Paediatric obesity and cardiovascular risk factors – a life course approach

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Porto

Biomedical

Journal

h tt p://w w w . p o r t o b i o m e d i c a l j o u r n a l . c o m /

Review

article

Paediatric

obesity

and

cardiovascular

risk

factors

–

A

life

course

approach

Joana

Araújo

a,∗

_,

_Elisabete

_Ramos

a,b

a_EPIUnit_–_Instituto_de_Saúde_Pública,_Universidade_do_Porto,_Porto,_Portugal

b_Departamento_de_{Epidemiologia}_Clínica,_Medicina_Preditiva_e_Saúde_Pública,_Faculdade_de_Medicina_da_Universidade_do_Porto,_Porto,_Portugal

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received31January2017 Accepted9February2017 Availableonline17March2017 Keywords:

Paediatricobesity Cardiovascularriskfactors Lifecourse

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s

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Childhoodobesityisincreasinglyprevalentworldwide,andPortugalpresentsoneofthehighest preva-lenceofobesityandoverweightamongtheEuropeancountries.Sincechildhoodobesityisariskfactor forobesityinadulthood,thehighprevalenceofoverweightandobesityinpaediatricagecurrently experiencedisexpectedtoleadtoevenhigherprevalenceofobesityinadulthoodinfuturedecades.

Itiswellknownthattheprenatalperiodandinfancyarecriticalorsensitiveperiodsforobesity devel-opment,butagrowingbodyofevidencealsosuggestsarelevantroleofchildhoodandadolescence.The exposuretosomefactorsduringtheseperiodsorspeciﬁctimeframeswithintheseperiodsmayconfer additionalriskforobesitydevelopment.

Paediatricobesityisassociatedwithcardiovascularriskfactorsbothintheshortormedium-term,but alsointhelongterm,conferringadditionalriskforfutureadulthealth.However,itisnotclearwhether therelationbetweenpaediatricobesityandadulthealthisindependentofadultadiposity.Thereisa moderatetohightrackingofobesityfrompaediatricageintoadulthood,whichmaypartiallyexplainthe associationwithadultoutcomes.Therefore,therehasbeenincreasinginterestonlifecourseframeworks tostudytheeffectofthedynamicsofadiposityacrosspaediatricageonadultoutcomes,namelyonthe cardiovasculardiseaserisk.Theuseofthisapproachtostudydeterminantsandconsequencesofobesity raisesmethodologicalchallengestosummarizetheexposuretoadiposity/obesityacrossthelifespan, beingtheidentiﬁcationofgrowthtrajectoriesandthequantiﬁcationofthedurationofobesityamong themostusedmethods.However,furtherinvestigationisstillneededtoexplorethebestmethodsto summarizeexposuretoadiposityanditsvariationacrosstime.

licenses/by-nc-nd/4.0/).

Paediatricobesity Prevalenceandtrends

Highprevalenceofobesityisamajorpublichealthconcernand obesityisacknowledgedasaglobalpandemic.1_The_Global_Burden

ofDisease(GBD) Study2013reportedanincreaseinworldwide prevalenceofoverweightandobesitybetween1980and2013.2

TheGBDStudy2013useddatafromsurveys,reports,andpublished studieswithphysicalmeasurementsorself-reportedheightand weight,andpresentsdetailedestimatesofoverweightandobesity byregionandcountry,forbothchildren andadults.2 _Data_from

thisreportestimated2.1billionoverweightandobeseindividuals

∗ Correspondingauthor.

E-mailaddress:joana.araujo@ispup.up.pt(J.Araújo).

worldwidein2013,reﬂectingtheriseof27.5%intheprevalence ofoverweightandobesityinadultsandof47.1%inchildreninthe periodfrom1980and2013.2_The_rate_of_increase_was_higher_from

1992to2002,andsloweddowninthepastdecade,particularly indevelopedcountries,butprevalenceisstillincreasinginmost countries.2

Considering theage strata,the analysisof trends in obesity prevalenceover successivebirthcohortsshowed thatthemost rapidweightgainshaveoccurredintheagegroupof20–40years,in bothdevelopedanddevelopingcountries,andthatpeakprevalence ofobesitywasmovingtoyoungeragesindevelopedcountries.2

Prevalence of obesityin paediatric agehasmarkedly increased since 1980,in particularin developed countries:from 1980to 2013it increasedfrom16.9% to23.8%in boys,and from16.2% to22.6% in girls.2 _In _Portugal, _information _on_national _data _on

paediatricobesitycollectedbyroutineisscarceandsurveillance initiativesonchildhood obesityhave beenimplementedjust in recentyears.3_Estimates_from_the_GBD_Study₂₀₁₃_using_secondary

http://dx.doi.org/10.1016/j.pbj.2017.02.004

2444-8664/©2017PBJ-AssociaçãoPortoBiomedical/PortoBiomedicalSociety.PublishedbyElsevierEspa ña,S.L.U.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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datasourcesreportedforPortugal28.7%ofoverweightand obe-sityinchildrenandadolescents(<20years)forboysand27.1%for girls,whichisabovetheaverageestimatefortheWesternEurope: 24.2%and22.0%,respectively.2_The_WHO_European_Childhood

