Paper III Vårtun Å, Flo K, Widnes C, Acharya G. Static and functional hemodynamic profiles of ...

13 Pages·2016·0.23 MB·English

by  Vårtun Åse

Paper III

Vårtun Å, Flo K, Widnes C, Acharya G.
Static and functional hemodynamic profiles of women with abnormal uterine Doppler at
22-24 weeks of gestation
PLoS One. 2016 Jun 16;11(6):e0157916.
RESEARCHARTICLE
Static and Functional Hemodynamic Profiles
of Women with Abnormal Uterine Artery
Doppler at 22–24 Weeks of Gestation
ÅseVårtun1☯*,KariFlo1☯,ChristianWidnes1,GaneshAcharya1,2☯
1 Women’sHealthandPerinatologyResearchGroup,DepartmentofClinicalMedicine,FacultyofHealth
Sciences,UiT-TheArcticUniversityofNorwayandDepartmentofObstetricsandGynaecologyUniversity
HospitalofNorthernNorway,Tromsø,Norway,2 DepartmentofClinicalSciences,Interventionand
Technology,KarolinskaInstitute,Stockholm,Sweden
☯Theseauthorscontributedequallytothiswork.
*[email protected]
Abstract
a11111
Objective
Tocomparecardiacfunction,systemichemodynamicsandpreloadreserveofwomenwith
increased(cases)andnormal(controls)uterineartery(UtA)pulsatilityindex(PI)at22–24
weeksofgestation.
OPENACCESS
Citation:VårtunÅ,FloK,WidnesC,AcharyaG MaterialsandMethods
(2016)StaticandFunctionalHemodynamicProfiles
Aprospectivecross-sectionalstudyof620pregnantwomen.UtAbloodflowvelocitieswere
ofWomenwithAbnormalUterineArteryDopplerat
22–24WeeksofGestation.PLoSONE11(6): measuredusingDopplerultrasonography,andPIwascalculated.MeanUtAPI(cid:1)1.16
e0157916.doi:10.1371/journal.pone.0157916 (90thpercentile)wasconsideredabnormal.Maternalhemodynamicswasinvestigatedat
Editor:ChristopherTorrens,Universityof baselineandduringpassivelegraising(PLR)usingimpedancecardiography(ICG).Pre-
Southampton,UNITEDKINGDOM loadreservewasdefinedaspercentincreaseinstrokevolume(SV)90secondsafterpas-
Received:September1,2015 sivelegraisingcomparedtobaseline.
Accepted:June7,2016
Results
Published:June16,2016
MeanUtAPIwas1.49amongcases(n=63)and0.76amongcontrols(n=557)(p<
Copyright:©2016Vårtunetal.Thisisanopen
0.0001).Eighteen(28.6%)casesand53(9.5%)controlsdevelopedpregnancycomplica-
accessarticledistributedunderthetermsofthe
CreativeCommonsAttributionLicense,whichpermits tions(p<0.0001).Themeanarterialpressureandsystemicvascularresistancewere83
unrestricteduse,distribution,andreproductioninany mmHgand1098.89±293.87dynes/cm5amongcasesand79mmHgand1023.95±213.83
medium,providedtheoriginalauthorandsourceare dynes/cm5amongcontrols(p=0.007andp=0.012,respectively).Heartrate,SVandcar-
credited.
diacoutputwerenotdifferentbetweenthegroups.Bothcasesandcontrolsrespondedwith
DataAvailabilityStatement:Allrelevantdataare asmall(4–5%)increaseinSVinresponsetoPLR,butthecardiacoutputremained
withinthepaper.
unchanged.Thepreloadreservewasnotsignificantlydifferentbetweentwogroups.
Funding:ThisstudywasfundedbytheRegional
HealthAuthorityofNorthernNorway(Helse-Nord),
Conclusion
GrantNo.SFP873/ID1646,GA.
PregnantwomenwithabnormalUtAPIhadhigherbloodpressureandsystemicvascular
CompetingInterests:Theauthorshavedeclared
thatnocompetinginterestsexist. resistance,butsimilarfunctionalhemodynamicprofileat22–24weekscomparedto
PLOSONE|DOI:10.1371/journal.pone.0157916 June16,2016 1/12
MaternalHemodynamics
controls.Furtherstudiesareneededtoclarifywhetherfunctionalhemodynamicassess-
mentusingICGcanbeusefulinpredictingpregnancycomplications.
