Prenatal Risk Factors and Outcomesin Gastroschisis A Meta-AnalysisFrancesco DrsquoAntonio MD PhDa Calogero Virgone MDb Giuseppe Rizzo MDc Asma Khalil MDa David Baud MD PhDdTitia E Cohen-Overbeek MD PhDe Marina Kuleva MDf Laurent J Salomon MD PhDf Maria Elena Flacco MDghLamberto Manzoli MD PhDgh Stefano Giuliani MD PhDb

abstractBACKGROUND AND OBJECTIVE Gastroschisis is a congenital anomaly with increasing incidence easy prenataldiagnosis and extremely variable postnatal outcomes Our objective was to systematically review theevidence regarding the association between prenatal ultrasound signs (intraabdominal bowel dilatation[IABD] extraabdominal bowel dilatation gastric dilatation [GD] bowel wall thickness polyhydramnios andsmall for gestational age) and perinatal outcomes in gastroschisis (bowel atresia intra uterine deathneonatal death time to full enteral feeding length of total parenteral nutrition and length of in hospital stay)

METHODS Medline Embase and Cochrane databases were searched electronically Studies exploring theassociation between antenatal ultrasound signs and outcomes in gastroschisis were considered suitablefor inclusion Two reviewers independently extracted relevant data regarding study characteristics andpregnancy outcome All meta-analyses were computed using individual data random-effect logisticregression with single study as the cluster unit

RESULTS Twenty-six studies including 2023 fetuses were included We found significant positive associationsbetween IABD and bowel atresia (odds ratio [OR] 548 95 confidence interval [CI] 31ndash98) polyhydramniosand bowel atresia (OR 376 95 CI 17ndash83) and GD and neonatal death (OR 558 95 CI 13ndash241) No otherultrasound sign was significantly related to any other outcome

CONCLUSIONS IABD polyhydramnios and GD can be used to an extent to identify a subgroup of neonateswith a prenatal diagnosis of gastroschisis at higher risk to develop postnatal complications Data are stillinconclusive on the predictive ability of several signs combined and large prospective studies are neededto improve the quality of prenatal counseling and the neonatal care for this condition

aFetal Medicine Unit Division of Developmental Sciences St Georgersquos University of London London United Kingdom bDepartment of Paediatric and Neonatal Surgery St Georgersquos HealthcareNational Health Service Trust and University of London London United Kingdom cDepartment of Obstetrics and Gynecology Universitagrave di Roma Tor Vergata Roma Italy dMaterno-Fetal andObstetrics Research Unit Department of Obstetrics and Gynaecology University Hospital Lausanne Switzerland eDepartment of Obstetrics and Gynaecology Division of Obstetrics andPrenatal Medicine Erasmus MC Rotterdam The Netherlands fMaterniteacute Hocircpital Necker-Enfants Malades Assistance Publique des Hocircpitaux de Paris Universiteacute Paris Descartes Paris FrancegDepartment of Medicine and Aging Sciences University of Chieti-Pescara Chieti Italy and hEMISAC (Epidemiologia e Management dellrsquoInvecchiamento e Salubritagrave degli Ambienti Confinati)CeSI Biotech Chieti Italy

Drs DrsquoAntonio and Giuliani designed and conceptualized the study extracted the data performed the statistical analysis wrote the manuscript and reviewed and revised themanuscript Dr Virgone designed and conceptualized the study extracted the data performed the statistical analysis wrote the manuscript and reviewed and revised themanuscript Drs Rizzo Khalil Cohen-Overbeeck Baud Kuleva and Salomon designed the study contributed to data extraction and reviewed and revised the manuscriptDrs Flacco and Manzoli designed the study performed statistical analysis and reviewed the manuscript and all authors approved the final manuscript as submitted

wwwpediatricsorgcgidoi101542peds2015-0017

DOI 101542peds2015-0017

Accepted for publication Apr 14 2015

Address correspondence to Stefano Giuliani MD PhD Department of Paediatric and Neonatal Surgery St Georgersquos Healthcare NHS Trust and University of LondonBlackshaw Rd London SW17 0QT United Kingdom E-mail Stefanogiulianinhsnet

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2015 by the American Academy of Pediatrics

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

FUNDING No external funding

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

PEDIATRICS Volume 136 number 1 July 2015 REVIEW ARTICLE by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

Gastroschisis is an abdominal walldefect located on the right side of theumbilicus that allows herniation of theabdominal content and its directexposure to the amniotic fluid for themajority of the pregnancy Theincidence of gastroschisis has risenworldwide in recent decades to reach2 to 5 per 10 000 live births1 Thepostnatal outcome is favorable in casesof simple gastroschisis (continuousand uncompromised intestine) witha survival rate 95 and lowmorbidity12 In contrast complexgastroschisis (intestinal atresianecrosis or perforation) is associatedwith worse survival rate (70ndash80)longer hospital stay and higher long-term morbidity23 The highly variablereturn to functional bowel (due tochronic intestinal inflammation) andthe occurrence of bowel atresia (BArequiring intestinal surgery insim10ndash20 of cases) are the mainfactors affecting length of hospital stay(LOS) as well as total parenteralnutrition (TPN) dependence andassociated neonatal complications (ierecurrent sepsis TPN cholestasisadhesive bowel obstruction)24ndash6

Different surgical techniques (primaryvs staged closure) to repair thisabdominal wall defect did not showsignificant differences in outcomes2

In developed countries prenataldiagnosis allows a 90 detection rateof gastroschisis within the secondtrimester of pregnancy7 A regularultrasound monitoring of the fetuswith gastroschisis aims to define sizeand quality of the herniated intestine(bowel dilatation or thickening)amount of amniotic fluid and fetalgrowth Prenatal definition of simpleand complex gastroschisis is importantto establish accurate prenatalcounseling and to plan delivery siteand postnatal medical and surgicaltreatments Recently severalultrasound signs such as boweldilatation polyhydramnios and bowelwall thickness (BWT) have beenreported to be associated with theoccurrence of unfavorable outcomesand in particular with BA58ndash11

However these studies were oftenbased on small sample sizes and theresults did not reach good evidenceexamining single data sets in isolation

The aim of this study was to definewhich prenatal ultrasound markerswere associated with postnataloutcome in gastroschisis A meta-analysis was conducted to pool anyrelative risk estimates from theexisting literature on the associationbetween various ultrasound signs andthe occurrence of atresia intrauterinedeath (IUD) and neonatal death(NND) LOS time to full enteral feeding(TFEF) and length of TPN (LTPN) inan attempt to determine if there wasan association and if so its magnitude

