UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl) UvA-DARE (Digital Academic Repository) The fetal origins of adult disease, the evidence and mechanisms Veenendaal, M.V.E. Link to publication Citation for published version (APA): Veenendaal, M. V. E. (2012). The fetal origins of adult disease, the evidence and mechanisms General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 18 Mar 2018
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UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
The fetal origins of adult disease, the evidence and mechanisms
Veenendaal, M.V.E.
Link to publication
Citation for published version (APA):Veenendaal, M. V. E. (2012). The fetal origins of adult disease, the evidence and mechanisms
General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.
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
3
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.
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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Chapter 3
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%).
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
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,
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.
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.
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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Fetal origins of hypertension in animals
3
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.
systolicbloodpressure:asystematicreviewoftheliterature.J Hypertens.2000;18:815-831.4. Almeida JR,Mandarim-de-Lacerda CA.Overweight is gender-dependent in prenatal protein-calorie
5. AlmeidaJR,Mandarim-de-LacerdaCA.Maternalgestationalprotein-calorierestrictiondecreasesthenumberofglomeruliandcausesglomerularhypertrophyinadulthypertensiverats.American Journal of Obstetrics and Gynecology.2005;192:945-951.
9. FrancoMDCP,DantasAPV,AkamineEH,KawamotoEM,FortesZB,ScavoneC,etal.Enhancedoxidativestress as a potentialmechanism underlying the programming of hypertension in utero. Journal of Cardiovascular Pharmacology.2002;40:501-509.
10. FrancoMDCP, Arruda RMMP, Fortes ZB, Ferreira de OS, CarvalhoMHC, Tostes RCA, et al. Severenutritionalrestrictioninpregnantratsaggravateshypertension,alteredvascularreactivity,andrenaldevelopmentinspontaneouslyhypertensiveratsoffspring.Journal of Cardiovascular Pharmacology. 2002;39:369-377.
11. FrancoMDCP,AkamineEH,AparecidadeOM,FortesZB,TostesRCA,CarvalhoMHC,etal.VitaminsCandEimproveendothelialdysfunctioninintrauterine-undernourishedratsbydecreasingvascularsuperoxideanionconcentration.Journal of Cardiovascular Pharmacology.2003;42:211-217.
12. HolemansK,GerberR,MeurrensK,DeCF,PostonL,VanAsscheFA.Maternalfoodrestrictioninthesecond half of pregnancy affects vascular function but not blood pressure of rat female offspring.British Journal of Nutrition.1999;81:73-79.
13. LandgrafMAV,MartinezLL,RastelliVMF,FrancoMDCP,Soto-SuazoM,TostesRDCA,etal.Intrauterineundernutritioninratsinterfereswithleukocytemigration,decreasingadhesionmoleculeexpressioninleukocytesandendothelialcells.Journal of Nutrition.2005;135:1480-1485.
14. OzakiT,NishinaH,HansonMA,PostonL.Dietaryrestriction inpregnantratscausesgender-relatedhypertensionandvasculardysfunctioninoffspring.Journal of Physiology.2001;530:141-152.
15. PerezH,RuizS,NunezH,WhiteA,GottelandM,HernandezA.Paraventricular-coerulearinteractions:Roleinhypertensioninducedbyprenatalundernutritionintherat.European Journal of Neuroscience. 2006;24:1209-1219.
16. PerezH,RuizS,NunezH,WhiteA,GottelandM.CoerulearactivationbyCRHanditsroleinhypertensioninducedbyprenatalmalnutritionintherat.International Journal of Neuroscience.2007;117:627-642.
17. Perez H, Soto-Moyano R, Ruiz S, Hernandez A, Sierralta W, Olivares R, et al. A putative role forhypothalamicglucocorticoidreceptorsinhypertensioninducedbyprenatalundernutritionintherat.Neuroscience Letters.2010;483:41-46.