Obe-sitySurveillanceInitiative(COSI)wasestablishedin16countriesto measuretrendsinoverweightandobesityinchildrenaged6.0–9.0 years.4_Data_collected_in_this_context_showed_that_Portugal_was_one

oftheEuropeancountriespresentingthehighestprevalenceof obe-sityandoverweight.4_In_2007/2008_prevalence_of_overweight_(>1

z-score,accordingtoWHOgrowthreference)was40.5%in 7-year-oldboysand35.5%ingirls;therespectiveestimatesin2009/2010 were31.5%and36.2%.4_A_previous_{cross-sectional}_national_study

developedin2002/2003hadreported20.3%ofoverweight (exclud-ingobesity)and11.3%ofobesechildrenaged7–9.5years,butusing theIOTFcriteria.5

ForPortugueseadolescents,repeatednationaldataonobesity is availablefromthe HealthBehaviour in School-agedChildren (HBSC),aWHOcross-nationalsurveyconductedeveryfouryears in44 countriesandregions acrossEuropeand North America.6

Theself-reporteddatashowedthatamongPortugueseadolescents fromthe6th,8thand10thgradestherewas18.2%ofoverweight andobesitycombinedin2014,accordingtotheIOTFreference, andprevalencewashigherinboys.7_The_comparison_with_previous

HBSCsurveysshowedstableestimatesofoverweightandobesity since2002.7,8

Objectivelymeasureddataonweightandheightofadolescents isnotcollectedatthenationallevelinPortugal,onaregularbasis. Onlycross-sectionalstudiesareavailableatnationallevelin ado-lescents,andsomecross-sectionalorcohortstudiesatregionalor locallevel.Anationalcross-sectionalschool-basedstudyin2008 includingover22,000childrenandadolescentsaged10–18years ofage,found17.4%ofoverweightand5.2%ofobesity,accordingto IOTFcut-offs.9_A_review_on_obesity_in_Portuguese_children_and

ado-lescentspublishedin2011,whichincludedstudiessince2007from speciﬁcregionsorcommunities,reportedestimatesbasedonIOTF cut-offsrangingfrom13.4%to28.6%inmalesandfrom8.8%to25.6% infemalesforoverweightforadolescents(10–19years);estimates forobesityvariedbetween3.2%and13.0%inmales,andfrom0.6% and5.8%infemales.10_Longitudinal_data_is_scarce,_but_in_the_EPITeen

cohort,whichrecruited13-year-oldadolescentsenrolledatschools ofPortoin2003/2004,theprevalenceofobesityatthebaselinewas 11.3%inboysand9.2%ingirlsandtheprevalenceofoverweight 16.9%and16.0%respectivelyforboysandgirls,accordingtothe CDCreference.11_Data_from_the_follow-up_of_participants_showed

ameandecreaseinthebodymassindex(BMI)z-scorebetween13 and17years,resultinginadecreaseintheprevalenceofobesityto 7.8%inboysand3.8%ingirls.12

Althoughthelackofharmonized,objectivelymeasureddata, and collectedona regularbasis onobesityinpaediatric agein Portugal,availabledatasuggestthatPortugalpresentsoneofthe highestprevalenceofpaediatricobesityandoverweightamongthe Europeancountries.2,4_Since_childhood_obesity_is_a_risk_factor_for

obesityinadulthood,thehighprevalenceofoverweightandobesity inpaediatricagecurrentlyexperiencedbyourcountry,aswellas inmostcountries,isexpectedtoleadtoanevenhigherprevalence ofobesityinadulthoodinfutureyearsanddecades.13,14

Criticalandsensitiveperiodsforobesitydevelopment

Agrowingbodyofevidenceshowsthattherearecriticalor sen-sitiveperiodsacrossthelifecourseforobesitydevelopment.15–17

Criticalperiodsrefertospecificstagesof thedevelopment dur-ingwhichexposuretospecificenvironmentalstimulimayconfer permanentanatomicalorfunctioningchangeswithconsequences forlong-termeffectsof specificoutcomes.16,18,19_These _are

spe-ciﬁctimeframes,duringwhichexposuresmayconferincreased

riskofdisease,butoutsidethosetimeframesexposuretothose factorsdonotconferadditionalriskofdisease.Asensitiveperiod referstotimeframesofalsorapiddevelopment,duringwhicha greatereffectofexposuretosomefactorisstrongerincomparison toexposureoutsidethatperiod,butthateffectmaybemodiﬁedor reversed.18,19

Foetal life is an example of a critical period, since tissues and organs systems undergo profound developmentand expo-suretospeciﬁcfactorsmayirreversibly“programme”physiological functioning,playinganimportantroleindiseaseaetiology.16,20,21

Adolescence,onthe otherhand,maybe considereda sensitive period sincea rangeof differentdevelopmentalstages occurat variabletimeperiods,andaspeciﬁccriticalperiodmaynotexist. However,intheliteraturetheprenatalperiod,infancy,childhood andalsoadolescenceareallusuallyidentiﬁedascriticalperiodsfor obesitydevelopment.

