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Title: Interpregnancy Interval Following Miscarriage And Adverse Pregnancy Outcomes
Language: English Date: 17 November 2016 Source: Human Reproduction Update. Chrishny Kangatharan, Saffi Labram, and Sohinee Bhattacharya
The
OBJECTIVEANDRATIONALE: OuraimwastodetermineifashortIPI(<6months)followingmiscarriageisassociatedwithadverse outcomesinthenextpregnancy.
Ethicalapproval
SubmittedonMay23,2016;resubmittedonSeptember14,2016;editorialdecisiononOctober27,2016;acceptedonOctober31,2016
ForPermissions,pleaseemail:journals.permissions@oup.com Human Reproduction Update Advance Access published November 17, 2016
TABLEOFCONTENTS
BACKGROUND: Ashortinterpregnancyinterval(IPI)followingadeliveryisbelievedtobeassociatedwithadverseoutcomesinthe nextpregnancy.TheoptimumIPIfollowingmiscarriageiscontroversial.Basedonasinglelarge-scalestudyinLatinandSouthAmerica,the WorldHealthOrganizationrecommendsdelayingpregnancyfor6monthsafteramiscarriagetoachieveoptimaloutcomesinthenext pregnancy.
SEARCHMETHODS: StudieswereretrievedfromMEDLINE,EmbaseandPubmed,withnotimeandlanguagerestrictions.Thesearch strategyusedacombinationofMedicalSubjectHeadingstermsformiscarriage,IPIandadverseoutcomes.Bibliographiesoftheretrieved articleswerealsosearchedbyhand.Allstudiesincludingwomenwithatleastonemiscarriage,comparingsubsequentadversepregnancy outcomesforIPIsoflessthanandmorethan6monthswereincluded.Twoindependentreviewersscreenedtitlesandabstractsfor
Qualityassessmentandriskofbias
............................. ......................................................................... ..................... HumanReproductionUpdate,pp.1 11,2016 doi:10.1093/humupd/dmw043
• Conclusion
• Methods
• Results Furthermiscarriage Pretermbirth Live birth Stillbirth Lowbirthweight Pre-eclampsia
http://humupd.oxfordjournals.org/201620,NovemberonWaterlooofUniversityatDownloadedfrom
Reviewprotocol
• Discussion
• Introduction
©TheAuthor2016.PublishedbyOxfordUniversityPressonbehalfoftheEuropeanSocietyofHumanReproductionandEmbryology.Allrightsreserved.
*Correspondenceaddress.ObstetricEpidemiology,DugaldBairdCentreforResearchonWomen’sHealth,AberdeenMaternityHospital, AberdeenAB252ZL,UK.Tel: +44-1224-438441;E-mail:sohinee.bhattacharya@abdn.ac.uk
Interpregnancyintervalfollowing miscarriageandadversepregnancy outcomes:systematicreview andmeta-analysis
Literature search Reviewmethods
ChrishnyKangatharan1,Saffi Labram2,andSohineeBhattacharya2,*
Statisticalanalysis
1DepartmentofMedicalEducation,UniversityofMaltaStPaul’sStreet,VallettaVLT1216,Malta 2InstituteofAppliedHealthSciences, UniversityofAberdeen,ForesterhillHealthCampus,AberdeenAB252ZL,UK
Reviewprotocol
Literaturesearch
Miscarriageisarelativelycommonoccurrence,affecting10 15%ofall pregnanciesintheUK(Bhattacharya etal ,2008).Itisdefinedas any pregnancylossthatoccursinthe first24weeks(Bhattacharya etal., 2008),althoughthegestationalweekcutoffvariesaccordingtoavailabilityofneonatalcare.Lossofapregnancythroughmiscarriageis associatednotonlywithpsychologicaldistressbutmayalsoaffectthe outcomesofthesubsequentpregnancyresultinginfurthermiscarriage,pre-eclampsiaandpretermdelivery(Bhattacharya etal ,2008). Birth spacingafteraninitialmiscarriagemayhelpmitigatesomeof theserisks.Thetimebetweentheendofapregnancyandthestartof anotheroneisdefinedastheinterpregnancyinterval(IPI)(Bentolila etal.,2013).TheoptimumIPIafteralivebirthhasbeenreportedto be18 23 months,forbettermaternalandperinataloutcomesinthe nextpregnancy(Conde-Agudelo etal., 2006).Intheirmeta-analysisof observationalstudies, CondeAgudelo etal. (2006) foundJshaped associationsbetweenIPIfollowingalivebirthandadverseoutcomes inthesubsequentpregnancy.Intervalsshorterthan20monthsand longerthan60monthsconferredthehighestriskofpretermbirth, lowbirthweight,andsmallforgestationalage;whileintervalsshorter than6monthsandlongerthan50monthswereassociatedwiththe highestriskofperinataldeaths.TheoptimumIPIafteramiscarriageis, however,controversial.Somecliniciansadvisecouplesnottodelay conceivingthenextpregnancy,asanincreasingIPIafteramiscarriage doesnotappeartoimprovebirthoutcomes(Basso etal., 1998; Goldstein etal., 2002; Love etal.,2010). Otherssuggestdelaying pregnancyforatleast18monthsbasedontheoptimumIPIaftera livebirth(Conde-Agudelo etal.,2006).TheWorldHealthOrganization (WHO)guidelinesrecommendwaitingforatleast6months beforetryingtoconceiveagainafteramiscarriage(WHO,2005). These guidelineswerebasedonasinglemulticentrestudyinLatinand SouthAmerica,whichfoundthatanIPIoflessthan6monthsfollowingmiscarriagewasassociatedwithadverseoutcomesinthenext pregnancy(Conde-Agudelo etal., 2004).Thisstudyhowever,was unable todistinguishbetweenmiscarriageandinducedabortionand thismayhaveaffectedtheir findings.Asincreasedmaternalageis
WIDERIMPLICATIONS: Thisisthe fi rstsystematicreviewandmeta-analysisprovidingclearevidencethatanIPIoflessthan 6monthsfollowingmiscarriageisnotassociatedwithadverseoutcomesinthenextpregnancy.Thisinformationmaybeusedtorevise currentguidance.
