the fetal origins of adult disease, the evidence and mechanisms

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The fetal origins of adult disease, the evidence and mechanisms

Veenendaal, M.V.E.

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Citation for published version (APA):Veenendaal, M. V. E. (2012). The fetal origins of adult disease, the evidence and mechanisms

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3The fetal origins of hypertension:

a systematic review and meta-analysis of the evidence from animal experiments of

maternal undernutrition

AnnetFMvanAbeelen*MarjoleinVEVeenendaal*

RebeccaCPainterSusanneRdeRooij

ShakilaThangaratinamJorisAMvanderPostPatrickMMBossuyt

SjoerdGEliasCunoSPMUiterwaalDiederickEGrobbeeGeorgeRSaadeBenWillemJMolKhalidSKhan

TessaJRoseboom*bothauthorscontributedequallytothiswork

Journal of Hypertension, accepted for publication

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Chapter 3

absTracT

Objective:Numerousexperimentsinanimalshavebeenperformedtoinvestigatetheeffectofprenatalundernutritiononthedevelopmentofhypertensioninlaterlife,withinconclusiveresults.Wesystematicallyreviewedanimalstudiesexaminingtheeffectsofmaternalundernutritiononsystolic,diastolic,andmeanarterialbloodpressureinoffspring.Methods:AsearchwasperformedinMedlineandEmbasetoidentifyarticlesthatreportedonmaternalundernutritionandhypertensioninexperimentalanimalstudies.Summaryestimatesof the effect of undernutrition on systolic, diastolic, andmean arterial blood pressure wereobtainedthroughmeta-analysis.results: Of the 6,151 articles identified, 194 were considered eligible after screening titlesand abstracts. After detailed evaluation, 101met the inclusion criteria andwere included inthereview.Bothmaternalgeneralandproteinundernutritionincreasedsystolicbloodpressure(generalundernutrition:14.5mmHg,95%CI10.8to18.3;proteinundernutrition:18.9mmHg,95%CI16.1to21.8)andmeanarterialpressure(generalundernutrition:5.0mmHg,95%CI1.4to8.6;proteinundernutrition:10.5mmHg,95%CI6.7to14.2).Therewassubstantialheterogeneityintheresults.Diastolicbloodpressurewasincreasedbyproteinundernutrition(9.5mmHg,95%CI2.6to16.3),whilegeneralundernutritionhadnosignificanteffect.conclusion:Theresultsofthismeta-analysisgenerallysupporttheviewthatinanimalsmaternalundernutrition‒bothgeneralandprotein-resultsinincreasedsystolicandmeanarterialbloodpressure.Diastolicbloodpressurewasonlyincreasedafterproteinundernutrition.Theresultsdependedstronglyontheappliedmeasurementtechniqueandanimalmodel.

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Fetal origins of hypertension in animals

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inTroDucTion

The fetaloriginshypothesisproposes thathypertensionoriginates in utero. Itpostulates thatundernutritionduringimportantperiodsofgrowthanddevelopmentduringfetallifecanresultinadaptationsinstructureandfunctionofthebody.Intheshorttermtheseadaptationsmaybebeneficialforfetalsurvival,butinthelongtermtheycanleadtocardiovascular,metabolic,andendocrinediseaseinadultlife. Hypertension is one of these long-term effects of maternal undernutrition1. Numerousstudies, indifferentpopulations,have reportedassociationsbetween small sizeatbirth, as aproxy for undernutrition during fetal development, and high blood pressure or hypertensionin later life2. Most studies found an inverse association between birth weight and bloodpressure,showingthatsmallsizeatbirthisassociatedwithraisedbloodpressureinlaterlife.Asystematicreviewofeightystudiesontheassociationbetweenbirthweightandbloodpressuredemonstratedthatakilogramincreaseinbirthweightisassociatedwitha2mmHgdecreaseinsystolicbloodpressure3. Birthweight,however,isonlyaproxyformaternalundernutritionduringgestationandtheepidemiological studies inhumansarenon-experimental, lacking theability toderivedefinitecausal conclusions. Animal studies can be used to experimentally investigate the effects ofmaternalundernutritiononbloodpressureintheoffspringinlaterlife.Avarietyofanimalspecies,includingthemouse,rat,andsheep,havebeenusedtostudythiseffect.Themodelsemployeddiffer, using various protein:lipid:carbohydrate ratios of the maternal diet during gestation,and varying timing and duration of dietarymanipulation. Some of these animal experimentsobservedsignificantlyraisedbloodpressureintheoffspringofundernourishedmothers,whileothersdidnot.Theseinconsistenciesmaybeduetodifferencesindietaryregimensorstrainsorspeciesofanimalsusedbutalsotolimitedsamplesizeandchance.Wethereforesystematicallyreviewedanimalstudiesonmaternalundernutritionduringgestationandbloodpressureintheoffspringandperformedameta-analysistoobtainprecisesummaryestimatesoftheeffectsofmaternalundernutrition.