Introduction
Pregnancyischaracterizedbyprofoundalterationsinmaternalsystemichemodynamicsand
cardiacfunction[1,2].Thesystemicvascularresistance(SVR)decreasesasearlyasfiveweeks
ofgestation,followedbyasignificantincreaseincirculatingbloodvolumeandcardiacoutput
(CO)[3–6].Increasedbloodvolumeandredcellmasscontributetoanincreaseinpreloadand
thefallinSVRleadstodecreasedafterload[7].Thesealterationsarelargelycompletedduring
thefirsthalfofpregnancy[3,5,8],andthecardiovascularadaptiontopregnancyresultsincar-
diacremodelingandincreasedleftventricularmassleadingtoalteredsystolicanddiastolicper-
formance[3,9–11].Changesincardiovascularfunctioncausedbyalteredpreloadand
afterloadmaybedifferentamongwomendevelopingpregnancycomplications,suchaspre-
eclampsia,comparedtothosewhoremainhealthy[12–14].
Increasedpulsatilityindex(PI)andpresenceofearlydiastolicnotchintheuterineartery
(UtA)Dopplervelocitywaveformshavebeenusedtoidentifywomenatriskofdevelopingpre-
eclampsia[15,16]andotherpregnancycomplications[17].However,UtADopplerhasnot
proventobeaneffectivescreeningtoolinlow-riskpregnancies.Usingechocardiography,
asymptomaticcardiacdiastolicdysfunctionhasbeenshowntobepresentatmid-gestation
(20–23weeks)inwomenwhosubsequentlydeveloppretermpreeclampsia[18].Therefore,
evaluationofmaternalcardiacfunctiontogetherwithUtADopplermightimproveinthepre-
dictionofpregnancycomplications.Furthermore,dynamicfunctionalassessmentofmaternal
cardiovascularfunctionseemstoprovidemorevaluableinformationthantheconventional
staticmeasurements[19–21].Changesincardiovascularfunctioninresponsetoatransient
increaseinvolumeloadcausedbypassivelegraising(PLR)hasbeenwidelyusedasamethod
offunctionalhemodynamicassessment,especiallyinintensivecareunits[22].
WehypothesizedthatpregnantwomenwithincreasedUtAPIhaveadifferenthemody-
namicprofileandanalteredresponsetoatransientvolumeloadcomparedtocontrols.The
specificaimofthisstudywastoinvestigatethedifferencesinstaticandfunctionalhemody-
namicprofilesofwomenwithhighandnormalUtAPI.
MaterialsandMethods
Studypopulation
Thiswasaprospectivecross-sectionalstudyof620pregnantwomenat22–24weeksofgesta-
tion.Pregnantwomenattendingtheantenatalclinicforroutineantenatalultrasoundscreening
at17–20weeksofgestationwereinformedaboutthestudyandinvitedtoparticipate.Those
whogaveinformedwrittenconsentwererecruitedconsecutively.Inclusioncriteriawereage
>18years,livesingletonpregnancywithandnoobviousfetalabnormalitydetectedonultra-
soundscan.Exclusioncriteriawere,diagnosisofamultiplepregnancy,andinabilitytocom-
municateinNorwegianorEnglish.
Thestudywasperformedduring2006–2013.PLRwasaddedtotheresearchprotocolstart-
ing2010.Theparticipantswereexaminedafterapproximately8hoursoffasting,inaquiet
roomwithtemperaturemaintainedatapproximately22°Cbetween8:00to12:00hours.Height
andweightwasmeasuredandusedforcalculationofbodymassindex(BMI)as:
BMI=weight/height2.Bodysurfacearea(BSA)wascalculatedusingtheDuBoisformulaas:
BSA(m2)=0.007184xHeight0.725xWeight0.425[23].
PLOSONE|DOI:10.1371/journal.pone.0157916 June16,2016 2/12
MaternalHemodynamics
Informationaboutthecourseandoutcomeofpregnancyincludingdeliverydatawas
obtainedfromtheelectronicmedicalrecords.Gestationalhypertensionwasdefinedasblood
pressure(cid:1)140/90mmHginapreviouslynormotensivewomenintheabsenceofproteinuria,
andpre-eclampsiaasbloodpressure(cid:1)140/90mmHgandproteinuriaof(cid:1)300mg/24hours
(or1+ormoreonaspoturinedipsticktest)orHELLP((hemolysis,elevatedliverenzymes,
lowplatelets)syndromeoccurringafter20weeksofgestation.Gestationaldiabeteswasdefined
asatwo-hourglucoseconcentrationof(cid:1)7.8–(cid:3)11.1mmol/Laftera75goralglucosetolerance
test.