Prenatalperiodandinfancy

Regardingtheprenatalperiod andinfancy,observationsthat maternalnutritioncouldimpactonoffspringobesitywereﬁrstly describedintheDutchHungerWinterStudyinthe1970s.22_This

studyshowedthat19-year-oldmaleswhohadbeenexposedto famine in the ﬁrst two trimesters of gestation, due to severe foodrationingimposedinthewinterandspring1944–1945 dur-ing the Second World War, had higher prevalence of obesity, incomparison tothose exposedin theothertrimesters.22_Later

epidemiological studiesby Barkeret al.23–25 _on_the _association

between rates of infant mortality and adult deaths (ecological analysis)and ontheassociationbetweenbirthweightand adult mortalityfromischaemicheartdiseaseconductedtothe develop-mentaloriginstheory,alsoknownasthe“Barker’shypothesis”.26

This theory suggests that undernutrition during gestation may leadtofoetalprogrammingthatchangesbody’sstructure, func-tion,and metabolismwithimplication in theaetiologyof adult coronaryheartdisease.26_This_theory_was_later_expanded_to_the

DevelopmentalOriginsofHealthandDisease(DOHaD)27,28

incor-poratingtheeffectofbroaderenvironmentalexposures(nutrition, environmentalchemicals,drugs,infections,orstress),notonlyin pregnancybutalsoin preconceptionperiodand ininfancy,due todevelopmentalplasticity,onwidespreadconsequencesforlater healthincludingobesity.Inlinewiththistheoryseveralstudies haveshownthatfactorssuchasmaternalobesity,nutritionand stress,exposuretochemicalsduringpregnancyandrapid post-natalweight gain are associated withobesity.29,30 _Mechanisms

mightincludeepigeneticprocesses,suchasDNAmethylation,that altergeneexpressionandincreasesusceptibilityforlaterdisease, but also sharedsocial inﬂuencesacross generations.19,29,30 _The

inter-generationaleffects of diseasesusceptibility seemsnot to berestrictedtoone generation,sincesomestudieshaveshown associationsacrossatleastthreegenerations.31

Childhood

Adiposityreboundoccurringatmid-childhoodisalso acknowl-edgedasacriticalperiodforobesitydevelopment.15,16_Adiposity

increasesduringtheﬁrstyearoflife,andthenadeclineisobserved untilaminimum(nadir)reachedatapproximately6yearsofage; the increase in adiposity registeredafter that nadir was ﬁrstly describedasadiposityreboundbyRolland-Cacheraetal.32_The

tim-ingoftheadiposityreboundwasshowntopredictlateradiposity levels;theearlier theageofadiposityrebound,thegreater the degreeofadiposityinadolescenceandin youngadulthood.32,33

Several studies have replicated the ﬁndings on the association betweenearlyadiposityreboundandobesitylaterinlife.16,34_As

shownbyTayloretal.,thedifferenceinBMIat18–21yearscanbe around3BMIunitshigherforthosewithearlyadiposityrebound (<5 years), compared to those with late rebound (>7 years).34

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However,theutilityofadiposityreboundforthepredictionoflater adiposityiscontroversial,sincethereboundisidentiﬁedbasedon atleast3serialBMImeasurements,meaningthatitcanonlybe identiﬁedafteritsoccurrence.Additionally,adiposityreboundis basedonBMIchanges,whichmaynotrepresentrealchangesin

bodyfat.34,35_Reverse_causation_may_also_be_a_possible_explanation

fortheassociationbetweentimingofadiposityreboundandlater adiposity,sinceearlyadiposityreboundhasbeensuggestedasa markerofearlyhighBMI36,37_and_of_accelerated_maturation.32,36

TwostudiesshowedthatBMIvalueatage7presentedthesame predictivevalueforlateradiposityidentiﬁcation,incomparisonto ageofadiposityrebound.36,37_Therefore,_although_age_at_rebound

seemstobepredictiveoflateradiposity,itisnotclearwhetheritis independentofchildhoodBMI,anditisdifﬁculttomeasuresince itrequiresseveralBMImeasurements.

Adolescence

Adolescenceis thesecondperiod of life,afterinfancy, char-acterizedbyintensegrowth.38_{Additionally,}_it_is_one_of_the_most

complexperiodsinhumangrowth,sinceinadditiontoincreasesin size,markedchangesinbodycompositionarealsoregistered,and morphologicalsignsofmaturationarevisible.16,38_Therefore,

ado-lescencemayalsobecriticalforthedevelopmentofobesity,dueto changesontheamountanddistributionofbodyfat.15,16,39_On_one

hand,fatcellnumberisdeterminedbytheendofadolescenceand reversaloffatcellnumberisnotpossibleduringadulthood.39,40

Ontheotherhand,sex-differencesintheprepubertalbody com-positionaremodest,buttheeffectofsexhormonesactingduring pubertaldevelopment,suchasoestrogeningirlsandtestosterone in boys, leads to sexualdimorphism in body composition.41,42

Femalesgainhigheramountsoffatmass,especiallyperipherally, butrelativelylowfat-freemass,whileinmalesthereisasubstantial acquisitionoffat-freemassduringthisperiod,butrelativelystable fatmass.41,42_Females_enter_puberty_earlier_and_experience_a_more

rapidpubertaltransition,andthereforestoptogrowatearlierages, whereasboyshavealongergrowthperiodandattainhigherﬁnal height.42_The_combination_of_these_changes_in_the_absolute_amount

offatandfat-freemassresultsinincreasingpercentageofbodyfat infemalesanddecreasinginmalesduringadolescence,resulting in25%and13%ofbodyfatonaverageinadulthood,respectively forfemalesandmales.38,41_{Sex-differences}_in_body_fat_distribution

areevidentinbodyshape.Infemales,thereisincreasedperipheral fataccumulationduringpuberty,especiallyonthehipsandthighs, leadingtoagynaecoidshape;initsturn,maleshaveanandroid bodyshape,withgreateraccumulationofcentralfat,andrelatively stableperipheralfat.41,42