METHODS

Protocol Eligibility CriteriaInformation Sources and Search

This review was performed accordingto an a priori designed protocol andrecommended for systematic reviewsand meta-analysis12ndash14 MedlineEmbase the Cochrane Libraryincluding the Cochrane Database ofSystematic Reviews Database ofAbstracts of Reviews of Effects andthe Cochrane Central Register ofControlled Trials were searchedelectronically in June 2014 usingcombinations of the relevant medicalsubject heading terms key wordsand word variants for ldquogastroschisisrdquoand ldquooutcomerdquo (Supplement 1) Thesearch and selection criteria wererestricted to English languageReference lists of relevant articlesand reviews were hand searched foradditional reports The PRISMA(Preferred Reporting Items forSystematic Reviews and Meta-Analyses) guidelines15 were followed(Supplementary Fig 2 Supplement 2)The study was registered with thePROSPERO database (registrationnumber CRD42014007640)

Study Selection Data Collection andData Items

Studies were assessed according to thefollowing criteria population outcome

gestational age at examination andultrasound signs explored Two authors(FD CV) reviewed all abstractsindependently Agreement aboutpotential relevance was reached byconsensus and full-text copies of thosearticles were obtained Two reviewers(FD CV) independently extractedrelevant data regarding studycharacteristics and pregnancy outcomeInconsistencies were discussed by thereviewers and consensus reached If1 study was published for the samecohort with identical end points thereport containing the mostcomprehensive information on thepopulation was included to avoidoverlapping populations For thosearticles in which information was notreported but the methodology wassuch that this information would havebeen recorded initially the authorswere contacted

Quality assessment of the includedstudies was performed using theNewcastle-Ottawa Scale (NOS) forcohort studies (Supplement 3)16

Summary Measures Synthesis of theResults and Risk of Bias

The ultrasound signs analyzed in thisreview were as follows

bull Intraabdominal bowel dilatation(IABD)

bull Extraabdominal bowel dilatation(EABD)

bull Gastric dilatation (GD)

bull BWT

bull Polyhydramnios

bull Small for gestational age (SGA)

The outcomes analyzed in thissystematic review were as follows

bull BA

bull IUD

bull NND

bull LOS

bull TFEF

bull LTPN

IABDwas defined as the dilatation of thebowel inside the abdomen irrespectiveof the presence of EABD EABD was

e160 DrsquoANTONIO et al by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

defined as the occurrence of thedilatation of the extruded part of thebowel only This choice was based on theassumption that EABD is almostinvariably present in fetuses withgastroschisis most likely representingthe consequence of bowel exposure tothe amniotic fluid whereas IABD is onlyoccasionally described in this conditionGD was defined as the enlargement ofthe stomach and BWT was themeasurement of the wall of the bowelinside or outside the defect SGA wasdefined as an estimated fetal weight5th or 10th percentile according to thecutoff adopted In view of the multitudeof cutoffs reported for all theseultrasound measurements a subanalysisaccording to the threshold chosen todefine an ultrasound sign as abnormalwas carried out when possible BA wasdefined as a congenital obstruction ofthe bowel lumen IUD was defined asfetal loss in the second and thirdtrimester of pregnancy and NND as theoccurrence of a death in the neonatalperiod up to 28 days of life LOS wasdefined as the time from birth todischarge home TFEF was defined asthe time necessary to achieve fullenteral nutrition and LTPN as the timeof full dependency on parenteralnutrition

Only studies reporting prenatalultrasound data of fetuses withgastroschisis were consideredsuitable for the inclusion in thecurrent systematic review postnatalstudies or studies from which casesdiagnosed prenatally could not beextracted were excluded Autopsy-based studies were excluded on thebasis that fetuses undergoingtermination of pregnancy are morelikely to show associated majorstructural and chromosomalanomalies Studies not reporting thesite of the dilatation (intra or extra-abdominal) were not consideredeligible for the inclusion

Studies published before 2000 werenot included in the currentsystematic review because advancesin prenatal imaging techniques has

led to a huge improvements in thediagnosis and definition of prenatalstructural anomalies Furthermorea recent systematic review exploringthe association between EABD andseveral adverse perinatal outcomesincluded studies published before200017

Case reports conference abstractsand case series with 3 casesirrespective of whether the anomalieswere isolated were also excluded toavoid publication bias

Statistical Analysis

Overall we evaluated separately theassociation between 6 potentialpredictors (IABD EABD GDpolyhydramnios SGA) and 6 adverseclinical outcomes (IUD NND BATFEF LTPN LOS) A sufficientnumber of studies with comparableoutcomes were available for only 3outcomes (IUD NND and BA) anda total of 6 3 3 = 18 separate meta-analyses were thus carried out Forthe other outcomes (LOS LTPN andTFEF) heterogeneity in the data didnot allow to perform a meta-analysis

The units of the meta-analysis weresingle comparisons of subjectswith abnormal versus normalultrasound signs in predicting eachof the selected clinical outcomesduring the scheduled follow-upAccordingly when a study reportedseparate relative risks for differentpatient characteristics (ie levelsof dilation) all subgroups weregrouped and a single estimate ofrisk was calculated for the studyUnfortunately the scarce number ofstudies did not permit meaningfulstratified meta-analyses to explorethe test performance in subgroupsof patients who may be less ormore susceptible to bias For thepurpose of this analysis whenmultiple cutoffs were reported thatshowing the highest degree ofassociation as reported by theauthors was selected to calculatethe ORs

We included observational cohortstudies in which

(a) many comparisons reported0 events in 1 group

(b) several comparisons reported0 events in both groups and

(c) exposed and unexposed groupsizes were frequently severelyunbalanced

Many of the most commonly usedmeta-analytical methods includingthose using risk difference (whichcould be used to handle total zero-event studies) can produce biasedestimates when events are rare1819

When many studies are alsosubstantially imbalanced the bestperforming methods are the Mantel-Haenszel odds ratio (OR) without zero-cell continuity corrections logisticregression and an exact method2021

Mantel-Haenszel ORs cannot becomputed in studies reporting 0 eventsin both groups the exclusion of whichmay however cause a relevant loss ofinformation and the potential inflationof the magnitude of the pooledexposure effect18 To keep all studiesinto the analyses we thus performedall meta-analyses using individual datarandom-effect logistic regression withsingle study as the cluster unit Thepooled data sets with individual datawere reconstructed using published 23 2 tables When 1 of the overallpooled arms showed no events weused exact logistic regression includingindividual studies as dummy variablesThe assessment of the potentialpublication bias was performed withEggerrsquos regression asymmetry test22

All analyses were performed usingStata version 130 (Stata Corp CollegeStation TX)

RESULTS

A total of 869 articles were identified73 were assessed with respect totheir eligibility for inclusion(Supplementary Table 8) Twenty-sixstudies were included in the