METhoDs

search strategyWeperformedasearchintheelectronicdatabasesMedline(1951–August2011)andEmbase(1980 – August 2011) to identify articles that reported on maternal undernutrition andhypertension in offspring in experimental animal studies. The search terms ‘undernutrition’,‘malnutrition’,‘famine’,‘starvation’,‘nutritiondisorder’,‘caloricrestriction’,‘proteinrestriction’,‘lowproteindiet’,‘lowcaloriediet’,‘bloodpressure’and‘hypertension’wereused.Therewerenolanguagerestrictions.

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Study selectionWe included papers describing outcomes in experimental animal models of maternalundernutrition that reportedonsystolicand/ordiastolicbloodpressureand/ormeanarterialpressureintheoffspring.Maternalundernutritionincludedlowproteinmalnutritionandgeneralcaloricmalnutrition.Studieshadtoreportoutcomesincomparisontocontrolanimalsthatwereborn to amother thatwas normally fed throughout pregnancy. After screening of titles andabstracts, two reviewers (AFMvA andMVEV) independently examined full text articles frompotentially eligible papers. Disagreementswere resolved in consensus discussions. Referencelistsofreviewsandincludedpaperswerehandsearchedtoidentifyadditionalstudies.

Data extractionFromallincludedpapers,tworeviewers(AFMvAandMVEV)independentlyextractedinformationonstudydesign,exposureperiod,animalspeciesandtypeofundernutrition,andsamplesize.Toassessriskofbias,dataonallocationconcealment,randomization,blindingwereextracted.Whenmorethantwoexperimentalgroupswereformed,wefocusedontheexperimentalgroupwithmalnutritionasearlyinpregnancyaspossibleandpreferablylimitedtopregnancyalone.Whenoutcomeinoffspringwasmeasuredatmultipletimepoints,wechosetheoldestageatwhichmeasurementsweretaken.Studiesthatreportedonfetalbloodpressurewereexcluded.Ifresultswereonlydisplayedgraphically,outcomewasreadaspreciseaspossible.Studiesthatreportedresultsasmeanandstandarddeviationorstandarderror,andnumberofanimalspergroupwereusedformeta-analysis.

Data analysisSummary estimates of the effects ofmaternal undernutritionwere obtained using a randomeffectsmodelformeta-analysis,whichaccountsforbothwithin-andbetween-studyvariability.Separateestimateswereobtainedforsex,modeltype(proteinorgeneralundernutrition),andoutcomemeasures(systolic,diastolicbloodpressureandmeanarterialpressure).Thesummaryeffectswereexpressedasmeandifferenceswith95%confidence intervals (CI).Weevaluatedheterogeneity in results across studies by calculating the I² statistic, which describes thepercentageofthevariabilityineffectestimatesthatisduetoheterogeneityratherthansamplingvariability. When significant statistical heterogeneity was detected, further stratification wasapplied to investigatewhether heterogeneity could be explained by different animal speciesormethodtomeasurebloodpressure(tailcuffand intra-arterial).Toevaluatetherobustnessofourresultsagainst influentialstudies,a leaving-one-outsensitivityanalysiswasperformed.To examinepotential publicationbiaswe constructed funnel plots.Datawere analyzedusingReviewManagerVersion5.1.