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18. Riviere G, Michaud A, Breton C, VanCamp G, Laborie C, Enache M, et al. Angiotensin-convertingenzyme2(ACE2)andACEactivitiesdisplaytissue-specificsensitivitytoundernutrition-programmedhypertensionintheadultrat.Hypertension.2005;46:1169-1174.
24. Olausson H, Uvnas-Moberg K, Sohlstrom A. Postnatal oxytocin alleviates adverse effects in adultratoffspring causedbymaternalmalnutrition.American Journal of Physiology - Endocrinology and Metabolism.2003;284:E475-E480.
25. XuY,WilliamsSJ,O’BrienD,DavidgeST.Hypoxiaornutrientrestrictionduringpregnancyinratsleadsto progressive cardiac remodeling and impairs postischemic recovery in adult male offspring. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2006;20:1251-1253.
26. Cleal JK, Poore KR, Boullin JP, KhanO, ChauR,HambidgeO, et al.Mismatchedpre- andpostnatalnutritionleadstocardiovasculardysfunctionandalteredrenalfunctioninadulthood.Proc Natl Acad Sci U S A.2007;104:9529-9533.
27. Gardner DS, Pearce S, Dandrea J, Walker R, Ramsay MM, Stephenson T, et al. Peri-implantationundernutritionprogramsbluntedangiotensin II evokedbaroreflex responses in youngadult sheep.Hypertension.2004;43:1290-1296.
28. GardnerDS,VanBonBWM,DandreaJ,GoddardPJ,MaySF,WilsonV,etal.Effectofpericonceptionalundernutrition and gender on hypothalamic-pituitary-adrenal axis function in young adult sheep.Journal of Endocrinology.2006;190:203-212.
29. Gilbert JS, LangAL,GrantAR,NijlandMJ.Maternalnutrient restriction in sheep:hypertensionanddecreasednephronnumberinoffspringat9monthsofage.J Physiol.2005;565:137-147.
32. Hawkins P, Steyn C, McGarrigle HHG, Calder NA, Saito T, Stratford LL, et al. Cardiovascular andhypothalamic-pituitary-adrenal axis development in late gestation fetal sheep and young lambsfollowing modest maternal nutrient restriction in early gestation. Reproduction, Fertility and Development.2000;12:443-456.
34. BertramC,KhanO,OhriS,PhillipsDI,MatthewsSG,HansonMA.Transgenerationaleffectsofprenatalnutrient restriction on cardiovascular and hypothalamic-pituitary-adrenal function. Journal of Physiology.2008;586:2217-2229.
36. KawamuraM,ItohH,YuraS,MogamiH,SugaS,MakinoH,etal.Undernutritioninuteroaugmentssystolic blood pressure and cardiac remodeling in adult mouse offspring: Possible involvement oflocal cardiacangiotensin system indevelopmentaloriginsof cardiovasculardisease.Endocrinology. 2007;148:1218-1225.
38. Alwasel SH, AshtonN. Prenatal programming of renal sodiumhandling in the rat.Clinical Science. 2009;117:75-84.
39. Augustyniak RA, Singh K, Zeldes D, Singh M, Rossi NF. Maternal protein restriction leads tohyperresponsivenesstostressandsalt-sensitivehypertensioninmaleoffspring.American Journal of Physiology - Regulatory Integrative and Comparative Physiology.2010;298:R1375-R1382.
40. BertramC, TrowernAR, CopinN, JacksonAA,Whorwood CB. Thematernal diet during pregnancyprograms altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroiddehydrogenase: Potential molecular mechanisms underlying the programming of hypertension inutero.Endocrinology.2001;142:2841-2853.
41. BezerraDG,LacerdaAndradeLM,PintodaCruzFO,Mandarim-de-LacerdaCA.AtorvastatinAttenuatesCardiomyocyte Loss in Adult Rats From Protein-Restricted Dams. Journal of Cardiac Failure. 2008;14:151-160.