Thepubertaltiminghasalsobeendescribedasadeterminant ofobesity.In females,severalstudieshaveshown thatthe ear-liertheageatmenarche,thehighertheriskoflaterobesity.43,44

Arecentreviewfoundthatfrom34studiesaddressingthe associa-tionbetweenageatmenarcheandadultBMI,themajority(30outof 34)reportedaninverseassociation.45_The_{meta-analysis}_of_the₁₀

cohortstudiesidentiﬁedinthereviewshowedthatgirlswithearly ageatmenarche(<12years)hadhigheradultBMIby0.34kg/m2 (95%CI 0.33–0.34).45 _In _boys,_studies _using_age _at_peak _height

velocityasanindicatorofmaturationalsoreportedaninverse asso-ciationbetweentimingofmaturationandlateradiposity.44,46

Additionally,somestudieshaveshownthatpubertaltimingis alsopredictorofbodyfatdistribution,however,evidenceisstill scarceandinconsistent,probablybecausetheeffectsofbodyfat distributionand oftotaladiposityaredifﬁculttoseparate.Data fromtheAmsterdamGrowthandHealthStudyshowedthatearly ageatmenarcheingirlswasassociatedwithatrunk-orientedfat distributionpattern,whileinboysageatpeakheightvelocitywas not.47_This_{sex-difference}_could_be_attributed_to_differences_in_the

indicatorofpubertaltiming,however,anotherstudyinmalesusing

alsoageatpeakheightvelocityshowedaninverseassociationwith centralfatmass:earlypubertalonsetwasassociatedwithhigher centralfatmass.46

Althoughpubertaltiminghasbeenrecognizedasanindicatorof lateradiposity,reversecausationcannotberuledout,sincesome studieshavealsoshownthathigherBMIatearlychildhoodwas associatedwithearlieronsetofpuberty.48,49_Therefore,_higher

adi-positymayinduceearliermaturation,andpubertaltimingmaybe amediatorbetweenearlyandlateradiposity.

Inadditiontophysiologicalchangestakingplaceduring ado-lescence, behavioural changes related to dietary, physical and sedentaryhabitsthatoccurduringthisperiodmayalsoincreasethe riskofobesity.39_Adolescence_is_marked_by_psychosocial_and

cogni-tivechangeswithimpactonincreasedautonomyandbehavioural change.Thereisatransitiononthefocusoftheadolescentfrom thefamilytothepeers,50,51_and_adolescents_{progressively}_feel_to

becapableof managingthemselvesontheirown, making deci-sions and solvingtheir ownproblems.52 _These_{transformations}

maybeaccompaniedbynewbehavioursacquisition,forinstance theinitiationofhealth-relatedbehaviourssuchassmoking,alcohol consumption,drugsuseorsexualbehaviours,53_and_also_changes_in

foodintakeandphysicalactivitypatterns.54,55_During_adolescence

anincreaseinsedentarybehaviourandadecreaseinphysical activ-ityisgenerallyobserved,54_being_the_decline_in_physical_activity

morepronouncedinadolescentgirls.56,57_These_changes_in_physical

activityandsedentarypatternsduringadolescencemayhave impli-cationsforweightgaininyouth.58_Regarding_food_intake,_changes

duringadolescence arerelated toincreasedadolescents’ auton-omyover what,whenandwhere theyeat,59,60_which_may_lead

tomoreunhealthyfoodchoices.Studieshaveshownadecreasein breakfastfrequency,andanincreaseinsnackingandfast-food con-sumptionduringtheperiodofadolescence.55,61_{Additionally,}_time

trendsinadolescents’foodconsumptionhavealsoshownincreased frequency ofsnacking, mealseaten awayfrom home,and con-sumptionoffastfoodandenergy-densesweetenedbeverages.62

Furthermore,exposuretomediaseemstoalsoplayanimportant roleinadolescents’habitsrelatedtotheriskofobesity,by promot-ingmoresedentaryactivities,consumptionofunhealthierfoods, andconveyingunrealisticthinnessastheidealforbeauty.63

Changes in food and physical activity and sedentary habits duringadolescencehaveimpactnotonlyduetoshort-term con-sequences on weight gain, but also long-term effects because thesebehaviours formedduring adolescence tendto trackinto adulthood.64–66

Trackingofpaediatricobesityintoadulthood

Agrowingbodyofevidencehasshownthatobesityin paedi-atricagetends totrackinto adulthood.Evidence fromtheFels Longitudinal study, which prospectively followed 555 partici-pantsthroughoutpaediatricage,showedthatBMIin childhood andadolescencewaspredictiveofoverweight/obesityatage35 years.67,68_Data_from_the_Bogalusa_Heart_Study_also_found_that_BMI

inchildhoodwasassociatedwithadultadipositylevels:overweight childrenwereaboutfourtimesmorelikelytobecomeoverweight adults.69_Different_studies_have_also_shown_that_the_risk_of_adult

obesityincreasedwithchildhoodageatBMImeasurement.67–70

Guo etal.68 _showed_that _the_probability _of_obesity_at ₃₅ _years

increasedwithincreasingageofparticipantswithBMIatorabove the95thpercentile:probabilityofadultobesitywaslowerthan30% forchildrenaged5yearswithBMIatorabovethe95thpercentile; between30%and60%forgirlsbetween5and12years,andforboys between5and18years,inthatpercentile;andabove60%forolder adolescents.IntheBogalusaHeartStudy,theprevalenceofobesity inadulthoodwas86%inmenand90%womenamongthosewho wereobeseatage15–17years,whileestimateswere76%and78%

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forthosewhowereobeseat9–11years.69_Whitaker_et_al.70_showed

thatoddsratioforadultobesitywas1.3(95%CI0.6–3.0)forobese childrenat1or2yearsofage,butmuchstronger(OR=17.5,95%CI 7.7–39.5)forobeseadolescentsat15–17yearsofage.