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rEsulTs

Thesearchresultedin6,151articles,ofwhich194wereconsideredpotentiallyeligible.Intotal,101primarystudiesmettheinclusioncriteriaandwereusedfordataextractionafterreadingfulltextarticles(AFMvAandMVEV)(Figure1).Thirty-fourstudiesreportedongeneral(caloric)undernutrition;18usingaWistar ratmodel4-21and4usingaSprague-Dawleyratmodel22-25,8usingasheepmodel26-33,2usingaguineapigmodel34,35,and2usingamousemodel36,37.Sixty-sevenstudies reportedonproteinundernutrition;47usingaWistar ratmodel38-84,15usingaSprague-Dawleyratmodel85-99,1usingaspontaneouslyhypertensiveratmodel100,and4usingamousemodel101-104.Theageofthestudiedanimalsrangedfromfourweeksinratstothreeyearsinsheep.

figure 1 Literature search results for studies reporting onmaternal undernutritionwith regard tohypertension.

6,151 poten�ally eligible studies iden�fied(database searches and references lists)

5,957 studies were excluded based on the inclusion criteria and �tle and abstract review

194 full text ar�cles were reviewed

93 studies were excluded for not having the required exposure / not repor�ng the outcome of interest / not

repor�ng data in a form fit for meta-analysis / non-animal or fetal studies

101 studies were included in the meta-analysis

risk of biasForty-five studies reported randomization, either randomization to the dietaryregimen5,8-11,13,18,20,21,25,27-30,32,33,40,42,48,70,72,79,81,83,92,93,103,104,orrandomizationinselectingthepupsfromthe litters thatwere studied12,22,24,45,55,57,60,68,74,82,99,102, or both6,7,14,41,67. Eighteen studies reportedblindingoftheinvestigator27,28,30,31,40,50,51,55-57,62,65,67,81,88,91,103,104.Onlyonestudyreportedthatthey

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performed a sample size calculation67. Funnel plots of all six outcomes showed symmetricalscatteringofthestudyresultsaroundthesummaryestimate.Therewasnoevidenceofasmallstudyeffectorpublicationbias.

Systolic blood pressure after maternal general undernutritionThirty studies provided data on systolic blood pressure in offspring after maternal generalundernutrition.Twenty-twostudieshadbeenperformedinrats4-25,twoinmice36,37, one in guinea pigs35,andfiveinsheep27,28,30-32. Intotal,384undernourishedanimalsand420controlanimalsweredescribed.Meansystolicbloodpressurewas14.5mmHg(95%CI10.8to18.3)higher inundernourishedanimalscomparedtocontrols(Figure2). Therewasconsiderableheterogeneity,withanI2of92%,whichpersistedafterstratifyingforsexormeasurementmethod.Stratifyingforspeciesdidnotreduceheterogeneityinthedifferentrodentmodels.Meta-analysisinsheeponly(37undernourishedanimalsand43controls)showednodifference in systolicbloodpressurebetweenundernourishedandcontrol animals,withameandifferencesystolicbloodpressureof-1.1mmHg(95%CI-6.4to4.3,I257%).Stratifyingformeasurementmethodshowedameandifferenceinsystolicbloodpressureof19.7mmHg(95%CI15.3to24.2,I292%)instudiesusingthetailcuffmethodanda4.2mmHg(95%CI-1.2to9.6,I281%)meandifferenceinstudiesusingintra-arterialcatheters. Threestudiesreportedbothblindingoftheinvestigatorandrandomization27,28,30.Separatelyanalysingthesestudiesreducedheterogeneity(I232%)andshowednosignificantdifferenceinsystolicbloodpressure(2.1mmHg,95%CI-3.0to7.2)aftermaternalgeneralundernutrition.

Systolic blood pressure after maternal protein undernutritionFifty-four animal studies provided data on systolic blood pressure in offspring aftermaternalproteinundernutrition. Fifty studieswereperformedusing rats40-42,44-71,74,76-78,80-88,90,91,93-95,100 andfourusingamousemodel101-104.We founda significantlyhighermeansystolicbloodpressurein animals prenatally exposed to a lowprotein diet (n = 1,421) compared to control animals(n =1,427),withameandifferenceinsystolicbloodpressureof18.9mmHg(95%CI16.1to21.8)(Figure3).Theresultsshowedconsiderableheterogeneity(I291%).Heterogeneitypersistedafterstratifyingtheanalysisforsexorspecies.Stratifyingformeasurementmethodshowedameandifferenceinsystolicbloodpressureof19.8mmHg(95%CI16.8to22.8,I291%)instudiesusingthe tail cuffmethodanda5.2mmHg (95%CI -2.1 to12.6, I2 0%)meandifference in studiesusing intra-arterial catheters.Separatelyanalysingstudies thatusedradiotelemetryshowedanon significant difference in systolic blood pressure (mean difference systolic blood pressure8.8mmHg,95%CI-9.8to27.3,I281%).

