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International Journal of GYNECOLOGY & OBSTETRICS by Diabetesasia.org

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International Journal of GYNECOLOGY & OBSTETRICS by Diabetesasia.org

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  1. Volume 131 Supplement 3 October 2015 ISSN 0020-7292 The International Federation of Gynecology and Obstetrics (FIGO) Initiative on Gestational Diabetes Mellitus: A Pragmatic Guide for Diagnosis, Management, and Care Publication of this Supplement was supported by funding from an unrestricted educational grant provided by Novo Nordisk. The International Federation of Gynecology and Obstetrics (FIGO) Initiative on Gestational Diabetes Mellitus: A Pragmatic Guide for Diagnosis, Management, and Care Ofcial publication of FIGO The International Federation of Gynecology and Obstetrics

  2. International Journal of GYNECOLOGY & OBSTETRICS Volume 131, Supplement 1 (2015) Volume131,Supplement3(2015) Amsterdam • Boston • London • New York • Oxford • Paris • Philadelphia • San Diego • St. Louis

  3. International Federation of Gynecology and Obstetrics (FIGO) Officers President: S. Arulkumaran (UK) E.C. Morales (Mexico) C.N. Purandare (India) G. Serour (Egypt) W. Holzgreve (Germany) G.C. Di Renzo (Italy) Vice-President: President-Elect: Past-President: Honorary Treasurer: Honorary Secretary: FIGO Chief Executive H. Rushwan (Sudan/UK) Executive Board Malaysia Paraguay South Africa Spain Taiwan Uruguay United Kingdom United States of America J.N. Martin A.A. Yahya A. Acosta B.D. Goolab J. Laílla Vicens T.-H. Su J.G. Allonso Tellechea T. Falconer Denmark Egypt Ethiopia Finland France Germany Japan Lebanon A.T. Pedersen N.A. Darwish Y.G. Ferede S. Grénman B. Carbonne W. Jonat T. Kimura F. El-Kak Argentina Australia & New Zealand C. Tippett Belgium Bolivia Brazil Canada Chile Colombia N.C. Garello F. Debiève C. Fuchtner N.R. de Melo J. Blake H. Munoz J.D. Villegas Echeverri International Editions and Collaborations IJGO India Editor-in-Chief: Editorial Office: E-mail: Dr Rohit V. Bhatt (rohit.v.bhatt@gmail.com) Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India ijgoindia@jaypeebrothers.com IJGO China Editor-in-Chief: E-mail: Dr Zhenyu Zhang Department of Ob/Gyn Chaoyang Hospital No. 8 Baijiazhung Rd Chaoyang District Beijing, 100020 China zhenyuzhang2000@yahoo.com The Secretariat of FIGO is at FIGO House, Suite 3, Waterloo Court, 10 Theed Street, London, SE1 8ST UK. Tel: +44 20 7928-1166 Fax: +44 20 7928-7099 E-mail: figo@figo.org Website: www.figo.org All enquiries concerning FIGO may be sent to the Honorary Secretary at that address. For information about FIGO:

  4. International Journal of GYNECOLOGY & OBSTETRICS Editor: R.M. Adanu (Ghana) Editor Emeritus: T.R.B. Johnson (USA) J. Sciarra (USA) Associate Editor: W. Holzgreve (Germany) P. Serafini (Brazil) J. Fortney (USA) Managing Editor: C. Addington (UK) Deputy Managing Editor: A. Cantor (UK) Associate Editors Ethical and Legal Issues in Reproductive Health: R. Cook (Canada) B. Dickens (Canada) Enabling Technologies: M. Hammoud (USA) FIGO Staging of Gynecologic Cancer: L. Denny (South Africa) Contemporary Issues in Women’s Health: V. Boama (Qatar) V. Guinto (Philippines) C. Sosa (Uruguay) Statistical Consultant: A. Vahratian (USA) Editorial Office: FIGO Secretariat, FIGO House Suite 3 - Waterloo Court, 10 Theed Street, London, SE1 8ST, UK Tel: +44 20 7928 1166 Fax: +44 20 7928 7099 E-mail: ijgo@figo.org

  5. The InternationalFederationofGynecologyandObstetrics (FIGO) InitiativeonGestationalDiabetesMellitus:APragmatic GuideforDiagnosis, Management, andCare MosheHod,AnilKapur,DavidA.Sacks,EranHadar, MukeshAgarwal,Gian CarloDi Renzo, Luis Cabero Roura,HaroldDavid McIntyre, Jessica L. Morris,Hema Divakar PublicationofthisSupplementwassupportedbyfundingfrom anunrestricted educationalgrantprovidedbyNovoNordisk.

  6. Contents The InternationalFederationofGynecology andObstetrics(FIGO) InitiativeonGestationalDiabetes Mellitus: APragmaticGuideforDiagnosis, Management, and Care Authors andcontributors Abbreviations 1. Executivesummary 2. Thetarget audienceoftheFIGO Initiativeongestationaldiabetesmellitus 3. Quality assessmentofevidence andgradingofstrengthofrecommendations 4. Gestationaldiabetesmellitus: Background,definition,epidemiology,pathophysiology 5. Diagnosinggestationaldiabetesmellitus 6. Glucosemeasurement: Technicalconsiderationsinlaboratory andpoint-of-caretesting 7. Managementofhyperglycemia duringpregnancy 8. Postpartummanagement 9. Preconceptioncare 10. Researchpriorities 11. Appendices Appendix1. Current approachestoGDM diagnosisinselectedcountries Appendix2.GestationalDiabetesFormulasfor Cost-Effectiveness: GeDiForCE Appendix3. Researchprioritiesingestationaldiabetes

  7. International JournalofGynecology andObstetrics131S3(2015)S173–S211 Contents lists available at ScienceDirect International JournalofGynecology andObstetrics journal homepage: www.elsevier.com/locate/ijgo The InternationalFederationofGynecology andObstetrics(FIGO) Initiativeongestationaldiabetesmellitus: Apragmaticguidefor diagnosis,management, andcare# MosheHoda,AnilKapurb,DavidA.Sacksc,EranHadard,e, MukeshAgarwalf,Gian CarloDi Renzog, Luis Cabero Roura h,HaroldDavid McIntyrei, Jessica L. Morrisj,*,Hema Divakark a Division of Maternal Fetal Medicine, Rabin Medical Center, Tel Aviv University, Petah Tikva, Israel b World Diabetes Foundation, Gentofte, Denmark c Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA d Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, Israel e Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel f Department of Pathology, UAE University, Al Ain, United Arab Emirates g Centre of Perinatal and Reproductive Medicine, Department of Obstetrics and Gynecology, University of Perugia, Perugia, Italy h Maternal Fetal Medicine Unit, Vall d’Hebron University Hospital, Barcelona, Spain i University of Queensland Mater Clinical School, Brisbane, Australia j International Federation of Gynecology and Obstetrics, London, UK k Divakars Specialty Hospital, Bangalore, India Contributors Acknowledgments In additiontothe authors,thefollowingpeopleprovided importantcontributionsduringthecreationofthedocument. Thanksgotointernationalexperts: TaoDuan,Huixia Yang, AndreVanAssche,UmbertoSimeoni,Tahir Mahmood,Biodun Olagbuji,EugeneSobngwi, MaiconFalavigna, Rodolfo Martinez, CarlosOrtega,Susana Salzberg, JorgeAlvariñas,Gloria Lopez Steward,Silvia Lapertosa, RobertoEstrade, Cristina Faingold, Silvia García,ArgyroSyngelaki,Stephen Colagiuri,YoelToledano, MarkHanson, andBlamiDao.Specialthanks,forFIGOguidance andcoordination,gotoPresidentSabaratnamArulkumaran, PresidentElect CNPurandare, ChiefExecutiveHamid Rushwan, and ChairoftheSMNH Committee,WilliamStones. Thefollowingexternalgroupsevaluatedthedocument and supportitscontents: EuropeanBoard and CollegeofObstetrics andGynaecology(EBCOG),TheSocietyofObstetricians and Gynaecologistsof Canada (SOGC), ChineseSocietyofPerinatal Medicine,DiabeticPregnancyStudyGroup(DPSG),African FederationofObstetrics andGynaecology(AFOG),SouthAsian FederationofObstetrics andGynecology(SAFOG),Australian DiabetesinPregnancySociety(ADIPS), InternationalAssociation ofDiabetesinPregnancyStudyGroups(IADPSG),European AssociationofPerinatal Medicine(EAPM),DiabetesinPregnancy StudyGroupof India (DIPSI), andtheDiabetesinPregnancyStudy GroupofLatinAmerica. In additiontotheFIGOExecutiveBoard, allrelevantFIGO Committees andWorkingGroupscontributed to andsupportedthedocument. Thisprojectwasfundedby anunrestrictededucationalgrant fromNovoNordisk. Conflictofinterest The authorshavenoconflictsofinteresttodeclare. WomenqueueforgestationaldiabetesservicesinBarranquilla, Colombia. Photographby JesperWestleyfortheWorldDiabetesFoundation. #ThisdocumentwasendorsedbytheFIGOExecutiveBoard atits annual meetingheldon May30−31,2015,in Melbourne,Australia * Corresponding author atFIGOHouse,Suite3,Waterloo Court,10TheedStreet, London,SE18ST.Tel.: +44207 9281166 E-mail address: Jessica@figo.org(J.L. Morris). 0020-7292/© 2015 InternationalFederationofGynecology andObstetrics.PublishedbyElsevier IrelandLtd.Allrightsreserved.

  8. S174 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 Listofabbreviations/acronyms ACOG ADA BMI CGM DIP FPG GCT GDM GI HbA1c IADPSG IDF IGT IOM LGA NICE NPH OAD OGTT PCOS POC SGA SMBG T2DM American CollegeofObstetrics andGynecology AmericanDiabetesAssociation Bodymassindex Continuousglucosemonitoring Diabetesmellitusinpregnancy Fastingplasma glucose Glucosechallengetest Gestationaldiabetesmellitus Glycemicindex Glycosylatedhemoglobin(hemoglobinA1c) InternationalAssociationofDiabetesinPregnancyStudyGroups InternationalDiabetesFederation Impairedglucosetolerance Instituteof Medicine Largeforgestational age National InstituteforHealth and CareExcellence NeutralprotamineHagedorninsulin Oral antidiabetic agents Oralglucosetolerancetest Polycysticovariansyndrome Pointofcare Smallforgestational age Self-monitoringofbloodglucose Type2diabetesmellitus

  9. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S175 1.Executivesummary Hyperglycemia isoneofthemostcommonmedicalconditions womenencounterduringpregnancy.The InternationalDiabetes Federation(IDF)estimatesthatoneinsixlivebirths(16.8%) areto womenwithsomeformofhyperglycemia inpregnancy.While16% ofthesecasesmaybeduetodiabetesinpregnancy(eitherpre- existingdiabetes—type1ortype2—which antedatespregnancy orisfirstidentifiedduringtestingintheindexpregnancy),the majority(84%)isduetogestationaldiabetesmellitus(GDM). TheoccurrenceofGDM parallelstheprevalenceofimpaired glucosetolerance(IGT),obesity, andtype2diabetesmellitus (T2DM)in a givenpopulation.Theseconditions areontherise globally. Moreover,the ageofonsetofdiabetes andpre-diabetes isdecliningwhilethe ageofchildbearingisincreasing.Thereis also anincreaseintherateofoverweight andobesewomenof reproductive age; thus,morewomenenteringpregnancyhave riskfactorsthatmakethemvulnerabletohyperglycemia during pregnancy. GDM is associatedwith a higherincidenceofmaternal morbidityincludingcesareandeliveries,shoulderdystocia,birth trauma,hypertensivedisordersofpregnancy(includingpre- eclampsia), andsubsequentdevelopmentofT2DM.Perinatal andneonatalmorbidities alsoincrease; thelatterinclude macrosomia,birthinjury,hypoglycemia,polycythemia, and hyperbilirubinemia.Long-termsequelaeinoffspringwithin uteroexposuretomaternalhyperglycemia mayincludehigher risksforobesity anddiabeteslaterinlife. Inmostpartsoflow-,lowermiddle-, anduppermiddle- incomecountries(whichcontributetoover85% ofthe annual globaldeliveries),themajorityofwomen areeithernotscreened orimproperlyscreenedfordiabetesduringpregnancy—even thoughthesecountries accountfor80% oftheglobaldiabetes burden aswell as90% of allcasesofmaternal andperinatal deaths andpoorpregnancyoutcomes. Giventheinteractionbetweenhyperglycemia andpoor pregnancyoutcomes,theroleofinuteroimprintingin increasingtheriskofdiabetes andcardiometabolicdisorders intheoffspringofmotherswithhyperglycemia inpregnancy, aswell asincreasingmaternalvulnerabilitytofuturediabetes andcardiovasculardisorders,thereneedstobe a greaterglobal focusonpreventing,screening,diagnosing, andmanaging hyperglycemia inpregnancy.TherelevanceofGDM as a priority formaternalhealth anditsimpactonthefutureburdenof noncommunicablediseasesisnolongerindoubt,buthowbest todealwiththeissueremainscontentious asthere aremany gapsinknowledgeonhowtoprevent,diagnose, andmanage GDM tooptimizecare andoutcomes.Thesemustbe addressed throughfutureresearch. The InternationalFederationofGynecology andObstetrics (FIGO)broughttogetherinternationalexpertstodevelop a documenttoframetheissues andsuggestkey actionsto address thehealthburdenposedbyGDM.FIGO’sobjective, asoutlined inthisdocument,is: (1)toraise awarenessofthelinksbetween hyperglycemia andpoormaternal andfetaloutcomes aswell as tothefuturehealthriskstomother andoffspring, anddemand a clearlydefinedglobalhealth agenda totacklethisissue; and (2)tocreate a consensusdocumentthatprovidesguidancefor testing,management, andcareofwomenwithGDM regardless ofresourcesetting andtodisseminate andencourageitsuse. Despitethechallengeoflimitedhigh-qualityevidence,the documentoutlinescurrentglobalstandardsforthetesting, management, andcareofwomenwithGDM andprovides pragmaticrecommendations,whichbecauseoftheirlevelof acceptability,feasibility, andeaseofimplementation,havethe potentialtoproducesignificantimpact.Suggestions areprovided for a varietyofdifferentregional andresourcesettingsbased ontheirfinancial,human, andinfrastructureresources, aswell asforresearchprioritiestobridgethecurrentknowledge and evidencegap. To addresstheissueofGDM,FIGOrecommendsthefollowing: Publichealthfocus:Thereshouldbegreaterinternational attentionpaidtoGDM andtothelinksbetweenmaternal health andnoncommunicablediseasesonthesustainable developmentalgoals agenda.Publichealthmeasurestoincrease awareness, access, affordability, and acceptanceofpreconception counselling, andprenatal andpostnatalservicesforwomenof reproductive agemustbeprioritized. Universaltesting:Allpregnantwomenshouldbetestedfor hyperglycemia duringpregnancyusing a one-stepprocedure andFIGOencourages allcountries anditsmember associations to adapt andpromotestrategiestoensurethis. Criteriafordiagnosis:TheWHOcriteria fordiagnosis ofdiabetesmellitusinpregnancy [1] andtheWHO andthe InternationalAssociationofDiabetesinPregnancyStudyGroups (IADPSG)criteria fordiagnosisofGDM [1,2] shouldbeused whenpossible.Keepinginmindtheresourceconstraintsin manylow-resourcecountries, alternatestrategiesdescribedin thedocumentshould alsobeconsideredequally acceptable. DiagnosisofGDM:Diagnosisshouldideallybebasedon laboratoryresultsofvenousserumorplasma samplesthat are properlycollected,transported, andtested.Thoughplasma- calibratedhandheldglucometersofferresultsthat areless accurate andprecisethanthosefromquality-controlledlabora- tories,itis acceptabletousesuchdevicesforthediagnosisof glucoseintoleranceinpregnancyinlocationswherelaboratory supportiseitherunavailableor at a siteremotetothepointof care. ManagementofGDM: Managementshouldbein accordance with availablenationalresources andinfrastructureevenifthe specificdiagnostic andtreatmentprotocols arenotsupportedby high-qualityevidence, asthisispreferabletonocare at all. Lifestylemanagement:Nutritioncounselling andphysical activityshouldbetheprimarytoolsinthemanagementofGDM. WomenwithGDM mustreceivepracticalnutritionaleducation andcounsellingthatwillempowerthemtochoosetheright quantity andqualityoffood andlevelofphysical activity.They shouldbe advisedrepeatedlyduringpregnancytocontinuethe samehealthylifestyle afterdeliverytoreducetheriskoffuture obesity,T2DM, andcardiovasculardiseases. Pharmacologicalmanagement: Iflifestylemodification alonefailsto achieveglucosecontrol,metformin,glyburide,or insulinshouldbeconsidered assafe andeffectivetreatment optionsforGDM. Postpartumfollow-upandlinkagetocare:Following a pregnancycomplicatedbyGDM,thepostpartumperiodprovides animportantplatformtoinitiatebeneficialhealthpracticesfor bothmother andchildtoreducethefutureburdenofseveral noncommunicablediseases.Obstetriciansshouldestablish linkswithfamilyphysicians,internists,pediatricians, andother healthcareproviderstosupportpostpartumfollow-upofGDM mothers andtheirchildren.Afollow-upprogramlinkedtothe child’svaccination andregularhealthcheck-upvisitsprovides anopportunityforcontinuedengagementwiththehighrisk mother−childpair. Futureresearch:Thereshouldbegreaterinternational researchcollaborationto addresstheknowledgegapsto betterunderstandthelinksbetweenmaternalhealth and noncommunicablediseases.Evidence-basedfindings are urgentlyneededtoprovidebestpracticestandardsfortesting,

  10. S176 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 References management, andcareofwomenwithGDM. Cost-effectiveness modelsmustbeusedforcountriestomakethebestchoicesfor testing andmanagementofGDM giventheirspecificburdenof disease andresources. [1] WorldHealthOrganization.Diagnosticcriteria andclassificationofhyper- glycaemia firstdetectedinpregnancy.WHO/NMH/MND/13.2.Geneva: WHO; 2013.http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_ MND_13.2_eng.pdf [2] InternationalAssociationofDiabetes andPregnancyStudyGroups ConsensusPanel, MetzgerBE,GabbeSG,PerssonB,BuchananTA, Catalano PA,et al. International associationofdiabetes andpregnancystudygroups recommendationsonthediagnosis andclassificationofhyperglycemia in pregnancy.Diabetes Care2010;33(3):676–82.