Impedancecardiography
Maternalsystemichemodynamicsandcardiacfunctionwasinvestigatedusingnon-invasive
impedancecardiography(ICG)(PhilipsMedicalSystems,Androver,MA,USA).Theuseof
ICGinpregnantwomenhasbeendescribedpreviously[2,20].Inshortfourpairsofsensors
wereused;twopairsappliedverticallyoneachsideattheaxillarylineofthoraxandtheother
twopairsplacedverticallyoneachsideoftheneck.Asphygmomanometercuffwasplacedon
theleftarmandconnectedtotheICGinstrumentforbloodpressuremeasurement.Central
venouspressure(CVP)andpulmonaryarteryocclusionpressure(PAOP)werepresetto4and
8mmHg,respectively.Variblesdescribingsystemichemodynamics,i.e.cardiacoutput(CO),
cardiacindex(CI),strokevolume(SV),strokeindex(SI),systemicvascularresistance(SVR)
andsystemicvascularresistanceindex(SVRI),aswellascardiaccontractilityandwork,i.e.
accelerationindex(ACI),velocityindex(VI),pre-ejectionperiod(PEP),leftventricularejec-
tiontime(LVET),systolictimeratio(STR)calculatedas(PEP/LVET)x100%,andleftventric-
ularcardiacworkindex(LCWI)werecontinuouslyrecordedbyICGanddisplayedonscreen.
Inaddition,thoracicfluidcontent(TFC)wassimultaneouslyrecordedbyICG.
ACIisdefinedasthepeakaccelerationofbloodflowfromleftventricleintoaorta,VIisthe
peakvelocityofthesystolicwaveofaorticbloodflow,PEPisthetimefromthebeginningof
electricalstimulationoftheventriclestotheopeningoftheaorticvalve(electricalsystole),
reflectingthepre-ejectionperiod(isovolumetricventricularcontractiontime),LVETisthe
timefromtheopeningtotheclosingoftheaorticvalve(mechanicalsystole)andLCWIisthe
workperformedbytheleftventriclenormalisedforbodysurfacearea.
Themeasurementswereperformedintwodifferentpositions,atbaselinewiththewomen
lyinginasemi-recumbentpositionandafterPLRasdescribedpreviously[20].Preloadreserve
wasdefinedaspercentincreaseinSV90secondsafterPLRcomparedtobaseline.
Thewomenweretoldnottospeakormovewhilemeasurementswereconducted.Baseline
measurementswererecordedafter10minutesofrestinasemi-recumbentposition.Upper
partofthebedwasthenloweredandthelowerpartofthebedwaselevatedto45°electronically
toachievePLR.Hemodynamicsmeasurementswererecordedagainatapproximately90sec-
ondsafterPLR.CardiovascularresponsetoPLRwasexpressedaspercentchangefromthe
baselinevalueas.Asingleoperator(ÅV)performedallICGmeasurementsunderidentical
conditions.
Dopplerultrasonography
UltrasoundexaminationwasperformedusinganAcusonSequoia512ultrasoundsystem
(MountainView,CA,USA)witha2.5–6MHzcurvilineartransducer.Twoexperiencedsonog-
raphers(CWandKF)performedallexaminationsstrictlyadheringtotheALARA(aslowas
reasonablyachievable)principle[24].Thepregnantwomanwasexaminedinasemi-recum-
bentpositiontoavoidpossiblecompressionofinferiorvenacavabythegraviduterus.Blood
flowvelocitywaveformswererecordedfromtheleftandrightUtAproximaltotheapparent
PLOSONE|DOI:10.1371/journal.pone.0157916 June16,2016 3/12
MaternalHemodynamics
crossoverwiththeexternaliliacarteryusingcolor-directedpulse-waveDoppleraspreviously
described[25].Onlinemeasurementsofvelocitieswereobtainedfromfourtosixuniform
Dopplervelocitywaveforms,andtheaveragevalueofthreesuccessivecardiaccycleswas
recordedforanalysis.UtAPIwascalculatedas:(peaksystolicvelocity—end-diastolicvelocity)/
time-averagedmaximumvelocity.ThePIvaluesfromtheleftandrightUtAwereaveragedand
usedforstatisticalanalysis.Thepresenceofabilateralorunilateraldiastolicnotchingwas
recorded.
Statisticalanalysis
DatawereanalyzedusingIBMSPSSstatistics(SPSSsoftware,version22.0,Chicago,IL,USA).
WomenweredividedintotwogroupsbasedontheUtAPI.ThosewithameanUtAPI(cid:1)1.16
(above90thpercentilefor22–24weeksofgestation)weredefinedascasesandthosewitha
meanUtAPI<1.16ascontrols.
Continuousvariablesarepresentedasmean±SD.Discretequantitativeandcategoricalvari-
ablesarepresentedasmedian(range)orn(%)asappropriate.Datadistributionwasevaluated
byvisualinspectionofplotsandassumptionofnormalitywastestedusingShapiro-Wilktest.
