

tion(n

=24

)

Moratorium

onindo

use

during

thestud

yresu

ltedin

16infants

unde

rgoing

prim

ary

ligationrather

than

prim

aryindo

trea

tmen

t.Merritt,37

1979

Retros

pective

coho

rtAu

gust

1975Oc

tobe

r197

7Co

mmon

PDAtrea

tmen

tap

proa

chDe

ath,

cogn

itive

delay

(BSIDMDI/PDI),

neurom

otor

abno

rmality

None

Indo

grou

p:95

%;

Liga

tiongrou

p:80

%85

%Preterm

infantswith

anHS

PDA(clin

ical6

echo

diag

nosis)

desp

iteco

nservativ

eman

agem

ent

(n=52

).Co

mpa

riso

n:Indo

only

(n=26

):BW

,14

336

405g;

Prim

aryLiga

tion(n

=26

):BW

,13

136

330g

Cats,38

1980

Retros

pective

coho

rt19

7519

79Co

mmon

PDAtrea

tmen

tap

proa

chin

197619

77,

usingPO

/PR

indo

metha

cin.

In19

78-

1979

,moved

toprim

ary

ligationifco

nservativ

etrea

tmen

tfailed

(noindo

).

Death

None

100%

neon

atal

outcom

esPreterm

infantswith

BW,2kg

with

HSPD

A(clin

ical

diag

nosis)

(n=28

).Co

mpa

riso

n:Indo

only(n

=9):

GA,2

9(26

33.5)wk;

BW,1

260(77019

00)g;

Indo

+Ligation(n

=3):G

A,30

(28

34)wk;

BW,

1565

(138

519

00)g;

Prim

aryLiga

tion(n

=13

):GA

,27.4(25

30)wk;

BW,1

090(93515

00)g

Mikha

il,39

1982

Retros

pective

coho

rtJa

nuary19

76Ja

nuary19

81Trea

tmen

tofH

SPDA

was

initially

cons

ervativ

e.Liga

tionpe

rformed

afterfailu

reof

cons

ervativ

etherap

y.

Death

None

100%

neon

atal

outcom

esVLBW

subs

et(n

=41

3)of

preterm

infantsdiag

nosed

with

HSPD

A.Co

mpa

riso

n:Co

nservativ

e(n

=16

1),

Prim

aryLiga

tion(n

=25

2)

Zerella

,4019

83Re

tros

pective

coho

rt19

7719

83Ep

ochA:

PDAtrea

tmen

tinitially

with

indo

with

ligationba

ckup

Death

None

100%

hosp

ital

discha

rge

VLBW

infantswith

severe

RDSan

dPD

A(clin

ical

and

echo

diag

nosis)

(n=38

).Co

mpa

riso

n:Indo

only

(n=9),Ind

o+Liga

tion(n

=11

),Prim

aryLiga

tion

(n=18

)

EpochB:

prim

aryPD

Alig

ation


TABLE1

Continue

d

FirstA

utho

r,Year

Type

ofStud

yPo

pulatio

nDenitio

nan

dDiag

nosisof

PDA

Trea

tmen

taOu

tcom

ebCo

variates

Follo

w-upCo

mplete

Wag

ner,4

119

84Pros

pective

coho

rtAp

ril1

979

March

1981

Trea

tmen

tallo

catio

nwas

rand

omized

and

decision

toproc

eed

with

ligation

stan

dardized

bystud

yprotoc

ol.

Retrolen

tal

brop

lasia,

death

None

100%

neon

atal

outcom

esSu

bset

ofpreterm

infants,17

50gwith

HSPD

A(clin

ical

andecho

diag

nosis)

enrolle

din

RCT

(Gerso

nyet

al84)trea

tedwith

surgical

ligation

(n=10

2).C

ompa

riso

n:Indo

+Ligation(n

=28

),Prim

aryLiga

tion(n

=74

)Ca

stan

on,42

1988

Retros

pective

coho

rt19

8219

86Co

mmon

PDAtrea

tmen

tap

proa

chDe

ath

None

100%

neon

atal

outcom

esPreterm

infantswith

HSPD

A(clin

ical

andecho

diag

nosis)

(n=48

).Co

mpa

riso

n:Co

nservativ

e(n

=21

),Indo

only

(n=9),Ind

o+Liga

tion

(n=3),P

rimaryLiga

tion(n

=15

)Trus

,4319

93Re

tros

pective

coho

rtJa

nuary19

88De

cembe

r19

90Co

mmon

PDAtrea

tmen

tap

proa

chBP

D(not

dene

d)No

ne10

0%BP

Dou

tcom

esPreterm

infantswith

BW,80

0gwith

HSPD

A(clin

ical

6echo

diag

nosis)

andtrea

tedwith

NSAIDs6

Liga

tion(n

=40

).Co

mpa

riso

n:Indo

only(n

=23

):GA

,25.76

2.0wk;

BW,6

396

97g;

Indo

+Ligation

(n=17

):GA

,24.66

1.3wk;

BW,6

626

85g

Perez,4

419

98Re

tros

pective

coho

rt19

9319

97Co

mmon

PDAtrea

tmen

tap

proa

chDe

ath

None

100%

neon

atal

outcom

esVLBW

infantswith

HSPD

A(clin

ical6

echo

diag

nosis)

(n=76

).Co

mpa

riso

n:AllL

igation(n

=40

):GA

,26

wk;

BW,8

47g;

Med

ical

Man

agem

ento

nly

(n=36

):GA

,28wk;

BW,9

97g

Koeh

ne,45

2001

Retros

pective

coho

rtJa

nuary19

87De

cembe

r19

98Co

mmon

PDAtrea

tmen

tap

proa

ch,e

xcep

tind

oco

urse

was

initially

0.2mg/kg

q12h3

3do

sesfollo

wed

by0.1mg/kg

q24

hfor

upto

6d.

Death,

CLD

None

100%

neon

atal

outcom

esVLBW

infantstrea

tedforHS

PDA(clin

ical

andecho

diag

nosis)

(n=15

6).C

ompa

riso

n:Indo

only

(n=67

):GA

,26.4wk;

BW,9

10(52514

80)g;

Indo

+Ligation(n

=34

):GA

,26.1wk;

BW,8

85(57814

50)g;

Prim

aryLiga

tion(n

=55

):GA

,26

.0wk;

BW,7

60(54012

50)g

Niinikos

ki,46

2001

Retros

pective

coho

rt19

8819

98Infants.1kg

trea

tedwith

indo

(0.2

mg/kg

q12

h3

3do

ses);infan

ts,10

00gtrea

tedwith

prim

arylig

ation

Death

None

100%

neon

atal

outcom

esVLBW

infantswith

HSPD

A(clin

ical

andecho

diag

nosis)

trea

tedwith

surgicallig

ation(n

=10

1).