  11. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S177 2.ThetargetaudienceoftheFIGO Initiativeongestationaldiabetesmellitus Thisdocumentisdirected atmultiplestakeholderswiththe intentionofbringing attentiontohyperglycemia inpregnancy, withparticularfocusongestationaldiabetes.GDM is a hitherto less-prioritizedbutcommonmedicalcondition associated withpregnancythathasseriousconsequences.Thisdocument proposestocreate a globalframeworkfor actiontoimprovethe diagnosis andcareofwomenwithGDM. Theintendedtarget audienceincludes: Healthcareproviders:Allthosewho arequalifiedtocare forwomenwithGDM andtheiroffspring(obstetricians, diabetologists,endocrinologists,internists,pediatricians,neo- natologists andgeneralpractitioners,midwives,nurses, advance practiceclinicians,nutritionists,pharmacists,communityhealth workers,laboratorytechnicians,etc.) Healthcaredeliveryorganizationsandproviders:govern- ments,federal andstatelegislators,healthcaremanagement organizations,healthinsuranceorganizations,international development agencies, andnongovernmentalorganizations. Professionalorganizations:international,regional, and nationalprofessionalorganizationsofobstetricians andgyne- cologists,endocrinologists,diabetologists,internists,family practitioners,pediatricians,neonatologists, andworldwide nationalorganizationsdedicatedtothecareofpregnantwomen withdiabetes.

  12. S178 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 3. Qualityassessmentofevidenceandgradingofstrengthofrecommendations In assessingthequalityofevidence andgradingofstrength ofrecommendations,thedocumentfollowstheterminology proposedbytheGradingof Recommendations,Assessment, Development andEvaluation(GRADE)WorkingGroup(http:// www.gradeworkinggroup.org/index.htm).Thissystemuses consistentlanguage andgraphicaldescriptionsforthestrength andqualityoftherecommendations andtheevidenceonwhich they arebased.Strongrecommendations arenumbered as1 and conditional(weak)recommendations arenumbered2.Forthe qualityofevidence,cross-filledcircles areused: ????denotes verylow-qualityevidence; ????lowquality; ????moderate quality; and????highqualityofevidence(Tables1 and2). Theoverallqualityofevidencewas assessedforeachofthe recommendations andexpressedusingfourlevelsofquality: verylow,low,moderate, andhigh(Table2). Considerations forqualityofevidenceincludeprimarilythestudydesign and methodology.Assuch,evidencebasedonrandomizedcontrolled trialsisconsideredhigh-qualityevidence,observationalstudies providemoderateorlowqualityofevidence, and allothers are verylow.However,otherparametersmustbeconsideredwhile assessingthelevelofevidence: riskofbias,studylimitations, directness,consistencyofresults,precision,publicationbias, indirectnessofevidence, andscarcityofevidence.Therefore, a limitedrandomizedtrialisdowngraded andlevelofevidence isconsideredmoderateorlow.Theselimitationsincludeloss tofollow-up,inadequacyof allocationconcealment,or an unblindedstudywithsubjectiveoutcomessusceptibletobias. Similarly, anobservationalstudymaybeupgradedifitsupplies large andconsistentestimatesofthemagnitudeof a treatment effect. Additionally,eachrecommendationisdenotedwithits strength(strongorweak)whileconsideringthebalanceof desirable andundesirableconsequences,qualityofevidence, values andpreferences, andresourceuse(Table2).Therefore, thequalityofevidenceisonlyonepossibleconsideration forthestrengthofevidence.Thedecisionto apply a possible examinationorinterventionis alsobasedonpotentialrisk− benefit,cost, andresource allocation.Somerecommendations maybebasedonlow-qualityevidencebutstillrepresent a benefitthatoutweighstherisks andburdens, andthereforemay bestronglyrecommended. ApregnantwomanwaitsforhergestationaldiabetesscreeninginTamilNadu, India.Photographby JesperWestleyfortheWorldDiabetesFoundation. Table1 Interpretationofstrong andconditional(weak)recommendations accordingtoGRADE.a 1 = Strongrecommendationphrased as “werecommend” 2 = Conditional(weak)recommendationphrased as “wesuggest” Forpatients Nearly allpatientsinthissituationwould acceptthe recommendedcourseof action.Formaldecision aids arenot neededtohelppatientsmakedecisionsconsistentwiththeir values andpreferences. Accordingtotheguidelines,performanceoftherecommended actioncouldbeused as a qualitycriterionorperformance indicator,unlessthepatentrefuses. Therecommendationcanbe adapted aspolicyinmost situations. Mostpatientsinthissituationwould acceptthesuggestedcourseof action. Forclinicians Decision aidsmayhelppatientsmake a managementdecision consistentwiththeirvalues andpreferences. Forpolicymakers Stakeholdersneedtodiscussthesuggestion. aAdaptedwithpermissionfromSwigloet al.Acaseforclarity,consistency, andhelpfulness: state-of-the-artclinicalpracticeguidelinesinendocrinologyusing thegradingofrecommendations, assessment,development, andevaluationsystem. J ClinEndocrinol Metab.2008;93(3):666-73. CopyrightEndocrineSociety (2008). Note: Bothcaregivers andcarerecipientsneedtobeinvolvedinthedecision-makingprocessbefore adoptingrecommendations. Table2 Interpretationofqualityofevidencelevels accordingtoGRADE.a Levelofevidence Definition High ???? Moderate ???? Low ???? Verylow ???? We areveryconfidentthatthetrueeffectcorrespondstothatoftheestimatedeffect. We aremoderatelyconfidentintheestimatedeffect.Thetrueeffectisgenerallyclosetotheestimatedeffect,butitmaybeslightly different. Ourconfidenceintheestimatedeffectislimited.Thetrueeffectcouldbesubstantiallydifferentfromtheestimatedeffect. Wehaveverylittleconfidenceintheestimatedeffect.Thetrueeffectislikelytobesubstantiallydifferentfromtheestimatedeffect. aAdaptedwithpermissionfromBalshemet al.GRADEguidelines: 3. Ratingthequalityofevidence. J ClinEpidemiol.2011;64(4):401-6. CopyrightElsevier(2011).

  13. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S179 4.Gestationaldiabetesmellitus:Background, definition, epidemiology, pathophysiology 4.1. Introduction Notwithstandingitsseverity,hyperglycemia thatis already present atconception andembryogenesisincreasesthe women’svulnerability andriskofcomplications.Awoman withundiagnoseddiabetes antedatingpregnancymay also haveundiagnoseddiabeticcomplicationsincludingretinopathy andnephropathy,whichmarkedlyincreasepregnancyrisks [5].Furthermore,hyperglycemia duringthecriticalperiodof organogenesismayleadto a highriskofspontaneous abortions andcongenital anomalies.Diabetesinpregnancy,becauseof the attendantgreaterriskofhyperglycemia,may alsoresultin aberrationsinfetalgrowth andmacrosomia.Thiscanleadto additionalshort-termcomplications,forexample,obstructed labor,shoulderdystocia,neonatalhypoglycemia,orriskof neurologicaldamage. Moreover,thereis a riskofonsetor exacerbationofmicrovascularcomplications,such asretinopathy ornephropathyduringpregnancy.Forthesereasons,ensuring meticulousglucosecontrolbeforeconception andthroughout pregnancyisrecommended. The age atonsetofT2DM isdecreasingglobally andmany womenwithpreviouslyunknownT2DM maybecomepregnant, withtheirdiabetesfirstdetectedduringroutinetestingin pregnancy.Alternatively,women athighriskofdiabetesmay beunabletowithstandthemetabolicstressofpregnancy and developdiabetesforthefirsttimeduringpregnancy(Figure2). Whenthelevelofhyperglycemia firstdetectedbytesting at anytimeduringthecourseofpregnancymeetsthecriteria for diagnosisofdiabetesinthenonpregnantstate,thecondition iscalledDIP.Thosecriteria are: fastingplasma glucose(FPG) ≥7.0mmol/Lor126mg/dL, and/or2-hour 75-goralglucose tolerancetest(OGTT)value ≥11.1mmol/Lor200mg/dL,or randomplasma glucose(RPG) ≥11.1mmol/Lor200mg/dL associatedwithsigns andsymptomsofdiabetes. InDIPthe vulnerabilitytocomplicationsishighbecauseofthedegree ofhyperglycemia andtheuncertainty astowhethertheonset ofhyperglycemia waspriortopregnancyordevelopedduring earlypregnancy.Whilediabetesdiagnosedforthefirsttimein pregnancymightbetype1ortype2, a diagnosisoftype2ismore likely. Comparedwithgestationaldiabetes,DIPismorelikelyto bedetected asearly asthefirsttrimesterprovided appropriate testingisundertaken. Despitedecadesofresearch,multiplestudies, andnumerous globalconsensusconferences, aspectsofhyperglycemia in pregnancy—particularlythoserelatedtoclassification and diagnosisofGDM—remaincontroversial [1].GDM diagnosis wasoriginallylinkedto anincreasedriskofmaternaldiabetes inlaterlife.Duetoremarkable advancesinrecentyears,the metabolicprocessesthatoccurduringpregnancy andtheir effectonintrauterinefetaldevelopmenthavebeenclarified. Consequently,clinicians aremore awareoftheneedtoprecisely identify andmanagemetabolicdysfunctioninpregnancy manifestedespeciallyby aberrantglucosemetabolism.Thishas ledto anincreasedfocusonthe abilitytopredict andprevent manypotentialfetal andmaternalcomplicationsintheindex pregnancy [1]. 4.2.Classificationofhyperglycemiainpregnancyand definitionofGDM ThedefinitionofGDM isevolving.Untilrecently,the accepted definitionwas “anydegreeofglucoseintolerancewithonsetor firstrecognitionduringpregnancy” [2].Becausethisdefinition includeswomenwithpre-existingdiabeteswhowerenot identifiedpriortopregnancy andbecausethisdefinitionblursthe linebetweenmorbidities associatedwithdiabetesinpregnancy andgestationaldiabetes,renewedefforts arebeingmadeto improvethedefinition andclassificationofhyperglycemia during pregnancy.Theseefforts are alsospurredbytheincreasing prevalenceofdiabetes andGDM [3] andofgreaterprevalenceof maternal andfetalcomplicationsresultingfromdiabetesmellitus antedatingpregnancy.Therefore,hyperglycemia firstdetected at anytimeduringpregnancyshouldbeclassifiedeither asdiabetes mellitusinpregnancy(DIP)orGDM [4]. 4.3.Diabetesinpregnancy DIPmayeitherhavebeenpre-existingdiabetes(type1or type2) antedatingpregnancy,ordiabetesfirstdiagnosedduring pregnancy(Figure1). Hyperglycemia in pregnancy Gesta?onal diabetes mellitus Diabetes in pregnancy Diagnosed before the start of pregnancy Diagnosed for the first ?me during pregnancy Type 2 Type 1 Type 1 Type 2 Figure1Typesofhyperglycemia inpregnancy.

  14. S180 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 Diabetes in pregnancy Gesta?onal diabetes mellitus Pregnancy in previously known diabetes Hyperglycemia during pregnancy that is not diabetes OR Hyperglycemia diagnosed for the first ?me during pregnancy that meets WHO criterion for diabetes mellitus in the nonpregnant state Hyperglycemia diagnosed for the first ?me during pregnancy May occur any?me during pregnancy including the first trimester May occur any?me during pregnancy but most likely a?er 24 weeks Figure2Thedifferencebetweendiabetesinpregnancy andgestationaldiabetesmellitus. 4.4.Gestationaldiabetesmellitus andobesity,excessiveweightgainintheindexpregnancy,short stature,polycysticovariansyndrome(PCOS),historyofdiabetes mellitusinfirstdegreerelatives, a pasthistoryofpoorpregnancy outcome(abortion,fetalloss),macrosomia inprevious and/or indexpregnancy,GDM in a previouspregnancy,pre-eclampsia, andmultifetalpregnancy [12]. Inpractice,slightlyoverhalfof thewomenwithGDM haveoneormoreoftheseriskfactors, supportingthecontentionthatidentificationofwomenwho haveGDM requirestestingof allpregnantwomen [13–16]. Whenhyperglycemia detectedduringroutinetestingin pregnancy(generallybetween24 and28weeks)doesnotmeet thecriteria ofDIPitiscalledGDM.Diagnosticcriteria and glucosecut-offvaluesofGDM havebeenproposedby a number oforganizations andprofessionalgroups and aredescribedlater inthisdocument. Duetoitsusualdiagnosis and appearancelaterinpregnancy andlessseverehyperglycemia,GDM implies a relativelymilder formofhyperglycemia comparedwiththatofDIP,butis nonetheless associatedwith a heightenedriskofpoorpregnancy outcome andfutureriskofdiabetes andcardiovasculardisease, andmustbemanaged appropriately. 4.7.Fetalandmaternalmorbidityassociated withGDM GDM is associatedwith a higherincidenceofmaternal morbidity,includingcesareandeliveries,birthtrauma,hyper- tensivedisordersofpregnancy(includingpre-eclampsia), and subsequentdevelopmentofT2DM.Perinatal andneonatal morbidities are alsoincreased; thelatterincludemacrosomia, shoulderdystocia andotherbirthinjuries,respiratorydistress, hypoglycemia,polycythemia, andhyperbilirubinemia.Long- termsequelaeinoffspringwithinuteroexposuretomaternal hyperglycemia includehigherrisksofobesity,impairedglucose metabolism, anddiabeteslaterinlife.Table3summarizesthe implicationsofGDM forboththemother andheroffspring fromfetalthrough adultlife [17–25] andFigure3showsthe short-termfetal andneonatalcomplicationsfromintrauterine exposuretomaternalhyperglycemia. 4.5.EpidemiologyofGDM Hyperglycemia isoneofthemostcommonmedical conditions associatedwithpregnancy.TheoccurrenceofGDM parallelstheprevalenceofimpairedglucosetolerance(IGT), obesity, andT2DM in a givenpopulation,conditionsthathave risengloballyduringrecentyears [6–8]. Moreover,the ageof onsetofdiabetes andpre-diabetesisdeclining,whilethe ageof childbearingisrisinginsomecountries.Anincreasingnumberof womenofreproductive age areoverweight andobese,thusmore womenenteringpregnancy arevulnerabletohyperglycemia duringpregnancy [9,10].GlobalGDM prevalenceratesshow widevariationsduetoethnicity andethnicheterogeneity among differentpopulationstested,which arefurtherexacerbated bythedifferentscreening anddiagnosticcriteria used.GDM prevalencehasbeenreportedtovarybetween1%−28% [11], whilethe InternationalDiabetesFederation(IDF)estimatesthat oneinsixlivebirths(16.8%) aretowomenwithsomeformof hyperglycemia inpregnancy; 16% ofthesemaybeduetoDIP, whilethemajority(84%)isrelatedtoGDM [8]. 4.8.Pathophysiology Pregnancyinduceschangesinmaternalmetabolismto accommodate andnurturethegrowthofthefetusinthewomb fromconceptionuntilfulltermbirth.Eventhoughthemother eatsintermittently,thefetusmustbenourishedcontinuously. Thisis achievedbycomplexinteractionsofthefeto-placental- maternalunit,throughsecretionofhormones andmetabolic mediatorsthatcreateinsulinresistance andmodifymaternal carbohydrate,lipid, and amino acidmetabolismtoensure adequatenutrientsupplytothefetus.Theseinteractions are gearedtocreate a harmoniousbalancebetweentheneedsofthe mother,thoseofthefetus, andthemother’s abilitytoprovidefor 4.6.Riskfactors PublicationsshowthatriskfactorsforGDM includeethnicity andmaternalfactorssuch asolder age,highparity,overweight

