Associations of maternal metabolic profile with placental and fetal cerebral and cardiac hemodynamics

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Full

length

article

Associations

of

maternal

metabolic

pro

ﬁle

with

placental

and

fetal

cerebral

and

cardiac

hemodynamics

Marjolein

N. Kooijman

a,b

,

Vincent

W.V.

Jaddoe

a,b

,

Eric

A.P.

Steegers

c

,

Romy

Gaillard

a,b,

*

a_The_Generation_R_Study_Group,_the_Netherlands b

DepartmentofPediatrics,theNetherlands

c

DepartmentofObstetricsandGynecology,ErasmusMC,UniversityMedicalCenter,Rotterdam,theNetherlands

ARTICLE INFO

Articlehistory: Received16July2020

Receivedinrevisedform12November2020 Accepted5December2020

Availableonlinexxx Keywords: Epidemiology

Maternalmetabolichealth Fetaldevelopment Dopplerultrasound Earlypregnancy

ABSTRACT

Objective:Maternalobesityandmetabolichealthaffectpregnancyoutcomes.Weexaminedwhether maternalmetabolicproﬁlesareassociatedwithplacentalandfetalhemodynamics.

StudyDesign:Inapopulation-basedprospectivecohortstudyamong1175womenweexaminedthe associationsofanadversematernalmetabolicprofileinearlypregnancywithplacental,fetalcerebral andcardiachemodynamicdevelopment.Weobtainedmaternalpre-pregnancyBMIbyquestionnaireand measuredbloodpressure,cholesterol,triglyceridesandglucoseconcentrationsatamediangestational ageof12.6(95%range9.6–17.1)weeks.Anadversematernalmetabolicprofilewasdefinedas4risk factors. Placental and fetal hemodynamics were measured by pulsed-wave-Doppler at a median gestationalageof30.3(95%range28.8–32.3)weeks.

Results:An adversematernal metabolicproﬁlewas associated witha 0.29Z-score higher (95%CI 0.08 0.50)fetalcerebralmiddlearterypulsatilityindex(PI),butnotwithplacentalorfetalcardiac hemodynamicpatterns.Whentheindividualcomponentsofanadversematernalmetabolicproﬁlewere assessed,we observedthat higher maternaltotalcholesteroland triglyceride concentrationswere associated withahigher cerebralmiddle arteryPI(Z-score, 0.09(95%CI 0.02 0.15),0.09 (95%CI 0.03 0.15)perZ-scoreincrease).HighertotalandHDLmaternalcholesterolconcentrationswerealso associatedwithahigheraortaascendenspeaksystolicvelocity(PSV)Z-score,0.08(95%CI0.01 0.14)), andalargerleftcardiacoutput(Z-score,0.08(95%CI0.00 0.15),respectively).

Conclusion: An adverse maternal metabolic proﬁle, especiallyhigher cholesterol and triglycerides concentrations,areassociatedwithincreasedfetalcerebralvascularresistanceandlargerfetalaorta ascendensdiameter,PSVandleftcardiacoutput,butnotwithplacentalvascularresistanceindices. Furtherstudiesareneededtoidentifylong-termconsequencesoftheobservedassociations.

Introduction

Maternalpre-pregnancyobesityisstronglyrelatedtometabolic

disturbances during pregnancy, including insulin resistance, an

adversecholesterolproﬁleand hightriglyceridesconcentrations

[1,2].Bothmaternalpre-pregnancyobesityandthesesubsequent

metabolic disturbances are major risk factors for pregnancy

complications andadversecardiovascularoutcomesin offspring

[3]. The mechanismsbywhich maternalpre-pregnancy obesity

leads to adverse fetal and childhood outcomes might involve

suboptimalearlyplacentaldevelopmentleadingtoplacentaland

fetalhemodynamicalterations[4].

Several studies have shown that maternal pre-pregnancy

obesity, gestational diabetes and hyperlipidemia are associated

withlargerplacentalweightatbirth[5–7].Anadversematernal

metabolicproﬁlemayalsoleadtoapro-inﬂammatorystateleading

to reduced placental vascularization, placental infarction and

reduced placenta growth [8]. Placental weight is only a crude

measureofplacentaldevelopmentandfunctionduringpregnancy.

Utero-placentalandfeto-placentalperipheralvascularresistance

canbeassessedbyDopplerultrasoundoftheuterineandumbilical

arteriesthroughoutpregnancy.Alteredvascularresistanceinthe

mainplacentalarteriesmaysubsequentlyleadtochangesinblood

circulationofthebrainandheartofthefetus.

We hypothesizedthat an adverse maternal early-pregnancy

metabolicproﬁleaffects earlyplacentaldevelopment leadingto

subsequentadaptationsintheplacental,fetalcerebralandcardiac

circulation. We examined in a population-based prospective

cohort study among 1175 mothers and their children, the

*Correspondingauthorat:TheGenerationRStudyGroup(Na-2915),Erasmus MC,UniversityMedicalCenter,POBox2040,3000CARotterdam,theNetherlands.

