184

European Journal of Endocrinology -20-0296 Systems Research,UniversityofBirmingham,UK, 1 and NHS FoundationTrust,Birmingham,UK 4 Birmingham HealthPartners,UniversityHospitalsNHSFoundationTrust,Birmingham,UK,and Anuradhaa Subramanian systematic review mothers withgestationaldiabetesmellitus:a Pubertal timinginboysandgirlsbornto achieving arethemainphysicaloutcomes of rapid growth,changesof bodycompositionand sexualcharacteristics, attainment ofadult-likesecondary physical, cognitiveandpsychological transformation.The childhood developmentcharacterisedbyfundamental marksanimportantperiodinthedynamics of Introduction tests. and oflimitedquality.Prospectivecohortstudiesshouldbeconducted,ideallycoupledwithobjectivebiochemical Conclusions: velocity andaslightincreaseinpubertaltempo. patterns inchildrenofmotherswithGDM,describinga3-monthadvancementtheageattainmentpeak height shift ofageatonsetgenitalandtesticulardevelopmentfirstejaculation.Onlyasinglestudyanalysedgrowth boys, therewassomeassociationbetweenmaternalGDMandearlierpubarche,butinconsistencyinthedirection of althoughforeachoftheseoutcomesonlyonestudyeachshowedastatisticallysignificantassociation.In from 4to10outof11).IngirlsbornmotherswithGDM,estimatessuggestearliertimingpubarche, and Results: for riskofbias.Resultsweretabulatedandnarrativelydescribedasreportedintheprimarystudies. Study selectionandextraction: studies uptoOctober2019. Data sources: Objective: parallel, pubertaltempohasincreasedinthegeneralpopulation,drivenbychildhoodobesity. Context: Abstract Department ofEndocrinologyandDiabetes,BirminghamChildren’sHospital, Women’sandChildren’s Institute ofAppliedHealthResearch,UniversityBirmingham,UK, https://doi.org/ https://eje.bioscientifica.com Clinical Study Krishnarajah Nirantharakumar

Seven articles(sixforgirlsandfourboys)wereincluded.Studyqualityscorewasmostlymoderate(ranging The incidenceofgestationaldiabetesmellitus(GDM)hasbeenontherise,drivenbymaternalobesity.In

To evaluatetheavailableevidenceonpubertaltimingofboysandgirlsborntomotherswithGDM. 10.1530/EJE

Pubertal timingmaybeinfluencedbythepresenceofmaternalGDM,thoughcurrentevidenceissparse

We searchedMEDLINE,EMBASE,CINAHLPlus,Cochranelibraryandgreyliteratureforobservational -20-0296 1 1 Two reviewersindependentlyselectedstudies,collecteddataandappraisedthestudies , Jan Idkowiak A Subramanianandothers Published by Bioscientifica Ltd. 1 , 2 , 3 Printed inGreat Britain © 2 2021Theauthors , 3 , 4 , Konstantinos A Toulis 3 Centre forEndocrinology, DiabetesandMetabolism, of breastdevelopment)and (appearance of fashion. Ingirls,thisusually startswiththelarche (onset production, typicalphysical changesoccurinasuccessive incremental, finelyorchestrated gonadalsex steroid axis with subsequent hypothalamic–pituitary–gonadal puberty. Asaconsequenceofthematuration ofthe and pubertaltiming Maternal gestationaldiabetes 2 Institute ofMetabolismand 1 , Shakila Thangaratinam Attribution 4.0International License. This workislicensed under a Downloaded fromBioscientifica.com at09/28/202106:22:29AM (2021) Endocrinology European Journalof [email protected] Email to JIdkowiak should be addressed Correspondence 184 184 3 , Wiebke Arlt :1 , 51–64 Creative Commons

51 –64 via freeaccess 2 , 3

European Journal of Endocrinology https://eje.bioscientifica.com metabolic morbidity associated with both conditions. could driveatransgenerational continuumand,thereby, not beenclearlyestablished yet.Ifconfirmed,suchalink and centralprecociouspuberty, acausalrelationshiphas studies exploringtherelationship betweenmaternalGDM assessment andthesignificantheterogeneityamong conceptualization of pubertal timing anditsclinical is scarce andconflicting.Duetothecomplexityin effect of GDM on sexual maturation and pubertal timing studies,butevidence onthe number ofobservational outcomes intheoffspringhasbeenevaluatedbyalimited this rise( changes inscreeningpracticesmighthavecontributed to decade andispredictedtofurtherincrease( countries, theincidenceofGDMhasdoubledinlast by maternalobesityhasalsobeenontherise;insome incidence ofgestationaldiabetesmellitus(GDM)driven earlier pubertaltimingdrivenbychildhoodobesity, the and childhoodobesity( chemicals, and,firstandforemost,abundanceofnutrients intrauterine environment,andendocrine-disrupting pulse generator. Theseincludepredisposinggeneticfactors, influencing thematurationofhypothalamicGnRH multifactorial andmaybeseenastheeffectoffactors morbidity ( increased riskofdiabetesandothercardio-vascular an adverseimpactonadultmetabolichealthincluding sexual behaviour( abuse, eatingdisorder, disturbedbodyimageandrisky such as poor academic performance, depression, substance isolation, potentiallyleadingtodetrimentaloutcomes more likelytoexperiencepsychologicaldistressandsocial to peerswhomatureontimeorlater, earlydevelopersare in alargecohortofchildrenthe1960s( assessment ofpubertalstagingperformedbyTanner years ingirlsand9boys,adefinitionbasedupon 2 children arediagnosedwithcentralprecociouspuberty( ( century 17 to13yearshasbeenrecognizedbetween19thand21st along with a steep decline in the age of menarche from . (development ofsperm)withtheoccurrencefirst puberty followedbypeakgrowthspurtandspermarche enlargement andpubarche arethefirstphysicalsignsof in menarche (firstmenstruation)( ), followed by apeakgrowthspurt culminating ), definedastheonsetofgonadarche beforetheageof8 Clinical Study The effectofmaternalGDMonpre-pubertalhealth Risk factors for early puberty are considered to be A seculartrendofadvancementinpubertaltiming 11 1 , 6 ). 2 , , 7 , 3 8 ). Consequently, increasingnumbersof ). 6 , 7 ). Earlypubertaltimingalsohas 9 ). Similartothetrendtowards A Subramanianandothers 1 ). Inboys,testicular 4 , 10 5 ). Compared ), although et al 1 . , (ii) testicularenlargement(testicular volume language terms(MESHandEmtree).Terms relating of amedicallibrariancombiningnaturalandstructured studies. Thesearch strategy wasconstructedwiththehelp from thescreenedarticlestoidentifyfurtherrelevant to obtainrelevantgreyliterature,and(iii)citationstracked (ii)GoogleScholar™searchlibrary), andexpertscontact databases (MEDLINE,EMBASE,CINAHLPlus,Cochrane results. Databasesincluded:(i)Electronicbibliographic retrieve anyadditionalstudiesbeforefinalsynthesisof in March 2019,withthesearch reruninOctober2019 to We carriedoutasystematicliteraturereviewsearch initially Searches Methods mothers withGDM. available evidenceonpubertaltiminginchildrenbornto Here, wehaveundertakenasystematicappraisalofthe pubic hair development/pubarche (Tanner stage: peak height velocity (PHV) and age at PHV; in boys, (i) ≥ ≥ (i) pubichairdevelopment/pubarche (Tanner stage: pubertal milestonesaccordingtoTanner ( was allowed to be described by the timing of the following GDM and pubertal timing in the offspring. Pubertal timing included, iftheystudiedtheassociationbetweenmaternal multiple exposuresoroutcomeswerealso and cross-sectionalstudies.Studiesthatconsidered We studies –cohort,case–control includedobservational Inclusion andexclusioncriteria consulted toreachconsensus. selection disagreements, a third reviewer (K.N.) was on PROSPERO(CRD42019150365). In case of study criteria mentionedinthepre-definedprotocolregistered selected whentheymettheinclusionandexclusion title, abstractandfulltextofthearticle.Articleswere screened bytworeviewers(A.S.andJ.I.)intheorderof of thisarticle). (see sectionon A listofsearch Table termsisprovided inSupplementary 1 ‘menarche’, ‘Tanner staging’,‘’ and‘growth’. Boolean operatorto‘puberty’,‘pubarche, ‘thelarche’, to ‘gestationaldiabetes’wascombinedwithan‘AND’ and pubertaltiming Maternal gestationaldiabetes B2), (iii)menarche and(iv)speedofpubertalgrowth as PH2), (ii)breastdevelopment/thelarche (Tanner stage: Records identifiedbythesearches wereindependently supplementary materials supplementary Downloaded fromBioscientifica.com at09/28/202106:22:29AM 184 :1 givenattheend 4 , 5 ≥ ): ingirls, 4 mLon ≥ PH2), 52 via freeaccess European Journal of Endocrinology with PRISMA guidelines (Supplementary Tablewith PRISMAguidelines(Supplementary 4)( (K.N.) wascontactedtosettle differences. (A.S. and J.I.) and in case of disparities, a third reviewer appraisal were performed by two independent reviewers the protocol-writingstage.Dataextractionandquality were pilot-testedwith one of the included studies at was alsodiscussedtoassessexternalvalidity. follow-up. Representativenessofthestudypopulation follow-up periodandcharacteristicsofpatientslost to multiple longitudinal outcome records; and (v) sufficient censoredtime-to-eventanalysis ormodelling interval account foruncertaintyinthetrueeventtimesuch as (iv) appropriatenessofstatisticalanalysisemployed to capture ofandadjustmentforconfoundingvariables; GDM diagnosisandpubertalstagingmeasurement;(iii) cohort fromthegeneralpopulation;(ii)objective giving risetosystematicdifferenceofthesampled selection bias,thatis,inclusioncriteriaorstudysetting validity of the included studies included: (i) potential Table 3).Elementsemployedinappraisingtheinternal questions (templateformisprovidedinSupplementary were gradedasloworhighriskforeachofthechecklist bias ofeachtheincludedstudiesandindividual appraisal checklist( considered. employed includingthelistofconfoundingvariables outcome/s consideredanddetailsonanalyticalmethods GDM exposedwomenwhousedinsulin, offspring sex, GDM exposure ascertainment criteria, proportion of source, andsetting,samplesize, studyperiod,country included studies: authors, study publication date, data mandated dataonthefollowingelementsfrom Microsoft Word® Table (Supplementary 2).Theform the specifics of this review to create a template form in The JBIdataextractionform( Data extractionandriskofbiasassessment subjects. chronological age,orstudiesconductedonnon-human pubertal staginginsteadoftimingdisregarding quantitative dataonpubertaltiming,studiesreporting articles,qualitativestudieswithout series orcommentary PHV andageatPHV. genitalia (Tanner stage: either orbothsides),(iii)maturationoftheexternalmale Clinical Study Data extractionandriskofbiasassessmentforms An adaptedversionoftheNewcastle–Ottawacritical Studies wereexcludediftheycasestudies, Findings ofthisrevieware reportedinaccordance 13 ) wasusedtoevaluatetheriskof ≥ G2), (iv)spermarche and(v) 12 A Subramanianandothers ) wasadaptedbasedon 11 ). PRISMA flowchart. Figure 1 articles didnotprovideacomparatorcohort( to aninsufficientnumberofsubjectswithGDM( not analyseGDMasapredictorforpubertaltimingdue outcomes wewereinterestedin( ( articles proceedings, oralpresentationsorcommentary excluded atthisstage:fourarticleswereconference 18 studiesforfull-textassessment.Elevenarticleswere were excludedonthebasisoftitleandabstract,leaving 248, 230werenotrelevanttotheresearch questionand searches, including57duplicates( We identified305studiesthroughelectronicdatabase Literature searchresults Results remaining studieswereincludedinthereview( not considerage/timing of puberty ( articles only reported Tanner stage at baselineand did predictors ofpubertaltiming( question ( objectives to our review studies had comparable primary populations studiedwerepredominantlyCaucasian.Four two inDenmark( studies wereconductedintheUSA( 26 studiesincludedinthisreview( The sevenprimary Study characteristics and pubertaltiming Maternal gestationaldiabetes 14 , , 27 15 , , 28 16 27 , , 17 29 , 28 ); twoarticlesdidnotincludeanyofthe , , 30 29 26 , , , 31 30 30 ) aredescribedin Downloaded fromBioscientifica.com at09/28/202106:22:29AM ) twostudieslookedatmultiple ) andoneinEngland( https://eje.bioscientifica.com 25 Fig. 1 18 , 31 , 184 19 23 ), andonelooked ). Oftheremaining :1 25 ); onearticledid , 24 , Table 1 ). The seven 27 21 , Fig. 1 , 31 28 22 20 . Four ). The , ); two ); two ). 53 29 25 via freeaccess ), , European Journal of Endocrinology https://eje.bioscientifica.com