Ethicalapproval
OUTCOMES: Sixteenstudiesincluding1043840womenwereincludedinthesystematicreviewanddatafrom10ofthesewere includedinoneormoremeta-analyses(977972women).WithanIPIoflessthan6months,theoverallriskoffurthermiscarriage(Risk ratio(RR)0.8295%CI0.78,0.86)andpretermdelivery(RR0.7995%CI0.75,0.83)weresignificantlyreduced.Thepooledrisksofstillbirth(RR0.8895%CI0.76,1.02);lowbirthweight(RR1.0595%CI0.48,2.29)andpre-eclampsia(RR0.9595%CI0.88,1.02)werenot affectedbyIPI.Similar findingswereobtainedinsubgroupanalyseswhenIPIof <6monthswascomparedwithIPIof6 12monthsand >12months.
AsearchstrategywasinitiallydevelopedinOvidMedlinethenmodified andruninotherdatabases PubMed(U.S.NationalLibraryofMedicine), Embase(Elsevier)andScopus.Thesearchstrategyusedacombination ofMedicalSubjectHeadings(MeSH)termsformiscarriage,IPIandadverseoutcomes.Thetermsformiscarriagewere:miscarriages,abortion,
inclusion.CharacteristicsofthestudieswereextractedandqualityassessedusingCriticalAppraisalSkillsProgrammecriteria.Asystematic reviewandmeta-analysiswereconductedtocompareshort(<6months)versuslong(>6months)IPIfollowingmiscarriageintermsof riskoffurthermiscarriage,pretermbirth,stillbirth,pre-eclampsiaandlowbirthweightbabiesinthesubsequentpregnancy.Review Manager5.3wasusedforconductingmeta-analyses.
Introduction
Methods
At firstaspecificprotocolwasdesignedwherethereviewquestionwas formulatedusingthePopulation,Exposure,ComparisonandOutcome (PECO)format.Thepopulation(P)ofinterestwaswomenwithatleast onepregnancyfollowingamiscarriage,exposure(E)wasIPIoflessthan 6monthscompared(C)toIPIof6monthsormore.Thepre-specified outcomes(O)ofinterestwerefurthermiscarriage,pretermbirth,stillbirth,pre-eclampsiaandlowbirthweightinthepregnancyfollowingmiscarriage.Alltypesofstudydesignwereassessedforeligibility.The criteriausedtoidentify,includeandexcludestudiesandthemethodsfor analysingdatawereallderivedfromthisformatandagreed apriori inthe reviewprotocol.Thereviewwasconductedandreportedaccording totheguidelinesoftheMeta-analysisofObservationalstudiesin Epidemiologygroup(MOOSEchecklist).Theprotocolwasregistered withPROSPERO(registrationnumberCRD42016038424).
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Keywords: interpregnancyinterval/miscarriage/recurrentmiscarriage/pregnancyoutcomes/pretermbirth/livebirth/stillbirth/ lowbirthweight/pre-eclampsia
independentlyassociatedwithincreasedriskofmiscarriage(Aref-Adib etal., 2008),delayingconceptionafteramiscarriagemayfurther increasethisrisk.Wethereforeperformedasystematicreviewwith meta-analyseslookingattherelationshipbetweenashortIPI(less than6months)comparedto6monthsormorefollowingamiscarriageandadverseoutcomesinthenextpregnancy.
Asthisstudywasasystematicreviewandmeta-analysisofaggregated publisheddata,formalethicalapprovalwasnotrequired.
Thetitlesandabstractsofthearticlesidentifiedbythissearchwereindependentlyscreenedbytworeviewers(C.K.andS.L.)forinclusioninthe reviewandthefulltextsofthosethatappearedrelevantwereretrieved. Bibliographiesoftheretrievedarticleswerealsosearchedbyhand. Wheretherewasinadequateinformationinthepublishedarticle,authors werecontactedtorequestadditionaldata.
Table I showsthecharacteristicsoftheincludedstudies(13cohort and3 RCTs)alongwiththeirqualityassessmentscores.Theauthors alsocarriedoutasecondarycohortanalysisofthewomeninthe threeRCTstolookattheeffectofashortIPIafterapreviousloss (Kaandorp etal.,2014; Makhlouf etal.,2014; Wong etal.,2015). Outof the16studies,fourweresetintheUSA(Goldstein etal., 2002; Makhlouf etal.,2014; Sapra etal.,2014; Wong etal.,2015), twoin Bangladesh(DaVanzo etal.,2007, 2012),twointhe Netherlands(Cox etal.,2010; Kaandorp etal.,2014)andoneeach inScotland (Love etal.,2010), Denmark(Basso etal.,1998), Sweden (Buchmayer etal.,2004),Egypt(ElBehery etal.,2013)Israel (Bentolila etal.,2013),Switzerland(Wyss etal., 1994),Uruguay (Conde-Agudelo etal.,2004)andSpain(Morgan-Ortiz etal.,2010). Moststudies lookedatIPIinmonths,whiletwostudieslookedatIPI intermsofmenstrualcyclesindays(Goldstein etal.,2002; Sapra etal.,2014).Allthestudiesusedapopulationofwomenwithone miscarriageor recurrentmiscarriages.