Weusedparametrictestsifthedistributionofdatadidnotdeviatesignificantlyfromnormal-
ity.Independentsamplest-testwasusedforcomparingcasesandcontrols.Pairedsamplet-test
wasusedforanalysisofdifferencesinhemodynamicvariablesmeasuredatbaselineandafter
passivelegraisingwithineachgroup.Chi-squaredtestwasappliedfortheanalysisofdiffer-
encesinproportionsbetweengroups.Statisticalsignificancewassetasp<0.05.
Ethicsstatement
ThestudyprotocolwasapprovedbytheRegionalCommitteeforMedicalResearchEthicsin
NorthNorway(Ref.nr.5.2005.1386and2010/586).Allstudyparticipantsgaveinformedwrit-
tenconsent.
Results
Atotalof620pregnantwomenwithsingletonpregnancyparticipatedinthestudy.Noneofthe
participantswerelosttofollowup,andinformationonthecourseofpregnancyandperinatal
outcomewasavailableforall.
Baselinecharacteristicsandpregnancyoutcome
Thebaselinecharacteristicsofthestudypopulationincludingneonataloutcomearepresented
inTable1.Therewerenosignificantdifferencesinageandbodymassindex(BMI)between
thetwogroups.Abouthalfoftheparticipantsinbothgroupswerenulliparous.Prevalenceof
bilateralnotchinginUtADopplerwaveformamongcaseswas23(36.5%)comparedwith4
(0.7%)amongcontrols(p<0.0001).
Amongcases,18women(28.6%)developedcomplicationscomparedto53women(9.5%)
amongcontrols(p<0.0001).Inthecasegroup,11women(17.5%)developedpre-eclampsia,
and5oftheseincombinationwithintrauterinegrowthrestriction(IUGR).Pre-eclampsiawas
diagnosedbefore37weeksin8women(72.7%)andbefore34weeksin4women(36.4%).In
thecasegroup,4women(6.4%)developedgestationalhypertensionand2women(3.2%)
developedgestationaldiabetes.
Amongcontrols,21women(3.8%)developedpre-eclampsiaincluding3womenwith
HELLPsyndrome.Pre-eclampsiawasdiagnosedbefore37weeksin2women(9.5%)and
before34weeksin2women(9.5%).Twentywomen(3.6%)developedgestationalhypertension
PLOSONE|DOI:10.1371/journal.pone.0157916 June16,2016 4/12
MaternalHemodynamics
Table1. BaselinecharacteristicsofthematernalstudypopulationandbirthoutcomeofneonatesofmotherswithnormalandhighmeanUtAPI.
Parameter NormalUtAPI(n=557) HighUtAPI(n=63) p-value*
Maternal
Age(years) 30(range18–44) 30(range19–40) 0.364
Bodymassindexatfirstexamination(Kg/m2)(20–24weeks) 26.08±4.02 27.35±5.29 0.069
Meanarterialpressureatbaseline,firstexamination(mmHg)(22–24weeks) 79.29±8.04 82.76±10.06 0.010
Nulliparous 290(52.1) 29(46.0) 0.365
Bilateralnotch(%) 4(0.7) 23(36.5) <0.0001
MeanUtAPI 0.76±0.18 1.49±0.40 <0.0001
Birthoutcome
Cesareansection(%) 58(10.4) 10(15.9) 0.2008
Gestationalageatbirth(weeks) 40(range25–42) 38(range25–42) 0.002
Birthweight(g) 3567±531 3063±771 <0.0001
Placentalweight(g) 625±138 540±149 <0.0001
5-minuteApgarscore 10(range2–10) 10(range5–10) 0.883
UmbilicalarterypH 7.23±0.09 7.24±0.06 0.554
Umbilicalarterybaseexcess(mmol/L) -4.78±3.52 -3.99±2.60 0.124
Datapresentedasn(%),median(range)ormean±SDasappropriate.
*representsthep-valueforthedifferencebetweennormalandhighUtAPIgroups(Independentsamplest-testorPearsonchi-squaredtest).
doi:10.1371/journal.pone.0157916.t001
and8women(1.4%)developedgestationaldiabetes.Twowomen(0.4%)hadplacentalabrup-
tionat32+4and41+3weeksofgestation.Bothofthesewomenhaduncomplicatedpregnancy
beforetheevent.Therewere2intrauterinefetaldeaths(0.4%)amongcontrols.Oneoccuredin
anulliparouswomanat26+6weeksofgestation(meanUtAPI=0.97),andtheotherinamul-
tiparouswomanat36+5weeksofgestation(meanUtAPI=0.81).Noobviouscausesforfetal
demisewerefoundatautopsy.
Thereweresignificantdifferencesbetweencasesandcontrolsregardinggestationalageat
delivery,birthweightandplacentalweightbutnotfor5-minuteApgarscoreandumbilical
arterybloodgasesandacid-basestatus(Table1).