Compa

riso

n:Indo

+Ligation(n

=25

),Prim

ary

Liga

tion(n

=76

)Little,47

2003

Retros

pective

coho

rtJu

ne19

98March

2001

Common

PDAtrea

tmen

tap

proa

chCLD(not

dene

d)No

ne10

0%ne

onatal

outcom

esNe

onates

with

HSPD

A(clin

ical

andecho

diag

nosis)

(n=21

2).C

ompa

riso

n:Indo

alon

e(n

=12

5),

Indo

+Ligation(n

=42

),Prim

aryLiga

tion(n

=30

)

Death

REVIEW ARTICLE


TABLE1

Continue

d

FirstA

utho

r,Year

Type

ofStud

yPo

pulatio

nDenitio

nan

dDiag

nosisof

PDA

Trea

tmen

taOu

tcom

ebCo

variates

Follo

w-upCo

mplete

ODo

novan,

4820

03Re

tros

pective

coho

rt19

9519

98Co

mmon

PDAtrea

tmen

tap

proa

chDe

ath

None

100%

neon

atal

outcom

esInfantstrea

tedforHS

PDA(clin

ical

andecho

diag

nosis)

(n=23

0).Exclude

dinfantswith

NEC

before

anytrea

tmen

t(n=6).C

ompa

riso

n:Indo

only(n

=10

8):G

A,26

.56

2wk;

BW,9

166

282g,

Indo

+Ligation(n

=66

):GA

,25.66

2wk;BW

,8266

233g;

Prim

aryLiga

tion(n

=50

):GA

,26.06

2wk;

BW,8

496

219g

Hwan

g,49

2005

Retros

pective

coho

rtJa

nuary19

99Ja

nuary20

02Trea

tmen

tallo

catio

nno

tde

scribe

d;indo

trea

tmen

t:0.2mg/kg

q12

h3

3do

ses

Death

None

100%

neon

atal

outcom

esELBW

infantswith

HSPD

A(clin

ical

andecho

diag

nosis)

(n=57

).Co

mpa

riso

n:Indo

alon

e(n

=19

):GA

,26.46

1.6wk;

BW,8

736

70g;

Indo

+Ligation(n

=8):G

A,25

.06

1.2wk;

BW,7

496

104g;

Prim

aryLiga

tion(n

=14

):GA

,26.56

2.3wk;

BW,7

846

145g;

Cons

ervativ

e(n

=16

):GA

,26.36

2.6wk;

BW,7

966

160g

Lee,

5020

06Re

tros

pective

coho

rt19

9520

00Trea

tmen

tallo

catio

nno

tde

scribe

d;us

e/no

nuse

ofNS

AIDS

know

nin

84%

Death,

CLD

(not

dene

d)No

neCLD:

86%;d

eath:

89%;R

OP:8

1%Preterm

VLBW

infantstrea

tedwith

surgical

ligation

who

sene

onatal

outcom

esarekn

own(n

=82

).Co

mpa

riso

n:Liga

tionon

ly(n

=17

),Indo

+Ligation

(n=65

)Pe

laus

a,51

2006

Retros

pective

coho

rt19

9420

02Trea

tmen

tallo

catio

nno

tdescribed

CLD,

ROP

(thresho

ld)

Match

edforGA

,BW

,gen

der

100%

neon

atal

outcom

esInfantswith

GA,30

wkwith

HSPD

Awho

faile

dmed

ical

trea

tmen

tand

unde

rwen

tsurgica

llig

ationwerematch

ed(byGA

,BW,g

ende

r)with

infantswho

received

only

med

ical

trea

tmen

t(n

=88

).Co

mpa

riso

n:NS

AID+

Liga

tion(n

=44

):GA

,25.66

1.6wk;

BW,7

766

218g;

NSAIDon

ly(n

=44

):GA

,25.76

1.5wk;

BW,7

966

205g

Kabra,

1120

07Pros

pective

coho

rt(sub

setof

RCT)

Janu

ary19

96March

1998

Subs

etof

RCTwhe

reinfantswererand

omly

assign

edto

PIor

plac

ebo;

trea

tmen

tde

cision

forlig

ation:

assign

edby

attend

ing

physician

Severe

ROP:

laseror

cryotherap

y$1eye

or stag

e$4;

CLD;

death;

CP;N

DI:com

posite

ofhe

aringor

vision

loss,

cogn

itive

orCP

ACS,

GA,g

ende

r,tw

ins,materna

led

ucation,

indo

dose

100%

neon

atal

outcom

es;

95%

18-to

21-m

ofollo

w-up

Infantswith

BW50

099

9gwith

HSPD

A(clin

ical

and

echo

diag

nosis)

(n=42

6).C

ompa

riso

n:Med

ical

Man

agem

ento

nly(n

=31

6):G

A,25

.66

1.8wk;BW

,77

16

126g;

AllL

igation(n

=11

0):G

A,25

.16

1.4wk;

BW,7

426

133g

Laug

hon,

5220

07Re

tros

pective

coho

rtJa

nuary19

97De

cembe

r20

04Trea

tmen

tallo

catio

nno

tdescribed

Death

None

100%

neon

atal

outcom

esAll2

3-to

30-wkGA

infantswith

ada

taba

sediag

nosis

ofPD

A.Co

mpa

riso

n:Co

nservativ

e(n

=38

86):GA

,27

wk(IQ

R:2629

);BW

,970

g(IQ

R:75

012

20);

Prim

aryLiga

tion(n

=70

1):G

A,25

wk(IQ

R:2427

);BW

,730

g(IQ

R:62

489

8)

CLD,

ROP(stage$3)


TABLE1

Continue

d

FirstA

utho

r,Year

Type

ofStud

yPo

pulatio

nDenitio

nan

dDiag

nosisof

PDA

Trea

tmen

taOu

tcom

ebCo

variates

Follo

w-upCo

mplete

Quresh

i,5320

08Re

tros

pective

coho

rt20

0020

05Trea

tmen

talloca

tion

notde

scribe

dCLD

BW,G

A,trea

tmen

ttype

Nots

pecied

Infantswith

BW,12

50gwith

PDA(clin

ical

andecho

diag

nosis)

(n=19

5).C

ompa

riso

n:Co

nservativ

e(n

=34

);Indo

only(n

=90

):GA

,27.4wk;BW

,9746

19g;

Prim

aryLiga

tion(n

=24

):GA

,26.36

0.2wk;

BW,8946

30g;Indo

+Ligation(n

=47

):GA

,26.36

0.5wk;

BW,8

456

43g

Only

univariate

resu

ltsavailable

Sato,54

2008

Retros

pective

coho

rtELBW

infantswho

unde

rwen

tPDA

ligationover

a3-ype

riod

(n=90

).Co

mpa

riso

n:Indo

+Ligation

(n=37

),Prim

aryLiga

tion(n

=43

).

Common

PDAtrea

tmen

tap

proa

chDe

ath,

ROP(stage

3/4/5),C

LD(not

dene

d)

None

Nots

pecied

Tsuc

hupp

ert,5

5

2008

Retros

pective

coho

rtJa

nuary19

85De

cembe

r20

05IfBW,12

50g,

received

indo

ifPD

Aseen

onecho

.IfB

W.12

50g,

received

indo

ifPD

Aclinically

sign

ica

nt.