E-mailaddress:r.gaillard@erasmusmc.nl(R.Gaillard).

https://doi.org/10.1016/j.ejogrb.2020.12.011

xxx–xxx

Pleasecitethisarticleas:M.N.Kooijman,V.W.V.Jaddoe,E.A.P.Steegersetal.,Associationsofmaternalmetabolicproﬁlewithplacentaland

fetalcerebralandcardiachemodynamics,EurJObstetGynecol,https://doi.org/10.1016/j.ejogrb.2020.12.011

ContentslistsavailableatScienceDirect

European

Journal

of

Obstetrics

&

Gynecology

and

Reproductive

Biology

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associationsofmaternalearlypregnancymetabolicproﬁleandits

separate componentswith placental, fetal cerebral and cardiac

hemodynamics. Methods

Designandstudypopulation

This study was embedded in the Generation R Study, a

population-based,prospectivecohortstudyfromfetallifeonwards

inRotterdam,theNetherlands[9,10].TheMedicalEthics

Commit-teeoftheErasmusMC,UniversityMedicalCenter,Rotterdam,had

approvedthestudy(2001).AllchildrenwerebornbetweenApril

2002 and January 2006. Detailed assessments of fetal and

childhoodgrowthanddevelopmentwereconductedinarandom

subgroupof1232Dutchmothersandchildren[11].Forthecurrent

analyses, twinpregnancies(n=15), andpregnanciesleadingto

perinataldeath(n=2)wereexcludedfromthisanalyses,resulting

in 1215 singleton live born children. First trimester maternal

metabolicproﬁlemeasurementsandthirdtrimesterplacentaland

fetalhemodynamicpatternswereavailablein1175mothersand

theirchildren(Fig.1).

Maternalmetabolicproﬁle

Atenrollment,we measuredmaternalheight(cm) without

shoes and clothing. Information about maternal weight just

beforepregnancywasobtainedbyquestionnaire.Wecalculated

BMI(kg/m2_)._First_trimester_blood_pressure_and_blood_samples

werecollectedatamediangestationalageof12.6(95%range

9.6–17.1) weeks, as described in detail [12,13]. Brieﬂy, blood

pressure measurements were performed when participants

were seated inupright position with back support and were

asked to relaxfor 5 min. A cuff was placedaround the

non-dominant upperarm,whichwassupportedatthelevelof the

heart, with the bladder midline over the brachial artery

pulsation. Incase of anupper armexceeding 33cm,a larger

cuff(32–42cm)wasused.ThemeanvalueoftwoBPreadings

overa60-secondintervalwasdocumentedforeachparticipant

[14,15]. All non-fasting blood samples were transported to a

dedicated laboratory facility in Rotterdam, the Netherlands

(STAR-MDC).Processingwasaimedtoﬁnishwithinamaximum

of 3 haftersampling andstored at 80C.Totalcholesterol,

HDL-cholesterol, triglycerides and glucose concentrations are

enzymaticassaysandweremeasuredwithc702moduleonthe

Cobas8000analyzer[13].Asameasureofametabolicsyndrome

like phenotype, we deﬁned an adverse maternal metabolic

proﬁleas4ofthefollowingriskfactors;BMIhigherthan25.0,

blood pressure, total cholesterol, triglycerides and glucose

concentrations belonging to the highest 25 % of our study

populationorHDL-cholesterolconcentrationsbelongingtothe

lowest25%ofourstudypopulation(16).

Thirdtrimesterplacentalandfetalhemodynamiccharacteristics

Utero-placental and feto-placental peripheralvascular

resis-tance were assessed by pulsed-wave Doppler at a median

gestationalageof30.3(95%range28.8–32.3)weeks,asdescribed

previously[17,18].

Uterinearteryresistanceindex(RI)wasmeasuredintheuterine

arteriesnearthecrossoverwiththeexternaliliacartery.Umbilical

arterypulsatilityindex(PI)wasdeterminedinafree-ﬂoatingloop

oftheumbilicalcord.AhigheruterineRIandumbilicalarteryPI

indicatedahigherperipheralvascularresistance[19,20].Middle

cerebral artery Doppler measurements were obtained in the

proximalpartofthecerebralarteries.ThemiddlecerebralarteryPI

quantiﬁesthe redistributionof blood ﬂow, and whenlower, in

favorofthefetalbrain.ReductionsinmiddlecerebralarteryPIisa

valid indicator of fetal circulatory redistribution [21,22]. An

indicatorof the ‘brain-sparingeffect’ is a raisedratio between

theumbilicalarteryPIandthecerebralarteryPI(U/Cratio)[23].

Cardiacﬂow-velocitywaveformsatthelevelofthemitralvalves

wererecordedfromtheapical4-chamberviewofthefetalheart.

PeakvelocitiesoftheEwaveandtheAwave,wererecorded.TheE/

Aratio,which isanindexfor ventriculardiastolicfunctionand

expresses bothcardiac complianceand preloadconditions,was

calculated[18].Cardiacoutﬂowﬂow-velocitywaveformsfromthe

aortawererecordedfromthe5-chamberviewandtheshort-axis

view of the fetal heart just above the semi-lunar valves,

respectively.Peaksystolicvelocity(PSV)andtheinnerdiameter

duringsystolewererecorded.Leftcardiacoutputwascalculatedin

millilitersperminutebymultiplyingthevesselareabythe

time-velocityintegralbyfetalheartrate.Allultrasoundexaminations

wereperformed with an ATL-Philipsmodel HDI 5000 (Seattle,

Washington, USA) equipped with a 5.0-MHz high-frequency,

curved-arraytransducer.

Fig.1.Flowchartofparticipantsincludedintheanalysis.

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Covariates

We obtained information on maternal educational level,

parity, and smoking during pregnancy from multiple

questionnairesduringpregnancybythemother.Third

trimes-ter estimated fetal weight was obtained during ultrasound

[24]. Infant sex was obtained from midwife and hospital

registries.