Oncethepotentiallyeligiblearticleswereretrieved,theywereassessed formethodologicalqualityusingtheCriticalAppraisalSkillsProgramme (CASP)checklistforcohortstudies(CriticalAppraisalSkillsProgramme (CASP),2016). Thefollowingwereextractedfromeachincludedarticle: titles,authors’ names, thetypeofstudy,characteristicsofthepopulation studied,thesettingofthestudy(thegeographicallocation),theoutcomes studied,themeasuredexposureIPI.
Results
Eightstudiesprovideddataonpretermbirth(Wyss etal.,1994; Buchmayer etal.,2004; Conde-Agudelo etal.,2004; Love etal., 2010; Morgan-Ortiz etal.,2010; Bentolila etal.,2013; Makhlouf etal.,2014; Wong etal.,2015), sevenonfurthermiscarriage (Wyss etal.,1994; DaVanzo etal.,2007,2012; Love etal.,2010;
Figure 1 showstheprocessforthesearchandidentificationofstudies. Thebibliographicsearchesidentified151publicationsand18others werefoundfromahandsearchofthereferences.Ofthese,38publicationswereconsideredrelevantandthefulltextreviewedforinclusion.Ofthese,13cohortstudies(Wyss etal., 1994; Basso etal., 1998; Goldstein etal ,2002; Buchmayer etal ,2004; Conde-Agudelo etal., 2004; DaVanzo etal., 2007,2012; Cox etal., 2010; Love etal., 2010; Morgan-Ortiz etal ,2010; Bentolila etal., 2013; ElBehery etal., 2013; Sapra etal., 2014)andthreeRCTs(Kaandorp etal., 2014; Makhlouf etal ,2014; Wong etal., 2015)mettheinclusioncriteria. However,sixofthesearticleshadinsufficientdataforinclusionin meta-analysis;theauthorsofthesepaperswerecontactedbutwere unabletoprovideadditionaldata.Therefore,10(Wyss etal., 1994; Buchmayer etal ,2004; Conde-Agudelo etal.,2004; DaVanzo etal , 2007, 2012; Love etal., 2010; Morgan-Ortiz etal ,2010; Bentolila etal.,2013; Makhlouf etal., 2014; Wong etal., 2015)studieswere includedinthemeta-analyses.
(iv)Ifthestudieshadtheoutcomesthatwererelevanttothisreview. Outcomeswerebroadlycategorisedintoprimaryandsecondary outcomesbasedonfrequencyandconsistencyofassociation reportedintheliterature,biologicalplausibilityandclinicalimportance.Primaryoutcomesweredefinedasfurthermiscarriage(less than24weeksofgestation)andpretermdelivery(deliverybefore 37weeksofgestation).Secondaryoutcomeswerelivebirth,stillbirth,pre-eclampsia,andlowbirthweight.Studieswereincludedif theyhadadverseoutcomesinthenextpregnancyandexcludedif theyonlyreportedadverseoutcomesinthesamepregnancy.
Statisticalanalysis
Alltheretrievedfulltextarticleswerethenassessedforinclusionin thereviewusingthepredefinedexclusionandinclusioncriteria.
(iii)IftheyhadstudiedIPIsforlessandmorethan6months.Studies wereexcludediftheydidnothavecomparisongroupsordidnot report findingsforIPIsoflessthan6months.Nevertheless,authors werecontactedtoseeiftheycouldprovideappropriatedataifthe rangeofIPIwasinconsistentwiththisinclusioncriterion.
Collaboration,2014.Copenhagen,Denmark).Datawereenteredfor eachoutcomeiftherewereatleasttwostudiesaddressingthatoutcome. TherawnumbersforeachoutcomeineachgroupofIPI(≥6months or <6months)asreportedintheprimarystudieswereenteredinthe softwaretocalculatethecruderiskratio(RR)andthe95%confidence interval(CI)using ≥6monthsasthereferencecategory.Thesewere thenweightedandpooledtoproduceforestplotsandpooledRRswith 95%CI.Statisticalheterogeneitywasassessedusingthe I2 statistic. Where I2 wasmorethan50%signifyingmoderatetolargestatisticalheterogeneity,arandomeffectsmodelwasused.
Studieswerealsoexcludediftheywerecasereports,reviewsor editorials.
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Qualityassessmentandriskofbias
spontaneousabortion,earlypregnancyloss.OthertermsforIPIwereinterconceptioninterval,timetobirth,birthspacingandbirthinterval.Terms foradverseoutcomeswerepregnancyoutcomes,adverseoutcomes. AfurthersearchwasconductedusingspecifictermsforIPI:longIPI,short IPI,morethan6monthsIPI,lessthan6monthsIPI.Aspecificsearchwas alsoconductedforthenamesofeachadverseoutcome,thesetermswere: furthermiscarriage,pregnancyloss,stillbirth,pretermbirth,lowbirthweight,pre-eclampsia.ThesesearchtermswerecombinedusingBoolean operators ‘AND’ or ‘OR’ asappropriate.Notimeorlanguagerestrictions wereappliedtothesearchstrategy.Tworeviewers(C.K.andS.L.)independentlyranthesearches.