Indo

0.2mg/kg

q12

h3

3do

ses(in

1980

s)an

d0.1mg/kg

q24

h3

6do

ses(afte

r19

80s).P

rimary

ligationpe

rformed

ifco

ntraindica

tion

toindo

.

Death,

CLD

None

100%

neon

atal

outcom

esInfants,35

wkGA

trea

tedforPD

A(ech

o6

clinical

diag

nosis)

(n=21

0).S

uccessfulM

edical

Clos

ure

grou

p(n

=15

4):B

W,1

.16

0.3kg

;versu

sFaile

dMed

ical

Clos

uregrou

p(n

=47

):BW

,1.16

0.3kg

.Co

mpa

riso

ns:PrimaryLiga

tion(n

=9),Ind

oalon

e(n

=16

8),Ind

o+Liga

tion(n

=33

)

Alexan

der,5

620

09Re

tros

pective

coho

rtJu

ne19

96Ap

ril2

005

Common

PDAtrea

tmen

tap

proa

chDe

ath

None

100%

neon

atal

outcom

esELBW

infantswith

HSPD

A(clin

ical

andecho

diag

nosis)

(n=25

8)Co

mpa

riso

n:Co

nservativ

e(n

=54

),Indo

only

(n=14

0),Ind

o+Liga

tion(n

=58

),Prim

ary

Liga

tion(n

=46

)Ko

,5720

09Re

tros

pective

coho

rtAp

ril1

992

March

2006

Trea

tmen

talloca

tion

notde

scribe

dDe

ath

None

100%

neon

atal

outcom

esAllV

LBW

infantswho

unde

rwen

tPD

Alig

ation.

Compa

riso

n:Indo

+Ligation(n

=37

),Prim

ary

Liga

tion(n

=4)

Mad

an,10

2009

Pros

pective

coho

rtJa

nuary20

00De

cembe

r20

0429

%received

PI.Treatmen

talloca

tionas

sign

edby

attend

ingph

ysician.

Severe

ROP:

laser/

cryotherap

y$1eye

orstag

e$4;CLD;

NDI

(18

21mo):

compo

site

ofhe

aringaids

,blindn

ess

$1eye,

severe

cogn

itive

delay,or

mod

erate

severe

CP

Center,G

A,BW

,ge

nder,P

I,labo

r,Ap

gar,

RDS,

IUGR

,AC

S,TO

RCH,

seps

is,m

arita

lstatus

,materna

lag

e

100%

(byinclus

ion

crite

ria)

Infants2328

wkan

d40

110

00gwho

survived

.72

hwith

HSPD

A(clin

ical6

echo

diag

nosis)

andha

d1821

mofollo

w-upas

sessmen

t(n

=28

38).Co

mpa

riso

n:Co

nservativ

e(n

=40

3):

GA,2

5.66

1.5wk;

BW,7

586

148g;

Indo

only

(n=15

25):GA

,25.46

1.3wk;

BW,7

456

139g;

Indo

+Ligation(n

=77

5):G

A,24

.86

1.3wk;

BW,

7196

134g;

Prim

aryLiga

tion(n

=13

5):G

A,25

.16

1.4wk;

BW,7

266

133g

REVIEW ARTICLE


TABLE1

Continue

d

FirstA

utho

r,Year

Type

ofStud

yPo

pulatio

nDenitio

nan

dDiag

nosisof

PDA

Trea

tmen

taOu

tcom

ebCo

variates

Follo

w-upCo

mplete

Quresh

i,5820

09Re

tros

pective

coho

rtInfantswith

BW,12

50gwith

PDA(ech

odiag

nosis)

(n=17

6).C

ompa

riso

n:Med

ical

Man

agem

ento

nly

(n=11

0):G

A,27

.4wk;

BW,9

036

36g,

includ

ing

Cons

ervativ

eon

ly(n

=26

),Indo

only

(n=84

),versus

AllL

igation(n

=66

),includ

ingPrim

ary

Liga

tion(n

=19

):GA

,25.56

0.3wk;

BW,8

086

47g;Indo

+Ligation(n

=47

):GA

,26.36

0.2wk;BW

,89

46

30g

Trea

tmen

tallo

catio

nno

tdescribed

Deathor

NDI

GA,B

W,P

DAscore,

IVH,

hypo

tens

ion

inrstwee

k

100%

neon

atal

mor

tality;85

%ne

urod

evelop

men

tal

follo

w-up

Vida

,5920

09Re

tros

pective

coho

rt20

0120

07Ibup

rofenwas

NSAID

used

;com

mon

PDA

trea

tmen

tapp

roac

h

Death,

CLD,

ROP

($stag

e3)

None

100%

neon

atal

outcom

esInfants,32

wkGA

with

HSPD

A(clin

ical

andecho

diag

nosis)

trea

tedwith

prim

aryNS

AIDtherap

y(n

=20

1).C

ompa

riso

n:NS

AIDon

ly(n

=14

9):G

A,27

wk(IQ

R:2528

);BW

,840

g(IQ

R:67

010

16);

NSAID+

Liga

tion(n

=52

):GA

,25wk(IQ

R:2426

.5);

BW,7

30g(IQ

R:59

591

5)Ch

iruvolu,

6020

10Re

tros

pective

coho

rtJa

nuary20

06De

cembe

r20

08Trea

tmen

tallo

catio

nno

tdescribed

Death;

CLD;

severe

ROP:.stag

e2

None

100%

neon

atal

outcom

esELBW

infantswith

PDA(clin

ical

andecho

diag

nosis)

(n=19

0).C

ompa

riso

n:Co

nservativ

e(n

=16

),NS

AIDon

ly(n

=55

),Prim

aryLiga

tion(n

=61

),NS

AID+

Liga

tion(n

=58

)Lope

s,61

2010

Retros

pective

coho

rt19

9920

04Trea

tmen

tallo

catio

nno

tdescribed

CP,cog

nitiv

ede

lay(M

DI,70

),de

afne

ss,

Psycho

motor

developm

ent

None

100%

neon

atal

outcom

es;

81%

18-m

ofollo

w-up

(ofc

ohor

t)

Coho

rtof

143infantswith

BW#80

0g(n

=93

).Co

mpa

riso

n:Co

nservativ

e(n

=12

),Indo

only

(n=31

),Indo

+Ligation(n

=42

),Prim

ary

Liga

tion(n

=8)