Statisticalanalyses

First,weassessedtheassociationsofanadversematernal

early-pregnancy metabolic proﬁle with placental, fetal cerebral and

cardiac hemodynamicsusing multiplelinearregressionmodels.

The modelswere adjusted for maternalage, educational level,

parity,smoking status during pregnancy, third trimester

gesta-tionalage,estimatedfetalweightandchildsex.Wealsoperformed

a sensitive analysis using birth weight instead estimated fetal

weight. Next, we examined the associations of each of the

individualcomponents ofan adverse maternalearly-pregnancy

metabolic proﬁle with placental, fetal cerebral and cardiac

hemodynamicsusingsimilarmodels.Forinterpretationpurposes,

we also presented these associations in a graph which shows

standardizedpredictedvaluesfortheseassociationsobtainedfrom

the regression models. For the associations of maternal

early-pregnancyblood pressure,cholesterol,triglyceridesand glucose

concentrationswithplacentalandfetalhemodynamicmeasures,

wefurtherexploredwhethertheassociationswereexplainedby

maternalpre-pregnancyBMI.Wealsotestedpotentialinteraction

betweenmaternalmetabolicfactorsandBMIforallofouranalyses.

Table1

Characteristicsofmothersandtheirchildrenaftermultipleimputation. Maternalcharacteristics

Totalgroup(N=1.175) Motherswithanadversemetabolic proﬁle(N=108,9.2%)

Motherswithoutanadverse metabolicproﬁle(N=728,62%)

P-value Maternalage 31.9(22.0–39.1) 32.4(23.6–39.5) 31.8(21.4–39.0) 0.7

Education(%) <0.001

Low(no,primary,secondaryeducation) 36.9(434) 50.9(55) 33.2(242) High(highereducation) 63.1(741) 49.1(53) 66.8(486) Pre-pregnancybodymassindex(kg/m2

) 23.5(4.0) 28.5(5.0) 22.7(3.2) <0.001

BMI>25.0 22.4(263) 80.6(87) 17.7(129) <0.001

Parity(%) 0.8

Nullipara 60.8(714) 61.1(66) 62.6(456)

Multipara 39.2(461) 38.9(42) 37.4(272)

Smokingduringpregnancy(%) 0.3

Nosmokingthroughoutpregnancy 76.1(894) 73.1(79) 77.7(567)

Yes 23.9(281) 26.9(29) 22.3(161)

Gestationalhypertension(%) 6.0(71) 12(11.1) 37(5.1) 0.03

Pre-eclampsia(%) 2.3(27) 5.6(6) 3.0(22) 0.04

Firsttrimestermaternalcharacteristics

Gestationalageatmeasurement,weeks 12.6(9.6–17.1) 12.9(9.5–17.0) 12.8(9.7–17.1) 0.7 Systolicbloodpressure(mmHg) 119(13) 134(12) 116(11) <0.001 Diastolicbloodpressure(mmHg) 70(10) 80(10) 68(9) <0.001 Totalcholesterol,mmol/L 4.9(0.9) 5.4(0.9) 4.8(0.8) <0.001 HDL-cholesterol,mmol/L 1.8(0.3) 1.6(0.3) 1.8(0.3) <0.001

Triglycerides,mmol/L 1.3(0.5) 1.8(0.6) 1.2(0.4) <0.001

Glucosemmol/L 4.4(0.8) 4.9(1.0) 4.3(0.8) <0.001

Thirdtrimesterfetalcharacteristics

Sex 0.1

Male 52.4(616) 59.3(64) 51.0(371)

Female 47.6(559) 40.7(44) 49.0(357)

Gestationalageatmeasurement,weeks 30.3(27.4–32.6) 30.2(28.6–32.3) 30.4(28.4–32.7) <0.01 Estimatedfetalweight,grams 1628(268) 1609(265) 1624(275) 0.6 Thirdtrimesterfeto-placentalhemodynamics

UterinearteryRI 0.49(0.08) 0.49(0.08) 0.49(0.07) 0.9

UmbilicalarteryPI 0.97(0.17) 0.97(0.16) 0.97(0.17) 0.6

Thirdtrimesterfetalcerebralhemodynamics

MiddlecerebralarteryPI 1.97(0.33) 2.07(0.30) 1.96(0.34) <0.01 Umbilical/Middlecerebralarteryratio 0.50(0.11) 0.48(0.09) 0.51(0.12) <0.01 Thirdtrimesterfetalcardiachemodynamics

Aortaascendensdiameter(cm) 0.64(0.07) 0.64(0.07) 0.65(0.07) 0.4 AortaascendensPSV(cm/s) 91.3(12.4) 92.1(13.6) 91.1(12.6) 0.5 Leftcardiacoutput(ml/min) 606(173) 593(165) 615(183) 0.3 MitralvalveE/Aratio 0.78(0.10) 0.78(0.09) 0.78(0.10) 0.9 Birthcharacteristics

ModeofDelivery(%) <0.01

Vaginal,spontaneous 69.6(818) 57.4(62) 70.3(512) Vaginal,deliveryinduced 10.5(123) 20.4(22) 10.2(74) Cesareansection 13.1(154) 18.5(20) 12.1(88)

Unknown 9.5(80) 3.7(4) 7.4(54)