Table 1 Characteristics of the included studies. Clinical Study

Sample size ¶,@ No. Reference Location Study database GDM diagnostic criteria Age of mothers Offspring sex GDM Controls Outcomes considered 1 (26)† USA and Sister study Self reports from family ‡<20 years: 1537 Girls 178 30 169 Adjusted RR for age at Puerto history (5%); menarche: Rico questionnaires 20–34 years: 25191 ≤ 10, 11, 12–13 (reference completed by the (76%); age group), 14 and ≥ offspring ≥35 years: 6380 15 years (19%) 2 (27) Denmark DNBC DNPR criteria based on NR Girls 238 256 Age adjusted OR for ≥ WHO criteria* + self Tanner B2 reports 221 237 Age adjusted OR for ≥

Tanner PH2 A Subramanianandothers NR Boys 192 182 Age adjusted OR for testicular volume ≥ 4 mL 206 203 Age adjusted OR for ≥ Tanner PH2 193 176 Age adjusted OR for ≥ Tanner G2 3 (28) USA KPCO linked to NDDG criteria** NR Girls 34§ 174 Age at PHV stratified by EPOCH study exposure status; PHV stratified by exposure status. β coefficients and P-value from accelerated failure time model and and pubertaltiming Maternal gestationaldiabetes P-value. NR Boys 43§ 166 Age at PHV stratified by exposure status; PHV stratified by exposure status. and beta coefficients andP -value from accelerated failure time model and P-value 4 (29) USA KPNC linked to Carpenter and Coustan ¶GDM: 33.0 (5.0); Girls 27 390 Adjusted HR: CYGNET criteria*** Control: 32.6 (5.9) ≥ Tanner B2 Downloaded fromBioscientifica.com at09/28/202106:22:29AM ≥ Tanner PH2 5 (30)† USA KPNC Carpenter and Coustan ¶UW:27.9(5.2) ; Girls 977 11 364 Adjusted HR for ≥ Tanner criteria*** NW: 29.9(5.1); B2 OW: 30.5(5.2); 931 10 839 Adjusted HR for ≥ Tanner OB: 30.3(5.3) PH2

6 (31) Denmark DNBC linked to the DNPR based on WHO @GDM: 31.9 (31.4– Girls 122 15 320 Adjusted mean monthly 184

Puberty Cohort criteria* + self reports 32.5) difference for: :1 Control: 30.6 Tanner B2, B3, B4, B5 (30.5–30.7) Tanner PH2, PH3, PH4, PH5 Menarche Axillary hair Acne 54 via freeaccess European Journal of Endocrinology