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figure 2Systolicbloodpressureaftermaternalgeneralundernutritionaccordingtosexoftheanimalandmeasurementmethod

M:Males,F:Females,TC:Tailcuff,IC:Intra-arterial,RT:Radiotelemetry.

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figure 3Systolicbloodpressureaftermaternalproteinundernutritionaccordingtosexoftheanimalandmeasurementmethod

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Figure3Continued


Sixstudiesreportedbothblindingoftheinvestigatorandrandomization55,57,67,81,103,104.Separatelyanalysing these studies reduced heterogeneity (I2 60%) and showed a significant but smallerdifference in systolic blood pressure (9.1 mmHg, 95% CI 5.6 to 12.6) after maternal proteinundernutrition.

Diastolic blood pressure after maternal general undernutritionTenanimalstudiesprovideddataondiastolicbloodpressureinoffspringaftermaternalgeneralundernutrition.Fivestudieshadbeenperformedinrats12,14,16,22,24,fourinsheep27,30-32,andoneinguineapigs35.Therewasnosignificantdifferenceindiastolicbloodpressure(1.6mmHg,95%CI-2.1 to5.3higher inprenatallyundernourishedanimals (n=95)comparedtocontrolanimals(n = 108) (I2 65%) (Figure 4).Meta-analysis of the effects on sheep only (29 undernourishedanimalsand31controls)demonstratedanon-significantdifferenceindiastolicbloodpressure(-3.5mmHg,95%CI-7.8to0.9,I220%).Heterogeneitywasnotfurtherreducedbystratificationforotherspecies,sex,ormeasurementmethod.Stratifyingformeasurementmethodshowedameandifferenceindiastolicbloodpressureof0.7mmHg(95%CI-9.7to11.1,I266%)instudiesusingthetailcuffmethodanda1.8mmHg(95%CI-2.5to6.1,I268%)meandifferenceinstudiesusingintra-arterialcatheters. Two studies reported both blinding of the investigator and randomization27,30. Separatelyanalysing these studies slightly reduced heterogeneity (I2 53%) and there was no significant

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difference indiastolicbloodpressure(-1.8mmHg,95%CI -10.6to6.9)aftermaternalgeneralundernutrition.

figure 4Diastolicbloodpressureaftermaternalgeneralundernutritionaccordingtosexoftheanimalandmeasurementmethod


Diastolic blood pressure after maternal protein undernutritionDataformeta-analysiswereavailablefromfouranimalstudies.Threestudieswereperformedin a rat model45,48,54 and one in a mouse mode101. In total, 48 animals had been prenatallyexposedtoalowproteindietand40animalswerecontrolfed.Meandiastolicbloodpressurewassignificantlyhigherinanimalsprenatallyexposedtoalowproteindietcomparedtocontrolanimals (mean difference diastolic blood pressure 9.5mmHg, 95%CI 2.6 to 16.3) (Figure 5).There was no heterogeneity (I2 0%). Stratifying for measurement method showed a meandifferenceindiastolicbloodpressureof11.0mmHg(95%CI-12.6to34.6)inthestudyusingthetailcuffmethodandan11.0mmHg(95%CI1.2to20.8)meandifferenceinthestudyusinganintra-arterial catheter. Separately analysing studies that used radiotelemetry showed smaller,

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nonsignificantdifferencesindiastolicbloodpressure(meandifferencediastolicbloodpressure7.0mmHg,95%CI-7.7to21.6,I248%). Therewerenostudiesthatreportedbothblindingandrandomization.

figure 5Diastolicbloodpressureaftermaternalproteinundernutritionaccordingtosexoftheanimalandmeasurementmethod