Statichemodynamics
Theresultsofmaternalsystemichemodynamicsandcardiacfunctionatbaselinemeasuredby
ICGarepresentedinTable2.Atbaselinearterialbloodpressuresandsystemicvascularresis-
tanceindex(SVRI)weresignificantlyhigheramongcasescomparedtocontrols,buttheheart
rate,SVandcardiacoutputwerenotdifferentbetweenthegroups.
Functionalhemodynamics
HemodynamicresponsetoPLRwasmeasuredin38casesand312controls.Theresponsefol-
lowingPLRdescribedaspercentchange(Δ%)inthemeasuredparametersfrombaselineto
PLRineachgroupispresentedinTable3.Thedirectionandmagnitudeofchangeweresimilar
forvariablesdescribingsystemicbloodflowandvascularresistance(Fig1).Asignificant
(p<0.001)decreasesinHR,MAPandSVRwasobservedbothamongthecasesaswellascon-
trolsduringPLR.Therewas,asignificantincreaseinSVamongcases(p=0.006)andcontrols
(p<0.001)followingPLR,buttheincreaseinCOwasnotsignificantinbothgroups.
Thedirectionandmagnitudeofchangesintheparametersdescribingcardiaccontractility
andworkinresponsetoPLRarepresentedinFig2.PLRcausedasignificant(p<0.001)
PLOSONE|DOI:10.1371/journal.pone.0157916 June16,2016 5/12
MaternalHemodynamics
Table2. MaternalsystemichemodynamicsandcardiacfunctionofthestudygroupwithnormalandhighUtAPImeasuredusingimpedance
cardiography.
Parameter NormalUtAPI(n=557) HighUtAPI(n=63) p-value*
Cardiacoutput(L/min) 6.11±1.32 6.02±1.34 0.617
Cardiacindex(L/min/m2) 3.35±0.54 3.28±0.58 0.370
Heartrate(/min) 79.30±11.59 79.75±13.05 0.777
Systolicbloodpressure(mmHg) 101.73±9.81 105.89±12.69 0.014
Diastolicbloodpressure(mmHg) 68.04±7.75 71.43±9.48 0.008
Meanarterialbloodpressure(mmHg) 79.24±7.97 82.94±10.16 0.007
Systemicvascularresistance(dynes/cm5) 1023.95±213.83 1098.89±293.87 0.012
Systemicvascularresistanceindex(dynesm2/cm5) 1836.93±331.15 1983.49±473.96 0.020
Strokevolume(ml) 79.16±16.31 78.17±16.12 0.651
Strokeindex(ml/m2) 43.43±6.40 42.65±6.68 0.363
Thoracicfluidvolume(1/kOhm) 27.78±4.59 26.81±4.63 0.113
Accelerationindex(1/100s2) 126.35±45.26 120.60±44.72 0.339
Leftventricularworkindex(kgm/m2) 3.45±0.74 3.55±0.82 0.341
Pre-ejectionperiod(ms) 83.03±15.76 85.11±15.45 0.320
Leftventricularejectiontime(ms) 263.05±31.54 263.68±31.62 0.880
Velocityindex(1/1000s) 77.62±22.77 73.62±23.32 0.188
Systolictimeratio(%) 32.60±7.86 33.22±7.55 0.549
Datapresentedasmean±SD.
*representsthep-valuebetweennormalandhighUtAPIgroupsatbaseline(Independentsamplest-test).
doi:10.1371/journal.pone.0157916.t002
Table3. Hemodynamicparametersmeasuredbyimpedancecardiographyatbaselineand90secondsafterpassivelegraising(PLR)inpregnant
womenwithnormalandhighUtAPI.