Apgarscore(5min),% 9.6(0.8) 9.5(0.8) 9.6(0.8) 0.1

Gestationalageatbirth,weeks 40.3(35.9–42.4) 40.0(34.7–42.4) 40.3(35.9–42.4) 0.6 Pretermbirth(<37weeks),% 4.2(49) 4.6(5) 4.0(29) 0.8

Birthweight,g 3517(541) 3539(584) 3499(529) 0.5

Lowbirthweight(<2500g),% 3.9(46) 4(3.7) 3.7(27) 0.9 Valuesaremeans(standarddeviation),medians(95%range)orvalidpercentages(absolutenumbers).RI:resistanceindex,PI:pulsatilityindex,PSV:PeakSystolicVolume. Motherswithandwithoutanadversemetabolicproﬁlewerecomparedusingindependentsamplest-testforcontinuousvariablesandchi-squaretestforcategorical variables.

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Nosigniﬁcantinteractionswerepresentandnofurtherstratiﬁed

analyseswereperformed.Finally,weexaminedtheassociationsof

change in maternal weight and blood pressure from

early-pregnancy until 30 weeks of pregnancy with third trimester

placental,fetalcerebralandcardiachemodynamicsusingthesame

multiple linear regression models. The percentages of missing

covariatevalueswithinthepopulationforanalyseswaslowerthan

13 %. Missing covariate data wereimputed using the multiple

imputations procedure (n = 5 imputations) and the imputed

datasetswereanalyzedtogether.Nomajordifferencesintheeffect

estimateswereobservedbetweenanalyseswithimputedmissing

dataandcompletecasesonly(datanotshown).Allmeasuresof

associationsarepresentedwithintheir95%conﬁdenceintervals

(CI).StatisticalanalyseswereperformedusingSPSSversion24.0

forWindows(SPSSInc.,Chicago,Illinois,USA).

Results

Participantscharacteristics

Table 1 shows the population characteristics. 22.5% of the

motherswereoverweightorobeseatthestartofpregnancyand

9.2%ofthemothershadanadversemetabolicproﬁleatthestartof

theirpregnancy.Duringpregnancy6.0%and2.3%ofthemothers

developed gestational hypertensionand pre-eclampsia,

respec-tively.Themediangestationalagewas40.3(35.9–42.4) andthe

Fig.2.Associationsofmaternaladversemetabolicproﬁlewiththirdtrimesterplacental(a),fetalcerebral(b)andfetalcardiachemodynamics(c). xxx–xxx

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mean birthweightofthechildrenwas 3517(SD541).TableS1

showstheparticipantcharacteristicsbeforemultipleimputation.

Thirdtrimesterplacentalhemodynamics

Fig. 2a shows no associations were present of an adverse

maternalmetabolicproﬁlewithuterinearteryRIand umbilical

artery PI. Similarly, none of the individual components of an

adversematernalmetabolicproﬁlewereassociatedwithplacental

hemodynamics(Table2,FigureS1).

Thirdtrimesterfetalcerebralhemodynamics

Motherswithanadversemetabolicproﬁlehada0.29(95%CI

0.08,0.50)Z-scoreincreaseinthefetalcerebralmiddlearteryPI

compared to mothers without an adverse metabolic proﬁle

(Fig. 2b). Whenwe assessed the individual components of an

adverse maternal metabolic proﬁle separately, higher total

maternalcholesterolandtriglycerideconcentrationswere

associ-atedwithahighercerebralmiddlearteryPI(Table3,FigureS2

Z-score,0.09(95%CI0.02,0.15),0.09(95%CI0.03,0.15)perZ-score

increase in total cholesterol and triglyceride concentrations,

respectively).Theseassociationswerenotexplainedbymaternal

BMI. No associations of maternal pre-pregnancy BMI, blood

pressure,HDL-cholesteroland glucoseconcentrationswithfetal

cerebralhemodynamicswerepresent.Theassociationswiththe

fetalU/Cratioweresimilar(Fig.2,Table2).

Thirdtrimesterfetalcardiachemodynamics

Anadversematernalmetabolicproﬁlewasnotassociatedwith

fetal cardiac hemodynamics (Fig. 2c). When we assessed the

associations of individual components of an adverse maternal

metabolic proﬁle with fetal cardiac hemodynamics, a higher

maternal diastolic blood pressure, total and HDL-cholesterol

concentrations wereassociated with a higher fetal left cardiac

output(Table4,Z-score0.08(95%CI0.02,0.15),0.07(95%CI0.01,

0.13),0.11(95%CI0.05,0.18)perZ-scoreincreaseindiastolicblood

pressure,totalandHDL-cholesterolconcentrations,respectively).

HighermaternalHDL-cholesterolconcentrationswereassociated

withalargeraortaascendensdiameterandaortaascendensPSV

(Z-score0.10(95%CI0.04,0.17),0.08(95%CI0.01,0.14)perZ-score

increase in HDL-cholesterol concentrations). Total maternal

cholesterol concentrations were also associated with a higher

aortaascendensPSV(Z-score0.08(95%CI0.01,0.14)perZ-score

increase in total cholesterol concentrations).These associations

were not explained byadjustment for maternal pre-pregnancy

BMI. No associations of maternal triglyceride or glucose

concentrations with fetal cardiac hemodynamics werepresent.