Boys 130 Adjusted mean monthly Clinical Study difference for: Tanner G2, G3, G4, G5 Tanner PH2, PH3, PH4, PH5 Spermarche Voice break Adult Voice Axillary hair Acne 7 (32)† UK Avon Longitudinal Self reports ¶29.0 (3.8) Boys 450 3263 Median age at transition to: Study of Parents Tanner PH > 1, PH > 2 and and Children PH > 3 based on multi-stage modelling A Subramanianandothers †Summarises the cohort from the primary study (potential contamination from mothers with pre-existing diabetes or patients with missing information on GDM); Data presented as ‡n (%); ¶Mean (s.d.); @Median (IQR); §10% contamination of the GDM exposed cohort with exposure to type 1 diabetes; *Danish National Patient Registry Criteria: GDM diagnosis is made based on WHO criteria (see subsequently) and in some cases if two or more glucose values measured exceeded the mean ± 3 s.d. on a curve based on a group of 40 healthy, nonobese, nonpregnant Danish women without a family history of diabetes, WHO criteria: fasting blood glucose > 7.0 mmol/L or random blood glucose > 11.1 mmol/L or 75 g oral glucose tolerance test at 2 h > 11.1 mmol/L; **NDDG criteria: 50 g oral glucose tolerance test at 1 h ≥7.8 mmol/L followed by a 100 g oral glucose tolerance test at 3 h > 7.8 mmol/L; ***Carpenter and Coustan criteria: fasting blood glucose > 5.3 mmol/L or 100 g oral glucose tolerance test at 1 h > 10 mmol/L, at 2 h > 8.3 mmol/L, at 3 h > 7.8 mmol/L. CYGNET, Cohort Study of Young Girls’ Nutrition, Environment and Transitions; DNBC, Danish national Birth cohort; DNPR, Danish National Patient Registry; EPOCH, Exploring Perinatal Outcomes among Children; HR, Hazard Ratio; KPCO, Kaiser Permanente of Colorado Health Plan; KPNC, Kaiser Permanante Northern California; NDDG, National Diabetes Data Group; NR, not reported; NW, normal weight; OB, obese; OR, Odds Ratio; OW, overweight; PHV, peak height velocity; RR, Risk Ratio; UW, underweight. considered, withrace/ethnicity andsocio-economicstatus GDM diagnosis.Variation inthecovariates wasobserved mentioned using Carpenter and Coustan thresholds for or misclassificationbias.Studies basedonKPNCcohorts status was only self-reported, indicating high riskof recall However, for theremainingtwostudies( two of those studies also considered self-reports ( registriesinfivestudies( information regardingGDMstatuswasobtainedfrom to pregnant women at risk of cancer. Exposure study byD’Aloisio country’s generalpractice or hospital setting except for the studied werereasonablyrepresentativeoftheirrespective for thesevenincludedstudiesin Newcastle Ottawacriticalappraisalchecklistissummarized The riskofbiasbasedonthereviewquestion-adapted Risk ofbiasassessment maternal GDMexposurestatus( while Monteilh outcomes: breastandpubichairdevelopmentin494 with their mothers ( positive maternalGDMstatusthroughtelephonecontact information onageatmenarche; 178ofthemself-reported 1 studies when considering multiple outcomes ( Northern California(KPNC)( Birth Cohort(DNBC)( potential foroverlappingpopulations(DanishNational sample fromthesamepregnancycohortsandthushad of thestudiesstratifiedtheirestimatesbyoffspringsex. reported outcomesforbothboysandgirls( only onthepubertaltiminginboys( pubertal timingingirls( mothers withGDMincludingpubertaltiming( at multiple developmental outcomes in the offspring of boys withpositivematernalGDMexposurestatus( ( with regardtothematernalsamplesize(417and12341) cohort (KPNC)andconsideredthesameoutcomesvaried maternal GDMstatus( peak heightvelocity;34girlsand43boyshadpositive and 209boyswithanthropometricrecordstocalculate boys, respectively( and genitaldevelopmentalstagein374,409369 458 girls, respectively, and testicular volume, pubic hair, and pubertaltiming Maternal gestationaldiabetes 28 ): D’Aloissio , Sample sizerangedwidelybothbetweenandwithin Three oftheincludedstudiesfocussedonlyon Two pairsoftheincludedarticlesderivedtheirstudy 29 ). Lauridsen t al. et t al. et et al. 26 25 et al. included33501daughterswith ). Hockett ). Grunnet included 450 boys withpositive 27 ( Downloaded fromBioscientifica.com at09/28/202106:22:29AM 26 25 included122and130girls ). Two studiesthatusedthesame 25 , ), whohadrestricted inclusion , 30 28 28 ) andKaiserPermanante https://eje.bioscientifica.com , , 31 et al. t al. et 29 29 Fig. 2 ). )). ), onestudyfocussed 31 184 considered multiple 26 included208girls ) andthreestudies , :1 . Allpopulations 27 26 25 , , 28 , 27 31 26 , , 29 ), GDM 26 ). 30 , Table , ). All 55 30 30 30 via freeaccess ). ), ), European Journal of Endocrinology https://eje.bioscientifica.com are givenin indicated byageatmenarche, pubarche andthelarche, between maternal GDM and pubertal onset in girls, as studiesreviewingtheassociation Results oftheprimary diabetes andpubertaltimingingirls Association betweenmaternalgestational ( recorded Tanner stageinlessthan80% oftheoffspring this intheiranalysis( censoring toaccountfor four studiesperformedinterval prohibiting thecaptureofprecisepubertaltiming,but times only during a series of pre-defined observation and ageatPHV( (SITAR)) oflongitudinalheightmeasurementsforPHV modelling (SuperimpositionbyTranslation AndRotation of thestagebreastdevelopment,andcomputational of testicularsize,breastpalpationforaccurateassessment outcomes, suchasorchidometer usefortheassessment reported utilizationofrecommendedmethodstomeasure staff infourstudies( timing intheoffspring. in theassociationbetweenmaternalGDMandpubertal representing the most popular confounders considered Assessment ofriskbias. Figure 2 30 Clinical Study , Outcome measurementswereperformedbyresearch 31 ), suggestingapossibilityofdropoutbias. Table 2 27 26 . , , 28 27 28 , , , 29 28 29 , , 30 29 ). Outcomeswererecorded , ); threeofthemspecifically 31 A Subramanianandothers ). Notably, twostudies adjusted HR: 1.04 (95% CI: 0.92, 1.17) and 2018 study of motherswithGDMcomparedtocontrols(2015study database assessingthehazardratiotoreach ( 2.55)) ( to motherswithGDM(adjustedOR:1.51(95%CI:0.90, 51% inageadjustedoddsforreaching ( considered pubertal Tanner stages of − (95% CI: articles thatstudiedthisassociation.Lauridsen GDM andpubarche ingirlsbasedonthefourprimary There wasaninconsistentassociationbetweenmaternal Pubic hairdevelopment/pubarche respectively) ( (adjusted HR:0.85(0.54–1.35) and1.06(0.95–1.18), wasnotevident 2018 studiesconductedby Kubo et al. GDM andoffspringageat thelarche inthe2015 and no longer evident. The association between maternal for offspringBMI,thesignificanceinthisassociation was (95% CI:1.18,3.34))( mothers comparedtocontrols(ageadjustedOR:1.99 the ageadjustedoddsof − 1.2); B4: in B2: mothers withGDM(adjustedmeanmonthlydifference a lowerageforallTanner stagesamong girlsbornto and without GDM. The direction of effect size suggest at Tanner breaststages2–5ingirlsborntomotherswith 28 association betweenbreastdevelopmentandGDM( between pubarche and maternal GDMalsostudiedthe The samefourstudiesthatstudiedtheassociation /thelarche (95% CI:1.52,5.83)). without GDMandapregravidBMI GDM and a pregravid BMI Tanner stage BMI andGDM,therewasa3-foldincreasedhazardof accounting forinteractionbetweenmaternalpregravid adjusted HR:1.24(95%CI:0.79,1.94))( difference inPH2: and 6.0monthsafteradjustment(adjustedmeanmonthly stages ingirlsofmotherswithGDMranging between 1.6 reported anearlierageatattainmentofallpubichair and pubertaltiming Maternal gestationaldiabetes 28 26 6.0 (95%CI: 7.9, 4.3))( , ) and2018( , 29 28 , − Table 2 , 30 4.6 (95%CI: 29 − − ). Lauridsen ). Grunnet 0.5 (95%CI: 4.4, 0);PH4: Table 2 ). Kubo 28 ≥ PH2 amonggirlsborntomotherswith 29 , − 29 ) usingdatasetsderivedfromthesame 10.8, − ). Grunnet ) ( 4.8 (95%CI: − et al. Table 2 10.1, 1.0);B3: et et al. Table 2 Downloaded fromBioscientifica.com at09/28/202106:22:29AM

− a − ≥ − 1.2)) ( conductedtwostudiesin2016 l. ( 1.6 (95%CI: B2 amonggirlsborntoGDM 3.2, 2.4);B5: ( 26 ≥ ). 30 ); however, onceadjusted 25 compared to mothers ) reportedanincreaseof t al. et ) reportedthemeanage Table 2 − < 7.7, 25 (adjustedHR:2.97 ≥ 184 ( − PH2 as an outcome ≥ 1.9 (95%CI: 26 :1 PH2 ingirlsborn − ). Threestudies − ) showedtwice Table 2 2.0); PH3: − 4.8, 1.6);PH5: ≥ 1.8 (95%CI: PH2 forgirls et al. ). When − ( − 56 5.0, 30 26 2.2 via freeaccess ) , European Journal of Endocrinology Pubic hairdevelopment/pubarche Outcome/study pubertal changes( by pubichairdevelopment( Table 2 ( PHV andageat ( ( ( ( Breast Development/Thelarche ( ( ( ( Clinical Study 28 29 31 30 27 29 31 30 27 ) ) ) ) ) ) ) ) ) Evidence summaryoftherelationshipbetweenmaternalGDMandpubertaldevelopmentintheirdaughtersidentified n = 1). Similar estimatesforpregravidBMI#GDM Unadjusted andadjusted(forrace/ethnicity, Crude andadjusted(formaternalageatmenarche, Mean ageatTannerstageB2,B3,B4,B5in Adjusted (forrace/ethnicity,maternalage, Age adjustedOR(95%CI)of n Similar estimatesfortheinteractionbetween Unadjusted andadjusted(forrace/ethnicity, Crude andadjusted(formaternalageatmenarche, Mean ageatTannerPH2,PH3,PH4,PH5in Adjusted (forrace/ethnicity,maternalage, Age adjustedOR(95%CI)of n PHV amongexposedandunexposedgirls Age atPHVstratifiedbymaternalGDM (%) (%) of ratio (95%CI)ofbreastdevelopmentstage household incomeandmaternalage)hazard stage B2,B3,B4,B5 monthly differenceinage(95%CI)atTanner cohabitation, parityandmaternalBMI)mean maternal ageatbirth,socioeconomicstatus, daughters ofmotherswithoutdiabetes and BMI)hazardratio(95%CI)of education, parity,smokingduringpregnancy maternal pregravidBMIandGDM: ratio (95%CI)of household incomeandmaternalage)hazard PH2, PH3,PH4,PH5 monthly differenceinage(95%CI)atTanner cohabitation, parityandmaternalBMI)mean maternal ageatbirth,socioeconomicstatus, daughters ofmotherswithoutdiabetes and BMI)HR(95%CI)of education, parity,smokingduringpregnancy in uteroafteradjustingforchild’s race/ethnicity boys andbetacoefficientfor exposuretoGDM for child’srace/ethnicity exposure toGDMinuteroafteradjusting exposure statusandbetacoefficientfor interaction ≥ TannerB2inGDMcasesandcontrols n ≥ = 4studies),breastdevelopment( TannerPH2inGDMandcontrols A Subramanianandothers Outcome metrics ≥ TannerPH2 ≥ TannerPH2 ≥ ≥ TannerB2 TannerPH2 ≥ TannerB2