Reviewmethods
(ii)IfthestudiesusedIPIasexposure.Studieswereexcludediftheydid notincludeIPIorthewomendidnothaveanyfurtherpregnancies.
(i)Ifthepopulationsstudiedwerewomenwithatleastonemiscarriage. Thestudieswithwomenwithnomiscarriagebutjustlivebirthsor inducedabortionswereexcluded.
Ifastudyvariedsignificantlyintermsofmethodologyor findingsfrom allotherincludedstudies,weperformedasensitivityanalysisexcluding thosestudiesfromthemeta-analysis.Insubgroupanalyses,wesplitthe comparatorgroupof >6monthsinto6 12monthsand >12monthsfor theprimaryoutcomesoffurthermiscarriageandpretermbirth.
Meta-analysiswasperformedwhereappropriateusingthesoftware ReviewManager5.3(TheNordicCochraneCentre,TheCochrane
Thecriteriadeterminingwhetheranarticlewasgoingtobeincludedwere:
Furthermiscarriage
Figure1 Flowdiagramofstudyidentificationandselectionprocessforsystematicreviewoftheassociationbetweeninterpgnancyintervalfollowingmiscarriageandsubsequentpregnancyoutcomes.
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Morgan-Ortiz etal.,2010; Bentolila etal.,2013; Wong etal.,2015), fouron livebirths(DaVanzo etal.,2007,2012; Love etal.,2010; Wong etal.,2015), fouronstillbirths(DaVanzo etal., 2007,2012; Love etal., 2010; Wong etal.,2015), fiveonpre-eclampsia(CondeAgudelo etal.,2004; Love etal.,2010; Bentolila etal.,2013; Makhlouf etal.,2014; Wong etal.,2015) andfouronlowbirthweight (Conde-Agudelo etal.,2004; Love etal.,2010; Bentolila etal.,2013; Makhlouf etal.,2014). Thestudyby Conde-Agudelo etal. (2004) did notdistinguish betweenspontaneousandinducedabortionsanda sensitivityanalysiswasperformedincludingandexcludingthisstudy. TheaveragequalityassessmentscoreusingCASPcriteriawas9.4
outof11,thereforealltheincludedstudieswereofgoodqualitywith lowriskofbias.Publicationbiaswasinvestigatedusingafunnelplot fortheoutcomefurthermiscarriagebutshowednoappreciableevidenceofthisbias(PlSupplementaryFig.S1).
Sevenofthe10studiesprovideddataonfurthermiscarriageaftera previousmiscarriage.TheriskofhavingafurthermiscarriagewithIPI oflessthan6monthswassignificantlyreducedwhencomparedtoIPI ofmorethan6months,withapooledRR(95%CI)of0.82(0.78,
Womenwith first pregnancymiscarriage <6monthsand >12months
Age,BMI,smoking,caffeineand alcoholintake 8
Love etal. (2010)
DaVanzo etal. (2012) CohortMatlabDHSSBangladesh (1977 2008)
Womenwithprevious miscarriage <6,6 12, >12months
Cohort Mexico Womenwithearly pregnancy lossinlast pregnancy
RCT/cohortEuniceKennedyShriver NationalInstituteRCT (2003 2008)
Miscarriage,ectopic,termination,stillbirth, livebirth,pre-eclampsia,placentapraevia, abruption,PPH,lowbirthweight,preterm delivery
IPI(inmonths): <2, 3 5,6 11,12 17, 18 23,24 59, >60
Age,BMI,smoking,voluntary/ involuntaryIPI,gynaecological history 10
Bentolila etal. (2013) CohortRPLclinicintheSoroka University MedicalCenter, Israel
Age,BMI,race,gestationalage ofpreviousloss 11
Age,durationofsubfertility,sperm motility,post-coitaltest 8
CohortSweden(1987 2000)Womenwithprevious pregnancyloss 0 3,3 6,6 12and >12intervals
Allpregnanciesincluding miscarriage <6,6 14,15 26, 27 50,51 74and >74months
DaVanzo etal. (2007) CohortMatlab,Bangladesh (1982 2002)
Pretermdelivery
Age,relationshipwithfather, smoking,mother’sbirthcountry, calendaryear 9
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Pretermbirth,pre-eclampsia,foetal/ neonataldeath,birthweight
7
Fourclinicaltrialsites inUSA
TableI Characteristicsandqualityof16studiesincludedinasystematicreviewoninterpregnancyintervalfollowingmiscarriageandadversepregnancy outcomes.