PEDIATRICS Volume 136 number 1 July 2015 e161 by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

systematic review (Fig 1) These 26studies included 2023 fetuses witha prenatal diagnosis of gastroschisis

The general characteristics of thestudies included in the systematicreview are reported in Table 1Quality assessment of the includedstudies was performed usingNewcastle-Ottawa Scale for cohortstudies Almost all the includedstudies showed an overall good ratewith regard to the selection andcomparability of the study groups andto the ascertainment outcome ofinterest (Table 2)16 The majorweaknesses of these studies wererepresented by their retrospectivedesign with the lack of a blind

assessment of antenatal imaging inrelation to the outcome exploreddifferent thresholds adopted todefined an ultrasound sign asabnormal and lack of a standardizedoutcome measure

The definitions of the ultrasoundsigns used in each study are shown inTable 3 Several cutoffs were usedamong the studies to define a scan asabnormal furthermore most of theincluded studies did not assess thereproducibility interobserver andintraobserver variability of a givensign Finally for most of theultrasound signs explored anobjective explanation in terms onhow (ie imaging plane ultrasound

machine setting type of scan) andwhen a given sign was assessed wasmissing (Table 3)

The assessment of the potentialpublication bias was problematicbecause of the scarce number ofstudies and sparse events Theformal tests for funnel plotasymmetry cannot be used when thetotal number of publicationsincluded for each outcome is 10because its power is too low todistinguish chance from realasymmetry20 Furthermore in 2 ofthe 3 comparisons including 10studies the number of events wastoo scarce to allow formal testing(n 15 overall) We were thus able

FIGURE 1Flow chart of studies included in the meta-analysis

e162 DrsquoANTONIO et al by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

to assess publication bias in 1 meta-analysis only (IABD as a predictor ofBA) we displayed the ORs ofindividual studies versus thelogarithm of their SE22 (ndash014428795 confidence interval [CI] =ndash1290532 to 1001958 P = 779)(Supplemental Figure 2)

IABD

Nine studies (673 fetuses) exploredthe association between IABD and theoccurrence of BA

Fetuses with ultrasound evidence ofIABD irrespective of the presence ofEABD had a significantly higher risk ofBA diagnosed at surgery (OR 548 95CI 31ndash98) whereas the risk of IUD orNND was not significantly higher thanfetuses without IABD (Table 4)

Three studies243441 explored theassociation between IABD and theoverall postnatal LOS These studiesused different thresholds ofdilatation to define the bowel asabnormal in the largest study24

fetuses with an IABD 14 mm hada significant prolonged LOScompared with those with lessdilated bowel (805 daysinterquartile range [IQR] 345ndash1365vs 475 days IQR 310ndash780 P 02) Likewise Nick41 using GA-corrected cutoff for bowel dilatationreported a median LOS of 84 days infetuses with dilatation comparedwith 265 days in those withoutwhereas Huh34 could not find anyassociation between IABD and lengthof hospitalization (Table 5)

Two studies2434 explored theassociation between IABD and the TFEFBoth did not report any significantincreased risk in fetuses showing IABDregarding this outcome (Table 6)

Finally the presence of IABD was notfound to be significantly associatedwith the LTPN (Table 7)

EABD

Ten studies (659 fetuses) exploredthe association between EABD andthe occurrence of bowel atresiaTA

BLE1

GeneralCharacteristicsof

theIncluded

Studies

Author

Year

Country

StudyDesign

GAat

Scan

Fetuses(n)

Prenatal

Ultrasound

SignsExplored

Outcom

e(s)

Explored

Overcash

a2014

UnitedStates

Retrospective

1wkbefore

delivery

191

SGA

BAN

NDGoetzinger

2014

UnitedStates

Retrospective

3376

26wk

94IABD

EABD

BWT

BAN

NDLOSLTPN

TFEF

Janoo

2013

UnitedStates

Retrospective

2ndash3wkfrom

delivery

25SGApolyhydram

nios

IUD

NND

Durfee

2013

UnitedStates

Retrospective

76d(0ndash69)before

delivery

84EABD

BWTSGA

IUD

Emila

2012

Canada

Retrospective

Thirdtrimester

83IABD

EABD

GDSGApolyhydramnios

BAGhionzolia

2012

UnitedKingdom

Retrospective

From

30wk

130

IABD

EABD

GDpolyhydramnios

BAOverton

2012

UnitedKingdom

Retrospective

Secondndashthirdtrimester

217

Polyhydram

niosSGA

IUD

NND

Kuleva

a2011

France

Retrospective

Thirdtrimester

105

IABD

EABD

GDSGAB

WT

BAIUD

NND

Ajayi

2011

UnitedStates

Retrospective

Secondndashthirdtrimester

74SGApolyhydram

nios

IUD

NND

Alfaraja

2011

Canada

Retrospective

Within

2wkof

delivery

98IABD

aGD

polyhydramnios

BAIUD

NND

LOS

TFEFLTPN

Mears

a2010

UnitedKingdom

Retrospective

Secondndashthirdtrimester

47IABD

EABD

BAaNN

DLTPN

Contro

a2010

UnitedKingdom

Retrospective

From

32wk

48IABD

EABD

polyhydram

nios

BAIUD

NND

Garciaa

2010

Brazil

Retrospective

3566

16wk

94EABD

BAIUD

NND

LOSTFEF

Huh

2010

UnitedStates

Retrospective

Secondndashthirdtrimester

43IABD

BAIUD

NND

LOSTFEF

Hidaka

2009

Japan

Retrospective

Secondndashthirdtrimester

11Polyhydram

nios

IUD

NND

Payne

2009

UnitedStates

Retrospective

Within

4wkof

delivery

155

Polyhydram

nios

LOS

Towers

2008

UnitedStates

Retrospective

Notstated

75Polyhydram

nios

IUD

Heinig

2008

Germ

any

Retrospective

Notstated

14EABD

BWT

IUD

BACohen-Overbeek

a2008

TheNetherlands

Retrospective

Secondndashthirdtrimester

24IABD

aEABD

SGApolyhydramnios

BAIUD

NND

Santiago-Munoz

2007

UnitedStates

Retrospective

Secondndashthirdtrimester

58SGAGD

IUD

Brantberga

2006

Norw

ayProspective

From

34ndash36

wk

60IABD

BAIUD

NND

Nick

2006

UnitedStates

Retrospective

Secondndashthirdtrimester

58IABD

SGA

BAIUD

LOSN

NDPuliglandaa

2004

Canada

Retrospective

Secondndashthirdtrimester

96SGA

BAAina-Mum

uney

2004

UnitedStates

Retrospective

28ndash36

wk

34GD

BAIUD

NND

LOSTFEF

Strauss

2003

UnitedStates

Retrospective

Notstated

60EABD

SGA

BAIUD

NND

Japaraj

2003

Australia

Retrospective

Within

2ndash3wkof

delivery

45EABD

BWTpolyhydram

niosSGA

IUD

NND

LOS

aAdditionalinform

ationprovided

bytheauthors

PEDIATRICS Volume 136 number 1 July 2015 e163 by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