Natarajan,

6220

10Re

tros

pective

coho

rtJa

nuary20

04De

cembe

r20

06Co

mmon

PDAtrea

tmen

tap

proa

ch;ibu

profen

andindo

used

CLD,

ROP(req

uiring

trea

tmen

t),d

eath

None

100%

neon

atal

outcom

esCo

hort

ofVLBW

infantswith

anHS

PDA(clin

ical

and

echo

diag

nosis)

trea

tedwith

surgical

ligation

(n=82

).Co

mpa

riso

n:Prim

aryLiga

tion(n

=28

),NS

AID+

Liga

tion(n

=54

)Rh

einlae

nder,63

2010

Retros

pective

coho

rtJa

nuary19

98De

cembe

r20

03Co

mmon

PDAtrea

tmen

tap

proa

ch;ind

o0.2mg/kg

q12

h3

3do

ses,then

0.1mg/kg

q24

hup

to6d;

ibup

rofen10

/5/5

mg/kg

q24

h

Death,

mor

talityat

2y,

CLD,

ROP.stag

e2,

hearingaids

,blindn

ess,

CP,cog

nitiv

ede

lay,

compo

site

poor

outcom

e,de

athor

poor

outcom

e

Compo

site

NDI:

CRIB,B

W,G

A,BP

D,ge

nder,

O 2da

ys,intub

ation

days,R

OP,IVH

,PVL,

surfac

tant

89.6%

2-you

tcom

e(dea

thor

NDI)

know

nVLBW

infantswith

PDA(clin

ical

andecho

diag

nosis)

trea

tedwith

NSAID6

Liga

tion(n

=18

2).

Compa

riso

n:NS

AIDon

ly(n

=13

0),N

SAID+L

igation

(n=52

).Infantswith

ductal

patenc

yafterNS

AID

therap

y(52of

54werethen

ligated

)had

lower

BW,

GA,h

ighe

rCR

IBscore,an

dmoreRD

S,mecha

nica

lventila

tion,

ventila

torda

ys.

Pelaus

a,64

2011

Retros

pective

coho

rtInfants,28

wkGA

with

anHS

PDAwho

survived

.7dan

dtrea

tedwith

surgical

ligationwere

match

edforGA

(61wk)

with

aninfant

with

PDA

who

received

only

med

ical

trea

tmen

t(n=72

).Co

mpa

riso

n:AllLigation(n

=36

):GA

,256

1.1wk;

BW,7

096

20g;

Med

ical

Man

agem

ento

nly

(n=36

):GA

,24.96

1.1wk;

BW,7

266

159g

Trea

tmen

tallo

catio

nno

tdescribed

Death,

developm

ental

issu

esat

4yof

age(spe

ech,

developm

ental

delays,C

P,AD

HD,a

utism,

deafne

ss,

blindn

ess)

Match

edforGA

(61wk)

Notsp

ecied


TABLE1

Continue

d

FirstA

utho

r,Year

Type

ofStud

yPo

pulatio

nDenitio

nan

dDiag

nosisof

PDA

Trea

tmen

taOu

tcom

ebCo

variates

Follo

w-upCo

mplete

Adrouc

he-Amrani,65

2012

Retros

pective

coho

rtAu

gust

2004Ju

ly20

09Co

mmon

PDAtrea

tmen

tap

proa

ch;sed

ibup

rofen

andindo

CLD,

ROP(the

seda

tano

tinc

lude

din

analysis)

None

100%

neon

atal

outcom

esELBW

infantswith

HSPD

A(clin

ical

andecho

diag

nosis)

(n=80

).Co

mpa

riso

n:NS

AIDon

ly(n

=48

):GA

,25.46

0.2wk;

BW,7

726

16g;

NSAID+

Liga

tion(n

=32

):GA

,24.96

0.2wk;

BW,

7266

24g

Heuc

han,

6620

12c

Retros

pective

coho

rt20

0120

07Trea

tmen

tallo

catio

nno

tdescribed

Mor

talityat

1y

None

100%

1-ymor

tality

outcom

ePreterm

infantswith

HSPD

A(clin

ical

andecho

diag

nosis)

with

persistent

need

forresp

iratory

supp

ort,trea

tedwith

surgical

ligation.

Trea

tmen

tgrou

ps(m

edian[IQ

R]):NS

AID+

Liga

tion(n

=71):

GA,26(25

27)wk;BW

,840

(73310

00)g;

Prim

ary

Liga

tion(n

=54

):GA

,26(25

27)wk;

BW,8

30(72710

69)g

Hsu,

3420

12c

Retros

pective

coho

rt19

9720

07Trea

tmen

tallo

catio

nno

tdescribed

30-d

postop

erative

mortality,ho

spita

lmortality

NICU

levela

ndun

specied

comorbiditie

s

100%

neon

atal

outcom

esVLBW

infantswith

aPD

A(ech

odiag

nosis)

(n=

1078

0).C

ompa

riso

n:AllL

igation(n

=24

97),

Med

ical

Man

agem

enton

ly(n

=82

83)

Mirea

,820

12c

Retros

pective

coho

rt20

0420

08Co

mmon

PDAtrea

tmen

tap

proa

chDe

ath,

ROP$stag

e3,

CLD;

compo

site

outcom

eno

tinc

lude

din

this

review

GA,A

CS,m

ultip

lebirths

,gen

der,

SGA,

SNAP

IIscore

Nots

pecied

Preterm

infantswith

GA#32

wk,

who

survived

$72

h,with

adiag

nosisof

PDA(diagn

osed

clinically6

echo

)(n

=35

56).Co

mpa

riso

n:Co

nservativ

e(n

=57

7):G

A,28

.36

2.3wk;

Indo

only

(n=20

26):GA

,27.06

2.1wk;

Indo

+Ligation

(n=62

6):G

A,25

.56

1.7wk;

Prim

aryLiga

tion

(n=32

7):G

A,26

.06

2.3wk

Moo

re,33

2012

cRe

tros

pective

coho

rtJa

nuary19

94De

cembe

r20

05Co

mmon

PDAtrea

tmen

tap

proa

chCLD;

severe

ROP:

anyne

edfor

lasertherap

y,de

ath

Death:

GA,A

CS,

SGA,

gend

erNo

tspe

cied

Infants2326

wkGA

with

HSPD

A(clin

ical

andecho

diag

nosis)

that

didno

tclose

after1co

urse

ofindo

(n=13

3).Ligated

infantsha

dlower

BWan

dmore

inotrope

usebu

tsim

ilarGA

tono

nligated

infants.

Compa

riso

n:Indo

only

(n=58

),Indo

+Ligation

(n=75

)Ja

wa,

3020

13c

Retros

pective

coho

rt20

0520

10Trea

tmen

tallo

catio

nno

tdescribed

CLD,

ROP.stag

e2,

Death,

CPat

2y

CLD;

ROP;

death:

GA;C

P:CLD,

IVH,

ROP,seps

is

100%

neon

atal

outcom

es;

2-yfollo

w-upno

tde

scribe

d

VLBW

infantswith

HSPD

A(clin

ical

andecho

diag

nosis)

(n=36

1).C

ompa

riso

n:Co

nservativ

e(n

=85

);Med

ical

Man

agem

ento

nly(n

=17

8):G

A,27

.16

0.7wk;

AllL

igation(n

=98

):GA

,25

.86

0.8wk

Tsui

3120

13c

Retros

pective

coho

rtJa

nuary20

06De

cembe

r20

10Trea

tmen

tallo

catio

nno

tdescribed

Severe

ROPrequ

iring

lasertrea

tmen

tNo

ne;u

nivariate

resu

ltsus

edin

this

review

100%

ROP

outcom

esVLBW

infantswith

PDA(n

=20

4).C

ompa

riso

n:Co

nservativ

eon

ly(n

=88

),Indo

only

(n=49

),Indo

+Ligation(n

=20

),Prim

aryLiga

tion(n

=47

)

REVIEW ARTICLE


study adjusted for postnatal pre-ligation confounders, by controllingfor IVH, hypotension, and a PDA-relatedillness severity score measured at thetime of the decision to treat the PDA.58

The possibility of survival bias was notaddressed by any cohort study.