43. CambonieG, ComteB, Yzydorczyk C,Ntimbane T,GermainN, LeNLO, et al. Antenatal antioxidantpreventsadulthypertension,vasculardysfunction,andmicrovascularrarefactionassociatedwith inutero exposure to a low-protein diet.American Journal of Physiology - Regulatory Integrative and Comparative Physiology.2007;292:R1236-R1245.
44. ElmesMJ,GardnerDS,Langley-EvansSC.Fetalexposuretoamaternallow-proteindietisassociatedwith altered left ventricular pressure response to ischaemia-reperfusion injury. British Journal of Nutrition.2007;98:93-100.
45. Fernandez-TwinnDS,EkizoglouS,WaymanA,PetryCJ,OzanneSE.Maternallow-proteindietprogramscardiac beta-adrenergic response and signaling in 3-mo-old male offspring. American Journal of Physiology - Regulatory Integrative and Comparative Physiology.2006;291:R429-R436.
47. Harrison M, Langley-Evans SC. Intergenerational programming of impaired nephrogenesis andhypertension in rats following maternal protein restriction during pregnancy. British Journal of Nutrition.2009;101:1020-1030.
48. Hu XW, Levy A, Hart EJ, Nolan LA, Dalton GR, Levi AJ. Intra-uterine growth retardation results inincreased cardiac arrhythmias and raised diastolic blood pressure in adult rats. Cardiovascular Research.2000;48:233-243.
49. Jackson AA, Dunn RL, Marchand MC, Langley-Evans SC. Increased systolic blood pressure in ratsinducedbyamaternallow-proteindietisreversedbydietarysupplementationwithglycine.Clinical Science.2002;103:633-639.
50. Jones SE, Bilous RW, Flyvbjerg A, Marshall SM. Intra-uterine environment influences glomerularnumberandtheacuterenaladaptationtoexperimentaldiabetes.Diabetologia.2001;44:721-728.
51. Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP. Maternal undernutrition during thepreimplantation period of rat development causes blastocyst abnormalities and programming ofpostnatalhypertension.Development.2000;127:4195-4202.
54. Langley-EvansSC,JacksonAA.Captoprilnormalisessystolicbloodpressureinratswithhypertensioninducedbyfetalexposuretomaternallowproteindiets.Comparative Biochemistry and Physiology - A Physiology.1995;110:223-228.
56. Langley-EvansSC,GardnerDS,JacksonAA.Maternalproteinrestrictioninfluencestheprogrammingoftherathypothalamic-pituitary-adrenalaxis.Journal of Nutrition.1996;126:1578-1585.
57. Langley-Evans SC, Phillips GJ, Gardner DS, Jackson AA. Role of glucocorticoids in programming ofmaternaldiet-inducedhypertensionintherat.Journal of Nutritional Biochemistry.1996;7:173-178.
59. Langley-Evans SC, Gardner DS, Jackson AA. Association of disproportionate growth of fetal rats inlategestationwith raised systolicbloodpressure in later life. Journal of Reproduction and Fertility. 1996;106:307-312.
60. Langley-EvansSC,JacksonAA.Ratswithhypertensioninducedbyinuteroexposuretomaternallow-proteindietsfailtoincreasebloodpressureinresponsetoahighsaltintake.Annals of Nutrition and Metabolism.1996;40:1-9.
62. Langley-EvansSC.Hypertensioninducedbyfoetalexposuretoamaternallow-proteindiet,intherat,ispreventedbypharmacologicalblockadeofmaternalglucocorticoidsynthesis.Journal of Hypertension. 1997;15:537-544.
63. Langley-Evans SC, Nwagwu M. Impaired growth and increased glucocorticoid-sensitive enzymeactivitiesintissuesofratfetusesexposedtomaternallowproteindiets.Life Sciences.1998;63:605-615.
65. Langley-EvansSC.Criticaldifferencesbetweentwolowproteindietprotocolsintheprogrammingofhypertensionintherat.International Journal of Food Sciences and Nutrition.2000;51:11-17.