Theevidenceprovidedbytheseandothermorerecentstudies wassummarizedinthreesystematicreviews,whichconsistently showthetrackingofobesityfromchildhoodintoadulthood. Ser-dulaetal.,13_in_a_review_including_studies_from₁₉₇₀_to_1992,_found

thatalthoughcorrelationbetweenBMIinchildhoodandadulthood variedconsiderably,obesechildrenwereatleasttwotimesmore likelytobeobeseinadulthood,incomparisontononobese chil-dren.Theirresultsalsosupportedastrongerassociationwithadult obesitywhenobesitywaspresentinolderchildren,comparedto younger.13_A_later_review_also_found_that_the_risk_of_overweight

trackingwashigherforyouthpresentinghigherlevelsofadiposity, andatolderages–riskofadultoverweightwasstrongerforthose whowereoverweightorobeseinadolescencethaninchildhood.14

Finally,asystematicreviewandmeta-analysispublishedin2016 andincludingﬁfteenprospectivecohortstudiesshowedthatthe riskofbeingobeseinadulthoodwasaboutﬁvetimeshigherfor obesechildrenandadolescents,incomparisontochildrenand ado-lescentswho were not obese.71 _Among_obese _adolescents,_80%

werestillobeseinadulthood.71

Paediatricobesityandcardiovascularriskfactors Obesity-relatedriskfactors

Obesity is associated with increased risk of various disor-dersfrom different systems, suchas cardiovascular, endocrine, pulmonary,gastrointestinal,andpsychosocial,72,73_and_also_with

cause-speciﬁcandall-causemortality.74–77_Overweight_and

obe-sitywereestimatedtocauseof3.4milliondeathsworldwidein 2010,76_and_it_has_been_suggested_that_the_increasing_trend_in

obe-sitymayrevertprogressesinlifeexpectancy.78

Theassociationbetweenobesityandcause-speciﬁcmortality isstronger for cardiovasculardiseaseand diabetes,in compari-sontootherdiseases.74,78_The_Prospective_Studies_{Collaboration,}78

analysingdatafrom57prospectivestudieswithalmost900,000 participants,showedthateach5kg/m2_higher_BMI_was_on aver-ageassociatedwithabout40%highervascularmortality(HR=1.41, 95%CI1.37–1.45),and120%higherdiabetesmortality(HR=2.16, 1.89–2.46),whileestimateswere10%forneoplasticand20%for respiratorymortality.Abdullahetal.alsoshowedthatthenumber ofyearslivedwithobesitywasdirectlyassociatedwiththe mortal-ityrisk,andwashigherforcardiovasculardisease-causethanfor cancer-causemortality.74

Given the strong association between obesity and cardiovascular-relatedmortality,andthehighprevalenceof obe-sity,aswellastheburdenofcardiovasculardiseasesworldwide, thestudyoftheassociationbetweenobesityandcardiovascular diseases isof great relevance froma publichealth perspective. Additionally,astheincreaseinchildhoodobesityoccurredmainly from1980s onwards,thefirst generationwith highprevalence ofobesitysinceearlyageshavenot reachedthelifedecadesof higherincidenceofcardiovascularevents(thefifthdecadeoflife onwards)yet.Therefore,themagnitudeofchildhoodobesity con-sequences,ingeneralandspecificallyoncardiovasculardiseases, arenotfully understoodyet,and there isparticularinterest on extendingevidenceontheeffectsofchildhood obesityonearly markersofcardiovasculardisease.

Cardiovascularevents,suchasstrokeandischaemicheart dis-ease,aremorefrequentfromtheﬁfthdecadeoflifeonwards.79,80

Therefore,limitedevidencefromlongitudinalstudiesisavailable ontheeffectofchildhoodobesityonadultcardiovascularevents,

due tothedifﬁcultoperationalizationofstudieswithsuchlong follow-upperiods.Theestablishmentofbirthcohortsintendingto followchildren throughoutthepaediatricageandduring adult-hoodwillprovideimportantinsightsintothisﬁeld,butuntilnow mostevidenceisavailableforcardiovascularriskfactors,rather thancardiovascularevents.