Main Results

Meta-analyses of univariate and mul-tivariate results for all treatmentgroup and subgroup comparisons arepresented in Table 2. The outcomesfor ligated compared with medicallytreated infants are as follows:

1. Death before discharge from theNICU: a meta-analysis of studiesthat reported an adjusted risk ofdeath revealed that infants whounderwent surgical ligation hadlower odds of death comparedwith those infants who were trea-ted medically (5 studies, 7159 par-ticipants; pooled aOR: 0.54; 95% CI:0.380.77; I 2 = 39%) (Fig 2A, Ta-ble 2). The association between li-gation and decreased mortalitywas seen across all subgroupcomparisons (Fig 2 BD, Table 2).

2. CLD: meta-analysis revealed thatsurgical ligation was associatedwith higher odds of CLD comparedwith medical management alone(4 studies, 6703 participants; pooledaOR: 2.51; 95% CI: 1.983.18; I 2 = 44%)(Fig 3A, Table 2).

3. Severe ROP: meta-analysis re-vealed that surgical ligation wasassociated with higher odds of se-vere ROP compared with medicalmanagement alone (3 studies, 3122participants; pooled aOR: 2.23; 95%CI: 1.623.08; I 2 =37%) (Fig 4A, Table 2).

4. NDI in early childhood: meta-analysis revealed that NDI washigher among infants who under-went surgical ligation comparedwith those treated medically (3studies, 3250 participants; pooledTA

BLE1

Continue

d

FirstAu

thor,Yea

rType

ofStud

yPo

pulatio

nDenitio

nan

dDiag

nosisof

PDA

Trea

tmen

taOu

tcom

ebCo

variates

Follo

w-upCo

mplete

Youn

,3220

13c

Retros

pective

coho

rtNo

vembe

r20

09No

vembe

r20

11Initial

trea

tmen

twith

ibup

rofen3on

ce-daily

doses(10/5/5mg/kg

);prim

arylig

ationifinfant

hemod

ynam

ically

unstab

le(exclude

dfrom

analysis)

ROP:

Anyplus

diseas

eor

need

forlaser

therap

y;CLD;

death

BW,G

A,initial

PDA

shun

tsize;

only

univariate

data

used

inmeta-an

alyses

100%

neon

atal

outcom

esVLBW

infantswith

HSPD

A(clin

ical

andecho

diag

nosis)

(n=11

5).C

ompa

riso

n:Ibup

rofen+

Liga

tion(n

=29

):GA

,27.86

2.8wk;

BW,1

.16

0.3kg

;PDA

diam

eter,3.16

1.0mm;Ibu

profen

only

(n=75

):GA

,30.46

3.14

wk;

BW,1

.56

0.6kg

;PD

Adiam

eter,2

.16

0.9mm

Alls

tudies

performed

surgical

ligationviaapo

sterolateral

thorac

otom

ywith

useof

aclip

orlig

ature.BW

andGA

areprovided

whe

navailable.

BW(ing)

ispresen

tedas

mea

ns6

SDsor

med

ians

(ran

ge)an

dGA

(inwk)

ispresen

tedas

mea

ns6

SDs

ormed

ians

(ran

ge)u

nlessothe

rwisesp

ecied

.ACS

,anten

atal

corticos

teroids;BW

,birth

weigh

t;BS

ID,B

ayleySc

ales

ofInfant

Developm

entII;CP,cereb

ralp

alsy;ech

o,echo

cardiogram

;ELB

W,extremelylowbirthweigh

t;HS

PDA,he

mod

ynam

icallysign

ica

ntPD

A;indo

,ind

ometha

cin;

IQR,

interqua

rtile

rang

e;MDI,m

entald

evelop

men

tinde

x;PD

I,ps

ycho

motor

developm

entinde

x;PI,p

roph

ylac

ticindo

metha

cin;

q,qu

aque

(Latin)SG

A,sm

allfor

gestationa

lage

;SNA

PII,

ScoreforNe

onatal

AcutePh

ysiology

II;VLBW

,verylow

birthweigh

t.aTh

eco

mmon

PDAtrea

tmen

tapp

roac

hindica

tesinitial

man

agem

ento

fHSP

DAwith

indo

metha

cin(w

ithor

with

outc

onservativeman

agem

ent).Ind

ometha

cinwas

administeredintraven

ously(0.2mg/kg3

3do

sesevery1224

h).S

urgica

lligationwas

performed

ifindo

metha

cintherap

yfaile

dor

was

contraindica

ted.

Trea

tmen

talloca

tionwas

assign

edby

theattend

ingph

ysician.

bCLDwas

dene

das

thene

edforoxygen

orpo

sitiv

e-pressu

reventila

tionat

36wkpo

stmen

strual

ageun

less

othe

rwisesp

ecied

.cAd

ditio

nald

ataor

analyses

wereprovided

bytheau

thor.


TABLE2

Meta-an

alyses

oftheEffect

ofPD

ATrea

tmen

tAs

sign

men

tSu

bgroup

onNe

onatal

andNe

urod

evelop

men

talOu

tcom

es

Outcom

eCo

mpa

riso

nNo

.ofS

tudies

(Univariate)

Pooled

OR(95%

CI)

No.o

fPa

rticipan

tsI2 ,

%No

.ofS

tudies

(Multiv

ariate)

Pooled

aOR

(95%

CI)