  15. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S181 Maternal excess circula?ng glucose, lipids, amino acids Fetal substrates transfer Fetal hyperinsulinemia Fetal substrate uptake Tissue oxygen consump?on Macrosomia Lung surfactant synthesis Hypoxia Altered oxygen delivery Erythropoie?n Myocardiopathy Polycythemia S?llbirth, perinatal asphyxia Respiratory distress syndrome Hyperbilirubinemia Figure 3 Intrauterineexposuretomaternalhyperglycemia: Fetal andneonatalcomplicationsintheshortterm.Adapted andrepublishedwithpermissionfromElsevier, from: Mitanchez D,Yzydorczyk C,SiddeekB,BoubredF,Benahmed M,SimeoniU.Theoffspringofthediabeticmother--short- andlong-termimplications.BestPract Res ClinObstetGynaecol2015;29(2):256–69. Table 3 Maternal andfetalmorbidity associatedwithgestationaldiabetesmellitus. Maternalmorbidity Fetal/neonatal/childmorbidity Stillbirth Neonataldeath Nonchromosomalcongenitalmalformations Shoulderdystocia Respiratorydistresssyndrome Cardiomyopathy Neonatalhypoglycemia Neonatalpolycythemia Neonatalhyperbilirubinemia Neonatalhypocalcemia Erb’spalsy(asconsequenceofbirthinjury) Programming andimprinting; fetaloriginsofdisease: diabetes,obesity,hypertension, metabolicsyndrome Early pregnancy Spontaneous abortions Pregnancy Pre-eclampsia Gestationalhypertension Excessivefetalgrowth(macrosomia,largeforgestational age) Hydramnios Urinarytractinfections Delivery Pretermlabor Traumaticlabor Instrumentaldelivery Cesareandelivery Postoperative/postpartuminfection Postoperative/postpartumhemorrhage Thromboembolism Maternalmorbidity andmortality Hemorrhage Puerperium Failuretoinitiate and/ormaintainbreastfeeding Infection Long-term postpartum Weightretention GDM insubsequentpregnancy Futureovertdiabetes Futurecardiovasculardisease theseneeds. Inresponsetoincreasinginsulinresistance,maternal insulinsecretionincreases andeuglycemia ismaintained.Thisis achieved atthecostofhighermaternalinsulinlevel andlower thannormalnonpregnantfastingglucoselevels. Insulinresistancecontinuestoincrease aspregnancy advances andiswellestablishedbythe24thweek.Aslong asthematernal pancreascontinuestoincreaseinsulinproduction andsecretion, hyperglycemia isprevented.Whenthiscapacityisoverwhelmed byrisinginsulinresistance,maternalhyperglycemia ensues. Maternalinsulinproductioncapacityisthusputunderimmense stressduringpregnancy.Thisexplainswhywomenwithpre- existinginsulinresistance(e.g.overweight,obese,orexcessive weightgainduringpregnancy,PCOS, IGT,ormetabolicsyndrome) orthosewithlower abilitytoproduceinsulin(e.g.shortstature, stunted) aremorepronetoGDM. 4.9.Fetalimplications Growth anddevelopmentofthehumanconceptusoccurs withinthemetabolicmilieuprovidedbythemother, andthefetus

  16. S182 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 istotallydependentontransferofnutrientsfromthematernal circulationvia theplacenta.Asearly as1954,Pedersenet al. [26] demonstratedthatnewbornsofdiabeticmotherssuffered fromhypoglycemia andhypothesizedthatthiswasduetofetal hyperinsulinism as a resultofincreasedtransplacentaltransfer ofsugar.VanAssche andGepts [27] laterconfirmedthepresence ofhyperplasia oftheinsulin-producingbeta cellsininfantsof diabeticmothers andpostulatedthatthehyperplasia wasrelated tobeta-cellhyperactivity andcouldhaveconsequencesinlater life. In animalexperiments,Aerts andVanAssche [28] showed thatmodificationsintheendocrinepancreasduringintrauterine lifecausedpersistentchangesthatmanifestinlater adultlife (inthesecondgeneration).Thoughnotperceptibleunder basalconditions,thesechangesbecome apparentinsituations stressingthebeta cell activity,such aspregnancy.Pregnancy insecondgenerationratsshowedincreasednonfastingblood glucose,withno apparent adaptationofthebeta cells.This inadequate adaptationtopregnancycausedchangesinthefetal endocrinepancreasinfetusesofthethirdgeneration,thereby suggesting a transgenerationaltransmissionofrisk. Itisnowevidentthat an abnormalintrauterineenvironmenthas consequencesinlaterlifemediatedthroughepigeneticchanges. Thisphenomenonisknown asdevelopmentalprogramming.An increasingbodyofevidencesupportsthehypothesisthatthe abnormalmetabolicenvironmentofthemotherwithdiabetes mellitusmay affectcertaindevelopingfetaltissues,organs, and controlsystems,eventuallyleadingtopermanentlong-term functionalimplicationsin adultlife.Thefetaltissuesmostlikely tobe affected areneuralcells, adipocytes,musclecells, and pancreaticbeta cells.Freinkel [29] introducedtheconceptof pregnancy as a “tissuecultureexperiment,” inwhichtheplacenta andthefetusdevelopin an “incubatingmedium” totallyderived frommaternalfuels.Allthesefuelstraversetheplacenta from thematernalcompartmenteitherwith(e.g.glucose,lipids)or against(e.g. amino acids)concentrationgradients andcontribute tothefetalmilieu.Sincetheseconstituents areregulated,in part,bymaternalinsulin,disturbancesinitssupplyor action influencethenutritionalenvironmenttowhichthefetusis exposed; maternalhyperglycemia leadstofetalhyperglycemia andeventuallytofetalhyperinsulinemia. AccordingtoFreinkel’shypothesis,the abnormalmixture ofmetabolitesfromthemothergains accesstothedeveloping fetusinutero,modifyingthephenotypicexpressioninnewly formedcells,whichinturndeterminepermanent,short- and long-termeffectsintheoffspring.Dependinguponthetimingof (embryonic–fetal)exposuretothe aberrantfuelmixture,different eventsmaydevelop.Earlyinthefirsttrimester,intrauterine growthrestriction andorganmalformation,describedby Freinkel as “fuel-mediatedteratogenesis” mayoccur.During thesecondtrimester, atthetimeofbraindevelopment and differentiation,behavioral,intellectual,orpsychologicaldamage mayoccur.Duringthethirdtrimester, abnormalproliferation offetal adipocytes andmusclecells,togetherwithhyperplasia ofpancreaticbeta cells andneuroendocrinecellsmaybe responsibleforthedevelopmentofobesity,hypertension, and T2DM mellituslaterinlife. failedtodevelopinutero.Womenwithdiabetesmellitushad a markedlyhigherriskofpoorpregnancyoutcome, asdescribed earlier.Thesecomplications,togetherwiththeincreasedrateof vasculardysfunction(retinopathy andnephropathy),contributed tohighermaternalmorbidity andmortality amongpatients withdiabetesmellitus. Moreover,hyperglycemia first appearing duringpregnancywas associatedwith a highriskofdeveloping diabetes andcardiovasculardiseasesinlaterlife [30–34]. Currently,pregnantwomenwithdiabetesmellitusenjoythe benefitsofextraordinaryprogressmadein all areasofmedicine andinobstetricsinparticular.State-of-the-arttoolshavebeen developedfordiagnosis,treatment, andfollow-upofbothmother andfetus,such asfetalheartratemonitors,ultrasonography, glucoseself-monitors, andinsulinpumps.As a result,leading medicalcentersworldwidereport a majorreductioninmaternal andfetalcomplicationsofdiabeticpregnanciesreachinglevels similartothoseinnormalpregnancy. Cliniciansworkinginthese centersrecognizeunequivocallythatearlydiagnosis, adequate treatment, andclosefollow-up areessentialtodecreasethe incidenceofmostcomplicationsofdiabetesinpregnancy andto achieve a successfuloutcome. Despitethesedevelopments,themajorityofwomenin low-,lowermiddle-, anduppermiddle-resourcecountries (contributingtoover85% ofglobaldeliveries annually), arenot properlyscreenedfordiabetesduringpregnancy.Thesecountries also accountfor80% oftheglobalburdenofdiabetes aswell as 90% oftheglobalburdenofmaternal andperinataldeaths and poorpregnancyoutcomes. Maternalvulnerabilitytofuturediabetes andcardiovascular disordersisrising.Giventheinteractionbetweenhyperglycemia andpoorpregnancyoutcomes andtheroleoftheinutero environmentinincreasingriskofdiabetes andcardiometabolic disordersinoffspringofmotherswithhyperglycemia in pregnancy,thereneedstobe a greaterfocusonpreventing, screening, diagnosing, and pregnancy,globally,butparticularlyinlow-resourcecountries. managing hyperglycemia in •FIGOrecommends andsupportsthecallforgreater attention andfocusonthelinksbetweenmaternal health andnoncommunicablediseasesinthesustainable developmental agenda. References [1] McIntyreHD, MetzgerBE, CoustanDR,DyerAR,HaddenDR,Hod M,et al. Counterpoint: EstablishingconsensusinthediagnosisofGDM followingthe HAPOstudy. CurrDiab Rep2014;14(6):497. [2] Proceedingsofthe4th InternationalWorkshop-ConferenceonGestational Diabetes Mellitus. Chicago, Illinois,USA.14−16 March1997.Diabetes Care 1998;21(Suppl.2):B1–B167. [3] Greene MF.Screeningforgestationaldiabetesmellitus.NEngl J Med 1997;337(22):1625–6. [4] WorldHealthOrganization.Diagnostic Criteria and Classificationof Hyperglycaemia FirstDetectedinPregnancy.http://apps.who.int/iris/bit- stream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf.Published2013. [5] OmoriY, JovanovicL.Proposalforthereconsiderationofthedefinitionof gestationaldiabetes.Diabetes Care2005;28(10):2592–3. [6] Mendez MA, Monteiro CA,PopkinBM.Overweightexceedsunder- weight amongwomeninmostdevelopingcountries.Am J ClinNutr 2005;81(3):714–21. [7] WorldHealthOrganization.Obesity andoverweight.FactsheetN°311.http:// www.who.int/mediacentre/factsheets/fs311/en/.Updated January2015. Accessed March202014. [8] InternationalDiabetesFederation. IDFAtlas.SixthEdition.Brussels,Belgium: InternationalDiabetesFederation; 2013. [9] WorldHealthOrganization.Globalstatusreportonnoncommunicabledis- eases2010.http://www.who.int/nmh/publications/ncd_report_full_en.pdf. Published2011. [10] Matyka KA.Type2diabetesinchildhood: epidemiological andclinical aspects.Br MedBull2008;86:59−75. 4.10.Maternalimplications UntilthediscoveryofinsulinbyBanting andBestin1921,very fewwomenwithdiabetesbasedonsevereinsulindeficiency becamepregnantspontaneously, andevenfewer achieved a successfulpregnancyoutcome.Atthattime, about50% of suchwomendiedduringpregnancyfromdiabetes-related complications(mainlyketoacidosis) and about50% ofthefetuses

  17. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S183 [11] JiwaniA, MarseilleE,LohseN,DammP,Hod M,Kahn JG.Gestationaldiabetes mellitus: resultsfrom a surveyofcountryprevalence andpractices. J Matern FetalNeonatal Med2012;25(6):600–10. [12] BergerH, Crane J,FarineD,ArmsonA,DeLa RondeS,Keenan-LindsayL, et al.Screeningforgestationaldiabetesmellitus. J ObstetGynaecol Can 2002;24(11):894–912. [13] Lavin JP Jr.Screeningofhigh-risk andgeneralpopulationsforgestationaldia- betes. Clinical application andcost analysis.Diabetes1985;34: S24–S27. [14] CoustanDR,Nelson C, Carpenter MW, CarrSR, RotondoL,Widness JA. Maternal age andscreeningforgestationaldiabetes: a population-based study.ObstetGynecol1989;73(4):557–61. [15] Moses RG, Moses J,DavisWS.Gestationaldiabetes: doleanyoungcaucasian womenneedtobetested? Diabetes Care1998;21(11):1803–6. [16] NeilsenKK,De Courten M,KapurA.Theurgentneedforuniversally appli- cablesimplescreeningprocedures anddiagnosticcriteria forgestational diabetesmellitus - lessonsfromprojectsfundedbytheWorldDiabetes Foundation.GlobHealthAction2012;5: 17277. [17] Rudge MV, Calderon IM, Ramos MD,Peraçoli JC,PimA.Hypertensivedis- ordersinpregnantwomenwithdiabetesmellitus.GynecolObstet Invest 1997;44(1):11–5. [18] YogevY, XenakisEM,LangerO.The associationbetweenpreeclampsia and theseverityofgestationaldiabetes: theimpactofglycemiccontrol.Am J ObstetGynecol2004;191(5):1655–60. [19] EhrenbergHM,Durnwald CP, CatalanoP, MercerBM.Theinfluenceofobes- ity anddiabetesontheriskofcesareandelivery.Am J ObstetGynecol. 2004;191(3):969–74. [20] Peters RK,KjosSL, XiangA,BuchananTA.Long-termdiabetogeniceffect ofsinglepregnancyinwomenwithpreviousgestationaldiabetesmellitus. Lancet1996;347(8996):227–30. [21] Kim C,NewtonKM,Knopp RH.Gestationaldiabetes andtheincidenceoftype 2diabetes: a systematicreview.Diabetes Care2002;25(10):1862–8. [22] LangerO, Rodriguez DA, XenakisEM, McFarland MB,Berkus MD,Arrendondo F. Intensifiedversusconventionalmanagementofgestationaldiabetes.Am J ObstetGynecol1994;170(4):1036–46; discussion1046–7. [23] ModanlouHD,KomatsuG,DorchesterW,Freeman RK,BosuSK. Large-for-gestational-ageneonates: anthropometricreasonsforshoulder dystocia.ObstetGynecol1982;60(4):417–23. [24] McFarland MB,Trylovich CG,LangerO.Anthropometricdifferencesinmac- rosomicinfantsofdiabetic andnondiabeticmothers. J MaternFetal Med 1998;7(6):292–5. [25] WendlandEM,Torloni MR,Falavigna M,Trujillo J,Dode MA, Campos MA, et al.Gestationaldiabetes andpregnancyoutcomes--a systematicreview oftheWorldHealthOrganization(WHO) andthe InternationalAssociation ofDiabetesinPregnancyStudyGroups(IADPSG)diagnosticcriteria.BMC Pregnancy Childbirth2012;12:23. [26] Pedersen J,Bojsen-MøllerB,PoulsenH.Bloodsugarinnewborninfantsof diabeticmothers.Acta Endocrinol(Copenh)1954;15(1):33–52. [27] VanAsscheFA,GeptsW.Thecytologicalcompositionofthefoetalendo- crinepancreasinnormal andpathologicalconditions.Diabetologia 1971;7(6):434−4. [28] AertsL,VanAsscheFA. Isgestationaldiabetes an acquiredcondition? J Dev Physiol1979;1(3):219–25. [29] FreinkelN.BantingLecture1980.Ofpregnancy andprogeny.Diabetes 1980;29(12):1023–35. [30] BellamyL, Casas JP,HingoraniAD,WilliamsD.Type2diabetesmellitus aftergestationaldiabetes: a systematicreview andmeta-analysis.Lancet 2009;373(9677):1773–9. [31] Ratner RE, Christophi CA, MetzgerBE,Dabelea D,BennettPH,Pi-Sunyer X, et al.Preventionofdiabetesinwomenwith a historyofgestationaldiabe- tes: effectsofmetformin andlifestyleinterventions. J ClinEndocrinol Metab 2008;93(12):4774–9. [32] Retnakaran R.Glucosetolerancestatusinpregnancy: a windowtothefuture riskofdiabetes andcardiovasculardiseaseinyoungwomen. CurrDiabetes Rev2009;5(4):239–44. [33] Retnakaran R,ShahBR. Mildglucoseintoleranceinpregnancy and riskofcardiovasculardisease: a population-basedcohortstudy. CMAJ 2009;181(6−7):371–6. [34] Kessous R,Shoham-Vardi I,ParienteG,Sherf M,SheinerE.An association betweengestationaldiabetesmellitus andlong-termmaternalcardiovascu- larmorbidity.Heart2013;99(15):1118–21.

