28/1/2016 Effectofhighparityonoccurrenceofanemiainpregnancy:acohortstudy

BMCPregnancyChildbirth.201111:7. PMCID:PMC3033858
Publishedonline2011Jan20.doi:10.1186/14712393117

Effectofhighparityonoccurrenceofanemiainpregnancy:acohortstudy
YahyaMAlFarsi, #1,2DanielRBrooks, #2MarthaMWerler, #2HowardJCabral, #2MohammedAAlShafei, #1andHenkC
Wallenburg#3
1
DepartmentofFamilyMedicineandPublicHealth,CollegeofMedicineandHealthSciences,SultanQaboosUniversity,Oman
2
DepartmentofEpidemiology,SchoolofPublicHealth,BostonUniversity,Boston,USA
3
DepartmentofObstetricsandGynecology,CollegeofMedicineandHealthSciences,SultanQaboosUniversity,Oman
Correspondingauthor.
#
Contributedequally.
YahyaMAlFarsi:ymfarsi@gmail.comDanielRBrooks:danbrook@bu.eduMarthaMWerler:mwerler@slone.bu.eduHowardJCabral:
hjcab@bu.eduMohammedAAlShafei:shafaee4@omantel.net.omHenkCWallenburg:hcswallenburg@hotmail.com

Received2010Feb15Accepted2011Jan20.

Copyright2011AlFarsietallicenseeBioMedCentralLtd.

ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

ThisarticlehasbeencitedbyotherarticlesinPMC.

Abstract Goto:

Background

Studiesthatexplorethecontroversialassociationbetweenparityandanaemiainpregnancy(AIP)wereoften
hamperedbynotdistinguishingincidentcasescausedbypregnancyfromprevalentcasescomplicatedby
pregnancy.Theauthors'aiminconductingthisstudywastoovercomethismethodologicalconcern.

Methods

AretrospectivecohortstudywasconductedinOmanon1939pregnanciesamong479parousfemaleparticipants
withavailablepregnancyrecordsinacommunitytrial.Wecollectedinformationfromparticipants,thecommunity
trial,andhealthrecordsofeachpregnancy.Throughoutthefollowupperiod,weenumerated684AIPcasesof
which289(42.2%)wereincidentcases.Highparity(HP,5pregnancies)accountedfor48.7%oftotal
pregnancies.Twosetsofregressionanalyseswereconducted:thefirstrestrictedtoincidentcasesonly,andthe
secondinclusiveofallcases.Therelationwithparityasadichotomyandasmultiplecategorieswasexaminedfor
eachsetmultilevellogisticregression(MLLR)wasemployedtoproduceadjustedmodels.

Results

InthefullyadjustedMLLRmodelsthatwererestrictedtoincidentcases,womenwithHPpregnancieshadahigher
riskofAIPcomparedtothosewhohadhadfewerpregnancies(RiskRatio,RR=2.9295%CI2.02,4.59)the
AIPriskincreasedinadoseresponsefashionovermultiplecategoriesofparity.InthefullyadjustedMLLR
modelsthatincludedallcases,theassociationdisappeared(RR=1.1195%CI0.91,1.18)andthedoseresponse
patternflattened.

Conclusions

ThisstudyshowstheimportanceofspecifyingwhichcasesofAIPareincidentandprovidessupportiveevidence
foracausalrelationbetweenparityandoccurrenceofincidentalAIP.

Background Goto:

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Despitebeingamajorpublichealthissue,anaemiainpregnancy(AIP)is,surprisingly,stillnotwellunderstoodin
termsofitsdefinition,prevalence,incidence,causes,andtheeffectivenessofironsupplementsinimproving
pregnancyoutcomes[1].