Mean arterial pressure after maternal general undernutritionElevenanimalstudiesprovideddataonmeanarterialpressureinoffspringaftermaternalgeneralundernutrition. Two studieswereperformedusing rats14,18, seven studies using sheep26,27,29-33, and two studies using guinea pigs34,35. Mean arterial pressure was significantly higher inundernourished(n=105)comparedtocontrolanimals(n =114)(5.0mmHg,95%CI1.4to8.6,I271%)(Figure6). Meta-analysis of the effects on sheep only (71 undernourished and 69 control animals)showedlessheterogeneitybutdemonstratednosignificantdifferenceinmeanarterialpressure(meandifferencemeanarterialpressure1.4mmHg,95%CI-3.1to5.9,I250%).Heterogeneitywasnotlowerafterstratificationforsexormeasurementmethod.Stratifyingformeasurementmethodshowedameandifferenceinmeanarterialpressureof13.0mmHg(95%CI7.4to18.6)inthestudyusingthetailcuffmethodanda4.2mmHg(95%CI0.6to7.8,I267%)meandifferenceinstudiesusingintra-arterialcatheters. Threestudiesreportedbothblindingoftheinvestigatorandrandomization27,30,34.Separatelyanalysing these studies did not change heterogeneity (I2 66%) and there was no significantdifference inmean arterial pressure (2.9mmHg, 95% CI -4.3 to 10.2) aftermaternal generalundernutrition.

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figure 6 Meanarterialpressureaftermaternalgeneralundernutritionaccordingtosexoftheanimalandmeasurementmethod


Mean arterial pressure after maternal protein undernutritionSeventeen rat studies reportedmeanarterialpressure inoffspringafterprenatalexposure toa low protein diet38,39,43,45,48,72-75,79,87,89,92,96-99. Mean arterial pressure was significantly higher inundernourished (n =208) compared to control rats (n =201) (meandifferencemeanarterialpressure10.5mmHg,95%CI6.7to14.2,I285%)(Figure7).Heterogeneitycouldnotbeexplainedbystratifyingforthedifferentratspeciesorsex.Stratifyingformeasurementmethodshowedameandifferenceinmeanarterialpressureof17.5mmHg(95%CI11.3to23.8,I20%)instudiesusing the tail cuffmethod and a 10.7mmHg (95%CI 6.6 to 14.7, I2 85%)meandifference instudies using intra-arterial catheters. Separately analysing studies that used radiotelemetryshowed smaller, non significant differences inmean arterial pressure (meandifferencemeanarterialpressure-0.9mmHg,95%CI-5.9to4.2,I20%). Therewerenostudiesthatreportedbothblindingandrandomization.

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figure 7Meanarterialpressureaftermaternalproteinundernutritionaccordingtosexoftheanimalandmeasurementmethod


Sensitivity analysisInaseriesofsensitivityanalyses,weevaluatedtherobustnessofourfindingsbyrepeatingtheanalysesanumberoftimes,eachtime leavingone studyoutof themeta-analysis. If a studyappearstobeanoutlier,withresultsverydifferentfromtherestofthestudies,thenitsinfluencewillbecomeapparent,astheresultwithoutthestudywouldbeverydifferentfromtheresultofthemeta-analysisoftheremainingstudies. Theobservedheterogeneityinthemeta-analysisfordiastolicbloodpressureaftermaternalgeneralundernutritionwas largelyduetothestudyofOzakietal14.Onremovalofthisstudy,the I2 decreased from 62% to 27%. The overall summary estimate, however, did not changesubstantially (-0.22mmHg, 95% CI -2.45 to 2.00).We could not identify differences in study

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design or characteristics in the study of Ozaki et al14 compared to the other studies whichcouldexplaintheinfluenceontheheterogeneity.Allothersensitivityanalyses,foreachoftheotherfiveoutcomemeasuresevaluated,confirmedthestabilityofouranalyses.Noinfluentialindividualstudycouldbeidentified.