  18. S184 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 5.Diagnosinggestationaldiabetesmellitus 5.1.Problemsofmultiplecriteria riskfactorshaspoorsensitivityfordetectionofGDM,itseems appropriatetorecommenduniversalratherthanriskfactor- basedtesting.This approachisstronglyrecommendedbyFIGO andisparticularlyrelevanttolow-,low−middle, andmiddle- resourcecountries,where90% of allcasesofGDM arefound and ascertainmentofriskfactorsispoorowingtolowlevelsof education and awareness, andpoorrecordkeeping. Inmanyof thesecountriesthereislittlejustificationforselectivetesting, as they alsohaveethnicpopulationsconsideredtobe athighrisk [13]. In2010the IADPSGproposedscreeningof allpregnantwomen with a singlestep 75-gOGTT [8].Thispositionhassincebeen supportedbytheADA andthe IDF(2014) [14].However,there continuestobe a lackofuniformityoftestingprotocolswithin andbetweenhospitalsinthesamecity,county, andcountry [15], let aloneinternationally. Thecaseforuniversaltesting(i.e.testing allpregnantwomen) withsomebiochemicaltesthasitssupporters [16,17].However, even among advocatesofuniversaltestingthereis a lackof uniformityin approachtotestingmethodology. (1)The50-gglucosechallengetest(GCT)hasbeenthemost populartestforthispurpose.Thisispartofthetwo- step algorithm(50-gGCTfollowedbythe100-gOGTT) still advocatedbyACOG andoffered as an alternative diagnosticstrategyinthelatestADAguideline. (2)The1-step 75-gOGTTin allwomenisendorsedbythe WHO, IDF, andmanyotherorganizationsthat agreewith therecommendationsofthe IADPSG. IntheoverallcostofprovidingcaretowomenwithGDM thecostof administering a glucosetolerancetest(GTT)to all pregnantwomenislikelytobeminimaliftheinitialfastingGTT levelresultcanbeusedtodecideifthefullGTTisneeded [18,19]. Insituationswherewomenmaynotbe abletocomefortesting in a fastingstate, a singlestep 75-g2-hournonfastingtest, as usedin India,maybe applied [20,21]. TheFIGOinitiativeforGDM ismeanttoprovide a practical guidefornational associationsto adopt andpromote a uniform approachtotesting,diagnosis, andmanagementofGDM for allcountries andregionsbasedontheirfinancial,human, and infrastructureresources. Globalhealthcareorganizations andprofessionalbodieshave advocated a plethora ofdiverse algorithmsforscreening and diagnosisofGDM.Unfortunately,eventheendocrine,diabetes, andobstetric associationswithinparticularcountriesoftenused markedlydissimilarprotocols andcut-offvaluesforscreening anddiagnosisofGDM.TheserecommendationsforGDM were criticizedforlackingvalidation, astheyweredevelopedbased ontenuousdata,theresultofexpertopinions,werebiased owingtoeconomicconsiderations,orconvenience-oriented [1],therebycreatingconfusion anduncertainty amongcare providers.Oneunderlyingyetfundamentalproblem, asshown consistentlybyseveralstudiesincludingtheHyperglycemia andAdversePregnancyOutcomes(HAPO)study,isthattherisk ofpoorpregnancyoutcomes associatedwithhyperglycemia is continuouswithnoclearinflectionpoints [2–6]. Itisthereforeclearthat anysetofcriteria forthediagnosis ofGDM proposedwillneedtoevolvefrom a consensus approach,balancingrisks andbenefitsinparticularsocial, economic, andclinicalcontexts [7]. In2010, International AssociationofDiabetesinPregnancyStudyGroups(IADPSG) proposedconsensusderivedcut-offvaluesforfasting,1-hour, and2-hour 75-gOGTTthresholdvalues,definingGDM based onoddsratiothresholdsof1.75incomparisonwiththemean, formarkersofdiabeticfetopathy(LGA,excessfetal adiposity, andfetalhyperinsulinemia)inthemultinationalobservational HAPOstudy [8].Thesecriteria havebeenwidely accepted andrecently adoptedbytheWHO andtheAmericanDiabetes Association(ADA) [9,10].However,LGA andfetal adiposity are alsodependentonfactorsotherthanmaternalglucose alone.Forexample,usingthe2-hourglucosecut-offvalueof 8.5mmol/L(153mg/dL)selectedbythe IADPSGmaynotbe asefficientinidentifyingwomen at-riskforfetalovergrowth asthoseidentifiedby a 2-hourglucosevaluecorresponding tothat at a slightlyloweroddsratioof1.5comparedwiththe mean.Thelattercorrespondstotheolder,WHOcriteria 2-hour valueof 7.8mmol/L(140mg/dL). Apartfromthedifferentcut-offvalues,thelackofconsensus amongthedifferentprofessionalbodiesfor an algorithmfor screening anddiagnosisofGDM isperhaps anevenlargerproblem. Despiterepeatedpleasfor a singleprocess andcriteria [11],the idealprotocolforthediagnosisofGDM continuestobedebated. •FIGO adopts andsupportsthe IADPSG/WHO/IDFposition that allpregnantwomenshouldbetestedforhyperglycemia duringpregnancyusing a one-stepprocedure. •FIGOencourages allcountries anditsmember associations to adapt andpromotestrategiestoensureuniversal testingof allpregnantwomenforhyperglycemia during pregnancy. 5.2. Universalversusselectivetesting SelectivetestingbasedonclinicalriskfactorsforGDM evolvedfromtheviewthatinpopulationswith a lowriskof GDM,subjecting allpregnantwomento a laboratorytestwas notconsideredcost-effective.Traditionally,theriskfactor-based approachwaspopularinEurope.Someofthe aforementioned riskfactorsusedwere: age andBMI (atvaryingthresholds); ethnicity; polyhydramnios; macrosomia (currentorpastpreg- nancy); GDM inthepast; unexplainedstillbirth; T2DM in a first- degreerelative; andPCOS.TheTorontoTri-hospitalGestational DiabetesProject [12] developed a scoringsystembasedon maternal age,BMI, andrace.However,variationsinriskfactors haveresultedindifferent approaches,generallywithpoor sensitivity andspecificity.Themajorproblemofriskfactor- basedscreeningisitshighdemandonthehealthcareproviders withmorecomplexprotocolsfortesting,whichresultinlower compliancebybothpatients andhealthcareproviders. Giventhehighratesofhyperglycemia inpregnancyin mostpopulations andthatselectivetestingbasedonknown 5.3.Diagnosticcriteria 5.3.1. Diabetes in pregnancy Thediagnosisofdiabetesinpregnancy asdefinedbythe WHOcriteria [9] shouldbebasedononeormoreofthefollowing resultsrecordedbyroutinetesting at anytimeduringthecourse ofpregnancy: (1)Fastingplasma glucose ≥7.0mmol/L(126mg/dL); and/or (2)2-hourplasma glucose ≥11.1mmol/L(200mg/dL) following a 75-goralglucoseload; or (3) Randomplasma glucose ≥11.1mmol/L(200mg/dL)inthe presenceofdiabetessymptoms.

  19. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S185 Additionally,theADA alsorecommendsHbA1c(≥6.5%), confirmedbyrepeattesting, assufficienttodiagnosediabetesin thepresenceor absenceofpregnancy [10]. 5.3.4. Risk models If a countrycannot afford anylaboratorytesting,riskmodels are available. Manyhavebeen advocatedfromstudiesin Canada [12],Denmark [30],Thailand [31], andVietnam [32].Theyuse a permutationofvariousclinicalriskfactors,including age,BMI, familyhistoryofdiabetesmellitus,GDM inpastpregnancies, LGAnewborns, andglycosuria.Theirwidespread applicabilityin largesettingsinlow-resourcecountrieshasnotbeentested and isnotrecommendedbyFIGO. Eightlow- andmiddle-resourcecountries—India, China, Nigeria,Pakistan, Indonesia,Bangladesh,Brazil, and Mexico— accountfor55% ofthegloballivebirths(70millionlivebirths annually) aswell as55% oftheglobalburdenofdiabetes(209.5 million) andshouldbekeytargetsfor anyfocusedstrategyon addressingtheglobalburdenofGDM pregnancies. Afewexamplesofcurrent approachestodiagnosesofGDM indifferentpartsoftheworld,particularlyfromthelarge burdencountrieswheresystematictestingforGDM isbeing implemented, areprovidedinAppendix1.Theseexampleshave inspiredFIGO’spragmaticoptions andguidanceforresource- constrainedsituations. 5.3.2. Gestational diabetes mellitus Aspertherecommendationofthe IADPSG(2010) andWHO (2013),thediagnosisofGDM ismadeusing a single-step 75-g OGTTwhenoneormoreofthefollowingresults arerecorded duringroutinetestingspecificallybetweenweeks24 and28of pregnancyor at anyothertimeduringthecourseofpregnancy: (1)Fastingplasma glucose5.1−6.9mmol/L(92−125mg/dL); (2) 1-hourpost 75-goralglucoseload ≥10mmol/L(180mg/dL); (3)2-hourpost 75-goralglucoseload8.5–11.0mmol/L (153−199mg/dL) •FIGO adoptstheWHO(2013)criteria fordiagnosisof diabetesmellitusinpregnancy. •FIGO adoptstheWHO(2013) and IADPSG(2010)criteria fordiagnosisofgestationaldiabetesmellitus.Giventhe resourceconstraintsinmanylow-resourcecountries, otherstrategiesdescribedherein areconsideredequally acceptable. 5.4.Cost-effectivenessofGDMtestingandmanagement FIGOsuggestsvariousoptionsfordiagnosisofGDM basedon resourcesettingsinTable4. Apartfrominfrastructure andcapacityconstraints,imple- mentationofuniversaltestingforGDM ischallengedbylackof goodevidencetosupportcost-effectivenessinboththehigh- and low-resourcecountries.Tofacilitatedecision-making,countries needreliableinformationonthecost andcost-effectivenessof GDM screening andtreatment.Almost allcost-effectiveness analyseshave assessedonlyshort-termcomplications [33], omittingconsiderationofreductionsinlong-termT2DM.Arecent studyfromtheUSAevaluatedthepotentialcost-effectivenessof newGDM screeningcriteria forbothtimeperiods [34].Another study,basedontheGestationalDiabetesFormulasfor Cost- EffectivenessorGeDiForCE Model [35] describedinAppendix2, showedthattheinterventions are “highlycost-effective” inboth Indian and Israelisettingswhenlong-termeffects aretakeninto account [36]. 5.3.3. Resource-based approach to diagnosis Implementationofguidelinesis a constantchallenge.The realityisthatmostlow-resourcecountries aroundtheworld areunabletoimplement a GDM detectionprogrambasedon a universal 75-gOGTTorrelyonjusthigh-riskwomenundergoing a 75-gOGTT.Thesechallenges andbarriershavebeenreviewed extensively [28].The applicabilityofthe IADPSGcut-offvaluefor fastingglucosetodiagnoseGDM,especiallyinthefirsttrimester hasbeencontestedin a recentstudyfrom China [29]. Recommendationsthat arerigid andimpracticalinreal-life settings areunlikelytobeimplemented andhencemayproduce littleornoimpact.Ontheotherhand,pragmaticbutlessthan idealrecommendationsmayproducesignificantimpactowing tomorewidespreadimplementation. TheFIGOapproachisthreepronged: (1) topromote, encourage, andadvocateidealevidence-basedguidance; (2) toofferpragmaticoptionsforresource-constrained situationsbasedonlocalexperiencebackedbylessthan optimalevidence; and (3) topromoteresearchaimedat improvingtheevidencebaseinboth well-resourcedand resource-constrainedcontexts. FIGOrecommendations arebasedon availableresources at countrylevel andevidenceoflocalpractice. Countriesworldwide fallintofourresourcecategories.There are alsovariationsseen within anycountry.An affluentcountrymayhavepocketsof poorlyfundedcare andconversely, a low- ormiddle-resource countrymayhavestate-of-the artcareintheprivatesectorfor a selectedfew. High-resource countries:countriesorregionssuch as Canada, WesternEurope, Japan,SouthKorea,USA,etc. Upper middle-resource countries:countriessuch asBrazil, China, Colombia,Hungary, Malaysia, Mexico, Romania,South Africa,Turkey,etc. Low middle-resource countries:countriessuch as India, Indonesia,Pakistan,Nigeria,Egypt,Vietnam,etc. Low-resource countries:countriessuch asBangladesh,Nepal, Cambodia,Kenya,Tanzania,Uganda,Ethiopia, Congo,etc. •Allcountrieshave anobligationtoimplementthebest GDM testing andmanagementpracticestheycan. •FIGO acknowledgesthatforglobalprogresstobemade, India, China,Nigeria,Pakistan, Indonesia,Bangladesh, Brazil, and MexicomustbekeytargetsforfocusedGDM attention References [1] Agarwal MM.Evolutionofscreening anddiagnosticcriteria forGDM world- wide. In: Kim C,Ferrara A,eds.GestationalDiabetesDuring andAfter Pregnancy. Illustratededition.London: Springer-VerlagLtd; 2010:35−48. [2] HAPOStudy Cooperative ResearchGroup, MetzgerBE,LoweLP,DyerAR, TrimbleER, ChaovarindrU,et al.Hyperglycemia and adversepregnancyout- comes.NEngl J Med2008;358(19):1991–2002. [3] SacksDA,Greenspoon JS,Abu-FadilS,HenryHM,Wolde-TsadikG,Yao JF. Towarduniversalcriteria forgestationaldiabetes: the 75-gramglucosetoler- ancetestinpregnancy.Am J ObstetGynecol1995;172(2Pt1):607–14. [4] Sermer M,Naylor CD,GareDJ,KensholeAB, Ritchie JW,FarineD,et al. Impact ofincreasingcarbohydrateintoleranceonmaternal-fetaloutcomesin3637 womenwithoutgestationaldiabetes.TheTorontoTri-HospitalGestational DiabetesProject.Am J ObstetGynecol1995;173(1):146–56. [5] JensenDM,DammP,SørensenB, Mølsted-PedersenL,Westergaard JG,Klebe J,et al. Clinicalimpactofmildcarbohydrateintoleranceinpregnancy: a studyof2904nondiabeticDanishwomenwithriskfactorsforgestational diabetesmellitus.Am J ObstetGynecol2001;185(2):413–9. [6] Schmidt MI,DuncanBB, ReicheltAJ,BranchteinL, Matos MC, Costa eForti A,et al.Gestationaldiabetesmellitusdiagnosedwith a 2-h 75-goral

  20. S186 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 Table4 Optionsfordiagnosisofgestationaldiabetesmellitusbasedonresourcesettings. Strategy Setting Whototest andwhen Diagnostictest Interpretationa Grade Fullyresourcedsettings Allwomen atbooking/first trimester MeasureFPG, RBG,orHbA1ctodetect diabetesinpregnancy 1|???? 24−28weeks Ifnegative: perform 75-g2-hourOGTT Fullyresourced settingsservingethnic populations athigh riskb Allwomen atbooking/first trimester Perform 75-g2-hourOGTTtodetect diabetesinpregnancy 2|???? 24−28weeks Ifnegative: perform 75-g2-hourOGTT Anysetting(basic); particularlymedium- tolow-resource settingsservingethnic populations atrisk Allwomenbetween24 and28 weeks Perform 75-g2-hourOGTT 1|???? Alternative strategies as currently used in specified countries China: Medium- tolow- resourcesettings servingpopulations at highrisk Allwomen atbooking/first trimester MeasureFPGtodetectdiabetesin pregnancy >7.0 mmol/Lor >126 mg/dL.FPG valuesbetween5.6 and6.9 mmol/L, (100−125 mg/dL)consider asGDM [18] 2|???? 24−28weeks Ifnegative: perform 75-g2-hourOGTT Or ToreducenumberofOGTTsmeasureFPG. Onlyinwomenwithvaluesbetween 4.5 mmol/L and5.0 mmol/L(81−90 mg/dL) perform 75-g2-hourOGTT 1|???? Value >5.1 mmol/Lor >92 mg/dL diagnosticofGDM 2|???? Indiansubcontinent: Medium- tolow- resourcesettings servingrural/semi- urban/urbanethnic populations athighrisk Allwomen atbooking/first trimester Measurefastingornonfasting2-hourvalue after 75-gOGTT Readingbetween 7.8 and11.0 mmol/L or140 and199 mg/dLindicatesGDM [19,20]c 2|???? 24−28weeks Ifnegative: repeattest LatinAmerica: Medium- tolow- resourcesettings Allwomen atbooking/first trimester MeasureFPGtodetectdiabetesin pregnancy >7.0 mmol/Lor >126 mg/dL. FPGvaluesbetween5.6 and 6.9 mmol/L(100−125 mg/dL), consider asGDM 2|???? 24−28weeks Ifnegative: perform 75-g2-hourOGTT 75-g2-hourglucosevalue >7.8 mmol/Lor >140 mg/dLis diagnosticofGDMd UK: allsettings Selectedwomen atbooking/as soon aspossiblee Perform 75-g2-hourOGTT FPGof5.6 mmol/Lor aboveor2-hour plasma glucoseof 7.8 mmol/Lor aboveisdiagnosticg 24−28weeks Ifnegative: perform 75-g2-hourOGTT Offered alsotootherwomenwith riskfactorsforGDMf Abbreviations: FPG,fastingplasma glucose; RBG,randombloodglucose; HbA1c,glycosylatedhemoglobin; GDM,gestationaldiabetesmellitus; OGTT,oral glucosetolerancetest. a Interpret asper IADPSG/WHO/IDFguidelinesunlessstatedotherwise. bAsians are athighriskofhyperglycemia duringpregnancy,whichmayincludepreviouslyundiagnoseddiabetes.Theproportionofpreviouslyundiagnosed diabetesishighestintheyoungest agegroupparticularly amongwomen [22]. InAsianpopulations,FPG andHbA1chavemuchlowersensitivityto diagnosediabetesthanthe2-hourpost-glucosevalue [23]. In a studyof11Asiancohorts,morethanhalfofthediabeticsubjectshadisolatedpostchallenge hyperglycemia [24]. In a studyin China,46.6% oftheparticipantswithundiagnoseddiabetes(44.1% ofthemen and50.2% ofthewomen)hadisolated increased2-hourplasma glucoselevels after anOGTT [25].Therefore,theneedtoidentifypostprandialhyperglycemia seemsespeciallyrelevantinAsian populations. cDiabetesinPregnancyStudyGroupin India (DIPSI)Guideline [8]. dLatinAmerica StudyGroup [26]. eWomenwith a pasthistoryofGDM orwomenwithglycosuria of2+ or aboveononeoccasionorof1+ or aboveontwoormoreoccasions(asdetectedby reagentstriptestingduringroutineprenatalcareinthecurrentpregnancy). fBMI above30(calculated asweightinkilogramsdividedbyheightinmeterssquared),previousmacrosomicbabyweighing4.5kgor above,familyhistoryof diabetes,first-degreerelativewithdiabetes,minorityethnicfamilyoriginwith a highprevalenceofdiabetes. gNational InstituteforHealth and CareExcellence(NICE) [27].