TheuncertaintyindefiningAIPisamajorobstacleinetiologicalresearchofAIP.Researchersshowatendencyto
confusecasesofanaemiacausedbypregnancy(incidentcases)withpreexistingcasesofanaemiacomplicatedby
pregnancy(prevalentcases).Thisambiguitystemsfrominconsistentsystemsofmeasurementcriteriafortheonset
ofanaemia.Someauthorsconsidered"anaemiaatfirstantenatalcarevisit"asameasureofoccurrenceofAIP[2],
whileothersconsideredanyantenatallowhemoglobin(Hb)measurementthroughoutthecourseofpregnancy[3].
AthirdsubsetofreportsprovidenoindicationofwhichHbmeasurementcutoffwasusedorthespecifictimingof
onsetmeasurement[46].

Ideally,ameasureofincidentcasesofAIPshouldspecifyapoint/periodintimethatismorerecentthantheonset
ofpregnancyandallowsforareasonablelatencyperiodforthecausalactionofpregnancyincausingincidentAIP.
Toourknowledge,thereisnouniversalstandardfortheexacttimingofmeasurementfortheonsetofanaemiathat
wouldclearlydifferentiatebetweenincidentandprevalentcases.

DuetothisvariationinthedefinitionsofAIP,estimatesoftheprevalenceandincidenceofAIPamongpregnant
womenareuncertain.TheWorldHealthOrganization(WHO)estimatestheprevalenceofanaemiaamong
pregnantwomentovarybetween53.8%and90.2%indevelopingcountries,whileindevelopedcountriesitis
estimatedtobe8.3%[7].However,manyofthesewomenwerealreadyanaemicbeforebeingpregnant.Asa
matteroffact,theWHOestimatestheprevalenceofanaemiatobe47.5%amongnonpregnantwomenin
developingcountriesand19%inwomenindevelopedcountries[1,7].Furthermore,theestimatedprevalenceof
anaemiavariesthroughoutthecourseofpregnancy.IntheUSA,forexample,theprevalenceofanemiaamong
pregnantwomenisestimatedtobe1.8%inthefirsttrimester,8.2%inthesecondtrimester,and27.4%inthethird
trimester[8].

AnotherfactorthataddstothecomplexityinmeasuringtheincidenceofAIPisthevariationamongresearchersin
specifyingthecutoffpointofHblevel.WhilesomeinvestigatorsdefinedAIPasHb<11.0g/dlasperthe
recommendationoftheWHO[9,10],othersadopteddifferentcutoffpointssuchas<10.0and<10.5g/dlwhich
hadbeenrecommendedbyotherpartiesintheUSA[11,12].

HighparityisamongthefactorswithetiologicpotentialincausingAIP[13].TheWHOdefineshighparity(HP)as
fiveormorepregnancieswithgestationperiodsof20weeks,andlowparity(LP)aslessthan5pregnancieswith
gestationperiodsof20weeks[14].

PriorstudiesprovidedinconsistentevidenceregardingthequestionofwhetherhighparityisassociatedwithAIP.
WhilesomestudiesfoundthatincreasingparitywasassociatedwithanincreaseintheriskofAIP[5,6,15,16],
othersreportednoevidenceofsuchanassociation[4,1719].Athirdgroupofstudiesreportedareductioninriskof
AIP[20,21].

ThisretrospectivecohortstudywasconductedinordertoexplorethepotentialrelationbetweenparityandAIP
withspecialattentiontothedistinctionbetweenprevalentandincidentcases.ThepopulationstudiedwereOmani
womancharacterizedbyahighprevalenceofbothHPandAIP.

Methods Goto:

ThestudytookplaceinBidbid,acitylocatedabout30kilometreswestofthecapital,Muscat.Thisstudywas
conductedincollaborationwithanongoingrandomizedcommunitytrialnamed:"DelayingtheDevelopmentof
DiabetesMellitusType2inOman",alsocalledthe"AMALstudy".Thisprojectwaslaunchedin2004,andit
aimstoestimatetheprevalenceofprediabetesamonganOmanipopulationandapplyappropriateinterventionsto
preventtheoccurrenceofdiabetes.TheAMALstudyenrolledatotalof1313subjects,824ofwhomwerewomen.
Amongthefemaleenrolees,283werenulliparouswomenandtheremaining541wereparous.