Discussion

Theresultsgenerallysupportthefetaloriginshypothesis.Wedemonstratedthatbothgeneralandproteinundernutritionduringgestationresultedinsignificantlyincreasedsystolicandmeanarterial blood pressure in the offspring, while diastolic blood pressure was only significantlyincreasedaftermaternalproteinundernutrition.Thelargesteffectofmaternalundernutrition–bothgeneralandprotein–wasfoundonsystolicbloodpressure,whichwassignificantlyincreasedinprenatallyundernourishedoffspring.Thiseffectwasstrongerintheproteinundernourishedanimals. This systematic review confirms the substantial variability in results from animalstudieswhich,inmostcases,cannotbeattributedtochancevariabilityonly:heterogeneitywasconsiderableinallmeta-analyses. Someofthestudiesincludedinthismeta-analysisusedonlymaleorfemaleanimals,whileothersusedbothordidnot specify sex.Only two studiesexplained their choice tousemaleanimalsalone80,86.Theauthorsofoneofthesepaperssuggestedthatusingmaleanimalsonlyreducesthevariability86.Furthermore,theauthorsoftheotherpaperreferredtothefindingthatmaleanimalshavebeenshowntobemorevulnerabletodevelopmentalprogrammingeffects80,97, sincemalefetusesgrowfasterthanfemalefetusesfromanearlystageofgestationandthismakesthemmorevulnerableiftheirnutritioniscompromised105,106.Maternalproteinrestrictioninratshasbeenassociatedwithfewernephronsandanincreasedbloodpressureamongmalebutnotfemale offspring97. Female gender seems to be relatively protective against the hypertensiveeffects of maternal protein restriction. However, this protection is lost with more severeproteinrestriction97.Themechanismofthisrelativeprotectionisunknown.Thismeta-analysisshows,however, thatthere isalso in femalesasignificanteffectofmaternalundernutrition–bothgeneralandprotein–onsystolicbloodpressureandofproteinundernutritiononmeanarterialpressure.Inaddition,theeffectsonbloodpressureareofsimilarsizeinmaleandfemaleoffspring. When looking at species separately, we found that sheep prenatally exposed to generalundernutritiondidnothave significantlyhigherbloodpressure. This in contrast toprenatallyundernourishedrodentoffspring,whereanincreaseinsystolicandmeanarterialpressurewasseen.Theprogrammingofanyoutcomemeasure,includingbloodpressure,maybeamplifiedintherat.Thesumweightoftheproductsofconceptionrelativetomaternalweightis25-35%inratsversus6-10%insheepand3-5%inhumans30.Thiscouldverywellexplainthefactthatwedidfindaneffectinrodentmodels,butnotinsheep.

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Inhumans,therelationbetweenmaternalundernutritionduringpregnancyandbloodpressurein theoffspring is lesswell studiedand theresultsareconflicting.TheHungerwinterFamiliesStudy,whichstudiedsubjects fromthree institutions in famine-exposedcitiesatanageof59years,foundthatpeoplewhohadbeenexposedtofaminein uterohadhigherbloodpressuresas adults107. The Dutch famine birth cohort study did not find significant effects of prenatalfamineexposureonbloodpressurebutobservedthatthoseexposedtofamineprenatallyhadahigherbloodpressureresponsetostress108.Incontrast,in uteroexposuretotheLeningradsiegebetween1941and1944ortotheChinesefamineof1959-1961wasnotassociatedwithraisedbloodpressureinlaterlife109,110. Othermeta-analysesofanimaldatashowedmarkedheterogeneity111,112.Theresultsofthepresentsystematicreviewareinlinewiththis.Stratifyingforsexorspeciesdidnotconsistentlyexplaintheheterogeneity.Thereforewechosetoprimarilyreportthepooledresultsofallstudies,sinceconsistencyoftheresultswouldindicatethattheeffectsofmaternalundernutritionarebasedonthesamemechanismsandapplytodifferentspecies.However,thesizeoftheeffectmightdifferbetweenspecies. We explored the potential sources of heterogeneity by conducting subgroup analyses foranimalmodel,animal speciesandanimal sex,but thisaccountedonly fora smallpartof theheterogeneity.Anotherpossiblesourceofheterogeneitycouldbethefactthataportionoftheincludedarticlesdidnothavebloodpressureas theprimaryoutcome.Thiscouldaccount forthevarietyinsamplesizeswefoundbetweenthestudies.Furthermore,thefactthatdifferentlaboratoriesusedifferentlycomposeddietsintheirexperimentscouldbeanotherexplanationfortheheterogeneity,reflectingtheinconsistenciesintheresults.Inastudycomparingtwolowproteindiets,onlyoneaffectedpostnatalsystolicbloodpressure65.Themaindifferencebetweenthe two dietswas the source and content of fat. That study demonstrated that exposure tolowproteinin uterodoesnotinitselfdeterminethedevelopmentofhypertensioninlaterlife.Thebalanceofothernutrientswithin thematernaldietsappears toplaya critical role65. Thestudies included in our meta-analysis used different diets for the low protein experiments,which couldexplainpartof theheterogeneity.Also, in thegeneralmalnutritionexperiments,differentregimenswereapplied.Restricteddietsvariedfrom30to70%ofnormalintake.Thesewiderangesofdietaryrestrictionhaveundoubtedlyaffectedtheoutcomeandattributedtothereported heterogeneity. Standardization of animal experimentswill improve comparability ofthesestudies. Methodological heterogeneitymust also be discussed as amajor reasonof the observedheterogeneity. The methodological quality of the included studies was poor, with only 18studies reporting on blinding of the investigators, and 46 reporting on randomization, eitherwhen allocating the diet or selecting the pups for themeasurements. In contrast to humanstudies, randomization, blinding, and sample size calculations are not standard practice inanimalexperiments. Ithasbeenshownthatanimal studies thatdonot report randomizationandblindingaremorelikelytoreportadifferenceinthestudygroupsthanstudiesthatdoreport