n

= 4),peakheightvelocity( ≥

B2 and pubertaltiming Maternal gestationaldiabetes

BMI BMI HR, adjusted: HR: crude:1.09(0.71,1.70);adjusted:1.24(0.79,1.94) PH5:crude: PH4: crude: PH3: crude: PH2: crude: Mean difference(months): Mean Age(years):PH2:11.3; HR adjusted:1.04(0.92,1.17) OR, adjusted:1.51(0.90,2.55); GDM: 99(44.8%);Controls:133(56.1%); PHV (cm/year):GDM:8.88;No8.04; β Age atPHV(years):GDM:10.85;No11.12 BMI BMI BMI BMI HR adjusted: HR: crude:1.01(0.65,1.57);adjusted:0.85(0.54,1.35) B5: crude: B4: crude: B3: crude: B2: crude: Mean difference(months): Mean age(years):B2:9.9;B3:11.6;B4:13.0;B5:15.7 HR adjusted:1.06(0.95,1.18) Estimate withadditionaladjustmentforBMIshown OR adjusted:1.99(1.18,3.34); GDM: 141(59.2%);controls:169(66.0%) BMI BMI coefficientand PH3: 12.5;PH4:13.4;PH5:15.3 coefficient: 0.10; PHV betweenexposedandtheunexposed) shows overlappingconfidenceintervalsofageat remains butstatisticallyNS) in primarystudy’sfigure(directionofeffect < < ≥ ≥ < < ≥ ≥ 25andGDM:1.06(0.48,2.36); 25andnoGDM:Referencecategory; 25#GDM:0.93(0.47,1.85) 25#NoGDM:1.18(0.88,1.57); 25#GDM:1.22(0.54,2.74); 25#NoGDM:Referencecategory; 25andGDM:2.97(1.52,5.83) 25andnoGDM:1.19(0.90,1.56); − − − − − 4.3; adjusted: 2.1; adjusted: 3.8; adjusted: 7.3; adjusted: − − − 7.8; adjusted: 2.6; adjusted: 3.1; adjusted: 5.4; adjusted: n = 1),menarche( Downloaded fromBioscientifica.com at09/28/202106:22:29AM P -value notreported(butfigure P < Estimates

0.001 https://eje.bioscientifica.com − − − − − 1.8 ( 0.5 ( 1.9 ( 4.6 (-10.1,1.0); − − − 6.0 (

1.6 ( 2.2 ( 4.8 ( 184 P P n − − − = 0.01 = 0.12 − 7.9, 4.3) 3.2, 2.4) 5.0, 1.2) − − − = 2)andother :1 10.8, 4.8, 1.6); 4.4, 0); 7.7, − − 2.0); 1.2); ( β Continued

57 via freeaccess ) European Journal of Endocrinology https://eje.bioscientifica.com to mothers with GDM compared to mothers without earlier onsetofmenarche by2.5monthsingirls born these findings,Lauridsen (adjusted RR:1.47(95%CI: 1.01,2.16)).Inkeepingwith significantly higherriskof earliermenarche ( born tomotherswithpregnancyhyperglycemiahad a ethnicity and family income ( age of12–13yearsafteradjustingforbirthdecade, ≥ earlier ( gestational ordiabeteshadnoincreasedrisk of et al. at menarche buttheevidenceisinconsistent.D’Aloisio Maternal GDMseemedtobeassociatedwithearlierage Menarche velocity thangirlsborntomotherswithoutGDM( with GDMhada10%higherethnicity-adjustedheight accelerated failuretimemodel,daughtersborntomothers ( confidence intervals in girls born to mothers without GDM, with overlapping years ingirlsborntomotherswithGDMand11.12 velocity (PHV)andageatPHV(APHV).APHVwas10.85 reflected by growth parameters including peak height maternal GDMandpubertaltiminginthedaughtersas Hockett Age atpeakheightvelocity ( Other pubertaloutcomes ( ( Menarche Outcome/study Table 2 AH, axillaryhair;B,breastdevelopment;HR,hazardratio;NS,notsignificant;OR,oddsPH,pubicPHV,peakheightvelocity;RR,riskratio. 15 years) in comparison to an arbitrary defined reference 15 years)incomparisontoanarbitrary Clinical Study 31 31 26 ( ) ) ) 25 ≤ ) found that girls born to mothers without pre- 10 and11years)orlaterageatmenarche (14and t al. et (Continued). ( 27 Crude andadjusted(formaternalageatmenarche, Crude andadjusted(formaternalageatmenarche, Mean ageatmenarcheindaughtersofmothers RR(95% CI)ofearlierorlatermenarcheinmothers ) examined the association between ) examinedtheassociationbetween of axillaryhairandacne monthly differenceinage(95%CI)atdevelopment cohabitation, parityandmaternalBMI)mean maternal ageatbirth,socioeconomicstatus, monthly differenceinage(95%CI)atmenarche cohabitation, parityandmaternalBMI)mean maternal ageatbirth,socioeconomicstatus, without diabetes birth decadeandrace/ethnicity childhood familyincome,interactionbetween after adjustmentforbirthdecade,race/ethnicity, with GDMcomparedtomotherswithout Table 2 t al. et Table 2 ( ). Using a log-logistic ). Usingalog-logistic A Subramanianandothers 30 Outcome metrics ) reportasignificant ). By contrast, girls ≤ 10 years) Table 2 ). with pubarche in their sons ( Three studiesevaluatedmaternalGDManditsassociation Pubic hairdevelopment(p and genitaldevelopmentareshownin among boysindicatedbyageatspermarche, pubarche between maternalGDMandpubertalonsetexclusively studiesreviewingtheassociation Results oftheprimary diabetes andpubertaltiminginboys Association betweenmaternalgestational CI: diabetes (adjustedmeanmonthlydifference: not includedintheanalysis fortransitionintostagesPH2 to predict age at transition into stages PH2–4. GDM was inclusion ofcovariatesbased onstatisticalsignificance 1.3)) ( PH4: − without GDM(adjustedmeanmonthlydifference for PH2: mothers withGDMcomparedtoboysborn to earlierageatpublichairstagesamongboysborn to 0.92, 3.28))( after adjustmentforage(adjustedOR:1.74(95%CI: GDM comparedtothosebornmotherswithout tanner stage ( and pubertaltiming Maternal gestationaldiabetes 26 1.4 (95%CI:

) reported 74% increase in the odds of having reached −

4.9, 0))( − Table 3

0.8 (95%CI: Acne: crude: AH: crude: Mean difference(months): Mean difference(months):crude: Mean age(years):13.0 ≥ 14 years:0.77(0.48,1.25); 12–13 years:referencecategory; 11 years:0.99(0.63,1.54); ≤ RR adjusted: 15years:0.98(0.60,1.60) 10years:0.98(0.53,1.84); adjusted: Table 3 ). Monteilh Table 2 ≥ − PH2 amongboysborntomotherswith 5.3, 2.4);PH3: − ). Lauridsen ). − − 4.4; adjusted: − 2.5 ( 3.4, 1.6);PH5: 3.8; adjusted: Downloaded fromBioscientifica.com at09/28/202106:22:29AM et al. − ubarche) 4.9, 0.0) Estimates ( 33 31 − et al. , 1.3 (95%CI: − ) performedastep-wise 34 3.6 ( − 2.6 ( , ( 184 − 30 35 1.7 (95%CI: − Table 3 7.3, 0.1) :1 − − ) reportedtrends ). Grunnet 4.1; 6.8, 1.6)

. − − 2.5 (95% 4.6, 1.9); − t al. et 58 4.7, via freeaccess

European Journal of Endocrinology Pubic hairdevelopment/pubarche Outcome/study spermearche ( pubic hairdevelopment( Table 3 ( ( Genital Development ( Testicular development ( ( ( Clinical Study 31 27 27 32 31 27 ) ) ) ) ) ) Evidence summary:TherelationshipbetweenmaternalGDMandpubertaldevelopmentintheirsonsidentifiedby n

= 1) andotherpubertalchanges( Crude andadjusted(formaternalageatmenarche, Mean ageatTannerstageG2,G3,G4,G5 Age adjustedOR(95%CI)of n Age adjustedOR(95%CI)oftesticular n Median ageattransition(95%CI)to Multistage modelling: Crude andadjusted(formaternalageat Mean ageatTannerstagePH2,PH3,PH4, Age adjustedOR(95%CI)of n (%)of (%)oftesticularvolume (%)of stage G2,G3,G4,G5 monthly differenceinage(95%CI)atTanner cohabitation, parityandmaternalBMI)mean maternal ageatbirth,socioeconomicstatus, in sonsofmotherswithoutdiabetes cases andcontrols volume cases andcontrols stage PH3 stage PH1, Tanner stagePH2,PH3,PH4,PH5 mean monthlydifferenceinage(95%CI)at status, cohabitation,parityandmaternalBMI) menarche, maternalageatbirth,socioeconomic PH5 insonsofmotherswithoutdiabetes and controls n = 3studies),testiculardevelopment( ≥ ≥ TannerstageG2inGDM TannerstagePH2inGDMcases ≥ 4 mL > Tanner stagePH2, A Subramanianandothers Outcome metrics ≥ 4 mLinGDM ≥ ≥ n TannerstageG2 TannerstagePH2