Theterm‘riskfactor’wasﬁrstdescribedbyWilliamB.Kannelin 1961,inthecontextoftheFraminghamHeartStudy.81_According

totheDictionaryofEpidemiology,82_a_risk_factor_is_a

characteris-ticthatisknowntobeassociatedwithincreasedprobabilityofan outcome,suchasadisease,beingdenominatedasariskmarkerif itisnotnecessarilyacausalfactor.IntheFraminghamHeartStudy, Kannelandcolleaguesfoundthatelevatedserumcholesterollevels, hypertensionandelectrocardiogramabnormalitiesincreasedthe riskofheartdisease.81_Since_then,_research_from_the_Framingham

HeartStudyand otherstudieshaveidentiﬁedotherriskfactors, suchas diabetes,smoking, physical inactivity,and obesity, and thesefactors areusually referred asclassical ortraditional risk factorsofcardiovasculardisease.83,84_Other_factors_more_recently

identiﬁedincludeinﬂammatorymarkers,abnormalblood coagu-lation,homocysteine, amongmanyothers,and aredescribedas novelcardiovascularriskfactors.83–85_An_extensive_list_of

indepen-dentcardiovascularriskfactorshavealreadybeenidentiﬁed,83_but

thepredictiveabilityandclinicalimplicationsofthenovelrisk fac-torsisnotsowellidentiﬁedyet,andtraditionalriskfactorsseems toexplainmostpartofthecardiovasculardiseasesincidenceand mortality.76,84,86_A_study_from_the_Global_Burden_of_Metabolic_Risk

FactorsforChronicDiseasesCollaborationquantiﬁedattributable deathsfromriskfactorsworldwidein2010,andshowedthat63%of deathsduetocardiovasculardiseases,chronickidneydisease,and diabeteswereattributabletothecombinedeffectoffourmetabolic riskfactors:highbloodpressure,BMI,glucoseandcholesterol.87_In

Portugal,estimatesfromGBDfor2013showedthathighsystolic bloodpressure, dietaryfactors,andhighbody-massindex were theleadingriskfactorsofDisability-AdjustedLifeYears(DALYs), mainlyrelatedtocardiovasculardiseasesanddiabetes.88

Childhood obesity has been found to be associated with increasedriskofcardiovascularriskfactorsasearlyasinpreschool agedchildren.89,90_Most_studies_have_addressed_the_association_for

obesityatspeciﬁcages,consistentlyshowingthathigher adipos-ityatanyageisassociatedwithincreasedriskofcardiovascular riskfactorsorevents.However,moststudieshavenottakeninto accountthedynamicsofadiposity/BMIacrossthepaediatricage, and the effectof different adipositytrajectories during thelife courseonadultcardiovascularriskproﬁleisnotsowellunderstood. Studies have evaluated the effect of childhood obesity on adult cardiovascularrisk factors, but theresults are controver-sial regarding theeffect of childhood obesityindependently of adultobesity.91–97_One_study_found_no_evidence_for_an_association

betweenchildhood obesityonadultcardiovascularoutcomes,91

but in general other studies have reported direct associations, although suggesting that the effect was mediated by adult obesity.94,95_Two_other_studies_found_an_association_of_childhood

obesity,buttheyhadnottakenintoaccountthepotential media-tionbyadultobesity.96,97_A_systematic_review_published_in₂₀₁₀

andincluding16studiesontheeffectofchildhoodobesityonadult cardiovasculardiseaseriskfoundthattheassociationobservedfor childhoodobesitywasdependentonthetrackingofBMIinto adult-hood,andthattherewaslittleevidencefortheindependenteffect ofchildhoodobesity.93_A_more_recent_systematic_review

includ-ingthirty-sevenstudieswhichanalyzedtheabilityofchildhood BMItopredictobesity-relatedmorbiditiesinadulthoodconcluded that childhood BMI wasnot a good predictorof adult morbid-ity, because most obesity-related morbidity occurred in adults whowerenormalweightchildren.92_However,_most_of_the

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relativelylowprevalenceofobesityinchildhood,and therefore it is important tounderstandif those ﬁndings would be repli-catedinmorerecentcohortswithhigherprevalenceofchildhood obesity.

Themeasurementofindependenteffectsofchildhoodobesity onmorbidity is challenging in terms of thestatistical analysis, sincechildhoodandadultobesityarestronglycorrelated.Several studieshave addressedthis question usingstandard regression models,adjustingtheassociationforadultBMIorobesity. Nonethe-less,thisadjustmentmayintroduceover-adjustmentbiases98_and

collinearityproblems.99_This_adjustment_may_also_interfere_with

theinterpretationoftheresults,sincetheadjustedestimates rep-resenttheeffectofchangeinadipositybetweenmeasurements, andnotonlytheeffectofchildhoodadiposityadjustedforadult adiposity.100_Therefore,_more_{sophisticated}_statistical_techniques,

suchasstructuralequationmodels,maybemoreappropriateto studytheeffectofchildhoodobesityonadultoutcomes.For exam-ple,inmodelssuchaspathanalysisdirectandindirecteffectscan beestimatedandresultsareeasilyinterpretable.101,102

Inthe studiesmeasuringtheassociationbetween childhood obesityandadultcardiovascularoutcomes,theneedoflong follow-up periods may determine some limitations, such as limited information ontheexposurefortheinterim periods.The asso-ciationsestimatedfor childhoodobesitymaybeconfoundedby subsequentchangesinobesitythroughoutthepaediatricagethat arenot measuredinsomestudies.Additionally, changes inthe gradeofadiposity,andthedurationofobesityarealsonottaken intoconsiderationinmostofthestudies.Therefore,thereis grow-inginterestinstudyingtheeffectofpaediatricobesityonadult outcomes,takingintoaccounttheexposureacrossthelifecourse oftheindividuals.