  21. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S187 glucosetolerancetest and adversepregnancyoutcomes.Diabetes Care 2001;24(7):1151–5. [7] McIntyreHD, ColagiuriS, RoglicG,Hod M.DiagnosisofGDM: a suggested consensus.BestPract Res ClinObstetGynaecol2015;29(2):194–205. [8] InternationalAssociationofDiabetes andPregnancyStudyGroups ConsensusPanel, MetzgerBE,GabbeSG,PerssonB,BuchananTA, Catalano PA,et al. International associationofdiabetes andpregnancystudygroups recommendationsonthediagnosis andclassificationofhyperglycemia in pregnancy.Diabetes Care2010;33(3):676–82. [9] WorldHealthOrganization.Diagnostic Criteria and Classificationof Hyperglycaemia FirstDetectedinPregnancy.http://apps.who.int/iris/bit- stream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf.Published2013. [10] AmericanDiabetesAssociation.Standardsof Medical CareinDiabetes -Classification andDiagnosisofDiabetes.Diabetes Care2015;38(Suppl 1);S8–S16. [11] SacksDB.Diagnosisofgestationaldiabetesmellitus: itistimeforinterna- tionalconsensus. Clin Chem2014;60(1):141–3. [12] Naylor CD,Sermer M, ChenE,FarineD.Selectivescreeningforgestationaldia- betesmellitus.TorontoTrihospitalGestationalDiabetesProject Investigators. NEngl J Med1997;337(22):1591–6. [13] NeilsenKK,De Courten M,KapurA.Theurgentneedforuniversally appli- cablesimplescreeningprocedures anddiagnosticcriteria forgestational diabetesmellitus - lessonsfromprojectsfundedbytheWorldDiabetes Foundation.GlobHealthAction2012;5:17277. [14] ColagiuriS,Falavigna M,Agarwal MM,Boulvain M, CoetzeeE,Hod M,et al.StrategiesforimplementingtheWHOdiagnosticcriteria andclassifica- tionofhyperglycaemia firstdetectedinpregnancy.Diabetes Res ClinPract 2014;103(3):364–72. [15] JiwaniA, MarseilleE,LohseN,DammP,Hod M,Kahn JG.Gestationaldiabetes mellitus: resultsfrom a surveyofcountryprevalence andpractices. J Matern FetalNeonatal Med2012;25(6):600–10. [16] Moses RG, CheungNW.Point: Universalscreeningforgestationaldiabetes mellitus.Diabetes Care2009;32(7):1349–51. [17] SimmonsD, Moses RG.Gestationaldiabetesmellitus: toscreenornotto screen?: Isthisreallystill a question? Diabetes Care2013;36(10):2877–8. [18] Agarwal MM,DhattGS,ShahSM.Gestationaldiabetesmellitus: simplifying theinternational associationofdiabetes andpregnancydiagnostic algorithm usingfastingplasma glucose.Diabetes Care2010;33(9):2018–20. [19] ZhuWW,FanL,YangHX,KongLY,SuSP,WangZL,et al.Fastingplasma glu- cose at24-28weekstoscreenforgestationaldiabetesmellitus: newevi- dencefrom China.Diabetes Care.2013 Jul;36(7):2038−40. [20] Anjalakshi C,BalajiV,Balaji MS,Ashalata S,SuganthiS,ArthiT,et al.Asin- gletestproceduretodiagnosegestationaldiabetesmellitus.Acta Diabetol 2009;46(1):51–4. [21] SeshiahV,BalajiV,ShahSN, JoshiS,DasAK,SahayBK,et al.Diagnosisof gestationaldiabetesmellitusinthecommunity. J AssocPhysicians India 2012;60:15–7. [22] Qiao Q,HuG,Tuomilehto J,NakagamiT,BalkauB,Borch-JohnsenK,et al.Age- andsex-specificprevalenceofdiabetes andimpairedglucoseregulationin11 Asiancohorts.Diabetes Care2003;26(6):1770–80. [23] RamachandranA, Ma RC,Snehalatha C.DiabetesinAsia.Lancet 2010;375(9712):408–18. [24] Qiao Q,NakagamiT,Tuomilehto J,Borch-JohnsenK,BalkauB, IwamotoY,et al. Comparisonofthefasting andthe2-hglucosecriteria fordiabetesindif- ferentAsiancohorts.Diabetologia 2000;43(12):1470–5. [25] YangW,Lu J,Weng J, Jia W, JiL, Xiao J,et al.Prevalenceofdiabetes among men andwomenin China.NEngl J Med2010;362(12):1090–101. [26] deSereday MS,Damiano MM,González CD,BennettPH.Diagnosticcrite- ria forgestationaldiabetesinrelationtopregnancyoutcome. J Diabetes Complications2003;17(3):115–9. [27] National InstituteforHealth and CareExcellence(NICE).Diabetesinpreg- nancy: managementofdiabetes anditscomplicationsfrompreconceptionto thepostnatalperiod.NICEguidelines [NG3].http://www.nice.org.uk/guid- ance/ng3/evidence.PublishedFebruary2015. [28] NielsenKK,KapurA,DammP,de Courten M,Bygbjerg IC.Fromscreeningto postpartumfollow-up - thedeterminants andbarriersforgestationaldiabe- tesmellitus(GDM)services, a systematicreview.BMC Pregnancy Childbirth 2014;14:41. [29] ZhuWW,YangHX,WeiYM,Yan J,WangZL,Li XL,et al.Evaluationofthe valueoffastingplasma glucoseinthefirstprenatalvisittodiagnosegesta- tionaldiabetesmellitusin China.Diabetes Care2013;36(3):586–90. [30] JensenDM, Mølsted-PedersenL,Beck-NielsenH,Westergaard JG,OvesenP, DammP.Screeningforgestationaldiabetesmellitusby a modelbasedonrisk indicators: a prospectivestudy.Am J ObstetGynecol2003;189(5):1383–8. [31] Phaloprakarn C,TangjitgamolS, Manusirivithaya S.Ariskscoreforselective screeningforgestationaldiabetesmellitus.Eur J ObstetGynecol ReprodBiol 2009;145(1):71–5. [32] TranTS,Hirst JE,Do MA, Morris JM, JefferyHE.Earlypredictionofgestational diabetesmellitusinVietnam: clinicalimpactofcurrentlyrecommended diagnosticcriteria.Diabetes Care2013;36(3):618–24. [33] PoncetB,TouzetS, RocherL,Berland M,Orgiazzi J, Colin C. Cost-effectiveness analysisofgestationaldiabetesmellitusscreeninginFrance.Eur J Obstet Gynecol ReprodBiol2002;103(2):122–9. [34] WernerEF,Pettker CM,ZuckerwiseL, Reel M,FunaiEF,Henderson J,et al. Screeningforgestationaldiabetesmellitus: arethecriteria proposedbythe international associationoftheDiabetes andPregnancyStudyGroupscost- effective? Diabetes Care2012;35(3):529–35. [35] LohseN, MarseilleE,Kahn JG.Developmentof a modelto assessthecost- effectivenessofgestationaldiabetesmellitusscreening andlifestylechange forthepreventionoftype2diabetesmellitus. 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  22. S188 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 6.Glucosemeasurement:Technicalconsiderationsinlaboratoryand point-of-caretesting Glucoselevels aregenerallymeasuredfromserum,plasma,or wholeblood.Today,mostglucosemeasurementsinlaboratories areperformedonserumorplasma.Theglucoseconcentration inwholebloodis approximately15% lowerthantheglucose concentrationinserumorplasma.Serumorplasma mustbe refrigerated andseparatedfromthecellsquicklytoprevent substantialmetabolismofglucosebythecellularfraction.The requirementthatserumsamplesmustbe allowedtoclotbefore serumglucoseistestedsignificantlyincreasesturnaroundtime forglucoseresultscomparedwithplasma results.Thus,faster laboratoryturnaroundtimeisonereasonthatplasma has becomethegoldstandardforglucosemeasurement.However, inmostlaboratorypanels(i.e.thecomprehensivemetabolic panel),serumisthemostsuitablesamplefor allotherlaboratory testsperformed, andso a “panel” glucoseisusually a serum glucose. Ifplasma isused,therapidseparationoftheredblood cellsfromtheplasma bycentrifugationis a criticalelement, becauseitisestimatedthatplasma glucoselevels arereducedby approximately10mg/dLperhourbyconsumptionofglucosein theredbloodcell’sglycolyticpathway. Previously,sodiumfluoride(gray-toptubes)wasoftenused as an anticoagulant andpreservativeofwholeblood,particularly when analysiswasdelayed.Arecentstudyshowedthatcitrate bufferinhibitedinvitroglycolysisfarmoreeffectivelythan fluoride [1].Lately,citratebufferhasbeen advocated as a rapidly effectiveglycolysisinhibitor.Themeanglucoseconcentrationin samplesstored at37°C decreasedbyonly0.3% at2hours and 1.2% at24hourswhenbloodwasdrawnintotubescontaining citratebuffer,sodiumfluoride, andethylenediaminetetraacetic acid(EDTA).Theuseofthesebloodcollectiontubes appearsto offer a practicalsolutiontotheglycolysisproblem [2].Plasma frombloodcollectedinfluoridetubesisgenerallyunsuitablefor measuringotherlaboratoryparameters. Glucoselevels alsovarydependingonthesourceofthe bloodsampleusedfor analysis,i.e. arterial,capillary,orvenous. Thevariationis attributedtovariationinglucoseextraction bytissues,perfusion,oxygenation,pH, andtemperature.On average, arterialglucoseconcentrations atnormalpartial pressureofoxygen are5mg/dLhigherthancapillaryblood and approximately10mg/dLgreaterthanvenousconcentrations. Exceptinintensivecaresituationsplasma glucoseisnormally measuredfromvenousorcapillaryblood. Glucosemeasurements arebasedonenzymaticreactions involvingoneofthefourenzymes: glucoseoxidase(GO),glucose 1-dehydrogenase(GD),glucokinase(GK),orhexokinase(HK). Themostwidelyusedmethodsofglucose analysisusethe enzymesGO,GK,orHK.GOisthemostspecificenzymereacting onlywithD-glucose.TheGKorHKmethodisconsideredmore accuratethantheGOmethod. Forpoint-of-caredevices,GOorGD aretheclassicmethodolo- gies.GK andHK arethebasisformanycentrallaboratorymethods. Additionalvariabilityinglucosemeasurementmayoccur becauseofdifferencesindifferent assays,collection andstorage ofsamples, andqualityofreagents(storageofteststrips)etc. Point-of-carebloodglucosemeasurementisbasedon capillarywholeblood,whilelaboratory-basedmeasurements areusuallybasedonvenousplasma. only accreditedlaboratoriesshouldbe allowedtoreport any patients’results,sincethey accountformajormedicaldecisions. Theminimumqualityspecifications aredocumentedby accrediting bodiessuch asthe CollegeofAmericanPathologists(CAP) and the InternationalOrganizationforStandards(ISO)15189,etc. Duetoconstraintsofresourcesor availableexpertise,more oftenthannot,results arereportedbyunaccreditedlaboratories. However,evenlow-resourcecountriescanproduceexcellent laboratoryresults; conversely anoverabundanceofresources doesnotguaranteegoodquality.Whatisrequiredismeticulous applicationofprocedures. Itisobligatorythateverylaboratory meticulouslydocument: (1)reproducibility(precision)byrecord- inginternalqualitycontroldaily andcalculatingthe Coefficient ofVariation(CV%)monthly; and(2) accuracy(bias)bycomparing itsresultsthroughproficiencytestingorcomparingitsresults to an accreditedlaboratory.Onceminimumrequirementsof precision aremetbygoodlaboratorypractices,thebiascanbe addressed.Forplasma glucose,theimprecisionshouldbeless than2.9%,the accuracy(bias)lessthan2.2%, and a totalerrorless than6.9%,basedonbiologicalvariationofglucose [3]. 6.2.Nearpatientorpoint-of-caretesting Ideally,theresultsofhandheldglucosemetersshouldmatch thoseoflaboratory analyzersof an accreditedlaboratory. Furthermore,thetargetsforscreeningofdiabetes,self- monitoringofglucose, and acutehospitalcriticalcaresettings arenotthesame. Nouniversalcriteria forthe analyticalperformanceofglucose metersexist.Generally,theperformanceoftheglucometeris consideredsatisfactoryif95% ofglucometervaluesfallwithin a specifiedpercentageofsimultaneouslymeasuredpatient plasma glucoseonlaboratory analyzers. Currentglucometer recommendations(comparedwithlaboratorymethods)range widelyfrom ±5% to ±20% [3]. In January2014,theUSFood and DrugAdministrationrecommendedqualityrequirements; however,they aretoostringent andhavethusbeencriticizedby mostprofessionalbodies [4]. Whenusing a glucometeritisimportanttoknowwhatvalueis beingreported,i.e.whetheritiswholebloodorplasma-correlated glucose. “Plasma correlated” referstoglucoseconcentrations measuredinsamplesofwholebloodbut areconvertedtovalues thatwouldbeexpectedofplasma measurements.Thesiteof bloodcollectionmaycreate additionalvariability. Ingeneral, bloodsamplesforglucometerreadingshouldbecollected fromthefingertips.Thetechniqueofglucometeruseisusually responsibleformoreinaccuracythantheglucometeritself. Technicalerrorsresultfromimpropercalibration andinadequate maintenance,in additiontothespecifictechniquesusedto measureglucose: photometricversuselectrochemical, aswell as thetypeofenzymeused(HKvsGOvsGD) [5]. Ideally,fordiagnosisofGDM,reliabletestresultsshould bebasedonvenousplasma samplesproperlycollected and transportedpriortolaboratorytesting.However,thisideal situationmaynotbepresentinmanyprimarycaresettings, particularlyinlow-incomecountrieswhereproperfacilities forcollection,transport,storageortestingmaynotexist. In thissituationFIGOrecommendsthatitis acceptabletouse a plasma calibratedhandheldglucometerwithproperlystored teststripstomeasureplasma glucose. Regularcalibration shouldbeundertakenwithstandardtestsolutions(usually suppliedbytheglucosemetermanufacturer).Using a glucose 6.1.Laboratorytesting An arrayofinstruments,fromthesimplesttothemost sophisticated, arecapableofmeasuringplasma glucose. Ideally,

  23. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S189 References meterinthissituationmaybemorereliablethanlaboratory testsdoneonsamplesthathavebeeninadequatelyhandled andtransported. [1] Gambino R,Piscitelli J,AckattupathilTA,Theriault JL,Andrin RD,Sanfilippo ML,et al.Acidificationofbloodissuperiortosodiumfluoride alone as an inhibitorofglycolysis. Clin Chem2009;55(5):1019–21. [2] SacksDB,Arnold M,BakrisGL,BrunsDE,HorvathAR,Kirkman MS,et al. Guidelines andrecommendationsforlaboratory analysisinthediagnosis andmanagementofdiabetesmellitus.Diabetes Care2011;34(6):e61–99. [3] SacksDB,ed.Guidelines and RecommendationsforLaboratoryAnalysisinthe Diagnosis and ManagementofDiabetes Mellitus.https://www.aacc.org/~/ media/practice-guidelines/diabetes-mellitus/diabetesmellitusentirelmpg. pdf?la=en.Published2011. [4] Polen M.AACC urgesNewYorkStatetorescindpolicydirectivethatcouldnega- tivelyimpactpatientsbyrestrictingtheuseofbloodglucosemeters.American Associationfor Clinical Chemistry; June17,2014.https://www.aacc.org/media/ press-release-archive/2014/aacc-urges-new-york-state-to-rescind-policy-directive [5] Schrot RJ,PatelKT,FoulisP.Evaluationofinaccuraciesinthemeasurementof glycemia inthelaboratory,byglucosemeters, andthroughmeasurementof hemoglobinA1c. ClinicalDiabetes2007;25(2):43–49. •GDM diagnosisshouldbeideallybasedonbloodtests donein an accreditedlaboratoryonproperlycollected and transportedvenousplasma samples. •FIGOrecommendstheuseof a plasma-calibratedhandheld glucometerwithproperlystoredteststripstomeasure plasma glucoseinprimarycaresettings,particularlyin low-resourcecountries,where a close-bylaboratoryor facilitiesforproperstorage andtransportofbloodsamples to a distantlaboratorymaynotexist.Thismaybemore convenient andreliablethantestsdoneoninadequately handled andtransportedbloodsamplesin a laboratory. It isrecommendedthatfromtimetotime a fewsamples are paralleltestedin an accreditedlaboratorytodocumentthe variability. •FIGOrecommendsthat alllaboratories andclinical servicesdocumenttheirbaselinequality andworktoward improvementirrespectiveoftheresources available.