Similarﬁndingswerepresentwhenweusedbirthweightinstead

of estimated fetal weight (results not shown). For visual

interpretationweshowedinFigureS3thestandardizedregression

prediction values of the multiple linear regression models of

maternal pre-pregnancy BMI,total cholesterol, triglycerideand

glucoseconcentrationswiththirdtrimesterfetalcardiac

hemody-namicsingraphformat.Table5showsthatmaternalweightgain

was associated with a largeraorta ascendens diameterand an

increaseincardiacoutput(Z-score0.02(95%CI0.01,0.04)and0.02

(95 % CI 0.01, 0.04) per increase in weight gain, respectively).

Higherincreaseinmaternalsystolicbloodpressurewasassociated

withahigher uterineartery RIandumbilical artery PI(Z-score

0.09,(95%CI0.03,0.15)and0.08(95%CI0.02,0.15)perincreasein

bloodpressure, respectively)and adecreasein aortaascendens

diameterandleftcardiacoutput(Z-score-0.07(95%CI-0.13,-0.01)

and-0.07(95%CI -0.13,-0.01)per increaseinblood pressure),

whereas a higher increase in diastolic blood pressure was

associatedwithahigherumbilical arteryPI(Z-score0.06 (95%

CI0.00,0.12)).

Discussion

Mainﬁndings

Inthispopulationprospectivecohortstudyweobservedthatan

adverse maternal early-pregnancy metabolic proﬁle, especially

highermaternalcholesterolandtriglyceridesconcentrations,were

associated withincreasedfetal cerebral vascularresistanceand

largerfetalaortaascendensdiameter,PSVandleftcardiacoutput,

butnotwithplacental vascularresistanceindices.These

associ-ationswerenotexplainedbymaternalBMI.

Interpretation

Maternalpre-pregnancyobesityisstronglyrelatedtometabolic

disturbancesduringpregnancy[1,2].Bothmaternalpre-pregnancy

obesityand thesesubsequent metabolicdisturbancesaremajor

risk factors for pregnancy complications and adverse birth

outcomes [3]. The underlying mechanisms are not known,but

mightberelatedtoimpairedplacentalgrowthandfunction[4].

The placenta can be considered as the interface between the

maternalandfetalenvironmentandthemajorregulatoroffetal

nutrition,growthandcardiovasculardevelopment[25].Multiple

studies have shown that maternal obesity is related to larger

placentalweight[26].Severalstudiesalsoshowedthatindividual

componentsofanadversematernalmetabolicproﬁle,suchashigh

bloodpressure,hightriglycerides,adversecholesterolproﬁleand

highglucoseconcentrationsareassociatedwithbothlowandhigh

placentalweightatbirth[27–29],whichsuggestvarious

mecha-nismsmaybeinvolved.Anadversematernalmetabolicpro_ﬁlemay

lead to a pro-inﬂammatory state leading to reduced placental

vascularization,placentalinfarctionandreducedplacentagrowth,

whereasanadversematernalmetabolicpro_ﬁlemayalsoleadto

increased nutrient transfer to the placental, larger placental

growthandacceleratefetalgrowth[8].

Placental weight is only a crude measurement of placental

development and function during pregnancy. More detailed

measures of placental function can be assessed by Doppler

ultrasoundoftheumbilicalanduterinearteriesduringpregnancy.

A higher uterine RI and umbilical arteryPI indicated a higher

peripheralvascularresistance [19,20]. Weobserved no

associa-tionsofmaternalmetabolicproﬁlewiththeuterineandumbilical

artery vascular resistance. A few other studies explored the

associations of individual components of an adverse maternal

metabolic proﬁle with uterine and umbilical artery vascular

Table2

AssociationsofearlypregnancymaternalBMI,bloodpressureandﬁrsttrimester metabolicconcentrationswiththirdtrimesterutero-placentalandfeto-placental hemodynamics(n=1175).

UterinearteryRI Z-score(95%CI)

UmbilicalarteryPI Z-score(95%CI) Pre-pregnancyBMI(Z-score) 0.06(-0.00,0.12) 0.06(-0.01,0.12) Systolicbloodpressure(Z-score) 0.07(-0.01,0.16) 0.00(-0.06,0.06) Diastolicbloodpressure(Z-score) 0.01(-0.05,0.08) 0.01(-0.07,0.06) Totalcholesterol(Z-score) 0.03(-0.09,0.03) 0.00(-0.06,0.06) HDL-cholesterol(Z-score) 0.00(-0.07,0.06) 0.05(-0.11,0.01) Triglycerides(Z-score) 0.01(-0.07,0.05) 0.05(-0.02,0.11) Glucose(Z-score) 0.06(-0.01,0.12) 0.01(-0.07,0.06) Valuesareregressioncoefficients(95%confidenceintervals)andreflectthechange inZ-scoreofplacentalindexesperZ-scorechangeinmaternalBMI,bloodpressure and metabolic concentrations. The models are adjusted for maternal age, educational level, parity, smoking status during pregnancy, third trimester gestationalageandestimatedfetalweight,andchildsex.RI:resistanceindex, PI:pulsatilityindex.

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resistanceinpregnancy.Apreviousprospectivestudyfocusedon

231womenaffectedbyhypertensivedisordersshowedahigher

uterine artery PI compared with normative pregnancies [30].