68. McMullenS,GardnerDS,Langley-EvansSC.Prenatalprogrammingofangiotensin IItype2receptorexpressionintherat.British Journal of Nutrition.2004;91:133-140.
69. McMullenS,Langley-EvansSC.Maternallow-proteindietinratpregnancyprogramsbloodpressurethrough sex-specific mechanisms. American Journal of Physiology - Regulatory Integrative and Comparative Physiology.2005;288:R85-R90.
71. NwagwuMO,CookA,Langley-EvansSC.Evidenceofprogressivedeteriorationofrenalfunctioninratsexposedtoamaternallow-proteindietinutero.British Journal of Nutrition.2000;83:79-85.
72. PaixaoADO,MacielCR,TelesMBB,Figueiredo-SilvaJ.RegionalBraziliandiet-inducedlowbirthweightiscorrelatedwithchangesinrenalhemodynamicsandglomerularmorphometryinadultage.Biology of the Neonate.2001;80:239-246.
51
Fetal origins of hypertension in animals
3
73. Pladys P, Sennlaub F, Brault S, Checchin D, Lahaie I, Le NLO, et al. Microvascular rarefaction anddecreasedangiogenesisinratswithfetalprogrammingofhypertensionassociatedwithexposuretoalow-proteindietinutero.American Journal of Physiology - Regulatory Integrative and Comparative Physiology.2005;289:R1580-R1588.
74. Plank C, Grillhosl C, Ostreicher I,MeissnerU, Struwe F, RauhM, et al. Transient growth hormonetherapy to ratswith lowprotein-inflicted intrauterinegrowthrestrictiondoesnotpreventelevatedbloodpressureinlaterlife.Growth Factors.2008;26:355-364.
76. Sayer AA, Dunn R, Langley-Evans S, Cooper C. Prenatal exposure to a maternal low protein dietshortenslifespaninrats.Gerontology.2001;47:9-14.
77. Sherman RC, Langley-Evans SC. Early administration of angiotensin-converting enzyme inhibitorcaptopril, prevents the development of hypertension programmed by intrauterine exposure to amaternallow-proteindietintherat.Clinical Science.1998;94:373-381.
79. SilvaLA,Veira-FilhoLD,BarretoIS,CabralEV,VieyraA,PaixaoAD.PrenatalUndernutritionChangesRenovascularResponsesofNimesulideinRatKidneys.Basic and Clinical Pharmacology and Toxicology. 2011;108:115-121.
80. SwaliA,McMullenS,Langley-EvansSC.PrenatalproteinrestrictionleadstoadisparitybetweenaorticandperipheralbloodpressureinWistarmaleoffspring.Journal of Physiology.2010;588:3809-3818.
82. TorresTDS,AguilaMB,Mandarim-de-LacerdaCA.Rosiglitazonereversescardiacadverseremodeling(fibrosisandvascularization)inperinatallowproteinratoffspring.Pathology Research and Practice. 2010;206:642-646.
83. Villar-MartiniVC,CarvalhoJJ,NevesMF,AguilaMB,Mandarim-de-LacerdaCA.Hypertensionandkidneyalterationsinratoffspringfromlowproteinpregnancies.Journal of Hypertension.2009;27:S47-S51.
84. Langley-Evans SC. Intrauterine programming of hypertension in the rat: Nutrient interactions.Comparative Biochemistry and Physiology - A Physiology.1996;114:327-333.
86. DaganA,HabibS,GattineniJ,DwarakanathV,BaumM.Prenatalprogrammingofratthickascendinglimb chloride transport by low-protein diet and dexamethasone.American Journal of Physiology - Regulatory Integrative and Comparative Physiology.2009;297:R93-R99.
87. GangulaPRR,ReedL,YallampalliC.Antihypertensiveeffectsofflutamideinratsthatareexposedtoalow-proteindietinutero.American Journal of Obstetrics and Gynecology.2005;192:952-960.