Ourtargetwastoenrollthe541parouswomenandtocollectrelevantinformationabouttheirpregnancies.Outof
the541parouswomen,532(98.3%)agreedtoparticipateafterreviewinganinformedconsent.Thestudywas
approvedbytheMedicalResearchandEthicsCommitteeatSultanQaboosUniversity.

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Theparticipantswereaskedtofilloutamaternalhealthcard(MHC)withdetailsofalltheirpregnancies.These
cardswereourprimarysourceofinformationforantenatalandclinicaldetailspertainingtopregnancies.MHCsare
registrycardsthatdocumentalltheeventsthatoccurredtothemotherthroughoutpregnancyandafterdelivery.The
cardscontainthefollowingsections:sociodemographics,prepregnancyriskfactors,pastmedicalhistory,obstetric
&gynecologicalhistory,clinicalfindingsateachvisit,investigations,detailsofdelivery,andpostnatalfindings.

TheparticipantsprovidedalistofalltheirpregnanciesandtheMHCs.Aftertheexclusionofmiscarriages,twin
pregnancies,andpregnancies<20weeksofgestation,thestudy'sfinalpopulationincluded1939singleton
pregnancieswithavailableMHCsamong479women.

AnincidentcaseofAIPwasdefinedasanepisodeofplasmahemoglobinlevellessthan11.0g/dlfirstdiagnosed
inthesecondtrimesterorlater,i.e.from12weeksonwards.Thecutoffpointwasdesignatedas11.0g/dlin
accordancewiththeWHOrecommendationandthelocalpracticeinOman.The12thweekwasspecifiedasthe
startingpointoftheeligibletimeframeforincidentcasesofAIPbecauseitisduringthebeginningofthesecond
trimesterthatpregnancyusuallycausesthesteepestreductioninHblevel[22].Ifacaseofanaemiawasdiagnosed
atbookingorduringthefirsttrimester,itwasthusconsideredtobeaprevalentcaseforthepurposeofthisstudy
andthepregnancywasexcludedinordertolimitthestudypopulationtothoseatriskofdevelopingAIP.

Initialcalculationsofthecumulativeincidence(risk)andtheaveragehemoglobinlevelofoccurrenceofAIPwere
madeforeachlevelofparity,everysingleunitbeingtreatedasalevel.Thecrudeandadjustedmeasuresofthe
effectofparityontheoccurrenceofAIPwereobtainedbyusingmultilevellogisticregression(MLLR)analysis
[23].MLLRwaspreferredforanalysisbecauseitaccountsforthedependencythatexistsamongpregnanciesthat
belongtothesamewoman.

TheMLLRmodelsweredevelopedforAIPasanoutcomeusingthehierarchical(PROCNLMIXED)regression
modellingofSASsoftware(withabinomialdistributionandlogitlinkfunction).Twolevelmodelswere
constructedwhichallowedforthegroupingofpregnancyoutcomeswithinwomeninordertoincluderesidualsfor
eachpregnancyandforeachwoman.Thustheresidualvariancewaspartitionedintotwocomponentsforeach
level,oneshowingthevarianceofresidualsbetweendifferentwomenandthesecondshowingthevarianceof
residualsbetweenpregnanciesinthesamewoman.Thisbilevelanalysisrevealedunobservedcharacteristicsthat
affectpregnancyoutcomesforthesamewoman,anditwastheseunobservedvariableswhichshowedthe
correlationbetweenoutcomesforpregnanciesinthesamewoman.Variablesdeemedsignificantatp<0.20ina
bivariatemodelwereusedinamultivariatemodel.Abackwardselectionprocedurewasthencarriedout,and
variablesmeetingthep<0.10significancelevelwereincludedinthefinalmodel.Theoddsratiosthatwere
producedbytheMLLRapproximatetheriskratioswhichmeasureofeffectoftherelationbetweenparityandAIP.
InallMLLRmodels,goodnessoffitwascheckedbyviaexaminingmaximumlikelihoodestimates.Thelevelof
statisticalsignificancewassetat0.05.