Among 10 women with familial hypercholesterolemia, it was

observedthatthePIoftheuterinearterieswassimilarat24weeks

ofgestation,andremainedunalteredat36weeksofgestation,in

contrasttoadecreaseinthereferencegroup[31].Anintervention

study among 290 pregnant women demonstrate a more

pro-nouncedgestationaldecreaseintheumbilicalarteryPIbetween24

and30weeksofpregnancyafterfollowingalow-cholesterol

low-saturatedfatdiet[32].TwostudiesamongChileanwomenshowed

acorrelationoftotal-andLDL-cholesterolconcentrations,butnot

triglycerideconcentrations,withlowersensitivityoftheumbilical

vein rings and reactivity, a phenomena that is likely due to

endothelial dysfunction[33,34]. Differences betweenourstudy

and previous studies maybe explainedby differencesin study

population.Westudiedwomenwithrelativelyhealthy

pregnan-ciesandassessed associationsacrossthefullrangeof maternal

metabolicfactors,whereasmanyofthepreviousstudiesfocused

on high-risk populations and women with clinically abnormal

metabolicparameters,suchasclinicalhypercholesterolemia.This

maysuggestthatassociationswithuterineandumbilicalvascular

resistance are only present at the extremes of these adverse

maternalmetabolicfactors,butnotacrossthefullrange.

Consequencesofimpairedplacentationmightleadto

redistribu-tionofbloodﬂow,withincreasedfetalbloodtothebrainandheartof

thefetusduetoreducedoxygensupplyanditsinﬂuenceonfetal

vasculardevelopment.ThemiddlecerebralarteryPIquanti_ﬁesthe

redistributionofbloodﬂow,andwhenlower,infavorofthefetal

brain. An indicatorof the ‘brain-sparing effect’ is a raised ratio

betweentheumbilicalarteryPIandthecerebralarteryPI(U/Cratio)

[23].Inlinewithpreviousstudiesfromthesamecohortweusedthe

Table3

AssociationsofearlypregnancymaternalBMI,bloodpressure,andﬁrsttrimestermetabolicconcentrationswiththirdtrimesterfetalcerebralhemodynamics(n=1175). Cerebralmiddleartery

PIZ-score(95%CI)

Umbilical/CerebralmiddlearteryPIratio Z-score(95%CI)

Pre-pregnancyBMI(Z-score) 0.05(-0.01,0.12) 0.01(-0.07,0.06) Systolicbloodpressure(Z-score) 0.05(-0.01,0.12) 0.03(-0.09,0.03) Diastolicbloodpressure(Z-score) 0.05(-0.02,0.11) 0.03(-0.09,0.04) Totalcholesterol(Z-score) 0.09(0.02,0.15)† 0.07(-0.13,-0.01)* +pre-pregnancyBMI 0.08(0.02,0.15)* 0.07(-0.13,-0.01)* HDL-cholesterol(Z-score) 0.04(-0.10,0.03) 0.02(-0.09,0.04) Triglycerides(Z-score) 0.09(0.03,0.15)† 0.03(-0.10,0.03) +pre-pregnancyBMI 0.09(0.02,0.15)†

Glucose(Z-score) 0.02(-0.04,0.09) 0.02(-0.09,0.04)

Valuesareregressioncoefficients(95%confidenceintervals)andreflectthechangeinZ-scoreoffetalcerebralindexesperZ-scorechangeinmaternalBMI,bloodpressureand metabolicconcentrations.Themodelsareadjustedformaternalage,educationallevel,parity,smokingstatusduringpregnancy,thirdtrimestergestationalageandestimated fetalweight,andchildsex.PI:pulsatilityindex.*=P<0.05,†=P<0.01.

Table4

AssociationsofearlypregnancymaternalBMI,bloodpressureandﬁrsttrimestermetabolicconcentrationswiththirdtrimesterfetalcardiachemodynamics(n=1175). Aortaascendensdiameter

Z-score(95%CI)

AortaascendensPSV Z-score(95%CI)

Leftcardiacoutput Z-score(95%CI)

MitralvalveE/Aratio Z-score(95%CI) Pre-pregnancyBMI(Z-score) 0.02(-0.09,0.04) 0.00(-0.07,0.07) 0.03(-0.10,0.04) 0.01(-0.05,0.08) Systolicbloodpressure(Z-score) 0.01(-0.06,0.07) 0.00(-0.07,0.07) 0.01(-0.06,0.07) 0.03(-0.03,0.09) Diastolicbloodpressure(Z-score) 0.04(-0.02,0.10) 0.03(-0.04,0.09) 0.08(0.02,0.15)† 0.01(-0.05,0.07)

+pre-pregnancyBMI 0.12(0.05,0.20)†

Totalcholesterol(Z-score) 0.02(-0.04,0.08) 0.08(0.01,0.14)* 0.07(0.01,0.13)* 0.01(-0.08,0.05) +pre-pregnancyBMI 0.08(0.01,0.15)* 0.07(0.01,0.14)*

HDL-cholesterol(Z-score) 0.10(0.04,0.17)† 0.08(0.01,0.14)* 0.11(0.05,0.18)† 0.05(-0.11,0.02) +pre-pregnancyBMI 0.10(0.04,0.16)† 0.07(0.00,0.14)* 0.11(0.04,0.17)†

Triglycerides(Z-score) 0.03(-0.10,0.03) 0.04(-0.03,0.10) 0.01(-0.06,0.07) 0.00(-0.06,0.07) Glucose(Z-score) 0.01(-0.07,0.05) 0.05(-0.02,0.11) 0.02(-0.08,0.05) 0.05(-0.12,0.02) Valuesareregressioncoefficients(95%confidenceintervals)andreflectthechangeinZ-scoreoffetalcardiachemodynamicsperZ-scorechangeinmaternalBMI,blood pressureandmetabolicconcentrations.Themodelsareadjustedformaternalage,educationallevel,parity,smokingstatusduringpregnancy,thirdtrimestergestationalage andestimatedfetalweight,andchildsex.PSV:PeakSystolicVolume.*=P<0.05,†=P<0.01.