Fetuses showing evidence of EABDwere not at increased risk of havingBA Likewise the risk of IUD and NND

in those fetuses was not significantlyhigher than that of the controlpopulation (Table 4)

Two studies3345 analyzed theassociation between EABD and LOSIn the study by Garcia et al34 theauthors found that fetuses withultrasound evidence of EABD 25 mmhad a significantly longer LOS(424 6 197 days) compared withthose without (333 6 223 days P =04) whereas Japarai usinga different threshold of dilatation(17 mm) did not find any associationbetween EABD and LOS (Table 5)

Only 1 study34 explored the associationbetween EABD and TFEF and found thatfetuses with EABD 25 mm hadsignificantly longer times to reach thefull enteral feeding (257 6 128 vs 1826 99 days P = 02) compared withthose without EABD (Table 6)

Finally the only study31 exploring theassociation between EABD and LTPNcould not find any significant associationbetween this ultrasound sign and theobserved outcome (Table 7)

GD

Five studies (449 fetuses) exploredthe association between GD andoutcome Fetuses with GD diagnosed

TABLE 2 Quality Assessment of the Included Studies According to Newcastle-Ottawa Scale

Author Year Selection Comparability Outcome

Overcash23 2014

Goetzinger24 2013

Janoo25 2013

Durfee26 2013

Emil27 2012

Ghionzoli6 2012

Overton28 2012

Kuleva3 2011

Ajayi29 2011

Alfaraj30 2011

Mears31 2010

Contro32 2010

Garcia33 2010

Huh34 2010

Hidaka35 2009

Payne10 2009

Towers36 2008

Heinig37 2008

Cohen-Overbeek38 2008

Santiago-Munoz39 2007

Brantberg40 2006

Nick41 2006

Puligandla42 2004

Aina-Mumuney43 2004

Strauss44 2003

Japaraj45 2003

A study can be awarded a maximum of 1 star for each numbered item within the Selection and Outcome categories Amaximum of 2 stars can be given for comparability See Supplement 2

TABLE 3 Description of Ultrasound Signs Used Among the Studies Included

Author Year IABD EABD GD BWT SGA (Percentile)

Overcash23 2014 mdash mdash mdash mdash 10thGoetzinger24 2014 6 10 14a 18 mm 6 10 14 18 mm mdash 3 mm mdash

Janoo25 2013 mdash mdash mdash mdash Not statedDurfee26 2013 mdash 8 mm mdash 1 mm mdash

Emil27 2012 Not stated Not stated Not stated mdash 10thGhionzoli6 2012 18 mm 18 mm Not stated mdash mdash

Overton28 2012 mdash mdash mdash mdash Not statedKuleva3 2011 6 mm 6 mm 2 SD 3 mm 10thAjayi29 2011 mdash mdash mdash mdash 10thAlfaraj30 2011 mdash mdash 2 SD mdash mdash

Mears31 2010 10 mm 10 mm mdash mdash mdash

Contro32 2010 6 mm 6 mm mdash mdash mdash

Garcia33 2010 15 20 25 30 mm mdash mdash mdash

Huh34 2010 Not stated mdash mdash mdash mdash

Hidaka35 2009 mdash mdash mdash mdash mdash

Payne10 2009 mdash mdash mdash mdash mdash

Towers36 2008 mdash mdash mdash mdash mdash

Heinig37 2008 mdash 15 20 25 mm mdash 3 mm mdash

Cohen-Overbeek38 2008 mdash 10 mm mdash mdash 10thSantiago-Munoz39 2007 mdash mdash GA dependent mdash mdash

Brantberg40 2006 Not stated mdash mdash mdash mdash

Nick41 2006 GA dependent mdash mdash mdash 10thPuligandla42 2004 mdash mdash mdash mdash 5thAina-Mumuney43 2004 mdash mdash GA dependent mdash mdash

Strauss44 2003 mdash 29ndash42 mm mdash mdash Not statedJaparaj45 2003 mdash 17 mm mdash 3 mm 10tha Most predictive cutoff in this study

e164 DrsquoANTONIO et al by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

prenatally were not at significantlyhigher risk of BA or IUD comparedwith those without However GD wassignificantly associated with theoccurrence of NND within the first 28days of life (OR 558 95 CI13ndash241)

Two studies3043 explored theassociation between GD and LOS Thestudy by Aina-Mumuney43 included34 fetuses with a prenatal diagnosis ofgastroschisis of whom 13 showedultrasound evidence of GD The authorsfound a significantly longer LOS infetuses with (75 6 57days) comparedwith those without (43 6 30) gastricdilatation whereas Alfaray30 in a largerstudy including 98 fetuses did not findany significant difference among the2 groups (Table 5) Furthermore nosignificant association was found interm of TFEF in fetuses with or withoutGD (Table 6) Finally none of thestudies included in this systematicreview analyzed the relationshipbetween GD and LTPN

Polyhydramnios

Ten studies (602 fetuses) analyzedthe association betweenpolyhydramnios and postnataloutcomes Fetuses withpolyhydramnios were at significantlyhigh risk of BA compared with thosewith normal amniotic fluid at the scan(OR 376 95 CI 17ndash83) (Table 5)However polyhydramnios was notsignificantly associated with eitherIUD or NND (Table 5)

Two studies1030 explored therelationship between polyhydramniosand LOS but failed to find a significantassociation (Table 5) There was nostudy analyzing the associationbetween polyhydramnios and TFEFFinally the only study30 investigatingthe association betweenpolyhydramnios and time on TPN didnot find any significant result(Table 7)

BWT

Three studies (244 fetuses) analyzed therelationship between BWT and adverse

outcome BWT was not associated withatresia IUD or NND (Table 4)

Only 1 study24 explored theassociation between BWT and LOS Inthis study fetuses with a BWT3 mm had significantly longer stayin the hospital (1005 median daysIQR 820ndash1960) compared with thosewithout (485 median days IQR310ndash815) (Table 5) In the samestudy the authors did not find anyassociation between BWT and TFEF(Table 6) or LTPN (Table 7)

SGA

Ten studies (700 fetuses) includedanalyzed the association between SGAand postnatal outcome ingastroschisis SGA fetuses were not atincreased risk of either bowel atresiaor IUD or NND compared withcontrols (Table 5) There were nostudies exploring the associationbetween SGA diagnosed at the scanand LOS TFEF and LTPN