No.o

fPa

rticipan

tsI2 ,

%

Death

AllL

igationversus

AllM

edical

Man

agem

enton

ly16

0.71

(0.54

0.94

)86

6756

50.54

(0.38

0.77

)71

5939

NSAIDan

dLiga

tionversus

Prim

aryLiga

tion

210.70

(0.51

0.96

)31

7025

0

NSAIDan

dLiga

tionversus

NSAIDon

ly18

0.77

(0.57

1.04

)66

8840

30.44

(0.37

0.53

)51

110

NSAIDan

dLiga

tionversus

Cons

ervativ

e7

0.35

(0.19

0.64

)26

5072

10.20

(0.13

0.31

)12

01

Prim

aryLiga

tionversus

NSAIDon

ly14

1.02

(0.71

1.46

)51

2337

20.65

(0.48

0.89

)40

060

Prim

aryLiga

tionversus

Cons

ervativ

e10

0.58

(0.41

0.83

)67

2257

20.29

(0.18

0.47

)92

80

CLD

AllL

igationversus

AllM

edical

Man

agem

enton

ly7

2.19

(1.43

3.34

)46

0382

42.51

(1.98

3.18

)67

0344

NSAIDan

dLiga

tionversus

Prim

aryLiga

tion

81.06

(0.75

1.50

)14

8930

0

NSAIDan

dLiga

tionversus

NSAIDon

ly12

2.49

(1.81

3.43

)38

4560

32.76

(2.10

3.62

)48

1753

NSAIDan

dLiga

tionversus

Cons

ervativ

e3

4.98

(2.57

9.67

)12

5850

13.12

(2.32

4.20

)11

03

Prim

aryLiga

tionversus

NSAIDon

ly5

1.60

(0.93

2.77

)26

4269

22.03

(1.57

2.61

)37

950

Prim

aryLiga

tionversus

Cons

ervativ

e4

4.13

(2.56

6.68

)52

7977

12.67

(1.89

3.77

)80

9

Severe

ROP

AllL

igationversus

AllM

edical

Man

agem

enton

ly5

3.97

(3.33

4.73

)35

1622

32.23

(1.62

3.08

)31

2237

NSAIDan

dLiga

tionversus

Prim

aryLiga

tion

61.04

(0.79

1.38

)12

080

0

NSAIDan

dLiga

tionversus

NSAIDon

ly7

3.72

(3.04

4.57

)27

520

21.82

(1.41

2.33

)20

800

NSAIDan

dLiga

tionversus

Cons

ervativ

e2

9.26

(4.85

17.70)

961

301

3.02

(1.73

5.27

)85

3

Prim

aryLiga

tionversus

NSAIDon

ly3

3.51

(2.61

4.72

)18

540

11.80

(1.25

2.59

)16

42

Prim

aryLiga

tionversus

Cons

ervativ

e4

5.06

(4.23

6.04

)50

500

12.98

(1.61

5.52

)50

3

NDI

AllL

igationversus

AllM

edical

Man

agem

enton

ly1

2.13

(1.32

3.45

)34

0

31.54

(1.01

2.33

)32

5048

NSAIDan

dLiga

tionversus

NSAIDon

ly1

0.65

(0.27

1.58

)14

1

21.39

(0.97

1.98

)24

4129

Prim

aryLiga

tionversus

NSAIDon

ly0

1

1.79

(1.11

2.89

)16

60

Deathor

NDI

AllL

igationversus

AllM

edical

Man

agem

enton

ly1

1.50

(0.97

2.33

)42

6

40.95

(0.58

1.57

)35

1271

NSAIDan

dLiga

tionversus

NSAIDon

ly1

1.02

(0.52

1.98

)18

2

11.03

(0.82

1.30

)23

00

Prim

aryLiga

tionversus

NSAIDon

ly0

1

1.54

(1.00

2.37

)16

60

Cogn

itive

impa

irmen

tAllL

igationversus

AllM

edical

Man

agem

enton

ly2

2.15

(1.34

3.44

)42

40

11.96

(1.14

3.37

)33

1

NSAIDan

dLiga

tionversus

NSAIDon

ly1

0.70

(0.28

1.80

)14

1

0

Prim

aryLiga

tionversus

NSAIDon

ly1

3.33

(0.32

34.99)

42

0

Cerebral

palsy

AllL

igationversus

AllM

edical

Man

agem

enton

ly3

2.65

(1.14

6.18

)70

964

21.51

(0.86

2.63

)61

60

NSAIDan

dLiga

tionversus

NSAIDon

ly1

2.06

(0.64

6.65

)14

1

0

Prim

aryLiga

tionversus

NSAIDon

ly1

4.27

(1.13

16.05)

42

0

AOR,

adjusted

odds

ratio

;OR,

odds

ratio

;NSA

ID,n

on-steroidal

anti-inam

matorydrug

;ROP

,retinop

athy

ofprem

aturity.

REVIEW ARTICLE


TABLE3

Risk

ofBias

Assessmen

t:Co

hort

Stud

iesa

FirstA

utho

r,Year

Selection

Compa

rability

Outcom

eOv

erallb

Represen

tativ

eness

ofExpo

sedCo

hort

SelectionofNo

nexpos

edCo

hort

Ascertainm

ent

ofExpo

sure

Demon

stratio

nTh

atOu

tcom

eof

Interest

Not

Presen

tatS

tart

Compa

rability

ofCo

hortson

Basisof

Design

/An

alysis

(Out

ofPo

ssible

2)

Metho

dology

Addresses

Confou

nding

byIndica

tion

Assessmen

tof

Outcom

eFollo

w-up

Long

Enou

gh

Adeq

uacy

ofFollo

w-upof

Coho

rts(toDischa

rge)

Adeq

uacy

ofFollo

w-up

ofCo

horts

(Lon

g-term

)

Merritt,1

9783

6*

**

*

No*

**

N/A

7/9

Merritt,1

9793

7*

**

*

No*

**

*8/10

Cats,1

9803

8*

**

*

No*

**

N/A

7/9

Mikha

il,19

8239

**

**

No

**

*N/A

7/9

Zerella

,198

340

**

**

No

**

*N/A

7/9

Wag

ner,19

8441

**

**

No

**

*N/A

7/9

Castan

on,1

9884

2*

**

*

No*

**

N/A

7/9

Trus

,199

343

**

**

No

**

*N/A

7/9

Perez,19

9844

**

**

No

**

*N/A

7/9

Koeh

ne,2

0014

5*

**

*

No*

**

N/A

7/9

Niinikos

ki,2

0014

6*

**

*

No*

**

N/A

7/9

Little,2

0034

7*

**

*

No*

**

N/A

7/9

ODo

novan,

2003

48*

**

*

No*

**

N/A

7/9

Hwan

g,20

0549

**

**

No

**

*N/A

7/9

Lee,

2006

50*

**

*

No*

*

N/A

6/9

Pelaus

a,20

0651

**

**

**No

**

*N/A

9/9

Kabra,

2007

11*

**

***

No*

**

*10

/10

Laug

hon,

2007

52*

**

*

No*

**

N/A

7/9

Quresh

i,20

0853

**

**

No

**

*N/A

7/9

Sato,2

0085

4*

**

*

No*

**

N/A

7/9

Tsch

uppe

rt,2

0085

5*

**

*

No*

**

N/A

7/9

Alexan

der,20

0956

**

**

No

**

*N/A

7/9

Ko,2

0095

7*

**

*

No*

**

N/A

7/9

Mad

an,2

0091

0*

**

***

No*

**

*10

/10

Quresh

i,20

0958

**

**

**Yes

**

**

10/10

Vida

,200

959

**

**

No

**

*N/A

7/9

Chiruvolu,

2010

60*

**

*

No*

**

N/A

7/9

Lope

s,20

1061

**

**

No

**

*

7/10

Natarajan,

2010

62*

**

*

No*

**

N/A

7/9

Rheinlae

nder,20106

3*

**

***

Yes

**

**

10/10

Pelaus

a,20

1164

**

**

*No

**

**

9/10

Adrouc

he-Amrani,

2012

65*

**

*

No*

**

N/A

7/9

Heuc

han,

2012

66*

**

*

No*

**

N/A

7/9

Hsu,

2012

34*

**

***

No*

**

N/A

9/9

Mirea

,201

28*

**

***

No*

**

N/A

9/9

Moo

re,2

0123

3*

**

***

No*

**

N/A

9/9

Jawa,

2013

30*

**

**

Yes

**

*

8/10

Tsui,2

0133

1*

**

*

No*

**

N/A

7/9

Youn

,201

332

**

**

**No

**

*N/A

9/9

N/A,

notap

plicab

le.