88. Habib S, Gattineni J, Twombley K, BaumM. Evidence that prenatal programming of hypertensionby dietary protein deprivation is mediated by fetal glucocorticoid exposure. American Journal of Hypertension.2011;24:96-101.
89. Hoppe CC, Evans RG, Moritz KM, Cullen-McEwen LA, Fitzgerald SM, Dowling J, et al. Combinedprenatal and postnatal protein restriction influences adult kidney structure, function, and arterialpressure. American Journal of Physiology - Regulatory Integrative & Comparative Physiology. 2007;292:R462-R469.
90. Manning J, Vehaskari VM. Low birth weight-associated adult hypertension in the rat. Pediatric Nephrology.2001;16:417-422.
92. Sathishkumar K, Elkins R, Yallampalli U, Yallampalli C. Protein restriction during pregnancy induceshypertensionandimpairsendothelium-dependentvascularfunctioninadultfemaleoffspring.Journal of Vascular Research.2009;46:229-239.
98. Woods LL, Ingelfinger JR, Rasch R. Modest maternal protein restriction fails to program adulthypertensioninfemalerats.American Journal of Physiology - Regulatory Integrative and Comparative Physiology.2005;289:R1131-R1136.
99. Woods LL, Morgan TK, Resko JA. Castration fails to prevent prenatally programmed hypertensioninmale rats.American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2010;298:R1111-R1116.
100. Otani L, ShirasakaN, YoshizumiH,Murakami T. Theeffectsofmaternalmildprotein restrictiononstroke incidence and blood pressure in stroke-prone spontaneously hypertensive rats (SHRSP).Bioscience, Biotechnology and Biochemistry.2004;68:488-494.
102. RexhepajR,BoiniKM,HuangDY,AmannK,ArtuncF,WangK,etal.RoleofmaternalglucocorticoidinduciblekinaseSGK1infetalprogrammingofbloodpressureinresponsetoprenataldiet.American Journal of Physiology - Regulatory Integrative and Comparative Physiology.2008;294:R2008-R2013.
103. Watkins AJ, Wilkins A, Cunningham C, Perry VH, Seet MJ, Osmond C, et al. Low protein diet fedexclusivelyduringmouseoocytematurationleadstobehaviouralandcardiovascularabnormalitiesinoffspring.Journal of Physiology.2008;586:2231-2244.
104. WatkinsAJ,UrsellE,PantonR,PapenbrockT,Hollis L,CunninghamC,etal.Adaptive responsesbymouseearlyembryos tomaternaldietprotect fetal growthbutpredispose toadultonsetdisease.Biology of Reproduction.2008;78:299-306.
105. Pedersen JF. Ultrasound evidence of sexual difference in fetal size in first trimester. Br Med J. 1980;281:1253.
to psychological stressors in adults after prenatal exposure to the Dutch famine. J Hypertens. 2006;24:1771-1778.
109. StannerSA,BulmerK,AndresC,LantsevaOE,BorodinaV,PoteenVV,etal.Doesmalnutritioninuterodeterminediabetesandcoronaryheartdiseaseinadulthood?ResultsfromtheLeningradsiegestudy,acrosssectionalstudy.British Medical Journal.1997;315:1342-1348.
110. HuangC,LiZ,WangM,MartorellR.Earlylifeexposuretothe1959-1961Chinesefaminehaslong-termhealthconsequences.The Journal of nutrition.2010;140:1874-1878.
111. Macleod MR, O’Collins T, Howells DW, Donnan GA. Pooling of animal experimental data revealsinfluenceofstudydesignandpublicationbias.Stroke.2004;35:1203-1208.
53
Fetal origins of hypertension in animals
3
112. Roberts I, Kwan I, Evans P, Haig S. Does animal experimentation inform human healthcare?Observations from a systematic review of international animal experiments on fluid resuscitation.BMJ.2002;324:474-476.