DISCUSSION

Main Findings

The findings from this systematicreview showed that IABD andpolyhydramnios are associated with anincreased risk of BA (OR 548 and 376respectively) Fetuses with GD are athigh risk of NND (OR 558) In view ofthe small sample size of the studiesincluded heterogeneity in outcomedefinition and the data displayed itwas not possible to draw any robustconclusion regarding the associationbetween prenatal ultrasound markersand LOS TFEF and LTPN

Limitations

Limitations and bias derive from thefeatures of the studies included in thisreview The main weaknesses of thesestudies were represented by theirretrospective design small sample sizedifferent thresholds used to define anultrasound sign as abnormal and bythe fact that most of the outcomeswere explored only by a limitednumber of studies The variability inTA

BLE4

Results

oftheMeta-Analyses

EvaluatingtheAssociationBetweenSelected

Ultrasound

SignsandVariousClinical

Outcom

es

Ultrasound

Sign

ABA

BIUD

CNN

D

Studies

n(Total

Sample)

RawDataa

Pooled

OR(95

CI)

Ref

Studies

n(Total

Sample)

RawDataa

Pooled

OR(95

CI)

Ref

Studies

n(Total

Sample)

RawDataa

Pooled

OR(95

CI)

Ref

IABD

9(673)b

44203

vs30470

b548

(31ndash98)

b5824273132344041

6(331)

194

vs4237

042

(00ndash57)

83234384041

7(452)

5126vs

10326

131

(04ndash39)

8243132344041

EABD

10(659)

26226

vs40433

134

(08ndash23)

582427313233373844

8(434)

3220vs

7214

056

(01ndash29)

826323337384445

7(378)

6164vs

16214

047

(02ndash12)

8313233384445

GD5(449)

1076vs

41373

123

(06ndash26)

5827

3043

4(295)

062

vs6233

074

(00ndash57)

8303943

3(234)b

557

vs3177

b558

(13ndash241)b

83043

Polyhydram

nios

5(380)b

1136vs36344b

376

(17ndash83)

b527303238

10(602)

145

vs10557

177

(02ndash157)

252829

30323536383945

7(460)

334

vs14426

398

(09ndash147)

252829

30323545

BWT

3(213)

534

vs17179

194

(06ndash62)

82437

4(237)

083

vs4154

086

(00ndash75)

8263037

3(244)

029

vs11215

083

(00ndash63)

82445

SGA

6(495)

14118

vs40377

115

(06ndash22)

82327384142

10(700)

3220vs

9480

075

(02ndash29)

8252628293839414445

5(576)

5155vs

10421

112

(04ndash35)

823282945

aNumberof

eventsTotaln

ofsubjectsintheexposedgroup(iebowelthickness)

versus

Numberof

eventsTotaln

ofsubjectsintheunexposedgroup(ienorm

albowel)Thetotalsam

pleof

themeta-analyses

does

notexactly

match

thetotal

samplederivedfrom

thesum

ofindividual

studiesas

reported

inTable1becauseforsomeoutcom

essignsthe

numberof

subjects

included

ineach

studyslightlyvariedAllrawdatasets

areavailableon

requestfrom

theauthors

bIndicatesthesignsassociated

with

anincreasedrisk

ofaspecificadverseoutcom

e

PEDIATRICS Volume 136 number 1 July 2015 e165 by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

the thresholds used to define anultrasound sign as abnormal did notallow any meaningful subanalysisaccording to the cutoff usedGestational age at examination isanother particular issue with most ofthe included studies not reporting thetime at scan In this scenario it isplausible that the relationship betweena given ultrasound sign and anoutcome may change according to thegestational age at scan

Comparison With Other SystematicReviews

A previous systematic review17

explored the prognostic value of EABD

in 273 fetuses with isolatedgastroschisis The authors analyzed 27years (1980ndash2007) of publishedliterature on the topic without findingany significant correlation betweenbowel dilatation and risk of adverseperinatal outcome They alsounderlined the inconsistent definitionof bowel dilatation used by differentauthors and the lack of randomizedcontrol trials In our systematic reviewwe analyzed a larger population withEABD (659 cases) and found a longerLOS (424 vs 333 days) comparedwith those without dilatation onlyconsidering an EABD cutoff 25 mmMore significant was the association

between IABD 14 mm and LOS (80vs 47 days) compared with fetuseswithout intestinal dilatation This wasexplained by the higher risk of BAassociated with IABD and thereforeincreased LOS

A second systematic review46

compared the postnatal outcome innewborns with simple and complexgastroschisis (atresia necrosisperforation or volvulus) The authorsshowed a significantly higher mortalityrate in complex compared withsimple gastroschisis (167 vs 22respectively) Moreover infants withcomplex gastroschisis showed worseoutcome in terms of later ability to feedorally longer time to reach full feedslonger time on parenteral nutritionand longer length of hospital stay46

Because of high data heterogeneity wewere not able to perform a meta-analysis for the following outcomesLOS LTPN and TFEF) Looking atselected papers (Table 5 and 6) andassuming that IABD was a prenatal signof complex gastroschisis we showedthat in the 3 largest series there wasa significant association betweenIABDEABD and longer LOS243341

In a recent systematic review ourgroup explored the role of prenatalultrasound in detecting non-duodenalsmall bowel atresia in otherwisenormal fetuses47 We found thatultrasound had a poor accuracy indetecting small bowel atresia eitherusing bowel dilatation orpolyhydramnios In gastroschisis wecould not define the accuracy ofprenatal ultrasound in detecting BAbut we could calculate a four timesincreased risk when IABD was present

Implication for Clinical Practice

BA in fetuses with gastroschisis islikely to be the result of an ischemicnecrosis from a constrictionobstruction at the level of theumbilical ring or a volvulus of theherniated bowel producing a vascularcompromise Our results showed thatboth IABD and polyhydramnios wereassociated with the presence of BA

TABLE 5 Results of the Systematic Review Evaluating the Association Between SelectedUltrasound Signs and LOS

Ultrasound Sign Definition Exposed Group Unexposed Group P

n LOS n LOS

IABDNick41 (2006)a GA dependent 10 840 48 265 0027Huh34 (2010)a Not stated 16 409 6 278 27 344 6 203 39Goetzinger24 (2014)b $14 mm 28 805 (345ndash1365) 66 475 (310ndash780) 02c

EABDJaparai45 (2003)a $17 mm 19 467 26 58 64Garcia33 (2010)a $25 mm 16 424 6 197 78 333 6 223 04c