Twoseriesoflogisticregressionmodelswereconductedwithdifferentcategorizationsofparity.Thefirstseries
treatedparityasadichotomousvariable:LP(<5)andHP(5).Forthesecondseries,paritywasincludedasa
categoricalvariablewiththefollowingcategories:1,23,45,67,89,and10.Withthiscategorization,wewere
abletoevaluateiftherewasadoseresponserelationbetweenparityandriskofAIP.

Eachseriesofanalysisalsoincludedtwosetsofsubanalyses:acrudemodelandanadjustedmodel.Inthecrude
model,paritywastheonlypredictoroftheoccurrenceofAIP.Intheadjustedmodel,thefollowingsignificant
confounderswereadjustedfor:maternalage,maternaleducationalstatus,familyincome,pasthistoryofAIP,year
ofdelivery,andinterpregnancytime.

InordertoexploretheeffectofchangingthedefinitionofAIPonthemeasuresofeffectoftherelationbetween
parityandAIP,twosecondaryanalyseswereconducted.First,therelationshipswerereexaminedresettingthe
cutoffvaluesforanaemiaathemoglobinlevels<10.5g/dland<10.0g/dl.Second,thestudypopulationwas
expandedtoincludeallpregnancieswithavailableMHCs(1939)andreexaminedincludingtheseadditional
prevalentandincidentcasesofanaemia.AllstatisticalanalyseswereperformedusingSASsoftwareversion9.1
(SASFoundation,Cary,NC).

Results Goto:

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Thestudypopulationincluded1939pregnanciesamong479women.However,mostoftheanalysesinthisstudy
excluded591ofthesepregnanciesbecausetheywereassociatedwithprevalentratherthanincidentcasesofAIP.
Thestudythusanalysedthe1348remainingpregnanciesatriskofdevelopingAIPamong341women.

Table1comparesimportantbaselinecharacteristicsoftheincludedLPandHPpregnanciesatthetimeofeach
pregnancy'soccurrence.Outofthe1348enrolledpregnancies,38.7%wereHPthesetendedtobeassociatedwith
highermaternalage.ThemajorityofHPpregnanciesoccurredinwomenwhowere25to35yearsold,whilethe
majorityofLPpregnanciesconcernedwomenwhowere20to25yearsofage.AmongHPpregnancies,30.1%
hadamaternalage35yearswhereasamongLPpregnanciesonly2.6%ofthewomenwere35yearsofage.

Table1
ComparisonbetweenLP(<5)andHP(5)Pregnancieswithavailable
MHCs

TherateofilliteracyamongHPpregnancieswasalmostthreetimesthatofLPpregnancies(58.2%vs.19.1%).
While62.5%ofLPpregnanciesoccurredinwomenwhoattendedstandardschools,only22.5%oftheHP
pregnanciesoccurredinwomenwhoattendedstandardschools.

HPpregnancieswereassociatedwithhigherfamilyincomecomparedtoLPpregnancies.Theproportionofvery
lowincome(<200Omanirials)amongLPpregnancieswas45.3%comparedto27.5%inHPpregnancies.

AmongHPpregnancies,41.6%hadapositivepasthistoryofAIPwhichwasthreetimesthatofLPpregnancies
(14.3%).TheproportionofpregnanciesthathadapositivehistoryofhematologicaldisordersintheHPgroupwas
almosttwicethatintheLPgroup(11.7%vs.6.4%).BothLPandHPpregnanciestendedtohaveacomparable
distributionofinterpregnancytime.

Duringthefollowupperiod,atotalof289incidentcasesofAIPwereenumeratedamongthe1348pregnancies
consideredtohavebeenatrisk.Table2detailsthemeanhemoglobinlevelandcumulativeincidence(risk)ofAIP
foreachcategoryofparity.Overall,riskofAIPincreasesalongwithparity.Theriskstartsashighas19.6among
theprimiparouspregnancies.Itthenslightlydropsoverincreasingparityunitsuntilparity4,whentheriskbeginsto
increasesteadily.