Mostevidenceabouttheconsequencesofchildhoodobesityis basedonthestudyofBMI,andthereforeontheeffectoftotal adi-posity.However,themethodologicalchallengesdiscussedherealso applytothestudyoftheeffectofbodyfatdistribution.Moreover, thereareadditionalchallengeswhenstudyingbodyfat distribu-tion,since itis not clearwhatis thebestindicatorof body fat distribution,namelytomeasureitseffectbeyondtheeffectoftotal adiposity.

LifecourseapproachtotheassociationofobesitywithCVrisk factors

Therecognitionthatchronicdiseaseshavelonglatencyperiods andtheirorigins earlyinlifeledtotheneed ofaddressingthe impactofdifferentexposuresactingacrossdifferentperiodsofthe lifespan,andoftakingintoaccountthetimingoftheexposures. Therefore,therehasbeenincreasinginterestonlifecourse frame-workstoconceptualizetheaetiologyofchronicdiseases.19,103–105

Thelifecourseepidemiologyisdeﬁnedasthestudyoflongterm effectsofbiological,behavioural,andpsychosocialfactorsacting atdifferentstagesofthelifespanonhealthordiseaserisk.18,19

Itaddressestheinﬂuenceoffactorsthatoperateacrossthe indi-vidual’slifecourse,andalsoacrossgenerations, recognizingthe importanceoftimeandtimingforestablishingcausalitybetween exposuresandoutcomes.104

Differenttheoreticalmodelsinlifecourseepidemiologyhave beenproposed.Thecriticalperiodmodelemphasizesthetiming of theexposure– an exposure actingat a speciﬁc period may havelonglastingandirreversibleeffectsonanatomicalstructure orphysiologicalfunctioning(‘biologicalprogramming’).18,19

How-ever,asdiscussedearlierinthispaper,theremayalsobesensitive periods,wheretheeffectofanexposureisampliﬁedwhen tak-ingplaceata speciﬁcperiod.18,19 _These_two_concepts_share_the

importanceofthetimingofexposuresfor therisk oflater out-comes.Anothermainclassoflifecoursemodelsisbasedonthe

accumulationofrisk,whichsuggeststhateffectsofexposures accu-mulateovertime.18,19_In_the_accumulation_risk_models,_the_timing

couldalsobeakeyissue,beingpossibletohavedevelopmental periodswhenexposureshavegreaterimpact.Dependingonthe exposuresandoutcomes,accumulationofriskmayoccurthrough independent,clusteredexposuresorchainsofrisk.18,19_In_the

con-textofnon-communicablediseases,themostcommonmodelis theriskclustering,wheredifferentadverseexposurestendto clus-ter(forexample,health-relatedbehaviours,oradverseexposures relatedtoadversesocialcircumstances).Thechainsofrisk,where oneadverseexposuremayleadtoanother,arealsocommon,and theaccumulationofriskmayhappeninanadditivewayorwith triggereffects,whentheﬁnallinkinthechainhasamarkedeffect ontheriskofdisease.18,19_All_of_these_models_are_a_simplistic

repre-sentationoftheeffectoflifecourseexposuresandmaybedifﬁcult todistinguish.Furthermore,thedevelopmentofchronicdiseases likelyresultsfromtheinterplayofcriticalperiodandaccumulation riskmodels.104,106

Giventhenaturalhistoryofcardiovasculardiseaseswithlong latency periods and the recognition that early life factors are linkedtothedevelopmentofthedisease,theuseofalifecourse approachmayprovideinsightintothecomprehensionofdisease aetiology.104,106_{Additionally,} _obesity_itself _is_also _inﬂuenced_by

factorsacting atdifferent stages over thelifecourse.107

There-fore,theapplicationofa lifecourseframeworkfor thestudyof theassociationsbetweenobesityandcardiovasculardiseasemay beofgreatrelevanceforunderstandingtheeffectsofearly obe-sityanditsdynamicsacrossthelifespanoncardiovascularhealth. Additionally,thisapproachhascontributedtothebetter under-standingoftheinteractionoffactorsoccurringthroughoutlifeand theassociationwithcardiovasculardiseases,andalsotothe devel-opmentofnewmethodologiestostudyhowexposuretoobesity acrosspaediatricageimpactsoncardiovasculardisease.

One strategy to summarize the exposure to obesity has been to speciﬁcally investigate the effect of obesity duration, usuallyassessedthroughtheageofobesityonset.94,108–113

How-ever,results areconﬂicting since whilesome studiesfound no association,109,110,112 _others_have_shown _that_higher_duration_of

obesitywasassociated withworst cardiovascularriskproﬁlein adulthood.94,108,111,113_One_of_those_studies_has_additionally_found

thattheincreasedriskofimpairedglucosemetabolismforthose withhigherdurationofobesitywaspartlyexplainedbyattained adultadiposity.94_Some_inconsistent_results_between_studies_may

be due to differences in the ageof participants under evalua-tionandinthedeﬁnitionoftheoutcomes.Additionally,theerror in themeasurement ofduration of obesityusingtheage ofits onsetmaydifferbetweenstudies,dependingonthetotallengthof follow-upandnumberofmeasurementsacrosstheperiodunder study.