GDAina-Mumuney43 (2003)b GA dependent 13 75 6 57 21 43 6 30 05c

Alfaraj30 (2011)a 2 SD 32 461 6 295 65 590 6 463 15PolyhydramniosPayne10 (2009)b mdash 10 41 (28ndash77) 31 (26ndash38) 131 402Alfaraj30 (2011) 14 6228 6 4997 80 5364 6 4074 481

BWTGoetzinger24 (2014)b 3 mm 6 1005 (820ndash1960) 88 485 (310ndash815) 03c

a Values expressed as median median and range or IQR or 95 CIb Values reported as mean or mean (6 SD)c P 05 is significant

TABLE 6 Results of the Systematic Review Evaluating the Association Between SelectedUltrasound Signs and TFEF

Ultrasound Sign Definition Exposed Group Unexposed Group P

n TFEF n TFEF

IABDHuh34 (2010)a Not stated 16 296 6 177 27 298 6 183 95Goetzinger24 (2014)b $14 mm 28 360 (250ndash520) 66 385 (215ndash655) 92

EABDGarcia33 (2010)a $25 mm 16 257 6 128 78 182 6 99 02c

GDAina-Mumuney43 (2003)b GA dependent 13 71 6 58 21 38 6 29 46Alfaraj30 (2011)a 2 SD 32 331 6 227 65 433 6 351 138

BWTGoetzinger24 (2014)b 3 mm 6 165 (110ndash220) 88 170 (120ndash210) 9

a Values reported as mean or mean (6 SD)b Values expressed as median median and range or IQR or 95 CIc P 05 is significant

e166 DrsquoANTONIO et al by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

This can be explained by anobstruction and blockage at the levelof the small bowel with accumulationof amniotic fluid (polyhydramnios)and proximal bowel dilatation (IABD)However EABD was not found to beassociated with BA IUD or NNDEABD is a common finding during theprenatal ultrasound of fetuses withgastroschisis it is usually the result ofthe prolonged exposure of theextruded bowel to the amniotic fluidand may not necessarily imply thepresence of bowel complications

Although advances in the neonatalcare have led to a dramatic reductionin mortality infants with gastroschisisare still at high risk of neonatal andlong-term morbidity It has beenobserved that most short- and long-term complications occur in cases inwhich an intestinal atresia ispresent48ndash50 Furthermore newbornswith gastroschisis and associated BAwere found to be more TPNdependent at higher risk of chronicliver damage (eg cholestasis) andhave severe infectiouscomplications551

Published series showed that only60 of the time was possible toconfirm an atresia at birth or duringthe first surgical procedure (primaryclosure or silo placement)495152

Even if a BA is identified at birth thesurgeon is often facing the dilemmawhether performing an early ora delayed repair of the interrupted

intestine51ndash53 The main surgicalconcerns in this situation are aboutthe degree of bowel inflammationedema necrosis and the increasedabdominal pressure after theabdominal wall closure that can allincrease the risk of surgicalcomplications For this reason beingable to predict the presence of BA innewborns with gastroschisis couldsignificantly help the surgeon to planthe repair either with an anastomosisor with a diverting ileostomy at thetime of the abdominal wall closure

Parental counseling54 should take intoaccount the presence of IABD andpolyhydramnios and their associationwith BA These signs are suspicious ofBA and the possibility of postnataland postsurgical complications shouldbe disclosed with parents during theprenatal period

GD was associated with theoccurrence of NND in the currentmeta-analysis GD may indicate thepresence of a proximal intestinalobstruction (midgut volvulus oratresia) which has been reported tobe associated with a higher risk ofmortality However it was notpossible to rule out otherconfounders such as prematurity thesize of the defect or postnatalmedical complications

Implications for Research

In view of the wide heterogeneity instudy design thresholds adopted to

define an ultrasound marker asabnormal gestational age atassessment and outcome definitionlarge prospective studies are neededto clarify the role of antenatalultrasound in stratifying the perinatalrisk in fetuses with gastroschisisIdeally these studies should take intoaccount objectively definedultrasound signs and assess theirreproducibility and association witha given outcome at a given gestationalage at examination The associationbetween an ultrasound sign anda given outcome may be due to othercofactors In this scenario regressionmodels should be used to find thosesigns independently associated witha given outcome

Furthermore predicative modelsusing different ultrasound signs aloneor in combination should beconstructed by including only thosesigns showing independent andsignificant association with a givenoutcome and the diagnosticperformance of the different signsshould be explored by taking intoaccount all the possible thresholdsThe number of ultrasound signsneeded to label a scan as suggestivefor a given outcome representsanother particular problem it mightbe hypothesized that reduction in thenumber of sonographic criteria mayincrease the sensitivity but is likely toreduce the specificity of the testConversely an increase in the numberof criteria needed to label a case aspositive would reduce sensitivity butwould improve specificity Finally eachultrasound sign should be evaluated inrelation to the optimal cutoff neededto more accurately predict a givenoutcome In this scenario largeprospective studies are needed tostandardize the different ultrasoundmeasurements and to providegestational age dependent cutoffs foreach ultrasound sign

Conclusions

Antenatal ultrasound can be used atsome extent to identify a subgroup ofneonates with a prenatal diagnosis of

TABLE 7 Results of the Systematic Review Evaluating the Association Between SelectedUltrasound Signs and LTPN

Ultrasound Sign Definition Exposed Group Unexposed Group P

n LTPN n LTPN

IABDMears31 (2010)a $10 mm 5 24 9 23 91Goetzinger24 (2014)b $14 mm 28 330 (220ndash720) 66 360 (200ndash550) 52

EABDMears31 (2010)a $10 mm 21 39 9 23 09

PolyhydramniosAlfaraj30 (2011)a mdash 14 5843 6 3634 81 4926 6 3092 320

BWTGoetzinger24 (2014)b 3 mm 6 455 (190ndash720) 88 355 (210ndash555) 91

P 05 is significanta Values reported as mean or mean (6 SD)b Values expressed as median median and range or IQR or 95 CI

PEDIATRICS Volume 136 number 1 July 2015 e167 by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

gastroschisis at higher risk to developpostnatal complications IABD andpolyhydramnios are associated withan increased risk of BA and GD isassociated with NND Largeprospective studies looking at theassociation of various ultrasoundsigns with antenatal and postnataloutcomes are needed to clarify therole of antenatal ultrasound inpredicting an adverse outcome and toimprove parental counseling for thisanomaly