= 1). >

Tanner > Tanner

n

=

2), genitaldevelopment(

and pubertaltiming Maternal gestationaldiabetes

PH PH PH crude: PH4 crude: PH3 crude: PH2 crude: Mean difference(months): Mean age(years):PH2:11.3;PH3:12.7;PH4:13.5; Estimate withadditionaladjustmentforBMIshown OR adjusted:1.74(0.92,3.28); GDM: 50(24.3%);Controls:60(29.6%) G5: crude:2.2;adjusted:2.6( G4: crude: G3: crude:1.1;adjusted:1.4( G2: crude: Mean difference(months): Mean age(years):G2:10.9;G3:12.5;G4:13.6;G5:15.5 Estimate withadditionaladjustmentforBMIshown OR Adjusted:1.24(0.72,2.14); GDM: 63(32.6%);No66(37.5%) Estimate withadditionaladjustmentforBMIshown OR, adjusted:0.77(0.42–1.41); GDM: 143(74.5%);No156(85.7%) PH Median ageatPH Median ageatPH In themodelwithoffspringheightandweightatage8, Median ageatPH Median ageatPH restricted combinedmodellevel insignificance attheunivariateanalysisor multivariate modellevelduetostatistical PH5: 14.7 remains andstillstatisticallyNS) in primarystudy’sfigure(directionofeffect remains andstillstatisticallyNS) in primarystudy’sfigure(Directionofeffect remains andstillstatisticallyNS) in primarystudy’sfigure(directionofeffect restricted combinedmodellevel insignificance attheunivariateanalysisor multivariate modellevelduetostatistical (years): 12.8(12.6–13.0); (years): 12.6(12.4–12.7); > > > 1: GDMwasnotacovariateinthecombined 2:InthemodelwithoffspringBMIatage8, 3:GDMwasnotacovariateinthecombined − − − − − − 2.6; adjusted: 0.2; adjusted:0.5( 0.4; adjusted:0.0( 1.7; adjusted: 1.9; adjusted: 1.9; adjusted: n

= Downloaded fromBioscientifica.com at09/28/202106:22:29AM > > > > 2), peakheightvelocity( 2insonsofGDMmothers 2(years):13.0(12.8–13.1) 2amongsonsofGDMmothers 2(years):12.8(12.7–12.8) Estimates https://eje.bioscientifica.com − P P − − − 1.7 (

0.8 ( 1.3 ( 1.4 ( = = 0.03 − − 0.05 P P 2.2, 7.4) − 1.9, 4.9); − P 184 − 2.5, 3.5); 3.8, 3.8); = 0.09 = 0.45 = 0.40 − − − 4.7, 1.3) 3.4, 1.6); 4.6, 1.9); 5.3, 2.4); :1 ( n Continued

= 1), 59 via freeaccess ) European Journal of Endocrinology ( PHV andageat Outcome/study stage genitaldevelopment;TannerPH,pubichair;VB,voicebreak. AH, axillaryhair;AV,adultvoice;HR,hazardratio;NS,notsignificant;OR,oddsPHV,peakheightvelocity;RR,riskTannerstageG, ( Other pubertaloutcomes ( Spermarche https://eje.bioscientifica.com Table 3 ( GDM andtheageatonset of malegenital development Two studiesconsideredthe associationbetweenmaternal Genital developmentandtesticular volume of transitiontoPH313.0(95%CI:12.8,13.1). CI: 12.6,13.0)comparedtotheentirecohort’s medianage to PH3forboysbornmotherswithGDMwas12.8(95% anthropometrics insteadofBMI,medianagetransition CI: 12.7,12.8).Inthemodelwithheightandweight compared totheentirecohort’s medianageof12.8(95% (95% CI: 12.4, 12.7) for boys born to mothers with GDM PH3 ( showed 2-monthadvancementintheageattransitionto the model with BMI, boys born to GDM exposed mothers anthropometrics measuresseparatelyrecordedatage8.In along witheitheroffspringBMIorheightandweight transition to stage PH3, GDM was included as a predictor selection stage ofthe analysis. In themodel predicting and PH4duetostatisticalinsignificanceatthepredictor 26 Clinical Study 31 31 28 , 30 ) ) ) Table 3 ). Grunnet (Continued). ). MedianageoftransitiontoPH3was12.6 Crude andadjusted(formaternalageatmenarche, Mean ageatVB,AV,AH,acneinsonsofmothers Crude andadjusted(formaternalageatmenarche, Mean ageatspermarcheinsonsofmotherswithout PHV amongexposedandunexposedgirlsboys Age atPHVstratifiedbyexposurestatusand et al. development ofAHandacne monthly differenceinage(95%CI)atVB,AV, cohabitation, parityandmaternalBMI)mean maternal ageatbirth,socioeconomicstatus, without diabetes monthly differenceinage(95%CI)atspermarche cohabitation, parityandmaternalBMI)mean maternal ageatbirth,socioeconomicstatus, diabetes after adjustingforchild’srace/ethnicity and betacoefficientforexposuretoGDMinutero adjusting forchild’srace/ethnicity coefficient forexposuretoGDMinuteroafter ( 26 ) reportedgenitalstage A Subramanianandothers Outcome metrics ≥ G2 in β