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onthesemethods113.Wecansupportthisinourstudy.Separatelyanalysingthemethodologicallysoundstudiesresultedinareductionordisappearanceoftheeffect.Improvementscanbemadeonthequalityofanimalstudiesbyapplyingstandardsforreportingsuchasthosethatareroutineinhumanstudies. Inrodentmodels,measurementsofbloodpressurearedonebythetailcuffmethodorbydirect intra-arterialmeasurementswhich encompass both direct indwelling catheters and 24hourradiotelemetry.Radiotelemetryisconsideredtobeadirect,minimallystressful,continuousbloodpressuremeasurement114.There isevidencesuggesting thatprenatalmalnutritiondoesnotprimarilyresultinincreasedbloodpressure,butinaheightenedstressresponseleadingtohigherbloodpressurelevels108,114.Thismaybereflectedinourfindingsofagreaterdifferencein systolic blood pressure and mean arterial pressure when measurements were performedwith the tail cuffmethod, which is considered to be a source of stress, compared to directintra-arterialmeasurements.Radiotelemetryhasonlybeenusedinthreestudies investigatingthe effects of a low protein diet. Separately analysing studies using radiotelemetry showedsmallerandnonsignificantpooledeffectestimatescomparedwiththeothermethods.Ofthetwostudiesthatreportedonsystolicanddiastolicbloodpressure,oneshowedan increase inbothsystolicanddiastolicbloodpressure101,whiletheotherreportednoeffect45.Twostudiesreportedonmeanarterialpressureafterlowproteinundernutrition,withonestudyreportingaverysmall increase45,while theother reportednoeffect39.Swaliet al. reportedan increaseinsystolicbloodpressurewhenmeasurementswereperformedbythetailcuffmethodwhileradiotelemetrydemonstratedlowermeanarterialpressureinthesameanimalsafterlowproteinundernutrition80. These resultsmay indicate that part of the increased blood pressure levelsfound after prenatal undernutritionmaybedue to an increased stress response. In our dataon systolic anddiastolic bloodpressure, althoughno longer significant, bloodpressure levelswerestillhigherafterprenatalundernutritionwhenmeasuredby radiotelemetry.This lossofsignificancemaybecausedbythesmallnumberofanimals.

conclusion

In summary, the results of this meta-analysis generally support the view that maternalundernutrition–both general andprotein – leads to an increased systolic andmeanarterialbloodpressureintheoffspringofmostanimals.Yet,studiesshowsubstantialheterogeneityintheresultswhichcouldnotbesufficientlyexplainedbyknowncharacteristicsoftheresearch.Also,theresultsdependedstronglyontheappliedmeasurementtechniqueandanimalmodel.Futureanimalstudiesshouldimprovetheirmethodologicalqualitybyapplyingrandomization,blinding,andsamplesizecalculationtechniques,topreventselection,performance,anddetectionbias.

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the fetal origins of adult disease, the evidence and mechanisms

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