Table5

Associationsofmaternalweightgainduringpregnancy,andthirdtrimesterbloodpressurewiththirdtrimesterfetalplacental,cerebralandcardiachemodynamics(n=1175). Maternalweightgain

duringpregnancy

Maternalthirdtrimestersystolic bloodpressure(Z-score)

Maternalthirdtrimesterdiastolic bloodpressure(Z-score) UterinearteryRI,Z-score(95%CI) 0.00(-0.01,0.01) 0.09(0.03,0.15)† 0.05(-0.01,0.11) UmbilicalarteryPI,Z-score(95%CI) 0.00(-0.02,0.01) 0.08(0.02,0.15)† 0.06(0.00,0.12)* CerebralmiddlearteryPI,Z-score(95%CI) 0.01(-0.02,0.01) 0.03(-0.03,0.09) 0.04(-0.02,0.10) Aortaascendensdiameter,Z-score(95%CI) 0.02(0.01,0.04)* 0.07(-0.13,-0.01)* 0.01(-0.05,0.07) AortaascendensPSV,Z-score(95%CI) 0.01(-0.02,0.01) 0.02(-0.09,0.04) 0.04(-0.11,0.02) Leftcardiacoutput,Z-score(95%CI) 0.02(0.01,0.04)† 0.07(-0.13,-0.01)* 0.00(-0.06,0.06) MitralvalveE/Aratio,Z-score(95%CI) 0.00(-0.01,0.02) 0.02(-0.08,0.04) 0.01(-0.05,0.07)

Valuesareregressioncoefficients(95%confidenceintervals)andreflectthechangeinZ-scoreoffetalhemodynamicsperchangeinmaternalweightgainandz-scorechange inbloodpressure.Themodelsareadjustedformaternalage,educationallevel,parity,smokingstatusduringpregnancy,thirdtrimestergestationalageandestimatedfetal weight,andchildsex.PSV:PeakSystolicVolume.*=P<0.05,†=P<0.01.

(7)

U/Cratio,andnottheCerebrumPlacentalratio(CPR)whichreﬂects

cerebral arteryPI/umbilicalartery PIratio. Thesemeasurements

havean inverse 1:1correlation[35–37]. To thebest ofour knowledge,

notmanydataonfetalhemodynamicreferencedataareavailable

andtheydescribedifferentpopulationswhichmakescomparisons

difﬁcult[38].However,ourstudyisfocusedontheassociationsof

maternalmetabolicfactorswithfetalhemodynamicparametersin

whichweshowdifferencesinthesefetalhemodynamicparameters

by maternal metabolic factors. Further studies are needed to

replicateourﬁndingsindifferentpopulationsandtoexaminethe

effectsonabsolutevaluesofthefetalhemodynamicparameters.We

observed that an adverse maternal early-pregnancy metabolic

proﬁle was associated with increased fetal cerebral vascular

resistance. These associations were mainly present for high

cholesterol and triglyceride concentrations. Higher cholesterol

concentrationswerealsoassociatedwithalargerfetalleftcardiac

output,largeraortaascendensdiameterandlargeraortaascendens

PSV.Ourﬁndingsthussuggestthatincreasedmaternalcholesterol

and triglycerides levels,stillwithinthenormalrange(reference

rangetotalcholesterolconcentrations,women50thcentile5.0(95%

range3.3–7.3),triglycerideconcentrations,50thcentile1.0(95%

range 0.4–2.9) (39)), lead to increased fetal cerebral resistance

indexes andaortaascendens diameter,aorta ascendensPSV and

cardiac output suggesting a ‘reverse’ redistribution in favor of

increased cardiac growth. The ﬁndings were not explained by

maternal BMI, suggesting effects of maternal cholesterol and

triglycerideconcentrationswithinthenormalrangewere

indepen-dentofBMI.Inlinewithourﬁndings,resultsfromthesamestudy

cohortalsoshowedthatmaternaltriglycerideandcholesterollevels

areassociatedwithincreasedfetalgrowthrateswhichresultedina

higherbirthweight[40].Theseﬁndingsmightsuggestthatthese

increasedmaternallipidlevelshaveconsequencesforfetalcardiac

developmentandmightleadtopersistentsubclinicalconsequences

inchildhood.Longitudinalstudiesreportedtrackingofriskfactors

for cardiovascular disease during childhood [41,42]. Also the

consequencesoffetaladaptationsmightnotbedetectableduring

fetallife,butmightbecomemoreevidentinearlyadulthood.Ithad

beensuggestedthatfetaladaptationscanbecompensatedformany

yearsuntilforexamplehypertensionoccurs[43].Nootherprevious

studies explored the associations of maternal cholesterol or

triglyceridesconcentrationswithfetalcerebralvascularresistance

orfetalcardiachemodynamics.However,theeffectestimatesare

smallandaremainlyrelevantonapopulationlevelprovidingfurther

insight intopathophysiological mechanisms.Further studies are

needed to replicate our ﬁndings, to explore these associations

throughoutpregnancyandtoassesstheconsequencesforbothbirth

outcomesandlong-termoffspringoutcomes.