and pubertaltiming Maternal gestationaldiabetes ( mothers withoutGDMafter adjustingforrace/ethnicity born tomotherswithGDM comparedtoboysborn Further, theyreporteda4%increased PHVamongboys years, respectively, withoverlappingconfidence intervals. to motherswithandwithoutGDMas12.6812.92 Hockett Age atpeakheightvelocity − − (adjusted meanmonthlydifferenceinG2: between maternalGDMandtheageatgenitalstages2–5 ( to motherswithGDM(adjustedOR:0.77(0.42–1.41)) for (testicularvolume The samestudydidnotreportasimilardirectionofeffect age, theyreportedanORof1.24(95%CI:0.74,2.14). boys ofmotherswithoutGDM;afteradjustingfortheir 63 (32.6%)boysofmotherswhohadGDMand66(37.5%) Table 3 Table 3 2.5, 3.5);G5:2.6(95%CI:-2.2,7.4))( 3.8, 3.8);G3:1.4(95%CI: ). Lauridsen ). Mean age(years):VB:13.0;AV:15.0;AH:13.3;Acne: Mean difference(months):crude:0;adjusted:0.7 Mean age(years):13.4 β PHV (cm/year):GDM:9.65;No9.28; β Age atPHV(years):GDM:12.68;No12.92 Acne: crude:0.8;adjusted:1.8( AH: crude: AV: crude: Mean difference(months):VB:crude: et al. coefficient:0.04; coefficientand 12.2 ( PHV betweenexposedandtheunexposed) shows overlappingconfidenceintervalsofageat − − 0.8 ( 2.9, 4.3) ( 27 − 4.6, 2.8); ) reported age at PHV among boys born − − 3.2; adjusted: 4.3; adjusted: et al. P Downloaded fromBioscientifica.com at09/28/202106:22:29AM ( -value notreported(butfigure P 30 < Estimates ) didnotfindanyassociation 0.001 − 1.9, 4.9);G4:0.5(95%CI: − − 2.9 ( 2.5 ( ≥ 4mL)inboysborn − 184 − − 2.1, 5.7) 7.4, 1.8); 8.4, 3.4); Table 3 :1 − − 1.8; adjusted: 0.0 (95%CI: ). 60 via freeaccess European Journal of Endocrinology offspring, thiseffectisrather modestornotevidentinthe GDM mightberelatedtoearly pubertaltimingintheir were associatedwithmaternal GDM( parameters suchasPHVandageatinboysgirls regression, thisoutcomewasnotanalysed( significant proportionofboysproposing Tanner stage invalidation of longitudinal recording indicated by a collect informationongenitaldevelopmentbutdue to born tomotherswithGDM( and spermarche didnotappeartobeaffectedinboys with maternalGDM.Thetimingofgenitalgrowth the direction, strength and significance of association examined menarche ( development ( compared toboys. GDM-related precocityofallpubichairstagesingirls while Lauridsen GDM-related oddsofpubarche inboyscomparedtogirls Specifically, Grunnert offspring sex-specificeffectofmaternalGDMonpubarche. population. Notably, therewasdiscrepancyinthe and girlsofmotherswithGDMcomparedtothecontrol with anearlierageatonsetofpubarche inbothboys critical events,suchasmenarche and spermarche. growth parameters(suchasPHVandageatPHV) pubic hair, breast(ingirls)andpenilegrowthboys), sexualcharacteristicssuchas development ofsecondary events’ that are considered to define puberty, that is, the as GDM children exposedtomaternalhyperglycemiamanifested we noted a subtle trend towards earlier pubertal timing in offspring gender. Althoughthecurrentevidenceislimited, maternal GDMandpubertaltiming;alsostratifiedby that comprehensivelyexplorestherelationshipbetween To ourknowledge,thisisthefirstsystematicreview Discussion difference: 0.7( anyassociation(adjustedmeanmonthly did notobserve maternal GDMandageatfirstejaculation.Thestudy Lauridsen Spermarche Clinical Study Four studiesthatexaminedtheonsetofbreast The pointestimatesinallthestudiesareconsistent We haveincludedstudiesthatreport‘maturational Although the present evidence suggests that maternal in utero t al. et 26 − . ( 2.9, 4.3))( t al. et , 30 28 ) studied the association between et al. , ( 25 29 30 ( , , ) reportamorepronounced Table 3 26 30 30 ) suggest more pronounced ) showedvariationsin ) and two studies that 26 A Subramanianandothers ). , 30 27 ). Onestudydid ). 31 ). Growth develops asaconsequence ofadrenalandrogenaction inboys,however, itislikelythat pubichair to distinguishifpubarche iscausedbyadrenalortesticular gonadarche frequentlyoverlap,itisclinicallynotpossible strictly independentofgonadarche. Asadrenarche and currently notwellunderstood,butrelatedandinfact as ( hair,development ofpubic(andaxillary) aneventknown production inlatechildhoodcontributestothe important tonotethattheriseofadrenalandrogen assessed bythestudiesanalysedinthisreview. Itis the mostconsistentprecocitiesofallpubertyparameters signal forpubertyinitiation( of offspringobesityasleptinisregardedapermissive ( plasma leptinlevelshavebeendocumentedinGDM which largelycorrelateswithbodyfatcontent.Higher confounded thisassociation.Thesameappliestoleptin, mother-offspring homeenvironment( such as phthalates, pesticides and bisphenol A inthe exogenous exposuretoendocrine-disruptingchemicals BMI on offspring pubertal timing. Furthermore, an is difficulttodissecttheeffectsofGDMandpre-pregnancy of GDM ( 35 between pre-pregnancyBMIandtimingofpuberty( adjustment foroffspringBMIz-score. between maternalGDMandageatPHVisattenuatedby analysis byHockett and pre-adolescenceBMI.Thisissupportedbythe pubertal timingcouldbemediatedbyoffspringadiposity the associationbetweenmaternalGDMandoffspring maintenance of pubertalmaturational events ( timing andprincipaldeterminantsfortheinitiation ‘over-nutrition’ can beconsideredpredictors of pubertal maternal GDMandoffspringadiposity( complex interplaybetweenGDMandpuberty. full rangeofpubertal‘maturationalevents’,suggestinga such asbirthweight(bothhigherandlower)( factors adjusted for in various studies, several other factors age at menarche. In addition to the already explored the offspring and the genetic influence of earlier maternal intrauterine effectofhyperglycemiaonpubertaltimingin it is plausible that a synergistic effect exists between the future risk of GDM has been established ( U-shaped associationbetweenageatmenarche and and pubertaltiming Maternal gestationaldiabetes 42 ). Highpre-pregnancyBMIisanestablishedriskfactor ) andmaycontributetogestationalprogramming Several studieshavesuggestedanegativeassociation Trends towardsearlierpubarche isprobablyone of Previous studieshavesuggestedarelationshipbetween 36 ); however, considering the available studies it 44 , 45 et al. ). Adrenarche isaphenomenon Downloaded fromBioscientifica.com at09/28/202106:22:29AM ( 27 43 ), inwhichtheassociation ). https://eje.bioscientifica.com 184 40 32 :1 , ). Adiposityand 41 37 ) couldhave ). Therefore, 33 ), hence, 38 , 61 39 34 via freeaccess ), , European Journal of Endocrinology https://eje.bioscientifica.com screening ( differ widelybycountry, fromnoroutinetouniversal diagnostic criteriaandtheapproach totestingforGDM GDM andpubertaltiming of children.Lastly, boththe in accurately discerning the association between maternal nature of the included studies were potential limitations and informativecensoringembeddedintheobservational agreement tohaveitrecorded( association betweenTanner stageofchildren andtheir bias the effect estimates asprevious studies report an did not agree to report their Tanner stage, which could years. Also,therewasahighpercentage ofchildrenwho longitudinal studies, ranging between 6 months and 1.5 stages oranthropometricsvariedacrosstheincluded ofTannerspanned betweensubsequentobservations attempt tostatisticallypooltheresults.Theinterval across allofthestudies,preventinganymeaningful these pairsofstudies. suggesting apossibleoverlapoftheparticipantsbetween their cohortsfromthesamedatabases( or significance of effectestimates. Two pairs ofderived betweenthesamplesizeandmagnitude was observed studies. However, itshouldbenotedthatnocorrelation was thewidevariationinsamplesizesofincluded interpreted inthecontextofitslimitations.Onethem excluded inoneofthestudies( affect pubertal timing, however, were only systematically producing tumours or hypothalamic abnormalities, can underlying sinisterpathologies,suchassexsteroid- due toinvasiveness,logisticsandcostimplications.Rare 52 peripheral causes for advancement in pubertal timing ( in objectificationas wellasdifferentiation ofcentral and overnight LH sampling as an outcome measure would aid axis via LHRH stimulation testing or pituitary–gonadal ( Tanner stagingfrequentlyoccurswhenbeingself-reported differences( observer to assesspubertalmilestones( Tanner staging is an unequivocally accepted clinical tool studies. setting but evenmore so basedon observational accurately isdifficult, bothintheindividualclinical particular abnormalglucosemetabolism( premature adrenarche havemetabolicdysfunction,in there issomeevidencesuggestingthatchildrenwith regarded asbenignvariantofnormal‘puberty’,however, in girls.Premature adrenarche has beentraditionally 50 Clinical Study ), albeitdifficulttoperforminlargerstudypopulations ). Assessmentoftheactivationhypothalamic– The summary measureswerewidelyheterogeneous The summary The findingsofthepresentreviewshouldbe To assess the dynamics of pubertal development 54 ). Routinescreeninghasbeen recommended 48 , 49 ) andover/underestimationof 29 47 A Subramanianandothers 53 ). ), butpronetointer- ). Therefore, interval ). Therefore,interval 26 46 , ). 28 , 29 , 30 51 ), , Future research isneeded tounderstandthebiological and recordingofwiderangeconfoundersatbaseline. ideally with standardized approaches in diagnosing GDM large-scale prospective cohort studiesshouldbeconducted, association betweenmaternalGDMandpubertaltiming, outcome measures. in thereportedassociationswithoffspring’s pubertal practices overtimecontributetoalargerheterogeneity that thosedifferencestogetherwithachangeofscreening different diagnosticcriteria( GDM wasdiagnosedbetween1991and2006basedon ( been observed recent years,ashifttowardsmilderGDMphenotypeshas a trendtotestanddiagnosemorecomprehensivelyin Since screening practices have changed over time with University ofBirmingham,forherinput intooursearchstrategy. The authorswould like tothankSusanBayliss,information specialistatthe Acknowledgement manuscript forpublication. preparation, review, or approval of the manuscript; decision to submit the the study; collection, management, analysis,and interpretation of the data; Care UK.Thefunders ofthestudy had no role in the: design and conduct of not necessarilythoseoftheNIHRorDepartmentHealthandSocial (Grant BRC-1215-20009). The viewsexpressedarethoseoftheauthorsand Birmingham NHS Foundation Trust and the University of Birmingham (NIHR) Birmingham BiomedicalResearch CentreattheUniversityHospitals Fellow. W A receives support from the National Institute for Health Research Innovation (UKRI)/Health Data Research(HDR) UK Innovation Clinical (Investigator GrantWT209492/Z/17/Z, and to WA).KNisaUKResearch Grant for Clinical Lecturers SGL020/1013, to J I) and the Wellcome Trust This work was supported by the Academy of Medical Sciences (Starter Funding author. the review or editorialprocessforthis paper, on which she is listed as an Wiebke Arlt istheEditor-in-Chief of EJE. Wiebke Arlt wasnot involved in Declaration ofinterest E​JE-20-0296 This islinkedtotheonline version ofthepaperat Supplementary materials on metabolichealth. continuum ofendocrine disturbance and adverseeffects to limit the progression of a potential transgenerational can helpintheidentificationofpotentialinterventions link betweenthematernal–fetalendocrinesystem.This outcomes (HAPO)studywerepublishedin2008( results from the hyperglycaemia and adverse pregnancy by theDiabetesinPregnancyStudyGroups(IADPSG)after and pubertaltiming Maternal gestationaldiabetes In ordertostrengthentheevidencebasefor . 56 ). Inthestudiesincludedinthisreview, Downloaded fromBioscientifica.com at09/28/202106:22:29AM Table 1 184 ), anditispossible https​://doi.org/10.1530/ :1 62 55 via freeaccess ). European Journal of Endocrinology References 12 17 16 15 14 13 11 10 8 7 6 2 1 9 5 4 3 Clinical Study Brickman W, Catalano P, Clayton PE, Deerochanawong C, Hunt S &Hellwig JP. Maternalobesity, gestationaldiabetes,and Hockett CW, Bedrick E, Zeitler P, Crume TL,Daniels SR&Dabelea D. Kubo A, Kushi LH,Laurent CA,Greenspan LC,Quesenberry CP Day FR, Elks CE, Murray A, Ong KK & Perry JRB. Puberty timing Day FR, Elks CE,Murray A,Ong KK&Perry JRB. Copeland W, Shanahan L,Miller S,Costello EJ,Angold A Mendle J, Turkheimer E Detrimentalpsychological &Emery RE. Tanner JM. Trend towardsearliermenarche inLondon,Olso, Patton GC &Viner R. Pubertaltransitionsinhealth. Stang A. CriticalevaluationoftheNewcastle-Ottawascalefor Behboudi-Gandevani S, Amiri M,BidhendiYarandi R &Ramezani Feig DS, Hwee J,Shah BR,Booth GL,Bierman AS&Lipscombe LL. Busch AS, Højgaard B,Hagen CP&Teilmann G. Obesityisassociated Marshall WA &Tanner JM. Variations inpatternofpubertalchanges Marshall WA &Tanner JM. Variations inthepatternofpubertal Sorensen K, Mouritsen A,Aksglaede L,Hagen CP, Mogensen SS& 1) A30. outcome follow-upstudy(HAPOFUS). of glucosemetabolism-hyperglycemia andadversepregnancy Tam WH Hamilton J, Lashley PM,Lawrence JM, Lebenthal Y, McCance DR, doi.org/10.1016/S1751-4851(16)30194-5) early-onset puberty. 2016 earlier pubertaltimingintheoffspring:EPOCHstudy. Exposure togestationaldiabetesmellitus(GDM)isassociatedwith pubertal onsetindaughters. & Ferrara A.Maternalpregravidobesityacceleratesthetimingof doi.org/10.1007/s10654-010-9491-z) health outcomesinmenandwomen:theUKBiobankStudy associated withdiabetes,cardiovasculardiseaseandalsodiverse ajp.2010.09081190) of Psychiatry women: aprospectivepopulation-basedstudy. & Maughan B.Outcomesofearlypubertaltiminginyoung dr.2006.11.001) Developmental Review outcomes associatedwithearlypubertaltiminginadolescentgirls. doi.org/10.1136/adc.44.235.291) Copenhagen, theNetherlandsandHungary. 1130–1139. analyses. assessment ofthequalitynonrandomizedstudiesinmeta- Briggs, 2014. Joanna BriggsInstituteReviewers’Manual2014Edition 019-0406-1) and MetabolicSyndrome on itsprevalence:asystematicreviewandmeta-analysis. Tehrani F. Theimpactofdiagnosticcriteriaforgestationaldiabetes dc13-2717) 2010. outcomes: alarge,population-basedstudyinOntario,Canada,1996– Trends inincidenceofdiabetespregnancyandseriousperinatal clinem/dgz222) and Metabolism with earlierpubertalonsetinboys. Scientific Reports in girls. (https://doi.org/10.1136/adc.45.239.13) changes inboys. Paediatrics evaluation anddiagnosisofprecociouspuberty. Juul A. Recentseculartrendsinpubertaltiming:implicationsfor (https://doi.org/10.1038/243095a0) 65 Diabetes Care (https://doi.org/10.2337/db18-116-OR) Archives ofDiseaseinChildhood 4-. (http​s;//doi.org/10.1016/j.jpeds.20 ​18.10.053) A42-A. et al. European Journal ofEpidemiology European Journal 2012 2010 (https://doi.org/10.1016/S0140-6736(07)60366-3) Gestationaldiabetes(GDM)andchildhood disorders 2020 2015 77 Archives ofDiseaseinChildhood 167 137–145. 2014 Nursing forWomen’s Health 105 2007 5 1218–1225. 2019 11208.(https://doi.org/10.1038/srep11208) 37 e1667–e1672. 27 1590–1596.(https://doi.org/10.2337/ Diabetes 11 (https://doi.org/10.1159/000336325) 151–171. 11. (https://doi.org/10.1176/appi. Journal ofClinicalEndocrinology Journal (https://doi.org/10.1186/s13098- 2015 A Subramanianandothers 1969 Diabetes (https://doi.org/10.1016/j. (https://doi.org/10.1210/ 2010 64 44 Nature (Supplement1)A427. 2016 American Journal American Journal 25 2018 291–303. 1970 ResearchHormone in 603–605. 1973 . InstituteJoanna Lancet 20 67 45 354. (Supplement 13–23. Diabetology 243 (https:// Diabetes 2007 (https:// . (https:// 95–96. 369