Table2
Crudecumulativeincidence(risk)ofAIPoversingleunitsofparity

Table3showstheresultsofthefirstseriesofanalysis,whichtreatedparityasadichotomy.Thecrudemodel
showedthattheriskofdevelopingAIPamongtheHPpregnancieswasmorethanfourtimeshigherthanthat
amongtheLPpregnancies(RR=4.3795%CI3.32,5.77).AfteradjustmentforallconfoundersusingMLLR,the
riskofAIPamongtheHPpregnancieswasstillaboutthreetimeshigher(RR=2.9295%CI2.02,4.59).

Table3
Crudeandadjustedlogisticregressionmodelsforeffectofparityon
occurrenceofAIP

Table3alsoshowstheresultsobtainedbyanalyzingparityasacategoricalvariable.Usingparity23asthe
referencecategory,thecrudemodelshowedthatprimiparityisassociatedwithanincreasedriskofAIP(RR=
2.3295%CI1.45,3.70).Asthelevelofparityincreases,theriskratiosindicateaprogressiveincreaseintherisk
ofAIP.Thehighestriskofanyparitycategoryisobservedamongtheparity89category(RR=9.9895%CI
6.95,12.05).Thedropintheriskratioobservedintheparity10categoryislikelytobeduetosparsedata.
Overall,thecrudemodelstronglysuggestsapositivedoseresponserelationbetweenparityandriskofoccurrence
ofAIP.

AdjustmentforconfoundersusingMLLRshowedadoseresponserelationbetweenparityandriskofAIPsimilar

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tothatobservedinthecrudemodel,withthehighestriskratioagainbeingobservedintheparity89category(RR
=5.6795%CI3.55,13.16).

Table4andFigure1showtheresultsofthesecondaryanalyseswithvaryingdefinitionsoftheoutcome.Over
dichotomousparity,theriskratioincreasedslightly,from2.92for<11.0g/dlto3.12for<10.0g/dl,whenthe
cutoffswerelowered.Overmultiplecategoriesofparity,taking<10.5g/dlasthecutoffvalueofthehemoglobin
levelproducedasimilarresultpatterntothatfoundwithacutoffvalueof11.0g/dl,althoughtheRRswerehigher.
Taking<10.0g/dlasthecutoffvaluealsoproducedasimilarpatternwithanevenfurtherincreaseintheRRs.

Table4
Secondaryadjustedanalyseswithvaryingdefinitionsoftheoutcome(AIP)

Figure1
Resultsofadjustedanalyseswithvaryingdefinitionoftheoutcome(AIP)

Table4alsoshowstheeffectofincludingprevalentcasesofAIPinadditiontoincidentcases.Forthecutoffvalue
ofHb<11.0g/dlcutoffvalue,addingprevalentcasesattenuatedtheriskofAIPoverdichotomousparity(RR
shiftedfrom2.92to1.11).Overmultiplecategoriesofparity,theRRseitherwereunaffectedorshowedaslight
increaseintheriskofAIPoverincreasingparityunits.Thepatternsuggestedthatincludingprevalentcasesshifted
theRRstowardsnull.SeeFigure1forcomparisonwithresultsobtainedfromtheprimaryanalysiswhichwas
restrictedtoincidentcases.

Discussion Goto:

Thisretrospectivepopulationbasedcohortstudywasconductedinordertoexplorewhetherparityhasaharmful
effectontheoccurrenceofAIP.OurresultsshowedthatHPpregnanciescarryaboutthreetimeshigherriskof
developingincidentAIPthanLPpregnancies,andthattheriskofAIPincreasesinadoseresponsefashionover
increasinglevelsofparity.