NormalUtAPI HighUtAPI p-
value*
Hemodynamic Baseline PLR(n=312) %change p- Baseline PLR(n=38) %change p-
parameter (n=312) value# (n=38) value#
SV(ml) 80.73±17.03 83.33±16.71 3.95±10.65 <0.001 80.37±17.24 83.74±16.53 5.02±9.63 0.006 0.557
SI(ml/m2) 44.49±6.64 45.90±6.30 3.88±10.68 <0.001 43.55±7.34 45.50±6.68 5.30±9.82 0.004 0.437
CO(L/min) 6.26±1.35 6.31±1.26 1.63±10.99 0.238 6.09±1.55 6.26±1.36 3.96±9.59 0.092 0.212
CI(L/min/m2) 3.45±0.56 3.48±0.49 1.64±11.05 0.223 3.29±0.66 3.39±0.53 4.13±9.65 0.067 0.185
HR(/min) 79.91±12.07 77.67±10.47 -2.24±8.61 <0.001 78.76±14.02 75.84±11.67 -3.16±5.62 0.001 0.521
BPS(mmHg) 101.26±9.81 99.94±9.70 -1.19±4.39 <0.001 107.58±13.47 106.13±11.34 -1.05±4.34 0.056 0.860
BPD(mmHg) 67.39±7.87 63.84±7.39 -5.09±5.38 <0.001 71.92±10.68 69.08±11.59 -4.08±5.35 <0.001 0.278
MAP(mmHg) 78.66±8.02 75.88±7.83 -3.45±3.89 <0.001 83.84±11.21 81.42±11.25 -2.89±3.35 <0.001 0.390
SVR(dynes/cm5) 993.34±225.74 941.61±178.96 -4.06±10.67 <0.001 1116.32±356.15 1040.53±304.38 -5.87±8.05 <0.001 0.313
SVRI(dynesm2/cm5) 1773.57±359.98 1681.45±266.07 -4.07±10.67 <0.001 2023.42±571.93 1886.84±487.50 -5.84±8.22 <0.001 0.322
TFC(1/kOhm) 29.64±4.46 30.63±4.40 3.73±7.97 <0.001 28.61±4.55 29.68±4.45 4.11±6.41 0.001 0.779
ACI(1/100s2) 139.45±49.84 133.68±42.57 -.18±26.06 0.001 127.21±51.13 120.63±46.80 -2.04±19.98 0.089 0.671
LCWI(kgm/m2) 3.53±0.73 3.41±0.67 -2.43±11.52 <0.001 3.59±0.90 3.57±0.76 .60±10.89 0.722 0.125
PEP(ms) 80.64±16.05 71.08±13.90 -10.50±15.32 <0.001 84.55±15.43 74.29±12.91 -10.55±16.25 <0.001 0.985
LVET(ms) 259.42±31.96 273.22±33.59 6.35±15.11 <0.001 265.71±32.41 277.63±33.98 5.71±16.78 0.074 0.808
VI(1/1000s) 85.66±24.20 81.70±20.47 -2.37±16.94 <0.001 76.61±26.40 75.66±23.30 .78±12.99 0.544 0.270
STR(%) 32.15±8.41 26.73±6.24 -14.06±21.06 <0.001 32.84±7.96 27.58±5.96 -12.38±23.86 <0.001 0.648
Dataarepresentedasmean±SD.%changeisthedifferencebetweenthemeasurementsobtainedatbaselineandPLRinpercent.
#representsthep-valueforthedifferencebetweenbaselineandPLR(pairedsamplet-test)withinnormalandhighUtAPIgroups.
*representsthep-valueforthedifferenceindelta%valuesbetweennormalUtAPIandhighUtAPIgroups(independentsamplet-test).Strokevolume
(SV),strokeindex(SI),cardiacoutput(CO),cardiacindex(CI),heartrate(HR),bloodpressuresystolic(BPS),bloodpressurediastolic(BPD),mean
arterialpressure(MAP),systemicvascularresistance(SVR),systemicvascularresistanceindex(SVRI),thoracicfluidcontent(TFC),accelerationindex
(ACI),leftventricularworkindex(LWCI),pre-ejectionperiod(PEP),left-ventricularejectiontime(LVET),velocityindex(VI)andsystolictimeratio(STR).
doi:10.1371/journal.pone.0157916.t003
PLOSONE|DOI:10.1371/journal.pone.0157916 June16,2016 6/12
MaternalHemodynamics
Fig1.Differencesinsystemicmaternalhemodynamicsbetweenpregnantwomenwithnormaland
high(UtAPI).Datapresentedasmean±standarderrorofmean(SEM).Maternalheartrate(HR),stroke
volume(SV),cardiacoutput(CO),meanarterialpressure(MAP)andsystemicvascularresistance(SVR).
Percentchange(Δ%)representingthechangefrombaselinetopassivelegraisingwithnormal(whitebars)
andhigh(greybars)UtAPI.
doi:10.1371/journal.pone.0157916.g001
decreaseinPEPandSTRinbothgroups,butthechangesinACI,LVET,VI,andLCWIwere
significantonlyincontrolgroup(Table3).Thedirectionofchangewasoppositeamongcases
andcontrolsforVIandLCWI(Fig2),butthemagnitudeofchangewasnotsignificantlydiffer-
entbetweenthegroups.
ResponsetoPLRwasnotdifferentbetweencasesandcontrolsforanyoftheparametersof
systemichemodynamicsandcardiacfunctioninvestigated.