Womenwith2ormore consecutivemiscarriage <6and >6monthsAdverseoutcomesinthenextpregnancyAge,ethnicity 11
Cox etal. (2010)
Livebirth,stillbirth,miscarriage Age,parity,education,household space,religion,plannedpregnancy, calendaryear 9
MultipleadversepregnancyoutcomesAge,parity,education,marital status,smokingBMI,gestational weightgain,geographicarea, hospitaltype,calendaryear
RCT/analysed ascohort
Wong etal. (2015)
ReferenceDesignSetting Population Exposure(IPI)Outcome Confounders QA Score
Makhlouf etal. (2014)
Sapra etal. (2014)
WomenwithmiscarriageNo.ofmenstrual cycles Pregnancy
Weekstoconception;timetolivebirthAge,BMI,no.ofmiscarriages, intervention,previouslivebirth, factorVLeidenmutation 7
Age,education,geographicarea, gravidity,calendaryear 10
ElBehery etal. (2013) CohortZagazigandSuez,Canal University Hospitals (2009to2012)
CohortScotland(1981 2000) Womenwith first pregnancymiscarriage 6monthlyintervals from <6to >24
Miscarriage,ectopic,livebirth,stillbirth;preeclampsia,placentapraevia,placental abruption,inductionoflabour,caesarean, preterm,lowbirthweight
Age,socialclass,smoking,calendar year 9
Morgan-Ortiz etal. (2010)
Conde-Agudelo etal. (2004)
Kaandorp etal. (2014) RCT/cohortALIFEtrialNetherlands (2004 2009) Womenwithunexplained recurrentmiscarriage 6,12and 24months
Buchmayer etal. (2004)
Womenwith ≥1previous miscarriage 3monthlyintervals 0to >12 Livebirth;pregnancyloss
</>6monthsFurthermiscarriage,pretermbirthand perinataloutcomes:agpar <7 None
CohortMichiganandTexas,USA (2005 2009)
Age,BMI,race,smoking,education, maritalstatus 11
Womenwithmiscarriage3and6month intervals Miscarriage,termination;stillbirth;early,late andpostneonatalmortality
Cohort LatinandSouthAmerica (1985 2002) Womendelivering singletonwithprevious historyofabortion (spontaneousorinduced).
Cohort38fertilitycentresinthe Netherlands Womenwith ≥1previous miscarriage 6 18monthsSpontaneousongoingpregnancy
Thereportedriskofstillbirthsinwomenafteramiscarriagewasnot significantlydifferentinthetwoIPIgroups(P = 0.09)RR(95%CI)of 0.88(0.76,1.02).Theriskvariedfrom1.56to0.71acrossthefour studiesincludedinthemeta-analysis(Fig. 2D).
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Goldstein etal. (200 2)
6 Kangatharan etal.
Confounders
Pre-eclampsia
TableI
Stillbirth
IPI,interpregnancyinterval;QA,qualityassessment;Rh,rhesus;PPH,postpartumhaemorrhage.
QA Score
Fourstudiespresenteddataonlivebirthsafteramiscarriage.Live birthswereobservedtobesignificantlyhigherwhenwomenhadan IPIoflessthan6monthsafteramiscarriage(P < 0.01),40%higher comparedtoanIPIof6monthsormore,RRof(95%CI)1.06(1.01, 1.11)(Fig. 2C).
MonthlyIPIPretermdelivery,lowbirthweight,growth retardation
Fourstudiespresenteddataonlowbirthweight,threeofthestudies definedlowbirthweightaslessthan2500g(Conde-Agudelo etal , 2004; Love etal., 2010; Bentolila etal.,2013)and1aslessthanthe fifth percentileforgestationalageadjustedbysexandrace(Makhlouf etal.,2014).Theoverallriskofhavinglowbirthweightbabiesaftera miscarriagewasnotsignificantlydifferentinwomenwithanIPIofless than6months(P = 0.07),comparedtowomenwithanIPIof6months ormoreincludingthestudyby Conde-Agudelo et al. (2004) RR(95% CI) of1.05(0.48,2.29)(Fig. 2E).Whenthisstudywasexcluded,the riskoflowbirthweightwassignificantlylowerwithIPIof <6months (pooledRR0.7495%CI0.68,0.81)(Fig. 2Elowerpanel).
Wyss etal. (199 4)
Outofthe10studiesincludedinmeta-analysis,eightreportedon pretermdeliveries.Weperformedameta-analysisincludingand excludingthestudyby Conde-Agudelo etal. (2004) Themetaanalysisincluding thestudyby Conde-Agudelo etal. (2004) resulted ina pooledRRof0.93(95%CI0.58,1.48)(Fig. 2B).Theincidenceof pretermdeliveries wassignificantlylower(P < 0.01)whenwomen withIPIoflessthan6monthswerecomparedtothosewithanIPIof morethan6months:pooledRR(95%CI)of0.79(0.75,0.83) (Fig. 2B)whenthestudyby Conde-Agudelo etal. (2004) was excluded.There wasnosignificantincreaseintheriskofpretermbirth whencomparedwithIPIof6to12months(pooledRR1.10,95%CI 0.64,1.89)orwithIPIof >12months(pooledRR1.06,95%CI0.57, 1.97).Thestudyby Conde-Agudelo etal. (2004) was includedinthe lattertwo meta-analyses.
CohortDenmark(1980 1992)
CohortWomenwith1previous miscarriage
Pretermbirth
Lowbirthweight
Age,socialclass,changeofsocial status 10
Womenwith1previous miscarriage
Livebirth
CohortUniversityofCalifornia, SanFr ancisco,USA
Population Exposure(IPI)Outcome
Unive rsityHospital Zurich,Switzerland (1986 1991) < 90days, > 90daysSubsequentmiscarriage,pretermbirthAgeandparity(previouslivebirth)8
Womenwithlivebirth followingmiscarriage
Basso etal. (199 8)
Continued ReferenceDesignSetting
Pretermdelivery,caesareansectionAge,ethnicity,education,parity, gravidity,Rhstatus,prior abortions/ectopic 7
Therateofpre-eclampsiadidnotappeartodifferinwomenwithIPI oflessthan6monthsafteramiscarriagecomparedtoIPI ≥6months, includingthestudyby Conde-Agudelo etal. (2004) pooled RR(95% CI)of 0.95(0.88,1.02)(Fig. 2F)andexcludingthestudy1.00(0.90,
0or2menstrual cycles,100days
0.86)(Fig. 2A).ComparedtoanIPIof6 12months, IPIof <6months reducedtheriskoffurthermiscarriage(pooledRR0.82,95%CI 0.77,0.88).Similarlythisriskwasfurtherreduced(pooledRR0.78, 95%CI0.74,0.83)whencomparedwithIPI >12months.