ThegreaterriskofAIPassociatedwithhigherparitymaybeexplainedbywomenhavingHPpregnancies'
increasedsusceptibilitytohemorrhage.Inahealthypregnancy,hormonalchangesleadtoanincreaseinplasma
volumewhichcausesreductioninhemoglobinlevel[22].Thishemodilutioneffectisconsiderednormalifthe
hemoglobinconcentrationdoesnotdropbelowacertainlevele.g.11.0g/dl.Comparedtothenonpregnantstate,
everypregnancycarriesanincreasedriskofhemorrhagebefore,during,andafterdelivery.Therefore,higherparity
exposeswomenmorefrequentlytoperiodsofhemorrhagerisk.Althoughthereisnoconsensuswithregardtothe
exactmechanismsbywhichHPincreasestheriskofhemorrhage,somereportshavesuggestedintermediariessuch
asincreasedvenousdrainagetothelowerpartoftheuterus,hyalinizationofbloodvessels,anddecreasedelasticity
oftheuterinewall[24].Noneoftheseproposedmechanismshavebeenconfirmed[14].

PrimiparouspregnancieswerefoundtobeatahigherriskofAIPcomparedtopregnancieswithparityof1to2.
HighratesofAIPamongprimiparouspregnanciesarecommonlyfoundtobeassociatedwithadolescenceand
smoking[25].Ourfindingcouldbeexplainedbybeingadolescentasthemajority(71.2%)wereassociatedwitha
maternaloflessthan20years.Otherriskfactorssuchasactiveorpassivesmokingareunlikelytoplayarolesince
noneofthewomeninourstudyreportedactivesmoking,andtheprevalenceofsmokinginoursourcepopulation
was6.3%.

Thestudy'sresultsshowedthattheassociationbetweenHPandAIPbecamemorepronouncedwhenthe
specificityofthedefinitionofAIPwasincreasedbyloweringthediagnosticcutoffvalue.Thisfindingemphasizes
theimportanceofspecifyinganappropriatediagnosticcutoffvalueforAIP.Becauseoneoftheobjectivesofthe
antenatalcareservicesisearlydetectionofanemiainthecourseofpregnancy,someauthorities,suchastheWHO,
recommendahighcutoffvalueinordertoincreasethesensitivityofthescreeningtestsandtherebyincreasetheir
abilitytodiscoverundiagnosedcasesofAIP.Despitetheutilityofthisrecommendationinclinicalpractice,itis
counterproductiveforetiologicresearch.Adoptinghighdiagnosticcutoffvaluesreducesthespecificityofthe

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diagnostictestandincreasestherateoffalsepositivesinthestudy,resultinginmisclassificationoftheoutcomevia
aformofinformationbias.Inthepresentstudy,theresultsobtainedwithhighcutoffvalueswereshiftedtowardsa
nullriskratiobecausethemisclassifiedoutcomewasnondifferentialoverthecategoriesofparity.

Thisstudyalsofoundthatincludingprevalentcasesintheanalysistendedtoconcealtheobservedassociation
betweenparityandAIPtodisappearandflattenthedoseresponsecurve.Thisfindingmaybeexplainedbythefact
thattreatingprevalentcasesasincidentcasesreducesthespecificityofthetest,whichagainleadstoamisclassified
outcome.SincethismisclassificationoccurrednondifferentiallyovertheLPandHPgroups,themeasuresofeffect
wereagainshiftedtowardsnull[26].

MostofthepreviousstudiesdidnotadequatelyspecifythetiminganddiagnosticcutoffvalueofAIP[36].The
mainreasonforthisappearstobethatthosestudiesdidnottreatAIPasthemainoutcome,butratherlistedit
amongmanyotherantenatalcomplications.TheirresultsthusprovidedinconsistentevidenceofwhetherHPis
associatedwithanincreasedriskofAIP.