and pubertaltiming Maternal gestationaldiabetes 23 22 21 20 19 18 31 30 29 28 27 25 24 26 Grunnet LG, Hansen S, Hjort L, Madsen CM, Kampmann FB, Grunnet LG, Hansen S,Hjort L,Madsen CM,Kampmann FB, Hockett CW, Harrall KK,Moore BF, Starling AP, Bellatorre A, Tertti K, Toppari J, Virtanen HE, Sadov S&Ronnemaa T. Metformin Ibanez L, Castell C,Tresserras R &Potau N.Increasedprevalence Persson I, Ahlsson F, Ewald U,Tuvemo T, Qingyuan M,vonRosen D Page KA, Romero A,Buchanan TA &Xiang AH.Gestational Li S, Zhu Y, Yeung E, Chavarro JE,Yuan C, Field AE,Missmer SA, Monteilh C, Kieszak S,Flanders WD, Maisonet M,Rubin C, Lauridsen LLB, Arendt LH,Ernst A,Brix N,Parner ET, Olsen J Kubo A, Deardorff J,Laurent CA,Ferrara A,Greenspan LC, Kubo A, Ferrara A,Laurent CA,Windham GC, Greenspan LC, Hockett CW, Bedrick EJ,Zeitler P, Crume TL,Daniels S&Dabelea D. D’Aloisio AA, DeRoo LA,Baird DD,Weinberg CR &Sandler DP. Davis JN, Gunderson EP, Gyllenhammer LE&Goran MI.Impactof Sauder KA, Perng W, Scherzinger A,Garg K,Ringham BM (https://doi.org/10.1900/RDS.2016.13.59) with gestationaldiabetes. treatment doesnotaffecttesticularsizeinoffspringborntomothers j.1365-2265.1999.00778.x) Clinical Endocrinology ofprecociouspubarche.first-degree relativesofgirlswithahistory of type2diabetesmellitusandimpairedglucosetolerancein 747–755. of longtermdiseases. in boysandgirls:implicationsforinterpretationoflinkwithrisk & Proos L.Influenceofperinatalfactorsontheonsetpuberty jpeds.2013.11.063) ofPediatrics Journal diabetes mellitus,maternalobesity, andadiposityinoffspring. dyx151) Epidemiology mellitus: asex-specificassociation. andadulthoodinrelationtogestationaldiabetes Mills JL, Hu FB&Zhang C.Offspringriskofobesityinchildhood, Holmes AK, Heron J,Golding J,McGeehin MA &Marcus M. Timing org/10.1016/j.fertnstert.2018.03.014) cohort study. of pubertaldevelopmentindaughters andsons:anationwide & Ramlau-Hansen CH.Maternaldiabetes mellitusandtiming kwy040) Epidemiology in adolescentgirls:apopulation-basedstudy. obesity andpregnancyhyperglycemiatimingofpubertyonset &Kushi LH. Associations Betweenmaternal Quesenberry CP 2016 timing ofpubarche indaughters. between maternalpregravidobesityandgestationaldiabetesthe &Kushi LH.Associations Deardorff J, Hiatt RA,Quesenberry CP jpeds.2018.10.053) ofPediatrics Journal timing andfasterpubertalgrowthintheoffspring:EPOCHstudy. Exposure todiabetesinuteroisassociatedwithearlierpubertal 2017 a clinicalstudywithintheDanishnationalbirthcohort. in adolescentoffspringofwomenwithgestationaldiabetesmellitus: et al. Thuesen ACB, Granstromi C,Strom M,Maslova E,Frikke-Schmidt R Prenatal andinfantexposuresageatmenarche. 741–745. metabolic profilesinLatinooffspring. gestational diabetesmellitusonpubertalchangesinadiposityand 019-04981-z) Diabetologia the ExploringPerinatalOutcomesamongChildren(EPOCH)study. Persistent effectsofinuteroovernutritiononoffspringadiposity: 2013 Adiposity, dysmetabolictraits,andearlieronsetoffemalepuberty 40 184 24 1746–1755. 277–284. 7–14. (https://doi.org/10.1093/oxfordjournals.aje.a010077) (https://doi.org/10.1016/j.jpeds.2012.10.001) 2019 2017 2018 Fertility andSterility Fertility (https://doi.org/10.1093/aje/kww006) 62 46 187 (https://doi.org/10.1097/EDE.0b013e31828062b7) 2014 2019 (https://doi.org/10.2337/dc17-0514) 2017–2024. 1999 1533–1541. American Journal ofEpidemiology American Journal 1362–1369. 164 206 Review ofDiabeticStudies Downloaded fromBioscientifica.com at09/28/202106:22:29AM 51 807–810. 105–112. 395–401. 2018 (https://doi.org/10.1007/s00125- American Journal ofEpidemiology American Journal (https://doi.org/10.1093/ije/ International Journal of Journal International (https://doi.org/10.1093/aje/ https://eje.bioscientifica.com Journal ofPediatrics Journal 110 (https://doi.org/10.1016/j. (https://doi.org/10.1016/j. (https://doi.org/10.1046/ 35–44. 184 American Journal of American Journal :1 2016 (https://doi. Epidemiology 1999 Diabetes Care 13 2013 et al. 59 150 ‐