Figure2 Forestplotspresentingtheassociationofinterpregnancyinterval(IPI)followingmiscarriagewithsubsequentpregnancyoutcomes. (A)ForestplotpresentingtheassociationofIPIsfollowingmiscarriagewithfurthermiscarriage.(B)ForestplotpresentingtheassociationofIPIs followingmiscarriagewithsubsequentpretermbirth.(C)ForestplotpresentingtheassociationofIPIsfollowingmiscarriagewithsubsequentlive birth.(D)ForestplotpresentingtheassociationofIPIsfollowingmiscarriagewithsubsequentstillbirth.(E)Forestplotpresentingtheassociationof IPIsfollowingmiscarriagewithsubsequentdeliveryoflowbirthweightbabies.(F)ForestplotpresentingtheassociationofIPIsfollowingmiscarriage withsubsequentpre-eclampsia.
Discussion
1.12)(Fig. 2Flowerpanel).Fiveofthetenstudiesprovideddataon pre-eclampsia.
Birthspacingisanimportantelementofreproductivecounselling. Couplesexperiencingamiscarriageneedtoknowtheoptimaltime toconceiveanotherpregnancyinordertohavethebestpossible outcomes.Inthissystematicreview,weevaluated6differentoutcomesandfoundthatanIPIoflessthan6monthsfollowingamiscarriagewasassociatedwithlowerrisksofhavingafurthermiscarriage andpretermdelivery,andincreasedoddsofhavinglivebirths.There werenodifferencesintherisksofstillbirth,pre-eclampsiaandlow birthweightbabiesbetweenanIPIoflessthan6monthsandof 6monthsormore.Basedonthepublishedevidencefrom10studies
wecanthereforeconcludethatdelayingapregnancyformorethan 6monthsafteramiscarriageisunnecessaryasashortIPI(lessthan6 months)resultsinnoworsepregnancyoutcomesbutmayalsobe associatedwithbetteroutcomesintermsofalowerriskoffurther miscarriageandpretermbirthandincreasedchanceoflivebirthin thenextpregnancy.
ThissystematicreviewwascarriedoutincompliancewiththecriteriaintheMOOSEchecklist.At firstafocussedreviewquestionwas framedusingthePECOformat,fromwhicharobustsearchstrategy andinclusionandexclusioncriteriaweredeveloped.Thestudieswere carefullyassessedforqualityindependentlybytworeviewersanddata extractedformeta-analyses.Themeta-analysisinthisreviewincluded 10studies.Thestudyby Conde-Agudelo etal. (2004) providedoutcome dataonfurthermiscarriage,pretermdelivery,lowbirthweight andpre-eclampsia.Whilethiswasalargeretrospectivestudy onwhichtheWHOguidelinesfordelayingpregnancyforatleast
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6months(WHO,2005)isbased,itdidnotdifferentiatebetween inducedandspontaneousabortionsanduseddatafrommanycountrieswhereinducedabortionisillegal(Conde-Agudelo etal., 2004). Therefore,theconclusionsfromthisstudyshouldbeinterpretedin
context.Themeta-analyseswererepeatedwithandwithoutthisstudy insensitivityanalyses.Theexclusionofthisstudyhadlargeeffectson thepooledoutcomeestimates.Inseveralcases,suchaspretermbirth, ashorterIPIwasassociatedwithmorefavourableoutcomes.
Figure2 Continued 8 Kangatharan etal.
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didnotdemonstrateanyappreciablepublicationbiasfortheoutcomeoffurthermiscarriage,butmayhavebeenpresentforsomeof thesecondaryoutcomeswithfewerpublications.Furthermoreconfi denceintheresultscouldbelimitedduetothesmallnumberof studiesusedinthemeta-analyses.Anumberoffactorsareassociated withpregnancyoutcomes,includingage,ethnicity,socialclass,smoking,alcohol,BMIandpreviousobstetrichistory.Howeverotherthan maternalage,thestudiesalsovariedinaddressingpotentialconfounders.Failuretoaddressallthepotentialconfoundersintheprimary studiesincludedinthisreviewcouldbeduetothefactthatthey werenotrecordedinthedatabases,oreithernotmeasuredor poorlymeasured.Thusthiscanberecognisedasapotentiallimitation
Figure2 Continued 9Optimuminterpregnancyintervalaftermiscarriage http://humupd.oxfordjournals.org/201620,NovemberonWaterlooofUniversityatDownloadedfrom
Meta-analysesandsystematicreviewscanbelimitedbyanumber offactors.Originaldatacollectionvariedacrossthedifferentstudies assomeusedthemother’srecallofthepreviouspregnancieswhile othersusedinformationfromdatabases.Thusqualityoftheoriginal dataisalimitingfactor.Inaddition,studiesvariedintheirdefinitionof certainoutcomessuchasmiscarriage.Whilesomestudiesmadedistinctionsbetweenwomenwithspontaneousandinducedabortions, otherscouldnot possiblyduetolegalconstraintsandreligiousand culturalstigmasassociatedwithinducedabortions.Anotherpotential biasispublicationbias,andalthoughtheliteraturesearchwasrigorouswewereunabletosearchunpublishedstudies,whichmayaffect ourresults.Weinvestigatedthispossibilityusingafunnelplotwhich
Intheirsystematicreviewofmechanismsunderpinningshortand longIPIwithadversepregnancyoutcomes, CondeAgudelo etal. (2012) found evidencetosupporthypothesesofmaternalnutritional depletion,folate depletion,cervicalinsufficiency,verticaltransmission ofinfectionsandabnormalremodellingofendometrialbloodvessels aspossibleexplanationsfortheassociationofadverseoutcomeswith shortIPI.Women’snaturaldeclineinreproductivecapacitywithage wastheonlyhypothesisproposedtoexplaintheassociationbetween
Thisisthe firstsystematicevidencesynthesistoassesstheeffectof shortversuslongIPIandbasedontheavailableevidencewecanconcludethatashortIPI(lessthan6months)followingmiscarriageisnot associatedwithadverseoutcomesinthesubsequentpregnancy.Couples wishingtoconceiveafteramiscarriagecanbecounselledthatdelaying pregnancydoesnotnecessarilyimproveoutcomes.Furtherresearch needstolookatanIPIoflessthan3monthstodetermineanoptimum cutoff,ifthereisone.Individualpatientdatameta-analysiscanoffer opportunitiestostudysmallsubgroupsand/orstratifybyotherriskfactorstodetermineapersonalisedoptimumIPIaftermiscarriage.