  24. S190 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 7.Managementofhyperglycemiaduringpregnancy Fetal andmaternaloutcomes aredirectlycorrelatedwith thedegreeofmaternalglycemiccontrol.Theprimarygoalof treatmentforpregnanciescomplicatedbydiabetesistoensure asclosetonormaloutcome aspossibleforthemother and offspringbycontrollingmaternalhyperglycemia. 7.1.2. Fetal well-being Fetal assessmentcanbe achievedby a fetalkickcount, biophysicalprofile, andcardiotocography(nonstresstest). Thereisnohigh-qualityevidencetosupport a particularfollow- upprotocol.However,itis assumedthatwithreassuringfetal well-being,pregnancyprolongationtotermcanbe achieved [1]. Recommendationsfor assessmentoffetalwell-being areshown inBox3. •FIGOrecognizesthatmanagementofdiabetesinpregnancy shouldbemadein accordwith availablenationalresources andinfrastructure,evenwithouthigh-qualityevidence, as itispreferabletothe alternativeofnoorpoorcare. 7.1.3. Timing and mode of delivery 7.1.Prenatalsupervision Maternalhyperglycemia andmacrosomia are associated withincreasedriskofintrauterinefetaldeath andother adverse outcomes.Therefore,inductionoflabormaybeconsidered at38−39weeks, althoughthereisnogood-qualityevidence tosupportsuch an approach.Thus,someguidelinessuggest that a pregnancywithgoodglycemiccontrol and a seemingly appropriateestimatedweightforgestational agefetusought tocontinueuntil40−41weeks [2–4].Giventhesignificantly greaterriskofshoulderdystocia at anybirthweight above3750 gforbabiesofwomenwithdiabetes,considerationmaybegiven toelectivecesareandeliverywhenthebestestimateoffetal weightexceeds4000g [5–10] (Figure4). Recommendationsfor timing andmodeofdeliveryinwomenwithGDM areshown inBox4. Thereisnoevidencetosupport a particularprotocolof prenatalcare andmonitoringforwomenwithdiabetes.The recommendationsinBox1 arebasedontheACOGpractice bulletin [1], aswell asconsensusonclinicalpractice. 7.1.1. Fetal sonographic assessment Monitoringfetalgrowthisbothchallenging andinaccurate, with a ±15% errormargin.Sincefetalmacrosomia isthemost frequentcomplicationofdiabetes,specialeffortshouldbe directedtowarditsdiagnosis andprevention. Recommendations forfetalgrowth assessment areshowninBox2. Box 1 Recommendations for prenatal supervision in women with gestational diabetes mellitus. Recommendations Resource setting Strength of recommendation and quality of evidence Routine prenatal care should include visits to: High 1|???? • Healthcare professionals skilled in care of women with diabetes in pregnancy (obstetrician, perinatologist, diabetologist, diabetes educator, nutritionist etc): 1−3 weeks as needed • Nurse: Weight, blood pressure, dipstick urine protein: 1-2 weeks as needed Prenatal follow-up determined locally according to available resource: Mid and Low 2|???? • A minimum of monthly check-ups with a healthcare provider knowledgeable in diabetes in pregnancy Box 2 Recommendations for fetal growth assessment in women with gestational diabetes mellitus. Recommendations Resource setting Strength of recommendation and quality of evidence Clinical and sonographic growth assessments every 2−4 weeks from diagnosis until term High 1|???? Periodic clinical and sonographic growth assessments from diagnosis until term Mid and Low 2|???? Box 3 Recommendations for fetal well-being surveillance in women with gestational diabetes mellitus. Recommendations Resource setting Strength of recommendation and quality of evidence Use cardiotocography and/or biophysical profi le or kick-count as indicated according to local protocol All 1|????

  25. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S191 7.2.Glucosemeasurements 7.2.3. Continuous glucose monitoring Bloodglucosecontrolcanbeevaluatedinoneofthreeways: glycosylatedhemoglobin(HbA1c),self-monitoringofblood glucose,orcontinuousglucosemonitoring. Thedeviceconsistsof a subcutaneousenzymaticsensor attachedto a nonimplantedtransmitterthatsendsreadings to a receiver andprovidesnumerous automatedreadingsof interstitialtissueglucose,calibratedtoreflectplasma glucose. Thecontinuousmeasurementenablesdetectionofvirtually allglucosefluctuations andhelpsmodifytreatment [17–19]. Continuousglucosemonitoringmayhelp achieve a smallHbA1c reductionin a nonpregnantpopulation [20,21]. Itcandetecthigh postprandialbloodglucoselevels andnocturnalhypoglycemia [22,23].However,noclearmaternalorneonatalbenefitshave beenreportedduringpregnancyinwomenwithGDM [24,25]. 7.2.1. HbA1c Thistestreflectsthe averageglucoselevelinthethreemonths priortomeasurement. Itiscorrelatedwiththeriskofcongenital malformations,notto anyother adversepregnancyoutcomes. Itisbestusedforpregnancyplanning andprenatalfollow-upin casesofdiabetesinpregnancy.HbA1cdoesnotreplacetheOGTT forthediagnosisofGDM.However,inwomenwithGDM,HbA1c maybeusedtoverifythereliabilityoftheirself-monitored glucosereports [11,12]. 7.2.4. Recommendations for glucose monitoring in women with GDM Theissueoftheoptimaldailyfrequency andtimingin relationshipto a mealforcheckingbloodglucoseinwomen withGDM remainsunresolved.Thereisno “evidence” from a randomizedcontrolledtrial(RCT)tosupport anyspecific frequency. Inthetwo RCTsforthemanagementofGDM,the studybyLandonet al. [26] statedthatpatientswereinstructedto testthemselvesfasting and2hourspostprandial,withoutstating howoftentheyshouldtestthroughouttheday; theACHOISstudy [27] recommendedthatpatientsshouldmonitortheirhome bloodglucoselevelsinitiallyfourtimes a day andthenused “daily 7.2.2. Self-monitoring of blood glucose Self-monitoringofcapillaryglucoseis achievedbymultiple dailymeasurementsofcapillarybloodglucosewith a handheld glucometer. Itonlyprovidesglucosevalues atthetimeof measurement andmissesinbetweenhyper/hypoglycemic events. Multiplestudieshaveshowntheutilityofself-monitoring ofbloodglucosein achievingtightglycemiccontroltoreduce pregnancycomplications [13–16]. Box 4 Recommendations for timing and mode of delivery in women with gestational diabetes mellitus. Recommendations Resource setting Strength of recommendation and quality of evidence As per local protocol or as suggested in Figure 4 All 2|???? 38−39 weeks <3800 g or appropriate for gestational age 3800−4000 g or large for gestational age >4000 g Poor control Poor compliance Previous stillbirth Vascular disease Yes No Offer elective cesarean delivery Continue to 40−41 weeks Induce labor Figure4Timingofdeliveryinwomenwithgestationaldiabetesmellitus anddiabetesinpregnancy.

  26. S192 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 monitoring atrotatingtimes.” In anobservationalstudy,Langer et al. [28] requestedpatientstotestthemselvesseventimes a day(althoughthey actuallytestedthemselves at a meanof4.2 times a day).Guidelines are alsoequivocal.TheNational Institute forHealth and CareExcellence(NICE)suggeststhatpersonnel should “advisewomenwhoneedintensificationofhypoglycemic therapytoincreasethefrequencyofself-monitoringtoinclude fasting and a mixtureofpre- andpost-prandiallevels” [29]. ACOGstates [1] “Thereisinsufficientevidenceconcerningthe optimalfrequencyofbloodglucosetestingofGDM.Basedon thedata availablethegeneralrecommendationisfour-times dailyglucosemonitoringperformed atfasting andeither at 1-houror2-hourintervals aftereachmeal.Oncethepatient’s glucoselevels arewell-controlledbyherdiet,thefrequencyof glucosemonitoringcanbemodified.” Inits2015clinicalpractice recommendations,theADAencouragespre- andpostprandial monitoringofbloodglucosebutdoesnotrecommend a specific frequencyoftesting [30]. Therecommendationsforglucosemonitoringinwomenwith GDM areshowninBox5. Thereisgeneral agreementthatmaternalhyperglycemia during labor anddeliveryis associatedwithneonatalhypoglycemia, inbothGDM [37] andT2DM [38–41].Otherreportsshowthat maternalhyperglycemia duringlaboris also associatedwith birth asphyxia andnonreassuringfetalheartratetracings [42,43]. Inwomenwithtype1diabetes(T1DM)ithasbeenshownthat targetingmaternalglucoselevelsintherangeof4.0−7.0mmol/L (72−126mg/dL)duringlaboris associatedwith a lowerriskof maternalhypoglycemia thanlowertargetlevels [44]. In addition, theselevelsduringlabor anddelivery arehelpfulinreducing theincidenceofneonatalhypoglycemia,birth asphyxia, and nonreassuringheartratetracings.Glycemictargetsforwomen withGDM aregiveninBox6. 7.3.3. Weight gain Theepidemicofobesity adversely affectsthehealthof anentirepopulation,buthasimportantconsequencesfor pregnancy andpostpartumoutcomes [45].Overweight andobese womenbeforepregnancy are at anincreasedriskforpregnancy complicationsincludingdiabetes,hypertensivecomplications, stillbirth, andincreasedriskforcesareandelivery.The Institute of Medicine(IOM)haspublishedrecommendationsforweight gainduringpregnancy,basedonprepregnancybodymassindex [46].Thereisnoevidenceforrecommendationsforweightgain specifictopregnanciescomplicatedbydiabetes.Accordingto IOM guidelinesforweight-appropriate andunderweightwomen, toensurenormalinfantbirthweight a recommendedweight gainwithnorestrictionincaloricintakeisrecommended.For overweight andobesewomenthereisnoconsensusregarding caloricintake andweightgainduringpregnancy.Someevidence suggeststhatweightreductionmaybe appropriate [47],whereas otherstudiesindicatethatinoverweight andobesewomen, weightlossorgainoflessthanorequalto5kgduringpregnancy is associatedwith anincreasedriskofSGA anddecreased neonatalfatmass,leanmass, andheadcircumference [48]. Recommendationsforweightgainduringpregnancy andduring pregnancyinwomenwithGDM aregiveninBoxes 7 and8. 7.3.Targetsoftherapy ThemaingoalfortreatmentofGDM istoprevent adverse effectsonthemother andfetus; themostimportant andproven factorto achievethisgoalisreductionofglucoselevelswithout unduehypoglycemia.Thisshouldbe achievedthroughout pregnancy andduringlabor anddelivery.Attemptsmustbe madeto achieveglucoselevels asclose aspossibletothoseseen innormalpregnancy. 7.3.1. Glucose control during pregnancy Elevatedglucosevalues,specificallypostprandialglucose levels, are associatedwith adversepregnancyoutcomesin patientswithhyperglycemia inpregnancy [31–33].Data suggest thatpostprandialglucoselevels aremoreclosely associatedwith macrosomia thanfastingglucoselevels [34,35].Nocontrolled studyhas, asyet,establishedtheoptimalplasma glucoselevel(s) topreventincreasedfetalrisk. 7.4.Lifestylemodification 7.3.2. Glucose control during labor and delivery 7.4.1. Nutritional therapy Neonatalhypoglycemia develops as a consequenceofthe heightenedfetalinsulinresponsetocopewithtransplacental transferofhighmaternalglucose.Afterdelivery,thesudden decreaseinglucosesupplytothenewborninthemidstofhigh insulinlevelsoffetaloriginresultsinhypoglycemia [35,36]. Severalobservationaltrialshavestudiedthecorrelationbetween glucoselevelsduringlabor andneonataloutcomes [37–43]. Nutritionaltherapyincludes anindividualizedfoodplanto optimizeglycemiccontrol. Itshouldbebasedonpersonal and culturaleatinghabits,physical activity,bloodglucosemeasure- ments, andtheexpectedphysiologicaleffectsofpregnancyonthe woman andherfetus. Medicalnutritionaltherapyinpregnancy canbedescribed as “a carbohydrate-controlledmealplanthat promotes adequatenutritionwith appropriateweightgain, Box 5 Recommendations for glucose monitoring in women with gestational diabetes mellitus. Recommendations Resource setting Strength of recommendation and quality of evidence Self-monitoring of blood glucose is recommended for all pregnant women with diabetes, 3−4 times a day: All 2|???? • Fasting: once daily, following at least 8 hours of overnight fasting • Postprandial: 2-3 times daily, 1 or 2 hours after the onset of meals, rotating meals on different days of the week Self-monitoring of blood glucose is recommended for all pregnant women with diabetes at least once daily, with documented relation to timing of meal Low 2|????

  27. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S193 Box 6 Recommendations for glycemic targets for gestational diabetes mellitus.a Recommendations Resource setting Strength of recommendation and quality of evidence Targets for glucose control during pregnancy: All 1|???? • Fasting glucose <5.3 mmol/L (95 mg/dL) • 1-hour postprandial <7.8 mmol/L (140 mg/dL) • 2-hour postprandial <6.7 mmol/L (120 mg/dL) Educate to recognize and treat signs of hypoglycemia: All 1|???? • Ingest 15 g of simple carbohydrate (sugar, rapidly absorbed tablets, sweetened liquids) Teach family members how to use the glucometer All 2|???? Target for glucose control during labor and delivery: All 1|???? • 4–7 mmol/L (72−126 mg/dL) a Source: American Diabetes Association [30]. normoglycemia, andthe absenceofketosis” [49].Nutritional interventionfordiabetes,specificallypregnancycomplicated withdiabetes,isconsistentlyconsidered a fundamentaltreat- mentmodality [50–53]. Itisthefirst-linetherapyin allwomen diagnosedwithGDM [54–55].However,thereispaucityofdata toprovideevidence-basedrecommendationsformostofthe nutritioninterventions.Studiesthathaveexaminedtheimpactof nutritionalpracticeguidelinesdemonstrateimprovedmetabolic controlforT1DM andT2DM [56,57], aswell as a positiveimpact onthemetabolicgoalsofGDM [58]. GDM andtheirbabies.Successfulpregnancyoutcomeshave beenreportedwithin a widerangeofcaloricintakerangingfrom 1500−2800caloriesperday [59–64].However,moststudies weresmallsized,uncontrolled, andreliedonself-reported dietaryintakes.Existingdata suggestthatseverecaloric restriction(lessthan1500calories/dayor50% restriction) increasesketonemia.Thisisofparticularsignificanceinwomen withT1DM inpregnancywherehighlevelsofthirdtrimester ketonebodiesmayimpairmentaldevelopmentoftheoffspring [60]. Modestcaloricrestriction(1600−1800calories/day,33% reduction)doesnotleadtoketosis [65,66].Dailyenergyintake of approximately2050caloriesin allBMI categoriesinwomen withGDM wasreportedtoreduceweightgain,maintain euglycemia, avoidketonuria, and achieve averagebirthweights of3542g [67,68]. 7.4.2. Calories Restrictingcalorieshasbeen a strategyforcontrollingweight gain,glucoselevels, and avoidingmacrosomia inwomenwith Box 7 Institute of Medicine recommendations for weight gain during pregnancy.a Prepregnancy body mass indexb Total weight gain, Kg Mean (range) rates of weight gain at the second and third trimester, kg/weeks) Underweight <18.5 12.5−18 0.51 (0.44−0.58) Normal weight 18.5−24.9 11.5−16 0.42 (0.35−0.50) Overweight 25.0−29.9 7−11.5 0.28 (0.23−0.33) Obese ≥30.0 5−9 0.22 (0.17−0.27) a Source: Institute of Medicine [46]. b BMI calculated as weight in kilograms divided by the height in meters squared. Box 8 Recommendations for weight gain during pregnancy with diabetes.a Recommendations Resource setting Strength of recommendation and quality of evidence Institute of Medicine revised guidelines for weight gain during pregnancy All 2|???? Weight reduction for obese and overweight women prior to pregnancy All 1|???? a Source: Institute of Medicine [46].