ACKNOWLEDGMENTS

We thank Ms Karen John-PierreNational Health Service liaison librarianSt Georgersquos University of London for herhelp with the literature searches Wethank the following colleagues for theircontributions to this systematic reviewin terms of additional explanations ontheir published data and unpublisheddata supplied Dr A Bhide Dr R ReissProf J Kingdom Prof M KnightDr M Nair Prof DA DeUgarte ProfM Brizot Dr A Brantberg ProfS Emil Dr E Skarsgard Dr R PayneDr M Ghionzoli Dr S Eaton Dr HCarnaghan Prof H Sago Dr K LakhooDr A Mears Dr A Long Dr A BadilloProf J Gillham Dr C Bradshaw ProfHC Huang and Dr R Davis

ABBREVIATIONS

BA bowel atresiaBWT bowel wall thicknessCI confidence intervalEABD extraabdominal bowel

dilatationGD gastric dilatationIABD intraabdominal bowel

dilatationIQR interquartile rangeIUD intrauterine fetal deathLOS length of hospital stayLTPN time on total parenteral

nutritionNND neonatal deathOR odds ratioSGA small for gestational ageTFEF time to full enteral feedingTPN total parenteral nutrition

REFERENCES

1 Gamba P Midrio P Abdominal walldefects prenatal diagnosis newbornmanagement and long-term outcomesSemin Pediatr Surg 201423(5)283ndash290

2 Bradnock TJ Marven S Owen A et alBAPS-CASS Gastroschisis one yearoutcomes from national cohort studyBMJ 2011343d6749

3 Cowan KN Puligandla PS Laberge JM et alCanadian Pediatric Surgery Network Thegastroschisis prognostic score reliableoutcome prediction in gastroschisisJ Pediatr Surg 201247(6)1111ndash1117

4 Jager LC Heij HA Factors determiningoutcome in gastroschisis clinicalexperience over 18 years Pediatr SurgInt 200723(8)731ndash736

5 Ghionzoli M James CP David AL et alGastroschisis with intestinal atresiamdashpredictive value of antenatal diagnosisand outcome of postnatal treatmentJ Pediatr Surg 201247(2)322ndash328

6 Arnold MA Chang DC Nabaweesi R et alRisk stratification of 4344 patients withgastroschisis into simple and complexcategories J Pediatr Surg 200742(9)1520ndash1525

7 Garne E Loane M Dolk H et al Prenataldiagnosis of severe structural congenitalmalformations in Europe UltrasoundObstet Gynecol 200525(1)6ndash11

8 Kuleva M Khen-Dunlop N Dumez Y Ville YSalomon LJ Is complex gastroschisispredictable by prenatal ultrasoundBJOG 2012119(1)102ndash109

9 Long AM Court J Morabito A Gillham JCAntenatal diagnosis of bowel dilatationin gastroschisis is predictive of poorpostnatal outcome J Pediatr Surg 201146(6)1070ndash1075

10 Payne NR Pfleghaar K Assel B JohnsonA Rich RH Predicting the outcome ofnewborns with gastroschisis J PediatrSurg 200944(5)918ndash923

11 Davis RP Treadwell MC Drongowski RATeitelbaum DH Mychaliska GB Riskstratification in gastroschisis canprenatal evaluation or early postnatalfactors predict outcome Pediatr SurgInt 200925(4)319ndash325

12 Henderson LK Craig JC Willis NS ToveyD Webster AC How to write a Cochranesystematic review Nephrology (Carlton)201015(6)617ndash624

13 NHS Centre for Reviews and DisseminationSystematic Reviews CRDrsquos Guidance forUndertaking Reviews in Health Care YorkUK University of York 2009

14 Leeflang MM Deeks JJ Gatsonis CBossuyt PM Cochrane Diagnostic TestAccuracy Working Group Systematicreviews of diagnostic test accuracy AnnIntern Med 2008149(12)889ndash897

15 Liberati A Altman DG Tetzlaff J et al ThePRISMA statement for reportingsystematic reviews and meta-analyses ofstudies that evaluate health careinterventions explanation andelaboration PLoS Med 20096(7)e1000100doi101371journalpmed1000100

16 Wells GA Shea B OrsquoConnell D et al TheNewcastle-Ottawa Scale (NOS) forassessing the quality if nonrandomizedstudies in meta-analyses OttawaCanada Ottawa Health ResearchInstitute 1999 Available at httpwwwohricaprogramsclinical_epidemiologyoxfordasp Accessed May 29 2014

17 Tower C Ong SS Ewer AK Khan K KilbyMD Prognosis in isolated gastroschisiswith bowel dilatation a systematicreview Arch Dis Child Fetal Neonatal Ed200994(4)F268ndashF274

18 Friedrich JO Adhikari NK Beyene JInclusion of zero total event trials in meta-analyses maintains analytic consistencyand incorporates all available data BMCMed Res Methodol 200775

19 Sweeting MJ Sutton AJ Lambert PCWhat to add to nothing Use andavoidance of continuity corrections inmeta-analysis of sparse data Stat Med200423(9)1351ndash1375

20 Bradburn MJ Deeks JJ Berlin JA RussellLocalio A Much ado about nothinga comparison of the performance ofmeta-analytical methods with rare eventsStat Med 200726(1)53ndash77

21 Higgins JPT Green S Cochrane Handbookfor Systematic Reviews of InterventionsThe Cochrane Collaboration 2011Available at httpwwwcochrane-handbookorg Accessed March 28 2014

22 Egger M Davey Smith G Schneider MMinder C Bias in meta-analysis detectedby a simple graphical test BMJ 1997315(7109)629ndash634

23 Overcash RT DeUgarte DA StephensonML et al University of California FetalConsortium Factors associated with

e168 DrsquoANTONIO et al by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

gastroschisis outcomes Obstet Gynecol2014124(3)551ndash557

24 Goetzinger KR Tuuli MG Longman REHuster KM Odibo AO Cahill AGSonographic predictors of postnatal bowelatresia in fetal gastroschisis UltrasoundObstet Gynecol 201443(4)420ndash425

25 Janoo J Cunningham M Hobbs GROrsquoBringer A Merzouk M Can antenatalultrasounds help predict postnataloutcomes in babies born withgastrochisis The West Virginiaexperience W V Med J 2013109(2)22ndash27

26 Durfee SM Benson CB Adams SR et alPostnatal outcome of fetuses with theprenatal diagnosis of gastroschisisJ Ultrasound Med 201332(3)407ndash412

27 Emil S Canvasser N Chen T Friedrich ESu W Contemporary 2-year outcomes ofcomplex gastroschisis J Pediatr Surg201247(8)1521ndash1528

28 Overton TG Pierce MR Gao H et alAntenatal management and outcomes ofgastroschisis in the UK Prenat Diagn201232(13)1256ndash1262

29 Ajayi FA Carroll PD Shellhaas C et alUltrasound prediction of growthabnormalities in fetuses withgastroschisis J Matern Fetal NeonatalMed 201124(3)489ndash492