Figure2 Continued 10 Kangatharan etal. http://humupd.oxfordjournals.org/201620,NovemberonWaterlooofUniversityatDownloadedfrom
inthisstudyasitcanleadtooverorunderestimatedresults. Despitethis,aconsistenteffectwasreportedbyallthestudiesconductedinavarietyofcountriesandsettings,whichleadsustobelieve thattheseassociationsarelikelytoexist.
Theresultsofthissystematicreviewareconsistentwithotherstudies(Basso etal.,1998; Goldstein etal.,2002; ElBehery etal.,2013) thatcouldnotbeincludedinthismeta-analysisastheydidnothave appropriatedata.Thestudyby ElBehery etal. (2013) showsthat womenconceivingwithin6monthsofamiscarriagehadgoodreproductiveoutcomesandareducedincidenceofcomplications,andthey notedthatlivebirthswerehighestwhenconceivingwithin6months (79.31%)comparedtoconceivingafter12months(71.6%).However, theydidnotfocusonanIPIofmorethan6months,butlookedonlyat lessthan6monthsIPIandmorethan12monthsIPI.Hencethisstudy couldnotbeincludedinthemainmeta-analysisbutonlyinthesubgroupanalysiscomparingIPIoflessthan6monthswiththatofmore than12months(ElBehery etal.,2013).Studiesby Basso etal. (1998) and Goldstein etal.(2002) showthattherearenoadverseoutcomes associatedwithshortIPIsbutalsothatadverseoutcomesincreaseas IPIincreases(Basso etal.,1998).Howevertheydidnotusethesame IPIgroupsasthissystematicreviewthereforecouldnotcontribute towardsthemeta-analyses.
longIPIsandadverseoutcomes(CondeAgudelo etal.,2012).In caseswhere theIPIstartswithamiscarriage,thewoman’sbodymay behavedifferentlytothatafteralivebirth.Forexample,thenutritionaldepletionorfolatedepletionhypothesissuggeststhatfromthe fifthmonthofpregnancyuntilaprolongedtimeafterdelivery,the storesofmaternalnutrients,suchasfolate,remainlowleadingtofolateinsufficiencyinwomenwithashortIPIafteraliveorstillbirth. Howeverafteramiscarriage,thereisaverysmallburdenonthefolatereserveandthusmiscarriageisnotverylikelytoleadtofolate deficiencyinthepostpartumperiod.Thiscouldexplainthereduced riskofadverseoutcomesinashortIPIafteramiscarriage(Smitsand Essed,2001). Insupportofthishypothesis,thereisevidencetosuggestthat latemiscarriages(after12weeksofgestation)areassociatedwithworseoutcomesinthesubsequentpregnancy(Edlow etal.,2007).Inaddition,mostwomenwhoattemptanotherpregnancysoon afteramiscarriagearelikelytobemotivatedtotakebettercareoftheirhealthandconsequentlyresultinbetterpregnancy outcomes(DaVanzo etal.,2007).Anotherplausiblereasonmaybe thatthose whoconceivesoonafteramiscarriagearenaturallymore fertileandconsequentlyhavebetterpregnancyoutcomes.
GoldsteinRRP,CroughanMS,RobertsonPA.Neonataloutcomesinimmediate versusdelayedconceptionsafterspontaneousabortion:aretrospectivecase series. ObstetGynecol 2002;186:1230 1236.
BhattacharyaS,TownendJ,ShettyA,CampbellD,BhattacharyaS.Doesmiscarriageinaninitialpregnancyleadtoadverseobstetricandperinataloutcomesin thenextcontinuingpregnancy? BJOG 2008;115:1623 1629.
Conclusion
Aref-AdibM,Freeman-WangT,AtaullahI.Theolderobstetricpatient. Obstet GynaecolReprodMed 2008;18:43 48.
Funding
DaVanzoJ,HaleL,RazzaqueA,RahmanM.Effectsofinterpregnancyintervaland outcomeoftheprecedingpregnancyonpregnancyoutcomesinMatlab, Bangladesh. BJOG 2007;114:1079 1087.