Discussion
PLRcausesatransientvolumeloadresultinginsignificantchangesinthemajorityofhemody-
namicvariables[20].Ithasbeenwidelyusedtopredictfluidresponsivenessinpatients
Fig2.Differencesincardiaccontractilityandworkbetweenpregnantwomenwithnormalandhigh
UtAPI.Datapresentedasmean±standarderrorofmean(SEM).Percentchangefrombaselinetopassive
legraising.Normal(whitebars)andhigh(greybars)UtAPI.Accelerationindex(ACI),leftventricularwork
index(LWCI),velocityindex(VI),pre-ejectionperiod(PEP),left-ventricularejectiontime(LVET),andsystolic
timeratio(STR).
doi:10.1371/journal.pone.0157916.g002
PLOSONE|DOI:10.1371/journal.pone.0157916 June16,2016 7/12
MaternalHemodynamics
admittedtointensivecareunit[26].Arecentstudyhasshownthatthewomenwithseverepre-
eclampsiaassociatedwitholiguriahavereducedpreloadreserve[21].Asfarasweknow,hemo-
dynamicresponsetoPLRinwomenatriskofpregnancycomplicationshasnotbeenreported.
OurstudydemonstratesthatpregnantwomenwithabnormalUtAPIhavehigherSVRIcom-
paredtocontrols,buttheirabilitytorespondtoasmallincreaseinpreloadcausedbytransient
autotransfusionispreserved.Wefoundsimilarpreloadreserveamongwomenwithhighas
wellasnormalUtAPIat22–24weeksofgestation.
Amajorstrengthofourstudyisthatitwasprospective,andwehadacompletefollowupon
allrecruitedparticipants.Therehavebeensomeconcernsaboutthereproducibilityandvalid-
ityofICGinpregnancy.However,ICGisasimplenon-invasivemethodwhichislessoperator
dependentcomparedtoechocardiography.Wehavepreviouslyfoundgoodrepeatabilityofthe
measurementsofSV,HRandCOandgoodagreementbetweenmeasurementsperformedin
semi-recumbentandleftlateralpositionsusingICG[2,27].OtherstudieshavevalidatedICG
asareliable,accurateandreproduciblemethodreportinggoodagreementandcorrelationof
ICGwithechocardiographyandthermodilution[28–33].Furthermore,Burlingameetalhave
reportedthattheICGhastheabilityofdetectingsmallchangesinmaternalSVassociatedwith
positionchanges,whereastheechocardiographylacksthesensitivitytodetectsmallchangesin
ejectionfraction(EF)[30].
Investigationofthepregnantwomenwasperformedbetween22to24weeksofgestation.The
placentalcirculationiswellestablishedbythisgestationalageandthisistheperiodingestation
whenUtADopplerismostoftenperformedinclinicalsettings.However,firsttrimesterscreen-
ingforpre-eclampsiausingUtADopplerincombinationwithotherbiochemicalmarkersis
gainingpopularityinrecentyears.Inthisrespect,itwouldhavebeeninterestingtostudyfunc-
tionalhemodynamicprofileduring11–14weeksofgestation.However,itwasnotfeasibleinour
settingasfirsttrimesterultrasoundscreeningisnotaroutineinNorwegiannationalhealthcare
system.Anotherlimitationofourstudyisthatthesamplesizewasinsuffienttoperformseparate
subgroupanalysescomparingwomenwhodevelopedearlyandlate-onsetpre-eclampsia.
AmbienttemperaturecanaffectSVR.Inourstudy,theroomtemperaturewasheldat22°C
duringallexaminations.Astudypublishedin2011indicatedahigherthermoneutralzonein
pregnancy[34].Anothermorerecentstudyreportedthatthethemoneutralzoneforaclothed
personatmetabolicrestisbetween17.5°C–24.0°C[35].Whatconstitutesthermoneutralzone
couldbedebatable,butwechosetokeeptheroomtemperaturesamethroughoutthewhole
studyperiodandthemeasurementsduringbaselineandPLRwereperformedatthesame
ambienttemperature.
WefoundthatapproximatelyonethirdofwomenwithhighUtAPIdevelopedcomplica-
tionsduringpregnancyandtheprevalenceofpre-eclampsiainourstudypopulationwas5.2%.
Similarresultshavebeenreportedbyothers[36–38].OurfindingsofUtAnotchingwerein
accordancewithGómezetal[17]whorecordedbilateralnotchesat19–22weeksin32.8%of
womenwholaterdevelopedpregnancycomplications,andwithMelchiorreetal[18]who
foundUtAnotchingin23.7%ofwomenwithUtAPI>95thpercentilecomparedto4.2%
amongcontrolsat20–23weeksofgestation.