  28. S194 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 consumptionofprocessed,highsugar,highfat,highsalt, and lowfiberfoods. Itisimportanttohighlightthatwomenwith GDM be advised(repeatedlyduringpregnancy)tocontinuethe samehealthyeatinghabitseven afterdeliverytoreducetherisk offutureT2DM andmetabolicsyndrome. Recommendationsfor nutritiontherapyinwomenwithGDM aregiveninBox9. 7.4.3. Carbohydrates Focusingontotal amount,quality, anddistributionof carbohydrateintakehelps achievemetaboliccontrolin all patientswithdiabetes.Thetotal amountofcarbohydrates, distributionofcarbohydratesindifferentmeals andsnacks, typeofcarbohydrates, andtheglycemicindex(GI)offoodscan allbemodifiedwithout affectingthetotalcaloricintake [69]. Carbohydratesshouldbedistributedthroughoutthedayinthree small- tomoderate-sizedmeals and2−4snacks.Anevening snackmaybeneededtoprevent acceleratedketosisovernight.A minimumof175gcarbohydrates/dayshouldbeprovided,which ishigherthanthe130g/dayrecommendedfornonpregnant women [70]. 7.4.7. Physical activity Physical activityinnonpregnantpatientswithdiabetes hasbeenshowntoimprovemetaboliccontrol,reduceinsulin resistance,reducecardiovascularrisk, andimproveweight control andoverallwell-being [78].WomenwithGDM may achievereducedglucoselevels(upto1.3mmol/L [23mg/ dL])with30minutesofphysical activity [79].Arecentmeta- analysissuggestedthatphysical activityinpregnancyprovided a slightprotectiveeffect againstthedevelopmentofGDM. Studiesevaluatingtype,timing,duration, andcompliance withphysical activityregimens arewarrantedtobestinform obstetricguidelines [80]. Regular aerobicexercisewithproper warm-up andcool-downhasbeenshowntolowerfasting and postprandialglucoseconcentrationsinseveralsmallstudiesof previouslysedentarywomenwithGDM.Safetyofprescribed exercisesforglucosemanagementhasnotbeendemonstrated; therefore,womenshouldbe advisedtomonitorfetal activity and bloodglucoselevelsbefore and afterexercise. Increasedphysical activitypostpartuminwomenwithhistoryofGDM is associated withsignificantlylowerriskofprogressiontoT2DM [81,82]. Recommendationsforphysical activityinwomenwithGDM are giveninBox10. 7.4.4. Glycemic index Theglycemicindexof a foodisdefined asthe area under thetwo-hourbloodglucosecurve(AUC)following a 12-hour fast andingestionof a foodwith a certainquantityof available carbohydrate(usually50g).TheAUC ofthetestfoodisdivided bytheAUC ofthestandard(eitherglucoseorwhitebread,giving twodifferentdefinitions) andmultipliedby100.The average GI valueiscalculatedfromdata collectedin10humansubjects. Boththestandard andtestfoodmustcontain anequal amountof availablecarbohydrate andusuallyrangesbetween50 and100. TheGI offoodsis also animportantfactor, asfoodwith a lowGI mayreducepostmealglycemicexcursion andflattentheglucose curve.Foodswith a highGI (>70)mayshowhigherpostprandial values,whilelowGI dietsinnonpregnantpatientswithdiabetes leadto an additional0.4% reductioninhemoglobinA1c [71].Low GI diethasbeenshowntoreducebirthweight [72–74] andcause a two-foldincreaseinratesofunderweightforgestational age babiesinnondiabeticwomen [74].Byextrapolation,thismay provide an advantageinreducingmacrosomia inwomenwith GDM anddiabetesinpregnancy.LowGI diets are associated withlessfrequentinsulinuse andlowerbirthweightthan incontroldiets,suggestingthatitisthemost appropriate dietaryinterventiontobeprescribedtopatientswithGDM [75].PregnancydoesnotchangetheGI valuesofspecificfoods. However,duetothewideinterindividualvariabilityinthe GI,eachwomanneedstodeterminewhichfoodsto avoidor consumeinsmallerportions at allmealsorduringspecifictimes oftheday,forthedurationofherpregnancy [76]. •FIGOrecognizesthatnutritioncounseling andphysical activity aretheprimarytoolsinthemanagementofGDM. •FIGOrecommendsthatwomenwithGDM receivepractical nutritioneducation andcounselingthatempowersthem tochoosetherightquantity andqualityoffood. •WomenwithGDM mustberepeatedly advisedtocontinue thesamehealthyeatinghabits afterdeliverytoreducethe riskoffutureT2DM. 7.5.Medicaltherapy 7.5.1. Oral antidiabetic agents Traditionally,whendietarytherapywasinsufficientto maintainnormoglycemia inwomenwithGDM,insulinwas theonly availablemedicaltherapy [83–85]. Inthepast,oral antidiabetic agents(OAD)werenotrecommendedduring pregnancyowingtothefearofpotential adversefetaleffects includingteratogenicity andneonatalhypoglycemia [86–90]. EarlierevidenceinsupportofOADwasweak andprincipally basedoncaseseriesinvolvingtheuseoffirst-generation sulfonylureas [86–88,91–95].Althoughneitherglyburidenor metformin are approvedforuseinpregnancy,theiruse as an adjuncttherapyinGDM hasbeenconsideredbyseveral organizations.Forexample,glyburidehasbeen acknowledged intheFifth InternationalWorkshop-ConferenceonGestational Diabetes Mellitus [96] andboth areconsideredintheNICE guidance [97] andACOGpracticebulletin [1].Useoforal agents isincreasing, andinsomesettingsthey arethefirstoptionwhen drugtreatmentisrequiredforwomenwithGDM. In a large nationwideretrospectivecohortstudyintheUSA,including 10 778womenwithdrug-treatedGDM,useofglyburide increasedfrom 7.4% in2000to64.5% in2011,becomingthe mostcommontreatmentsince2007 [98]. 7.4.5. Fiber Fiberintake,particularlysolublefiber,isbeneficialin loweringserumlipidlevels andreducingglucoseexcursions. LowGI foodsoftenhavehigherfibercontent.Whilegoodquality studies arenot availabletodeterminethebenefitsoffiber-rich dietsinpregnantwomenwithdiabetes,preferenceshouldbe giventofoodsrichinfiber.Upto28gfiberintakeperdayis recommendedforpregnantwomen [77].Fiber alsohelpsreduce constipation,whichis a commonprobleminpregnancy. 7.4.6. Nutritional education Whileprovidingindividualdietcounselingistheideal option,itismostoftennotfeasiblebecauseoflackofresources. WomenwithGDM andDIPmustreceivepracticaleducation thatempowersthemtochoosetherightquantity andquality offood.Thiscanbe achievedthroughteachingportionsizesor usingtheplatemodel and a culturally appropriatefoodpyramid orcolorcodingoffood.Nutritionaleducationshouldemphasize healthiercookingmethods andreductionormoderationin

  29. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S195 Box 9 Recommendations for nutrition therapy in women with gestational diabetes mellitus. Recommendations Resource setting Strength of recommendation and quality of evidence All We recommend that the following principles should be adhered for all pregnant women with diabetes: 1|???? • Design an appropriate diet with respect to prepregnancy BMI, desired body weight, physical activity, habits, and personal and cultural preferences. • Provide routine follow-up and diet adjustments throughout pregnancy to achieve and maintain treatment goals. • Offer training, education, support, and follow-up by a qualifi ed dietician experienced in care of women with diabetes. Issues for discussion include: weight control, food records, carbohydrate counting, prevention of hypoglycemia, healthy foods, and physical activity. We suggest that caloric intake be calculated based on prepregnancy BMI and desirable weight gain as follows: All 2|???? • 35−40 kcal/kg desirable body weight for underweight women • 30−35 kcal/kg desirable body weight for normal weight women • 25−30 kcal/kg desirable body weight for overweight women We recommend limiting carbohydrate intake to 35%–45% of total calories, with a minimum of 175 g carbohydrate per day, distributed in three small-to-moderate sized meals and 2−4 snacks. All 1|???? For obese women, caloric intake may be reduced by 30%, but not below 1600−1800 kcal/d All 2|???? For women with diabetic nephropathy, protein may be lowered to 0.6−0.8 g/kg ideal body weight All 2|???? Box 10 Recommendations for physical activity in women with gestational diabetes mellitus. Recommendations Resource setting Strength of recommendation and quality of evidence We suggest that appropriate, personally adapted, physical activity be recommended for all women with diabetes: All 2|???? • Planned physical activity of 30 min/day • Brisk walking or arm exercises while seated in a chair for 10 min after each meal. • Women physically active prior to pregnancy should be encouraged to continue their previous exercise routine. Subsequently,theseobservationswereconfirmedin a seriesof clinicalstudiesevaluatingtheoutcomeofinfantsborntomothers receivingglyburideduringthesecond andthirdtrimestersfor GDM [104–107] aswell asforT2DM [108].Arecentsystematic review andmeta-analysis [109] showsthatcomparingglyburide treatmentwithinsulinresultsin about100ghigherbirthweight, two-foldhigherneonatalhypoglycemia, andmorethantwo-fold highermacrosomia intheglyburidegroup.Themagnitudeofthe differenceintheseoutcomesisrelevantforclinicalpractice. Inhead-to-headcomparisonbetweenmetformin andgly- buride,theformerwas associatedwithlessmaternalweight gain(pooledmeandifference −2.06kg [95% CI, −3.98to −0.14]), lowerbirthweight(pooledmeandifference −209g [95% CI, −314 to −104]),lessmacrosomia (pooledriskratio0.33 [95% CI,0.13to 0.81]), andfewerLGAnewborns(pooledriskratio0.44 [95% CI, 0.21to0.92]).The averagetreatmentfailurewas26.8% (48/179) 7.5.1.1. Glyburide Thisis a secondgenerationsulfonylurea. Itstransfer acrossthe placentalbarrierwasfirstevalu atedinsingle-cotyledonplacental models,whereinnosignificanttransferofglyburidewasfound, evenwhenmaternalglyburideconcentrationsweremuchhigher thanthetherapeuticconcentrations [99,100].Followingthese observations,Langeret al. [101] conducted an RCTtocompare theefficacy andsafetyofglyburide(n=201) andinsulin(n=203) inthemanagementofwomenwithGDM.Thisstudyfoundno differencesintherateofmaternal andneonatal adverseoutcomes betweentheglyburide andinsulintreatedgroups, aswell as nodetectionofglyburideincordblood.Furthermore,glycemic control andpregnancyoutcomeswerecomparable. Otherstudies [102,103] suggestedthatglyburidemaybe activelytransportedfromfetustomother andthatthefetus maybeexposedto about9%−70% ofthematernalconcentration.

  30. S196 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 inthemetformingroupversus23.5% (40/170)intheglyburide group. Metforminwas associatedwithhigherfastingblood glucoseduringtreatment(pooledmeandifference0.15mmol/L (0.00to0.30). Recently,Dhulkotia et al. [123] conducted a systematic review andmeta-analysisof RCTscomparingtheeffectsoforal hypoglycemic agents(glyburide andmetformin)withinsulin inGDM patients.Sixstudiescomprising1388subjectswere includedinthe analysis.Therewerenosignificantdifferences betweentheOAD andinsulingroupswithregardtomaternal fastingorpostprandialglycemiccontrol,rateofneonatal hypoglycemia,birthweight,orrateofLGAinfants.The authors concludedthatglycemiccontrol andpregnancyoutcomeswere similarfororalhypoglycemic agents andinsulin. Moreover, theysuggestedthatglyburide andmetforminshouldbeused asthefirst-line agentsinGDM management.Furthermore, as oralhypoglycemic agents areconsiderablymoreconvenient and lessexpensivethaninsulin [124] anddonotrequireintensive educationregardingtheiruse atthetimeoftherapyinitiation; they areclearlypreferredbymostpatients [125,126] andthus enhancetreatment adherence.These advantages areparticularly beneficialinsituationswhereinsulinisnotreadily availableor whenpatientsrefuseinsulintherapy. Additionally,metforminmay alsosignificantlyreduceseveral adversematernal andneonataloutcomes,includingpregnancy inducedhypertension,neonatalhypoglycemia, andtheneed forNICU admission [119].TreatmentofGDM withmetformin, comparedwithinsulin,is associatedwithsignificantlylower weightgain, andlowerincidenceofpregnancyinduced hypertension,butwith a higherrateofpretermlabor [127]. Inthemeta-analysisbyBalsellset al. [109],metformin—when comparedwithinsulin—was associatedwithlessmaternalweight gain(pooledmeandifference −1.14kg [95% CI, −2.22to −0.06]), lowergestational age atdelivery(pooledmeandifference −0.16 weeks [95% CI, −0.30to −0.02]), andmorepretermbirths(pooled riskratio1.50 [95% CI,1.04to2.16]).Atrendwasobserved toward a lowerrateof anyneonatalhypoglycemia (pooledrisk ratio0.78 [95% CI,0.60to1.01]); the averagetreatmentfailure inthemetformingroupwas33.8% (229/678).Forsecondary outcomes,metforminwas associatedwithlowerpostprandial bloodglucose(pooledmeandifference −0.14mmol/L [95% CI, −0.22to −0.05]),lessmaternalweightgainsincestudyentry (pooledmeandifference −1.23kg [95% CI, −1.72to −0.73]),less pregnancyinducedhypertension(pooledriskratio0.53 [95% CI, 0.31to0.90]), andlesssevereneonatalhypoglycemia (pooled riskratio0.62 [95% CI,0.42to0.94]) [109]. 7.5.1.2. Metformin Metforminhasbeenshowntofreelycrosstheplacental barrier [110],reachingconcentrationsinfetalcirculationof50% ormoreofthosemeasuredinmaternalserum.Thefetuscanbe exposedtoconcentrations ashigh asorevenhigherthanthose measuredinmaternalserum [111].Severalstudieshavereported outcomesinwomen,mainlywomenwithPCOSexposedto metformin atthetimeofconception andduringearlypregnancy [112–114].Theratesof adverseoutcomes,includingcongenital malformations andneonatalhypoglycemia,weresimilartothose reportedinthegeneralpopulation [112]. Inthe MetformininGestationalDiabetes(MiG)trial,the largest RCTcomparingmetforminwithinsulin, Rowanet al. [115] randomized 751womenwithGDM at20−33weekstotreatment witheithermetforminorinsulin. Metforminwas associated with a significantlylowerrateofneonatalhypoglycemia (3.3% vs8.1%; P<0.008),butwith a higherrateofpretermbirth(12.1% vs 7.6%; P=0.04)thaninsulin.Therewerenodifferencesbetween thegroupswithregardtotherateofcongenital anomaliesor otherseriousmaternal andneonatal adverseevents. In a two- yearfollow-upofoffspringfromthe MiGtrial,offspringof motherstreatedwithmetforminhadmoresubcutaneousfat intheshoulder andupper armregionscomparedwiththose wheretheinitialmedicaltreatmentwasinsulin [116].Aone-year follow-upofwomen andoffspringfrom an RCTofwomenwith PCOStreatedwithorwithoutmetforminduringpregnancy [117], foundthat althoughwomeninthemetformingroupgained lessweightduringpregnancy,theyhad a higherBMI oneyear postpartum andthattheoffspringinthemetformingroupwere significantlyheavier(0.5kg) at1yearof age.Anothersimilarbut smallerstudyfromthesame authorsfoundsignificantlyhigher fastingglucosein8-year-oldoffspringofwomentreatedwith metformin [118]. In a meta-analysisof10studiesthat assessedtheeffect ofexposuretometformin,therateofcongenital anomalies andneonatalmortalitywasnotincreased [119].Aprospective studyof126infantsofmotherstreatedwithmetforminfor PCOSduringpregnancyreportedno adverseeffectsonthe infants’weight,length,motor activity,orbehavior atthe ageof 18months [120]. Inthe MiGtrial [115],therateofcomposite neonatalmorbidity(neonatalhypoglycemia,respiratorydistress, needforphototherapy,birthtrauma,5-minuteApgarscore <7,or prematurity)wascomparableinthemetformin andtheinsulin groups. In addition,therewerenodifferencesinthedegreeof glycemiccontrol andinumbilicalcordinsulinlevelsbetweenthe metformin andinsulingroups. Metforminwas associatedwith a lowerweightgainduringpregnancy(0.4 ± 2.9vs2 ± 3.3kg; P<0.001).Furthermore,themajorityofwomeninthemetformin groupstatedthattheywouldchoosetoreceivetheir assigned treatment again(76.6% vs27.2%; P<0.001).Nevertheless, metforminwas associatedwith a failurerateof46.3% (defined as a requirementfor additionalinsulin). In a smaller andmorerecentrandomizedstudycomparing metforminwithglyburide, Mooreet al. [121] assigned149women withGDM whohadfaileddiettreatmenttoeithermetformin orglyburide.Thefailureratein achieving adequateglycemic controlinthemetformingroupwas34.7%,whichwasmorethan two-foldhigherthanintheglyburidegroup(16.2%; P=0.01). In anotherrecent RCT [122], 72womenwithGDM wererandomized fortreatmentwithmetforminorglyburide; thefailurerateof metformin andglyburidewas25% and23.8%,respectively. 7.5.1.3. Recommendations for pharmacological treatment Intheshortterm,inwomenwithGDM requiringdrug treatment,glyburideseemsinferiortobothinsulin andmetformin, whilemetformin(plusinsulinwhenrequired)performsslightly betterthaninsulin [109]. Recommendationsforpharmacological treatmentinwomenwithGDM aregiveninBox11. Itisimportanttonotethatthereisnolong-termevidence onthesafetyofOADs. 7.5.2. Insulin therapy Whenbloodglucosetargetscannotbereachedbydiet and/ orOADs,insulinisrequired.Thereisnoevidencesupporting the advantagesof anyonetypeofinsulinorregimenofinsulin over another.Thus,insulintype andregimensshouldbe individualized [128–131]. Itisbeneficialtopairrapid-acting withintermediateorlong-actinginsulin,inordertosimulate thephysiologicinsulinsecretionthroughouttheday. In womenwithdiabetes,insulinrequirementsgraduallyincrease throughoutpregnancy: 0.7 units/kg/dayinthefirsttrimester; 0.8units/kg/dayfromweek18; 0.9units/kg/dayfromweek 26; and1.0units/kg/dayfromweek36untildelivery. Insome instanceslowerdosesmaysuffice.