DaVanzoJ,HaleL,RahmanM.Howlongafteramiscarriageshouldwomenwait beforebecomingpregnantagain?Multivariateanalysisofcohortdatafrom Matlab,Bangladesh. BMJOpen 2012;2
KaandorpSP,vanMensTE,MiddeldorpS,HuttenBA,HofMH,vanderPostJA, vanderVeenF,GoddijnM.Timetoconceptionandtimetolivebirthinwomen withunexplainedrecurrentmiscarriage. HumReprod 2014;29:1146 1152.
LoveER,BhattacharyaS,SmithNC,BhattacharyaS.Effectofinterpregnancyintervalonoutcomesofpregnancyaftermiscarriage:retrospectiveanalysisofhospital episodestatisticsinScotland. BMJ 2010;341:3967.
SmitsLJ,EssedGG.Shortinterpregnancyintervalsandunfavourablepregnancyoutcome:roleoffolatedepletion. Lancet 2001;358:2074 2077.
Conde-Agudelo A,BelizanJM,BremanR,BrockmanSC,Rosas-BermudezA.Effect oftheinterpregnancyintervalafteranabortiononmaternalandperinatalhealth inLatinAmerica. IntJGynaecolObstet 2004;89:S34 S40.
11Optimuminterpregnancyintervalaftermiscarriage
Theresultsofthissystematicreviewandmeta-analysesshowthatan IPIoflessthan6monthsisassociatedwithnoincreaseintherisksof adverseoutcomesinthepregnancyfollowingmiscarriagecompared todelayingpregnancyforatleast6months.Infact,thereissomeevidencetosuggestthatchancesofhavingalivebirthinthesubsequent pregnancyareincreasedwithanIPIoflessthan6months.Thereis nowampleevidencetosuggestthatdelayingapregnancyfollowinga miscarriageisnotbeneficialandunlesstherearespecificreasonsfor delaycouplesshouldbeadvisedtotryforanotherpregnancyassoon astheyfeelready.
Conde-AgudeloA,Rosas-BermudezA,CastañoF,NortonMH.Effectsofbirth spacingonmaternal,perinatal,infant,andchildhealth:asystematicreviewof causalmechanisms. StudFamPlann 2012;43:93 114.
Authors’ roles
BuchmayerSM,SparénP,CnattingiusS.Previouspregnancyloss:risksrelatedto severityofpretermdelivery. ObstetGynecol 2004;191:1225 1231.
MakhloufMA,CliftonRG,RobertsJM,MyattL,HauthJC,LevenoKJ,VarnerMW, ThorpJMJr,MercerBM,PeacemanAM etal.Adversepregnancyoutcomes amongwomenwithpriorspontaneousorinducedabortions. AmJPerinatol 2014;31:765 772.
Theauthorsdeclarethattheyhavenoconflictofinterest.
Supplementarydata
WyssP,BiedermannK,HuchA.Relevanceofthemiscarriage-newpregnancy interval. JPerinatMed 1994;22:235 241.
ReportofaWHOTechnicalConsultationonBirthSpacing. WHO[Internet] 2005. http://www.who.int/maternal_child_adolescent/documents/birth_spacing.pdf SapraKJ, McLainAC,MaisogJM,SundaramR,BuckLouisGM.Successivetimeto pregnancyamongwomenexperiencingpregnancyloss. HumReprod 2014;29: 2553 2559.
BassoO,OlsenJ,ChristensenK.Riskofpretermdelivery,lowbirthweightand growthretardationfollowingspontaneousabortion:aregistry-basedstudyin Denmark. IntJEpidemiol 1998;27:642 646.
WongLF,SchliepKC,SilverRM,MumfordSL,PerkinsNJ,YeA,GalaiN, Wactawski-WendeJ,LynchAM,TownsendJM etal.Theeffectofaveryshort interpregnancyintervalandpregnancyoutcomesfollowingapreviouspregnancy loss. ObstetGynecol 2015;212:375.e1 375.e11.
Conflictofinterest
CriticalAppraisalSkillsProgramme(CASP). CriticalAppraisalSkillsProgramme(CASP) [Internet]. 2016. http://www.casp-uk.net/#!casp-tools-checklists/c18f8
BentolilaY,RatzonR,Shoham-VardiI,SerjienkoR,MazorM,BashiriA.Effectof interpregnancyintervalonoutcomesofpregnancyafterrecurrentpregnancy loss. JMaternFetalNeonatalMed 2013;26:1459 1464.
Thisresearchprojectdidnotreceiveanyfunding.
Morgan-OrtizF, Muñoz-AcostaJ,Valdez-QuevedoR,Quevedo-CastroE,BàezBarrazaJ.Effectofpost-abortioninterpregnancyintervalonobstetricandperinataloutcomes. GinecolObstetMex 2010;78:46 52.
C.K.conductedtheinitialliteraturesearches,reviewedtheincluded papers,conductedthemeta-analysesandwrotethe firstdraft.S.L. repeatedthesearches,qualityassessedtheincludedstudiesandcommentedonthedraft.SBdesignedthereviewquestion,developedthe protocol,supervisedC.K.andS.L.
EdlowAG,SrinivasSK,ElovitzMA.Second-trimesterlossandsubsequentpregnancyoutcomes:Whatistherealrisk? AmJObstetGynecol 2007;197
Conde-AgudeloA,Rosas-BermúdezA,Kafury-GoetaA.Birthspacingandriskof adverseperinataloutcomes:ameta-analysis. JAMA 2006;295:1809 1823.
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Supplementarydataareavailableathttp://humupd.oxfordjournals.org/.
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