Wefoundsomedifferencesinbaselinematernalsystemichemodynamics,especiallyarterial
bloodpressureandSVR,betweenwomenwithnormalandabnormalmeanUtAPI,butboth
groupsrespondedsimilarlytoPLR.Valensiseetal[39]investigated36womenwithabnormal
UtARI(>0.58)andbilateralnotchusingDopplerechocardiography,andfoundthat41.7%of
womenwholaterdevelopedcomplicationshadsignificantlyhigherMAPandSVRcompared
tonormaloutcomegroup.Inanothersimilarstudy,theyfoundsignificantlyhigherMAPand
SVRbutlowerCOinwomendevelopingearlyPE(<34weeksofgestation)comparedtocon-
trols,buttheMAPwassimilar,SVRwaslower,andCOwashigherinthelatePEgroup[12].
PLOSONE|DOI:10.1371/journal.pone.0157916 June16,2016 8/12
MaternalHemodynamics
KhaliletalreportedhigherUtAPIandMAPinearlypregnancyinwomenwholaterdeveloped
pretermpre-eclampsiacomparedtonormalcontrolsandthedifferencesincreasedwithgesta-
tionalage[40].
Inapreviousstudy,wefoundthatthehealthypregnantwomenat22–24weekshavesmall
preloadreserveastheSVincreasedonlybyameanof1.6mlfollowingPLR[20].Inthepresent
studywomenwithhighUtAPI,demonstratedaslightlyhigherincreaseinSV(3.4ml)compared
tothosewithnormalUtAPI(2.6ml),butthedifferencewasnotsignificant.Heartrateandblood
pressuresdecreasedsignificantlyinbothgroupsfollowingPLR.Thethoracicfluidcontent(TFC)
increasedbyapproximately4%afterPLRindicatingincreasedimpedancerelatedashiftinblood
volumetosupradiaphragmaticcompartmentfromthelowerpartofthebody.
Thecardiaccontractilityvariables,ACIandVI,arerelatedtothesystolicflowandaortic
compliance,whereasthePEPandLVETrespectivelyreflectthetimerequiredbytheleftventri-
cletobuildupthepressurenecessarytoopentheaorticvalveandthedurationofventricular
ejection.AreductioninACI,VIandLVETandanincreaseinPEP,andLCWImayindicate
reducedcardiaccontractility.STRthatrepresentstheratioofelectricaltomechanicalsystole
wasdecreasedbyPLRinbothgroups.Thedirectionofchangeintheseparameterssuggests
thatthesmallincreaseinpreloadcausedbyPLRdidnotresultinimprovedcardiaccontractil-
ity.Althoughthemagnitudeofchangeswasnotsignificantlydifferentbetweengroups,itwas
interestingtonotethattheLCWIandVIchangedinoppositedirectionafterPLRamongcases
(positiveresponse)andcontrols(negativeresponse)(Fig2).
IthasbeenshownthatdifferentstatesofhydrationcanmodifytheresponsetoPLR[41],
andthatreducedplasmavolumetendstoincreasethepreloadresponse.Theobserveddiffer-
encesbetweengroupscouldberelatedtodifferencesinvolumestateamongwomenwithhigh
andnormalUtAPI.
Investigatorshaveuseddifferentcut-offsofmeanUtAPItopredictpregnancycomplications
[15,42],andallthosevaluesarehigherthanours.WedefinedameanUtAPI(cid:1)90thpercentileat
22–24weeksforourstudypopulationasabnormal.Fifty-threeoutof557women(9.5%)witha
meanUtAPIbelowthiscut-offdevelopedcomplicationsduringpregnancy.Thiscouldimplythat
thecut-offvaluesforidentifyingwomenwhoaresusceptibletocomplicationslaterinpregnancy
aresettoohigh.Combiningmaternalriskfactorsandobstetrichistory,andUtADopplerwiththe
assessmentofsystemichemodynamicsandcardiacfunctionusingsimplenon-invasivemethods
mightimprovethesensitivityandspecificityofpredictingpregnancycomplications[43].
Conclusion
Insummary,pregnantwomenwithabnormalUtAPIhadhigherbloodpressureandsystemic
vascularresistanceindex,butsimilarfunctionalhemodynamicprofileat22–24weekscom-
paredtocontrols.Furtherstudiesareneededtoclarifywhetherhemodynamicassessment
usingICGcanbeusefulinpredictingpregnancycomplications.
Acknowledgments
ThisstudywassupportedbyagrantfromtheNorthernNorwayRegionalHealthAuthority.
Wewanttothankthemidwivesattheantenatalclinicfortheirhelpinrecruitingparticipants
forthestudy.
AuthorContributions
Conceivedanddesignedtheexperiments:GA.Performedtheexperiments:ÅVKFCW.Ana-
lyzedthedata:ÅVCWGA.Contributedreagents/materials/analysistools:ÅVKFCWGA.
Wrotethepaper:ÅVKFGA.
PLOSONE|DOI:10.1371/journal.pone.0157916 June16,2016 9/12