65. 162 63

via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com

44 43 42 41 40 39 38 37 36 35 34 33 32 Clinical Study Idkowiak J, Lavery GG, Dhir V,Idkowiak J, Lavery GG, Barrett TG,Stewart PM, Krone N Elias CF. Leptinactioninpubertaldevelopment:recentadvancesand Kautzky-Willer A, Pacini G,Tura A, Bieglmayer C, Schneider B, Fisher MM &Eugster EA.Whatisinourenvironmentthateffects Macaluso M &Ho SM. Ehrlich S, Lambers D,Baccarelli A,Khoury J, Wang Y, Dinse GE&Rogan WJ.Birthweight,earlyweightgainand Deng X, Li WY, Luo Y, Liu SD,Wen Y &Liu Q.Association Ong KK,Hughes IA,Acerini CL&Dunger DB.The Petry CJ, Torloni MR, Betrán AP, Horta BL, Nakamura MU,Atallah AN, Brix N, Ernst A,Lauridsen LLB,Arah OA,Nohr EA,Olsen J, Brix N, Ernst A,Lauridsen LLB,Parner ET, Arah OA,Olsen J, Li WY, Liu Q,Deng X,Chen YW, Association Liu SD&Story M. Logan KM, Gale C,Hyde MJ,Santhakumaran S&Modi N. & Arlt W. Premature adrenarche: novellessonsfromearlyonset 23 unanswered questions. org/10.1007/s001250051595) gestational diabetes. Ludvik B, Prager R&Waldhäusl W. Increasedplasmaleptinin org/10.1016/j.reprotox.2013.03.012) puberty? (https://doi.org/10.1055/s-0036-1586500) mellitus. Endocrine disruptors:apotentialriskfactorforgestationaldiabetes 101–109. pubertal maturation:alongitudinalstudy. ijerph14111377) and PublicHealth and meta-analysis. between smallfetusesandpubertytiming:asystematicreview 853–859. diabetes ismediatedbyinsulinresistance. association betweenageatmenarche andlaterriskofgestational 789X.2008.00541.x) Obesity Reviews diabetes: asystematicreviewoftheliteraturewithmeta-analysis. Moron AF &Valente O. PrepregnancyBMIandtheriskofgestational 1684–1694. cohort study. and timingofpubertyinsonsdaughters:apopulation-based Henriksen TB &Ramlau-Hansen CH.Maternalpre-pregnancyobesity 338. in relationtopubertaltimingthechildren. mass index,smokinginpregnancy, andalcoholintakeinpregnancy Henriksen TB &Ramlau-Hansen CH.Maternalpre-pregnancybody Health analysis. between obesityandpubertytiming:asystematicreviewmeta- archdischild-2015-309750) Neonatal Edition and meta-analysis. Diabetes inpregnancyandinfantadiposity:systematicreview 3016.2010.01168.x) Epidemiology Britishcohort. enrolled inacontemporary of maturationandpredictorsTanner stagetransitionsinboys 9–15. (https://doi.org/10.1186/s12887-019-1715-0) 2017 International Journal ofEnvironmental Research Journal International andPublic American Journal ofPerinatology American Journal (https://doi.org/10.1016/j.tem.2011.09.002) Reproductive Toxicology (https://doi.org/10.1007/s00592-018-1162-7) (https://doi.org/10.1111/j.2047-6310.2011.00022.x) (https://doi.org/10.1093/ije/dyz125) 2011 14 International Journal ofEpidemiology Journal International 1266. 2009 2017 2017 25 International Journal ofEnvironmental Research Journal International Archives ofDiseaseinChildhood.Fetaland Diabetologia 75–87. 10 (https://doi.org/10.3390/ijerph14101266) 102 14 Trends inEndocrinologyandMetabolism 194–203. 1377. F65–F72. (https://doi.org/10.1111/j.1365- 2014 (https://doi.org/10.3390/ 2001 (https://doi.org/10.1111/j.1467- (https://doi.org/10.1136/ 44 A Subramanianandothers 44 2016 7–14. 164–172. Acta Diabetologica Pediatric Obesity Paediatric andPerinatal 33 BMC Pediatrics (https://doi. 2019 1313–1318. (https://doi. 48

2012

2018 2019 2012 7

55 19

Accepted 8October2020 Revised versionreceived17September 2020 Received 30March2020

and pubertaltiming Maternal gestationaldiabetes 49 48 47 46 45 56 55 54 53 52 50 51 Chavarro JE, Watkins DJ, Afeiche MC,Zhang Z,Sánchez BN, Rosenfield RL, Bordini B& Yu C. Comparisonofdetectionnormal Carlsen E, Andersen AG,Buchreitz L,Jorgensen N,Magnus O, Slora EJ, Bocian AB,Herman-Giddens ME,Harris DL,Pedlow SE, Mendle J, Beltz AM,Carter R&Dorn LD.Understandingpuberty Liimatta J, Utriainen P, Laitinen T, Voutilainen R &Jaaskelainen J. Auchus RJ &Rainey WE.Adrenarche –physiology, and biochemistry Koivunen S, Kajantie E,Torkki A, Bloigu A,Gissler M,Pouta A& HAPO StudyCooperativeResearch Group,Metzger BE,Lowe LP, Li-zhen L, Yun X, Xiao-Dong Z,Shu-bin H,Zi-lian W, Adrian Baird J, Walker I, Smith C& Inskip H. Kaplowitz P, Bloch C&SectiononEndocrinology, American Cantonwine D, Mercado-García A, Blank-Goldenberg C,Meeker JD, j.1365-2605.2000.00240.x) ofAndrology Journal examination includingestimationoftesticularsize. variationintheresultsofclinicalandrological Inter-observer 2017 against physicianassessmentsandhormonelevels. Téllez-Rojo MM Matulevicuus V, Nermoen I,Petersen JH,Punab M,Suominen J 291–299. PROS. of tannerstagingandorchidometer usewithboys:astudyfrom Dowshen SA &Wasserman RC. Assessinginter-raterreliability(IRR) jora.12371) of Research onAdolescence and itsmeasurement:ideasforresearch inanewgeneration. 3 ofprematureadrenarche.history Cardiometabolic riskprofileamongyoungadultfemaleswitha org/10.1046/j.1365-2265.2003.01858.x) human disease. (https://doi.org/10.1530/EJE-11-0223) excess. org/10.1530/EJE-15-0294) ofEndocrinology European Journal of theshiftfromriskfactor-basedtocomprehensivescreening. Vääräsmäki M. Thechangingfaceofgestationaldiabetes:the effect (https://doi.org/10.1056/NEJMoa0707943) outcomes. McCance DR, Hod M Dyer AR, Trimble ER, Chaovarindr U, Coustan DR,Hadden DR, bmjopen-2018-023014) review. and diagnosisofgestationaldiabetesmellitus:systematic Sandra D &Bin L.Evaluationofguidelinesonthescreening of Southampton,2017. Longitudinal Studies and inCohort StatusandAgeofOnsetPuberty Pubertal Determining org/10.1542/peds.2015-3732) signs ofearlypuberty. Academy ofPediatrics.Evaluationandreferralchildrenwith 2012 hormone agonisttest. puberty inboysbyahormonalsleeptestandgonadotropin-releasing 1771–1783. 186 97 Journal ofPediatricEndocrinologyand Metabolism Journal BMJ Open 4596–4604. 172.e3–178.e3. (https://doi.org/10.1515/jpem.2009.22.4.291) New England Journal ofMedicine New EnglandJournal (https://doi.org/10.1210/js.2019-00193) et al. Clinical Endocrinology 2019 European Journal ofEndocrinology European Journal . MRCLifecourseEpidemiologyUnit,University 2000 Validity ofself-assessedsexualmaturation (https://doi.org/10.1210/jc.2012-2722) et al. Journal ofClinicalEndocrinologyandMetabolism Journal Pediatrics 9 e023014. 2019 (https://doi.org/10.1016/j.jpeds.2017.03.050) 23 Hyperglycemiaandadversepregnancy Downloaded fromBioscientifica.com at09/28/202106:22:29AM 248–253. 29 2016 2015 Journal oftheEndocrineSociety Journal 82–95. (https://doi.org/10.1136/ 2004 137 173 Review ofMethodsfor (https://doi.org/10.1046/ (https://doi.org/10.1111/ e20153732. 2008 623–632. 184 60 288–296. :1 358 2011 Journal ofPediatrics Journal International International 1991–2002. (https://doi. 2009 (https://doi. 165 (https://doi. 189–207. 22 Journal Journal

2019 et al. 64 via freeaccess