Whilesomestudiesprovidedinformationabouttheirdiagnosticcriteriahowever,significantmethodological
differencesrenderanycomparisonoftheirfindingswithourresultscomplexandgenerallyunenlightening.Among
thesestudies,thestudyconductedbyBuggetal.appearstohavebeenthemostcomprehensive[2]:itwasanage
matchedretrospectivecohortstudyintheUnitedKingdomconductedonapopulationof794womenusingtwo
criteriatodefineofAIPcases:1)bookingHb<10.0g/dland2)anyantenatalHb<10.0g/dl.Beyondmatching
forage,therewasnoadjustmentforconfounders.Withbothdefinitions,anincreasedriskofAIPwasfoundamong
HPwomen.ThefindingsreportedbyBuggetal.agreewithourfindingofanincreasedriskofAIPwithHPthis
agreementmaybeattributabletobothstudies'adoptionofahighlyspecificdefinitionofAIP.

Theresultsofthepresentstudyarenotwithoutassumptions.Byconsideringonlypregnanciesthathadreachedthe
12thweekofgestation,weimplicitlyhypothesizedalatencyperiodof12weeksfortheactionofparity.This
hypothesismightnotbecorrect.Nonetheless,iftheactuallatencyperiodislongerthan12weeks,wewouldinfer
thatourresultswereaffectedbynondifferentialmisclassificationoftheoutcomeandwerebiasedtowardsnull.If
thisisthecase,thenactualmeasurementsoftheeffectofparitywouldlikelyrevealanevenhigherriskofAIP
amongHPcomparedtoLPpregnancies.Ontheotherhand,theactuallatencyperiodisunlikelytobeshorterthan
12weeksbecausethephysiologicalmechanismsthroughwhichparityinducesAIP,e.g.hemodilutionand
hemorrhage,havelimitedactionbeforethesecondtrimester[22].

OurresultsmayhavebeenaffectedbyselectionbiasduetotheexclusionofpregnancieswithmissingMHCsfrom
theanalysis.Thepossibleexistenceandmagnitudeofsuchaselectionbiaswasassessedbyconductingaparallel
analysisofpregnanciesoccurringonlyinwomenwithnomissingMHCs(datanotshown).Theresultssuggesteda
doseresponserelationsimilartothatobservedintheanalysisofallpregnanciesitwasthereforeconcludedthatthe
impactofthisselectionbias,ifany,wasinsubstantial.

Conclusions Goto:

Inconclusion,increasingparityappearstoincreasetheriskofoccurrenceofAIPinadoseresponsefashion.This
studyshowstheimportanceofdifferentiatingprevalentandincidentcasesofAIP.Inclusionofprevalentcases
shiftstheassociationtowardsthenullandflattensthedoseresponserelation.Finally,thestudyshowsthe
importanceofclearlyspecifyingadiagnosticcutoffvalueofhemoglobinlevelindefiningAIP,asincreased
specificityofthedefinitionenhancedtheobservedassociation.

Competinginterests Goto:

Theauthorsdeclarethattheyhavenocompetinginterests.

Authors'contributions Goto:

YMFformulatedthestudyconceptandcollecteddata.Hecontributedtodataanalysis,literaturereview,andwrite
upofthemanuscript.DRBandMMWconceptualizedthemethodsandcontributedinreviewingresultsandwrite
upofthemanuscript.HJCconceptualizedtheregressionmodellingtechniques,reviewedtheresultsand
contributedtothewriteup.MAScontributedtothedesignanddatacollectioninthefieldandcontributedtothe

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writeup.HCWrevisedthescientificbackgroundofthestudyandcontributedtotheliteraturereviewandwriteup
ofmanuscript,especiallytheDiscussion.Allauthorsreadandapprovedthefinalmanuscript.

Prepublicationhistory Goto:

Theprepublicationhistoryforthispapercanbeaccessedhere:

http://www.biomedcentral.com/14712393/11/7/prepub

Acknowledgements Goto:

TheauthorsacknowledgeDr.KamleshBhargava,principalinvestigatoroftheAMALStudy,andtheAMAL
Studyresearchteamforalltheirlogisticalsupport,withoutwhichthisstudywouldnothavebeenpossible.

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