Another study has suggested the use of “obese-years” as a goodindicatorofobesity-relatedhealthrisks.114_Abdullah_et_al.114

showed that the obese-years, which summarizes duration and grade of obesity, was associated with increased diabetes inci-dence,suggestingthatobese-yearswasabetterindicatorofthe healthrisksthanBMIordurationofobesityalone.However,both approaches,thedurationofobesityandtheobese-years,onlytake intoaccounttimelivedwithobesity(BMIatorabove30kg/m2_),_and donotconsiderﬂuctuationsofadipositywithinnormalBMIranges. These approaches assume that health risks are associated only toBMIvaluesaboveaspeciﬁcthreshold,whichisnotsupported bypreviousevidence.77_Therefore, _in_general_the_assessment_of

thedynamicsofadiposityhasbeensimplistic, andmoststudies donotevaluatedurationandgradeofadiposity.Forthatreason, newmethodologiestoassesstheexposuretoadiposity,including durationanddegreeofBMIwithinthewholeBMIspectrum,are warranted.

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Anotherinterestingapproachtoaddressthelifetimerisk asso-ciatedwithobesityistheidentiﬁcationofadipositytrajectories over thelife course.The studyof growthtrajectories in paedi-atricagehasbeenrecognizedofgreatrelevanceforsurveillance and for clinicalpractice,but it is alsovery useful foraetiology research.115 _Studies _have _applied _different _{methodologies} _for

growthmodellinginpaediatricage.Somestudieshaveidentiﬁed individualgrowthtrajectories,116–128 _through_the_application_of

mixed-effectsmodels,where random effects captureindividual variationacrosstime.Otherstudieshaveappliedagroup-based statisticalmethod,wheresubpopulationscharacterizedbydistinct developmentaltrajectoriesareidentiﬁed.129–153_Only_part_of_these

hasstudied the effect of growth trajectories on cardiovascular riskfactorsormetabolicoutcomes.131,133,144,145,148,152_Generally,

studieshavefoundthatgroupsexperiencinggrowthtrajectories characterizedbyhigheradiposity,andspeciallywithearlyobesity onset,areassociatedwiththemostunfavourablecardiovascular outcomes. Ventura and colleagues131 _showed _that _girls _in _the

‘upward percentile crossing’ trajectory from5 to15 years had highestmetabolicriskfactorsat15years,whilethe‘delayed down-wardpercentilecrossing’presentedsimilarlevelsincomparison tothe‘50th percentiletracking’.IntheRaineStudy,133 _those_in

increasingtrajectoriesfrombirthto14yearspresentedthehighest insulinresistancelevelsat14years,whiletheoutcomeinthose fromdecliningtrajectorieswassimilartothoseinthereference trajectory(‘Optimalgrowth’). Data fromtheIsleofWightbirth cohortalsofoundhighersystolicanddiastolicbloodpressureat 18years inthedelayedoverweighttrajectory incomparisonto the ‘normal’ trajectory, but still smallerthan the values found for the early persistent obesity trajectory.144 _In _the _EPITeen

cohort,fromPorto,Portugal,the‘HigherBMIgrowth’trajectory frombirthuntil21years,145_as_well_as_the_‘High,_{increasing’}_BMI

trajectory identiﬁed in the same cohort, but speciﬁcallyin the period between 13 and 21 years,148 _were _associated _with_the

mostunfavourable cardiovascular risk proﬁleat 21 years. Data fromtheBirthtoTwenty(Bt20)cohortshowedthattrajectories ofearlyonsetobesityoroverweightfrom5to18yearshadhigher bloodpressurelevelsinlateadolescence.152 _On_the_other_hand,

trajectorieswithadecliningtrendpresentedingenerallevelsof cardiovascularriskfactorsbetweenthetrajectoriesofstablehigh adiposityorincreasingtrends,andthenormaloroptimalgrowth trajectories.131,133,144,148,152_As_trajectories_with_declining

adipos-itytrendsapproachﬁnaladipositylevelsofthenormaltrajectories, theseresultsmaysuggestthatexcessivegainsinadiposityduring thepaediatricagesareassociatedwithadversecardiovascularrisk factors,partlybecauseitislikelytoresultinhighﬁnalBMI. Conclusions

Thisreviewhighlightstherelevanceoftakingintoaccountthe exposuretoadipositythroughoutthelifespantobetterunderstand theroleofadiposityasdeterminantofmorbidityandmortality. However, this life courseapproach raisesmethodological chal-lengesthathavenotyetbeenfullyaddressedandsolved.Although itisstillunclearwhatthebestapproachis,thestudyoftheeffect ofBMI atdifferentages withadjustmentfor ﬁnal attainedBMI is recognizedto present limitations. On the otherhand, meth-odsthattakeintoaccountvariationsinadiposityacrosstime,and alsoacrosstheentireBMIspectrum,maybeconsideredas supe-riorapproaches.Nevertheless,furtherinvestigationisneededto explorethebestmethodstosummarizethedynamicsofadiposity acrosstime.

Conﬂictofinterest

Theauthorsdeclarenoconﬂictofinterest.

Acknowledgements

ThisstudywasfundedbyFEDERthroughtheOperational Pro-gramme Competitiveness and Internationalization and national fundingfromtheFoundationforScienceandTechnology–FCT (Por-tugueseMinistryofScience,Technologyand HigherEducation), undertheUnidadedeInvestigac¸ãoemEpidemiologia–Institutode SaúdePúblicadaUniversidadedoPorto(EPIUnit) (POCI-01-0145-FEDER-006862; Ref. UID/DTP/04750/2013); and the PhD Grant SFRH/BD/78153/2011(JoanaAraújo),co-fundedbytheFCTandthe POPH/FSEProgramme.

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