Strengthsandlimitations

Themainstrengthofthisstudyisthelargepopulation-based

cohortstudied.Toourknowledge,thisisthelargeststudy,which

examined theeffects ofmaternalmetabolicfactorsonplacental

andfetalhemodynamics.Thepopulation-basedsettingenabledus

to assess maternal metabolic factors and placental and fetal

hemodynamicmeasuresacrossthefullrange,ratherthanonlyin

mothersorfetuseswithcomplications.However,becauseofour

relativelyhealthypopulation,itshouldbefurtherstudiedwhether

theobservedassociationsaregeneralizabletohigh-risk

popula-tions.Weobservedthatincreasedweightgainwasassociatedwith

anincreasedthirdtrimesterfetalcardiacaortaascendensdiameter

and leftcardiacoutput.Anincreaseinmaternalthird trimester

systolicbloodpressurewasassociatedwithanincreaseduterine

and umbilical arteryresistance index,but a smallerfetal third

trimester aorta ascendens diameter and left cardiac output.

Interestingly, we did not found associations of ﬁrst trimester

maternal BMI and blood pressure with third trimester fetal

hemodynamics.Weonlymeasuredmaternalglucose,cholesterol

andtriglycerideconcentrationsonceduringpregnancy.However,

it has been suggested that impaired glucose control in early

pregnancypersiststhroughoutpregnancy[44].Similarly,

choles-terolandtriglycerideconcentrationsareelevatedduringallthree

trimestersofpregnancyinwomenwithgestationaldiabetes[45].

Furtherstudiesareneededwithrepeatmaternalglucoseandlipids

concentrationsmeasurementsthroughoutpregnancytoreplicate

ourﬁndingsandtoidentifythecriticalperiodsforfeto-placental

hemodynamic adaptations. In the present study, we evaluated

multipleassociations;thismighthaveledtochance_ﬁndingsdueto

multipletesting.However,becauseofthecorrelationsbetweenthe

fetal hemodynamic measures we did not correct for multiple

testing.Missingfetalhemodynamicmeasurementscouldleadto

selectionbiasandlossofpower.Ourresultswouldbebiasedifthe

associations between maternal metabolic factors and fetal

hemodynamics differ between those included and those not

includedinthestudy.Althoughthisseemsunlikely,itcannotbe

excluded. Finally, although we had information about a large

number of confounders, the inﬂuence of residual confounding

shouldbeconsidered,asinanyobservationalstudy.

Conclusions

An adverse maternal metabolic proﬁle, especially higher

maternalcholesterolandtriglyceridesconcentrationsstillwithin

thenormalrange,wereassociatedwithincreasedfetalcerebral

vascularresistanceandincreasedfetalcardiachemodynamics,but

notwithplacentalvascularresistanceindices.

Contributiontoauthorship

MNKandRGwereresponsibleforthestatisticalanalyses,the

interpretationofthedataandtherevisionsofthemanuscript.MNK

alsowrotetheﬁrstdraftofthemanuscript.RGwasresponsiblefor

theoriginalresearchidea,andsupervisedMNKwithdataanalysis,

interpretation of the data, and writing and revision of the

manuscript. EAPS contributed to the interpretation of the data,

andcriticallyrevisedthemanuscript.VWVJinitiatedanddesigned

thestudy,wasresponsiblefortheinfrastructureinwhichthestudy

was conducted, contributed to the original data collection, and

criticallyrevisedthemanuscriptforimportantintellectualcontent.

Allauthorsreadandapprovedtheﬁnalversionofthemanuscript.

Detailsofethicsapproval

Writteninformedconsentwasobtainedfromallparticipants.

ThestudywasapprovedbytheMedicalEthicsCommitteeofthe

ErasmusMedicalCenter,Rotterdam(December2001,

MEC198.782.2001.31).

Dataavailabilitystatement

DatarequestscanbemadetothesecretariatofGenerationR.

Funding

TheGenerationRStudyisﬁnanciallysupportedbytheErasmus

MedicalCenter,Rotterdam,theErasmusUniversityRotterdamand

theNetherlandsOrganizationforHealthResearchand

Develop-ment.VWVJreceivedagrantfromtheNetherlandsOrganization

for Health Research and Development (NWO, ZonMw-VIDI

016.136.361)andaEuropeanResearchCouncilConsolidatorGrant

(ERC-2014-CoG-648916). RG received funding from the Dutch

HeartFoundation(grantnumber2017T013),theDutchDiabetes

(8)

Foundation (grant number 2017.81.002) and the Netherlands

Organization for Health Research and Development (ZonMW,

grantnumber543003109).

DeclarationofCompetingInterest

None.

Acknowledgments

TheGenerationRStudyisconductedbytheErasmusMedical

CenterinclosecollaborationwiththeSchoolofLawandFacultyof

SocialSciencesoftheErasmusUniversityRotterdam,the

Munici-pal Health Service Rotterdam area, Rotterdam, the Rotterdam

Homecare Foundation, Rotterdam and the Stichting

Trombose-dienstand ArtsenlaboratoriumRijnmond(STAR),Rotterdam.We

gratefullyacknowledgethecontributionofparticipatingmothers,

general practitioners, hospitals, midwives and pharmacies in

Rotterdam.

AppendixA.Supplementarydata

Supplementarymaterialrelatedtothisarticlecanbefound,inthe

onlineversion,atdoi:https://doi.org/10.1016/j.ejogrb.2020.12.011.

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