aMod

ied

Newca

stle-Ottaw

ascale(Sup

plem

entalInformation2).

bMaxim

um9(for

stud

iesrepo

rtingne

onatal

outcom

es)or

10(for

stud

iesrepo

rtingne

urod

evelop

men

talo

utco

mes).


aOR: 1.54; 95% CI: 1.012.33; I 2 =48%) (Fig 5A, Table 2). There wasa trend toward higher NDI amonginfants treated with NSAIDs andligation compared with infantstreated with NSAIDs alone (2 stud-ies, 2441 participants; aOR: 1.39;95% CI: 0.971.98; I 2 = 29%) (Fig5B, Table 2).

5. Death or NDI in early childhood: 4studies reported the composite out-come comparing all surgically andmedically treated infants. Madanet al10 reported on the neurodevel-opmental outcomes of 2838 infantswith birth weights of 400 to 1000 gwho survived .72 hours and had

a symptomatic PDA and follow-up at18 to 21 months corrected GA.Kabra et al11 performed a secondaryanalysis of the Trial of IndomethacinProphylaxis in Preterm Infants.Pelausa et al64 performed a retro-spective cohort study comparinga small group of ligated preterminfants with a group of medicallytreated infants matched for GA,body weight, and gender. Qureshiet al58 reported a multivariate anal-ysis of a retrospective cohort ofpreterm infants with PDA, adjustingfor PDA-related illness severity atthe time of the decision to treatthe PDA. Meta-analysis of these

studies revealed no difference inthe composite outcome of deathor NDI between surgically and med-ically treated infants (4 studies,3512 participants; pooled aOR: 0.95;95% CI: 0.581.57; I 2 = 71%) (Fig 6,Table 2). Most of the statistical hetero-geneity between these 4 studies isaccounted for by 1 study,58 whichwas the only study to report a signif-icant protective effect of surgical liga-tion. Importantly, this study was alsothe only one in this review to controlfor confounding by indication.

6. Cognitive impairment: only 1 study11

reported an adjusted estimate ofcognitive impairment and found

FIGURE 2Adjusted estimates of death. A, All Ligation versusAllMedicalManagement only. B, NSAIDand Ligation versusNSAID only. C, Primary Ligation versusNSAIDonly. D,Primary Ligation versus Conservative. df, degrees of freedom; IV, inverse variance; Mgmt, management.

REVIEW ARTICLE


increased odds associated with liga-

tion compared with medical manage-

ment alone (331 participants; aOR:

1.96; 95% CI: 1.143.37) (Table 2).

7. Cerebral palsy: meta-analysis re-vealed that there was no difference

in the odds of cerebral palsy11,63

between those who underwent sur-

gical ligation and those treated

medically (2 studies, 616 partici-

pants; pooled aOR: 1.51; 95% CI:

0.862.63; I 2 = 0%) (Fig 5C, Table 2).

DISCUSSION

In this systematic review and meta-analysis of the effects of PDA treatmentassignment on neonatal and neuro-developmental outcomes, we identiedthat surgical ligation is associated with

FIGURE 3Adjusted estimates of CLD. A, All Ligation versus All MedicalManagement only. B, NSAID and Ligation versus NSAID only. C, Primary Ligation versus NSAID only. df,degrees of freedom; IV, inverse variance; Mgmt, management.

FIGURE 4Adjusted estimates of severe ROP. A, All Ligation versus All MedicalManagement only. B, NSAID and Ligation versus NSAID only. df, degrees of freedom; IV, inversevariance; Mgmt, management.


decreasedmortality but increased NDI inearly childhood when compared withmedical treatment alone. There are sev-eral possible explanations for the di-vergence of these competing outcomes:rst, surgical ligation may improve thesurvival of infants but be simultaneouslyneurologically detrimental; second, sur-gical ligationmay improve the survival ofinfants, but infants referred for ligationmay be at higher preligation risk of NDI(confounding by indication); and nally,the decrease in mortality may be inu-enced by survival bias (where medicallytreated infants with a PDA die before

being referred for ligation), with theincrease in NDI explained by either con-founding by indication or a true detri-mental effect of ligation.

Several aspects of treatmentwith ligationhave been proposed as contributing to anincreased risk of NDI, such as surgical oranesthesia effects or postoperative he-modynamic compromise. Early surgicalmortality associated with PDA ligation isreported to be low.49,56,66 Direct surgicalmorbidities include bleeding, pneumo-thorax, and left vocal cord paresis (VCP).The incidence of left VCP is variable butmay complicate 5% to 50% of PDA liga-

tions and is associated with an increasedrisk of death, extubation failure, CLD, needfor gastrostomy tube, and gastroesoph-ageal reux disease.66,147149 Recentstudies have reported an association be-tween the use of halothane gases for an-esthesia in young children and NDI.150,151

Preterm infants are at risk of postligationhemodynamic instability, which may re-sult in cerebral hypoperfusion, neuronalinjury, and subsequent NDI.152157 In ourreview, only 1 of the included studies30

reported on an association of VCP andNDI, and no study described an associa-tion between postligation hemodynamic

FIGURE 5Adjusted estimates of NDI in early childhood (A, B) and cerebral palsy (C). A, All Ligation versus All MedicalManagement only. B, NSAID and Ligation versus NSAIDonly. C, All Ligation versus All Medical Management only. df, degrees of freedom; IV, inverse variance; Mgmt, management.

FIGURE 6Adjusted estimate of the composite outcome of death or NDI in early childhood: All Ligation versus All Medical Management only. df, degrees of freedom; IV,inverse variance; Mgmt, management.