30 Alfaraj MA Ryan G Langer JC Windrim RSeaward PG Kingdom J Does gastricdilation predict adverse perinatal orsurgical outcome in fetuses withgastroschisis Ultrasound ObstetGynecol 201137(2)202ndash206

31 Mears AL Sadiq JM Impey L Lakhoo KAntenatal bowel dilatation ingastroschisis a bad sign Pediatr SurgInt 201026(6)581ndash588

32 Contro E Fratelli N Okoye BPapageorghiou A Thilaganathan B BhideA Prenatal ultrasound in the predictionof bowel obstruction in infants withgastroschisis Ultrasound ObstetGynecol 201035(6)702ndash707

33 Garcia L Brizot M Liao A Silva MMTannuri AC Zugaib M Bowel dilation asa predictor of adverse outcome inisolated fetal gastroschisis PrenatDiagn 201030(10)964ndash969

34 Huh NG Hirose S Goldstein RB Prenatalintra abdominal bowel dilation isassociated with postnatalgastrointestinal complications in fetuses

with gastroschisis Am J Obstet Gynecol2010202396e1ndash6 doi101016jajog200910888

35 Hidaka N Murata M Yumoto Y et alCharacteristics and perinatal course ofprenatally diagnosed fetal abdominalwall defects managed in a tertiarycenter in Japan J Obstet Gynaecol Res200935(1)40ndash47

36 Towers CV Carr MH Antenatal fetalsurveillance in pregnancies complicatedby fetal gastroschisis Am J ObstetGynecol 2008198686e1-5 doi 101016jajog200803024

37 Heinig J Muumlller V Schmitz R Lohse KKlockenbusch W Steinhard J Sonographicassessment of the extra-abdominalfetal small bowel in gastroschisisa retrospective longitudinal study inrelation to prenatal complications PrenatDiagn 200828(2)109ndash114

38 Cohen-Overbeek TE Hatzmann TRSteegers EA Hop WC Wladimiroff JWTibboel D The outcome of gastroschisisafter a prenatal diagnosis or a diagnosisonly at birth Recommendations forprenatal surveillance Eur J ObstetGynecol Reprod Biol 2008139(1)21ndash27

39 Santiago-Munoz PC McIntire DD BarberRG Megison SM Twickler DM Dashe JSOutcomes of pregnancies with fetalgastroschisis Obstet Gynecol 2007110(3)663ndash668

40 Brantberg A Blaas HG Salvesen KAHaugen SE Eik-Nes SH Surveillance andoutcome of fetuses with gastroschisisUltrasound Obstet Gynecol 200423(1)4ndash13

41 Nick AM Bruner JP Moses R Yang EYScott TA Second-trimester intra-abdominal bowel dilation in fetuses withgastroschisis predicts neonatal bowelatresia Ultrasound Obstet Gynecol 200628(6)821ndash825

42 Puligandla PS Janvier A Flageole HBouchard S Mok E Laberge JM Thesignificance of intrauterine growthrestriction is different from prematurityfor the outcome of infants withgastroschisis J Pediatr Surg 200439(8)1200ndash1204

43 Aina-Mumuney AJ Fischer AC BlakemoreKJ et al A dilated fetal stomach predictsa complicated postnatal course in casesof prenatally diagnosed gastroschisis AmJ Obstet Gynecol 2004190(5)1326ndash1330

44 Strauss RA Balu R Kuller JA McMahonMJ Gastroschisis the effect of labor andruptured membranes on neonataloutcome Am J Obstet Gynecol 2003189(6)1672ndash1678

45 Japaraj RP Hockey R Chan FYGastroschisis can prenatal sonographypredict neonatal outcome UltrasoundObstet Gynecol 200321(4)329ndash333

46 Bergholz R Boettcher M Reinshagen KWenke K Complex gastroschisis isa different entity to simple gastroschisisaffecting morbidity and mortality-a systematic review and meta-analysisJ Pediatr Surg 201449(10)1527ndash1532

47 Virgone C DrsquoAntonio F Kalhil A Jonh RManzoli L Giuliani S Accuracy of prenatalultrasound in detecting jejunal and ilealatresia a systematic review and meta-analysis [published online ahead of printAugust 24 2014] Ultrasound ObstetGynecol doi101002uog14651

48 Abdullah F Arnold MA Nabaweesi Ret al Gastroschisis in the United States1988ndash2003 analysis and riskcategorization of 4344 patientsJ Perinatol 200727(1)50ndash55

49 Snyder CL Miller KA Sharp RJ et alManagement of intestinal atresia inpatients with gastroschisis J PediatrSurg 200136(10)1542ndash1545

50 Phillips JD Raval MV Redden C WeinerTM Gastroschisis atresia dysmotilitysurgical treatment strategies fora distinct clinical entity J Pediatr Surg200843(12)2208ndash2212

51 Kronfli R Bradnock TJ Sabharwal AIntestinal atresia in association withgastroschisis a 26-year review PediatrSurg Int 201026(9)891ndash894

52 Alshehri A Emil S Laberge JM SkarsgardE Canadian Pediatric Surgery NetworkOutcomes of early versus late intestinaloperations in patients with gastroschisisand intestinal atresia results froma prospective national database J PediatrSurg 201348(10)2022ndash2026

53 Fleet MS de la Hunt MN Intestinalatresia with gastroschisis a selectiveapproach to management J PediatrSurg 200035(9)1323ndash1325

54 Lepigeon K Van Mieghem T VasseurMaurer S Giannoni E Baud DGastroschisismdashwhat should be told toparents Prenat Diagn 201434(4)316ndash326

PEDIATRICS Volume 136 number 1 July 2015 e169 by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2015-0017 originally published online June 29 2015 2015136e159Pediatrics

Lamberto Manzoli and Stefano GiulianiTitia E Cohen-Overbeek Marina Kuleva Laurent J Salomon Maria Elena Flacco

Francesco DAntonio Calogero Virgone Giuseppe Rizzo Asma Khalil David BaudPrenatal Risk Factors and Outcomes in Gastroschisis A Meta-Analysis

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015-0017DCSupplementalhttppediatricsaappublicationsorgcontentsuppl20150623peds2Supplementary material can be found at

References

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ISSN 60007 Copyright copy 2015 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on May 24 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2015-0017 originally published online June 29 2015 2015136e159Pediatrics

Lamberto Manzoli and Stefano GiulianiTitia E Cohen-Overbeek Marina Kuleva Laurent J Salomon Maria Elena Flacco

Francesco DAntonio Calogero Virgone Giuseppe Rizzo Asma Khalil David BaudPrenatal Risk Factors and Outcomes in Gastroschisis A Meta-Analysis

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ISSN 60007 Copyright copy 2015 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

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