REVIEW ARTICLE


instability and NDI. Infants with lower GAand weight,1 kg at the time of ligationare at highest risk of postligation hemo-dynamic instability, possibly due todecreased myocardial adaptability to al-tered loading conditions.158 This ndingraises the possibility that age at ligationmay contribute to the risk of NDI; how-ever, a post hoc analysis of the Trial ofIndomethacin Prophylaxis in PretermInfants found no association between thetiming of PDA ligation and the risk ofNDI.11

Despite the reported association be-tween ligation and NDI, observationalstudies to date have not adequately dif-ferentiated theeffect of biasversusa truedetrimental effect of ligation. In general,observational studies are subject to biaswhen treatment assignment is not in-dependentofbaselineprognostic factors.Many of the included studies did notperformanyadjustment forconfounders.Infants who underwent surgical ligationof their PDA had signicantly differentbaseline characteristics compared withtheir medically treated peers, with gen-erally lowerGAandbirthweight (Table 1).The presence of these major con-founders limits the validity of unadjustedcomparisons. In addition, most of themultivariate analyses included in thisreview only adjusted for antenatal orperinatal covariates (Table 1). This set ofcovariates, if complete, would be suf-cient to balance baseline prognosticfactors for interventions that occurshortly after birth. However, PDA ligationoften occurs several weeks after birth,and the interval accumulation of PDA-associated comorbidities inuences bothtreatment assignment and outcomes.

Themost importantsourceofbias in theincluded multivariate studies is con-founding by indication, in which infantswith higher illness severity, whomay beat higher risk of NDI,159,160 may be morelikely to be assigned to ligation. Only 1study58 adjusted for preligation post-natal confounders, such as IVH or the

duration/intensity of mechanical ven-tilation at the time of the decision totreat the PDA. In the setting of surgicalligation, severe IVH is a potential con-founder. It has been associated withPDA ligation45,52,62 and NDI161165 and isnot typically on the causal pathwaybetween PDA ligation and NDI. Most IVH(90%) occurs in the rst week of life,166

preceding the timing of surgical liga-tion reported inmost studies.33,45,48,50,59

Other potential key confounders includeprolonged duration of mechanical ven-tilation, severe hypotension, postnatalsepsis, and NEC, which increase illnessseverity but are also associatedwith PDAligation, death, NDI, CLD, and ROP.167175

These morbidities, however, can occurbefore, during, or after PDA treatmentsand thus may be considered con-founders in some infants and outcomesin others. Therefore, data on the timingof these confounders relative to ligationshould be incorporated into multivari-able models examining the impact ofsurgical treatment.

The lowermortality in the ligated groupmay be attributable, in part, to survivalbias. The PDA treatment algorithms inmany of the included studies (Table 1)cited that infants were treated with li-gation when indomethacin failed orwas contraindicated. Ligation was of-ten undertaken later in life relative tomedical therapy, meaning that ligatedinfants were more likely to have al-ready survived the period of high earlyneonatal mortality. This implies thatsome of the sickest infants, treatedinitially with conservativemanagementand/or indomethacin, may have diedbefore becoming eligible for ligation,resulting in selection bias in assem-bling the cohort of ligated infants. Thisissue was present inmost of the cohortstudies, and thus our ndings of de-creased mortality should be inter-pretedwith caution. Future studies thatcompare surgical ligation with medicaltherapy should ensure careful match-

ing of the control population with con-sideration of age at ligation.

The possibility of survival bias is sup-ported by ndings of the subgroupmeta-analyses. Survival bias associ-ated with ligation would be expected tomanifest as an apparent survival ad-vantage when ligation is performedlater in life, but that ligation performedat a similar day of life as medicaltherapy would have similar mortalityrates.We found that infants treatedwithNSAIDs and ligation had lower adjustedodds of death compared with infantswhounderwent treatmentwithprimaryligation, NSAIDs alone, or conservativemanagement (Table 3). In studies inwhich ligation was performed early inlife (either as primary therapy or im-mediately after failure of indomethacinin the rst week of life), there was nodifference in mortality compared withmedically treated infants.12,84

If ligation truly improved survival (andsurvival bias was not a factor), thena reduction in rates of surgical treat-ment might be expected to increasemortality, assuming that the clinicalcharacteristics of infants remained thesame. Two studies14,17 reported nochange in mortality across epochs af-ter moving to a delayed selective liga-tion strategy from an early routineligation strategy after indomethacinfailure. However, other studies havereported an increase inmortality whensurgical ligation was no longer avail-able176 and when ligation was notperformed in infants with a persistentPDA after failure of medical therapy.177

This nding suggests that both survivalbias and a true survival benet ofsurgical ligation may be present.

We found that infants exposed to PDAligation also had increased CLD andsevere ROP. This is biologically sup-ported by the potential cardiorespira-tory instability and inammatory effectsassociated with surgical ligation178180

and was shown in a secondary analysis


of anRCTof early prophylactic ligation inextremely low birth weight infants.9,77

Given its association with NDI, this riskof CLD may represent a plausible path-way for the increased NDI associatedwith ligation.181183 Nonetheless, con-founding by indication remains an im-portant source of bias in these studiesas well. Only 1 study controlled forpostnatal sepsis,10 a known risk factorfor CLD,184 and this study did not dif-ferentiate between sepsis that occurredbefore or after surgical ligation. In ad-dition, ventilator dependence is com-monly considered an indication forligation in infants in whom medicaltherapy had failed or was contra-indicated,33,44,47,48,62 and yet it is alsoa risk factor for CLD.185 Given the asso-ciation between CLD and ROP and deathor NDI,181,182,186 it is important, whenanalyzing these outcomes, to adjust forpreligation respiratory morbidity.

Conclusions and Implications

This systematic reviewandmeta-analysisidentied an association between PDAligation and decreased odds of death;

increased odds of CLD, ROP, and NDI inearly childhood; and no difference in thecomposite outcome of death or NDI.However, this association comes pre-dominantly from observational studiesthat inadequatelyaddressedsurvivalbiasand confounding by indication. Many ofthese studies also lacked standardizedechocardiographicandclinical criteria todene a hemodynamically signicantPDA. Our review highlights the difcultyfaced by clinicians considering surgicalligation. The clinician must navigate lit-erature that reports an association withsignicant morbidity, albeit fraught withmethodologic biases and clinical un-certainty regarding patient selection andthe optimal timing for surgery.

This study provides direction to improvetheavailable evidence toguidecliniciansabout thePDA ligationdecision.Whereasan RCT examining 2 different PDA treat-ment protocolswould be instructive, thevariability in practice among centersmay reduce the external validity of sucha trial. Observational studies are there-fore needed that adjust for preligation

time-dependent covariates to fully elu-cidate the effects of PDA ligation.

Strengths and Limitations

This review encompasses a comprehen-sive search and explicit inclusion andexclusion criteria and poses clinicallyimportant questions. There was low tomoderate clinical and statistical hetero-geneity in most studies included in thisreview. This meta-analysis is limited by apaucity of studies that performed multi-variate analyses and the insufciency ofthese studies in addressing survival biasand confounding by indication for post-natal morbidities, such as ventilator depen-dence, IVH, sepsis, or NEC, that occurredbefore treatment with surgical ligation.

ACKNOWLEDGMENTSWe thank Ms Elizabeth Uleryk, BA MLS, Di-rectorHospital Library&Archives, TheHos-pital for Sick Children, for her assistancewith conducting the literature search andDrLuciaMireaMt. SinaiHospital, DrGregoryMoore (University of Ottawa), andDr Nicholas Barrowman (University of Ot-tawa) for providing additional study data.

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