  31. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S197 Box 11 Recommendations for pharmacological treatment in women with gestational diabetes mellitus. Recommendations Resource setting Strength of recommendation and quality of evidence Insulin, glyburide, and metformin are safe and effective therapies for GDM during the second and third trimesters, and may be initiated as fi rst-line treatment after failing to achieve glucose control with lifestyle modifi cation. Among OADs, metformin may be a better choice than glyburide [109]. All 2|???? Insulin should be considered as the fi rst-line treatment in women with GDM who are at high risk of failing on OAD therapy, including some of the following factors [129]: High 2|???? • Diagnosis of diabetes <20 weeks of gestation • Need for pharmacologic therapy >30 weeks • Fasting plasma glucose levels >110 mg/dL • 1-hour postprandial glucose >140 mg/dL • Pregnancy weight gain >12 kg Box 12 Recommendations for insulin treatment in women with gestational diabetes mellitus. Recommendations Resource setting Strength of recommendation and quality of evidence The following insulins may be considered safe and effective treatment during pregnancy: regular insulin, NPH, lispro, aspart and detemir. All 1|???? Regularsolublehumaninsulin andneutralprotamine Hagedorn(NPH)humaninsulin arecommonlyusedfortreating diabetesduringpregnancy.However,the actionofregularhuman insulinistooslowtocontrolpeakpostprandialbloodglucose. However,lowerpostprandialmaternalglucoseconcentrations withrapid-actinginsulin analogshavenotbeen associatedwith a diminutionin adversematernal,fetal,orperinataloutcomes. AlthoughNPHisconsidered asintermediate actinginsulin [132],itsbasalinsulin actioninpregnantwomenmayrequire 2−3dailyinjections. Consequently,theriskofhypoglycemia is increased,particularly atnight.Thesedisadvantagesinhuman insulincanbeovercomebytheuseofshort-acting(lispro and aspart) andlong-acting(detemir andglargine)insulin analogues, orcontinuousinsulininfusionin a pump. wasimprovedinthegroupreceivinginsulin aspart [148].Based ontheresultsofthisstudy,theFDAchangedthepregnancyuse warningfromcategory C tocategoryB. 7.5.2.3. Insulin detemir Insulindetemiris a long-actinginsulin analoguethatwas firstevaluatedinpregnancyinvolving10womenwithT1DM treatedthroughoutpregnancy [149].No adversematernalor neonataleffectsweredocumented.Several RCTsinnonpregnant womenhaveshownthat,comparedwithNPHinsulin,detemir is associatedwith a lowerrateofhypoglycemia andlessweight gain [150–152]. In2014, a large RCTcomparedinsulindetemir withhumanNPHinsulin, anddemonstrateditsefficacy andsafety duringpregnancyinwomenwithT1DM [153].Nospecificsafety issueswereidentified [154].UseinGDM hasnotbeenspecifically investigatedbutisexpectedtohavethesameefficacy andsafety asdemonstratedinpregnantwomenwithT1DM [155]. 7.5.2.1. Insulin lispro Transplacentaltransportoflispro appearstobeminimal [133–135], andwithoutdocumentedteratogeniceffects [136] or adversematernaloutcome [137,138].Womenreceivinglispro werereportedtohave a significantlylower area underthecurve forglucose,insulin, and C-peptidecomparedwithwomen treatedwithregularhumaninsulin [139–142] andsimilar pregnancyoutcomes [143,144]. 7.5.2.4. Insulin glargine Thereispaucityofdata ontheuseofinsulinglargineduring pregnancy.Fromthelimitedstudies,however,it appearstobe safe andwelltolerated [156,157]. 7.5.2.5. Recommendations for insulin treatment RecommendationsforinsulintreatmentinwomenwithGDM aregiveninBox12. 7.5.2.2. Insulin aspart Pettittet al. [145] werethefirsttocomparetheefficacyof insulin aspartwiththatofregularhumaninsulinin15women withGDM,demonstratingimprovedglycemiccontrolwith insulin aspart.The InsulinAspartPregnancyStudyGroup conductedthelargestevaluationtodateofinsulin aspartusein pregnancy.Atotalof322womenwithT1DM wererandomized toreceiveeitherinsulin aspartorregularinsulin.Theratesof majorcongenitalmalformations [146],maternal andcordblood levelsofinsulin antibodies [147],hypoglycemicevents, and pregnancyoutcomeswerecomparable,whileglycemiccontrol References [1] CommitteeonPracticeBulletins--Obstetrics.PracticeBulletinNo.137: Gestationaldiabetesmellitus.ObstetGynecol2013;122(2Pt1):406–16. [2] Tita AT,Landon MB,Spong CY,LaiY,LevenoKJ,Varner MW,et al.Timingof electiverepeatcesareandelivery atterm andneonataloutcomes.NEngl J Med2009;360(2):111–20. [3] Rosenstein MG, ChengYW,Snowden JM,Nicholson JM,DossAE, CaugheyAB. Theriskofstillbirth andinfantdeathstratifiedbygestational ageinwomen withgestationaldiabetes.Am J ObstetGynecol2012;206(4):309.e1–7.

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  35. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S201 8.Postpartummanagement Thepostpartumperiodiscrucial,notonlyintermsof addressingtheimmediateperinatalproblems,but alsointhe longtermforestablishingthebasisforearlypreventivehealth forbothmother andchild,who are at a heightenedriskfor futureobesity,metabolicsyndrome,diabetes,hypertension, and cardiovasculardisorders. glycemicstatusshouldbere-evaluatedwith a 75-goralOGTT at6−12weeks afterdelivery [9,10].Diagnosis atthattime shouldbebasedonthecurrentlyrecommendedWHOcriteria fordiabetes [11],impairedfastingglucose(IFG), andimpaired glucosetolerance(IGT)inthenonpregnantstate.Women whodonothavediabetesorpre-diabetes, accordingtothese definitions, arestill atriskofprogressiontodiabetes andother cardiovascularproblems andrequireongoingsurveillance [10] accordingtolocalprotocol.Thereisnoclearguidance aboutthe typeoftests(shouldthesewomenundergo annualOGTTs,orcan fastingplasma glucoseorHbA1cmeasurementsuffice?)orthe frequency anddurationforongoingsurveillance.Whenguidance existsitisoftenglucosecentric,missingoutotherimportant parametersbutmostimportantlyitispoorlyimplemented. •FIGOsupportstheconceptthatthepostpartumperiod inwomenwithGDM provides animportantplatformto initiateearlypreventivehealthforboththemother and thechildwho areboth at a heightenedriskforfuture obesity,metabolicsyndrome,diabetes,hypertension, and cardiovasculardisorders. 8.1. Immediatepostpartumperiod 8.1.5. Reducing long-term risk of T2DM and cardiovascular disease Irrespectiveoftheglycemicstatusonearlypostpartum testing,itshouldbe assumedthatwomenwithGDM havethe sameor a higherleveloffutureriskofdiabetes andcardiovascular disease aspeoplewithpre-diabetes andtheyshouldbe advised tomaintain a healthylifestylewith an appropriatediet,regular exercise, andnormalbodyweight.Furthermore,toensureoptimal healthbefore attemptingtheirnextpregnancytheyshouldseek consultationwithhealthcareprovidersknowledgeable about diabetespreventionpriortodiscontinuationofcontraception. Progressiontodiabetesismorecommoninwomenwith a historyofGDM comparedwiththosewithout a GDM history. Both “intensivelifestyle” andmetforminhavebeenshown tobehighlyeffectiveindelayingorpreventingdiabetesin womenwith IGT and a historyofGDM [12].Data fromthe DiabetesPreventionProgramOutcomesStudy(DPPOS)have beenpublished [13] andshowthatthebenefitsoflifestyle intervention andmetforminseenintheDPPstudycontinue over a longerperiod.DPPOSis a long-termfollow-upoftheDPP participantstoinvestigatewhetherthedelayinthedevelopment ofdiabetesobservedduringDPPissustained andto assessthe long-termeffectsoftheinterventionsonhealth.DPPOSfollowed participantsfromtheDPPstudyfor an additional 7 years,during whichtimethelifestyle andmetformingroupswereencouraged tocontinuethoseinterventions, and allparticipantswereoffered grouplifestyleclasses.Over10years,womenwithhistoryof GDM assignedtoplacebohad a 48% higherriskofdeveloping overtdiabetescomparedwithwomenwithout a historyof GDM. Inwomenwith a historyofGDM, “intensivelifestyle” andmetforminreducedprogressiontodiabetescomparedwith placeboby35% and40%,respectively.Amongwomenwithout a historyofGDM, “intensivelifestyle” reducedtheprogressionto diabetesby30%,whilemetformindidnotreducetheprogression todiabetes [13]. AspartoftheongoingDiabetes andWomen’sHealthStudy, a cohortof4554womenfromtheNurses’HealthStudy II whohad a historyofGDM werefollowedupfrom1991to2007. Compared withwomenwhomaintainedtheirtotalphysical activitylevels, womenwhoincreasedtheirtotalphysical activitylevelsby 7.5 MET-h/wkormore(equivalentto150minutesperweekof moderateintensityphysical activity)had a 47% lowerriskof T2DM (RR 0.53; 95% CI,0.38−0.75); the associationremained significant after additional adjustmentforBMI [14]. Increasing physical activitymighthaveloweredtheriskofprogressionfrom GDM toT2DM. Postpartumcareis a critical area thatshouldnotbe overlookedbecauseofthelong-term andintergenerational consequences.However,there aremanybarriersto achieving 8.1.1. Infections Motherswithdiabeteshave anincreasedriskofinfection andthusrequireextra attentioninordertodetectearlysigns ofgenitourinary,uterine, andsurgicalsiteinfections(episiotomy andcesareandelivery),particularlyifthedeliveryhasbeen prolongedorrequiredoperativeintervention.Womenwith diabetesinpregnancy are at a higherriskcomparedwithwomen withGDM.Thelarge-sizedoffspringofdiabeticmothersdonot sucklewell; thismayleadtomilkretention andhigherriskof breast abscess.Apartfromneonateswithinfantrespiratory distresssyndromeorthosewith aspirationduringbirth,therisk ofinfectionintheoffspringofdiabeticmothersisnohigherthan intheoffspringofnondiabeticwomen [1]. 8.1.2. Breastfeeding MotherswithGDM anddiabetesinpregnancyshould beencouraged andsupportedininitiating andmaintaining breastfeeding.Breastfeedinghasbeenshowntobeprotective againsttheoccurrenceofinfant andmaternalcomplications [2],includingreductioninchildhoodobesity,T2DM, and evenT1DM [3–6]. Moreover,breastfeedinghelpspostpartum weightloss.TreatmentwithinsulinorcommonlyusedOADs, such asglyburide andmetformin,isnot a contraindicationto breastfeeding aslevelsofOADmedicationsinbreastmilk are negligible anddonotcausehypoglycemia inthebaby. 8.1.3. Contraception WomenwithGDM anddiabetesshouldbeencouragedto spacetheirpregnanciesinordertomaintain and achieveoptimal healthbetweenpregnancies.This alsohelpsreducetheriskof GDM ordiabetesin a subsequentpregnancy. Inwomenwith diabetes,pregnancyplanninghelpsensurethatconceptioncan occurwhenthemother’smetabolichealthisoptimaltoreduce risksofspontaneous abortionsorcongenitalmalformations. Thesewomenmusthave accessto andshouldreceive advice aboutsafe andeffectivemethodsofcontraception [7,8].With advancesincontraceptivetechnology,clinicianscannowoffer theirpatients a relativelylargerangeofoptionsensuringefficacy, efficiency, andsatisfactionwithregardtoindividualpreferences. 8.1.4. Postpartum glucose testing For allwomendiagnosedwithhyperglycemia forthefirst timeduringpregnancy(GDM anddiabetesinpregnancy),the

  36. S202 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 thisobjective [15].Followingdelivery,womenwithGDM seldom presentwithdiabetes; andthey arenolongerpregnanttherefore unlikelytovisitphysiciansorobstetriciansforcheck-ups.They arethuslikelytobeconsideredlosttofollow-up.However,these womendovisithealthservicesfocusedonthewell-beingof theirbabies(forinstanceforthechild’svaccinationprogram and tomonitorthechild’sgrowth anddevelopment) and arelikelyto doso atregularintervalsfor atleast5years [16].Obstetricians, familyphysicians,internists,pediatricians, andotherhealthcare providersmustlinkpostpartumfollow-upof a GDM mother withthechild’svaccination androutinepediatriccareprogram, toensurecontinuedfollow-up andengagementofthehigh-risk mother−childpair. publishedevidence.Am J ClinNutr2006;84(5):1043–54. [5] GundersonEP.Breastfeeding aftergestationaldiabetespregnancy: subse- quentobesity andtype2diabetesinwomen andtheiroffspring.Diabetes Care2007;30(Suppl2):S161–8. [6] PlagemannA,HarderT,FrankeK,Kohlhoff R.Long-termimpactofneonatal breast-feedingonbodyweight andglucosetoleranceinchildrenofdiabetic mothers.Diabetes Care2002;25(1):16–22. [7] SkoubySO, Mølsted-PedersenL,PetersenKR. Contraceptionforwomenwith diabetes: anupdate.Baillieres ClinObstetGynaecol1991;5(2):493–503. [8] BeydounHA,Beydoun MA,TamimH.Howdoesgestationaldiabetes affectpostpartumcontraceptioninnondiabeticprimiparouswomen? Contraception2009;79(4):290–6. [9] MetzgerBE,BuchananTA, CoustanDR,deLeiva A,DungerDB,HaddenDR, et al.Summary andrecommendationsoftheFifth InternationalWorkshop- ConferenceonGestationalDiabetes Mellitus.Diabetes Care2007;30(Suppl 2):S251–60. [10] AmericanDiabetesAssociation.Standardsofmedicalcareindiabetes--2011. Diabetes Care2011;34(Suppl1):S11–61. [11] WorldHealthOrganization.Diagnostic Criteria and Classificationof Hyperglycaemia FirstDetectedinPregnancy.http://apps.who.int/iris/bit- stream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf.Published2013. [12] Ratner RE, Christophi CA, MetzgerBE,Dabelea D,BennettPH,Pi-Sunyer X, et al.Preventionofdiabetesinwomenwith a historyofgestationaldiabe- tes: effectsofmetformin andlifestyleinterventions. J ClinEndocrinol Metab 2008;93(12):4774–9. [13] Aroda VR, Christophi CA,EdelsteinSL,ZhangP,HermanWH,Barrett-Connor E,et alTheeffectoflifestyleintervention andmetforminonpreventingor delayingdiabetes amongwomenwith andwithoutgestationaldiabetes: thediabetespreventionprogramoutcomesstudy10-yearfollow-up. J Clin Endocrinol Metab2015;100(4):1646–53. [14] BaoW,TobiasDK,BowersK, Chavarro J,VaagA,GrunnetLG,et al.Physical activity andsedentarybehaviors associatedwithriskofprogressionfrom gestationaldiabetesmellitustotype2diabetesmellitus: a prospective cohortstudy. JAMA Intern Med2014;174(7):1047–55. [15] NielsenKK,KapurA,DammP,de Courten M,Bygbjerg IC.Fromscreeningto postpartumfollow-up - thedeterminants andbarriersforgestationaldiabe- tesmellitus(GDM)services, a systematicreview.BMC Pregnancy Childbirth 2014;14:41. [16] KapurA.Pregnancy: a windowofopportunityforimprovingcurrent and futurehealth. Int J GynecolObstet2011;115(Suppl1):S50–1. •FIGOencouragesobstetricianstoestablishconnections withfamilyphysicians,internists,pediatricians, and otherhealthcareproviderstosupportpostpartumfollow- upofGDM motherslinkedtotheregularcheck-up and vaccinationprogramofthechildtoensurecontinued engagementofthehigh-riskmother−childpair. References [1] LinderN,LahatY,KoganA,FridmanE,KouadioF, MelamedN,et al. Macrosomic newbornsofnon-diabeticmothers: anthropometricmeasurements andneo- natalcomplications.ArchDis ChildFetalNeonatalEd2014;99(5):F353–8. [2] Mayer-DavisEJ, Rifas-ShimanSL,ZhouL,HuFB, Colditz GA,Gillman MW. Breast-feeding andriskforchildhoodobesity: doesmaternaldiabetesor obesitystatusmatter? Diabetes Care2006;29(10):2231–7. [3] O’Reilly M,AvalosG,Dennedy MC,O’SullivanEP,DunneFP.Breast-feeding is associatedwithreducedpostpartummaternalglucoseintolerance after gestationaldiabetes. Ir Med J 2012;105(5Suppl):31–6. [4] Owen CG, Martin RM,WhincupPH,SmithGD, CookDG.Doesbreastfeed- inginfluenceriskoftype2diabetesinlaterlife? Aquantitative analysisof

  37. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S203 9.Preconceptioncare Preconceptioncareis a setof assessmentmeasures and interventionsundertakenpriortoconception.These are aimed atidentifying andmodifyingmedical,behavioral, andsocial riskstowomen’shealthduringpregnancy,whichmayprevent ormitigate adversepregnancyoutcomes [1]. Pregnanciesshouldbeplanned andmaternal assessment withpossibleinterventionsshouldoccurpriortoconceptionto improvepregnancyoutcome andmaternalhealth [2].Thismay notonlyimproveimmediatematernal,perinatal, andneonatal outcomes,butpossiblymayhavelong-termbeneficialeffects onboththemother andherbaby,lastingwellinto adulthood andimpactingnextgenerationoffspring,throughepigenetic changes andintrauterinefetalprogramming.Keyorganizations havepublishedextensiveguidelines andrecommendations forpreconceptioncare,includingtheAmericanAcademyof Pediatrics,ACOG, andthe CentersforDisease Control and Prevention [3–5]. Itisestimatedthat30%−90% ofwomenhave atleastoneconditionorriskfactor,such as anemia,under nutrition,obesity,diabetes,hypertension, andthyroiddisorders, etc.thatmaybenefitfrom an appropriatepreconception intervention [6,7].However,only30%−50% ofpregnancies are planned andreceiveproperpreconceptioncare [7–14].Thekey challengeisincreasing awareness and acceptanceoftheconcept ofpreconceptioncounseling andtoincrease affordability and accesstopreconceptionservicestowomenofreproductive age. Universalpreconceptioncare, as a concept,isstill a challenge inmostpartsoftheworld,where a significantproportionof womendonothave accesstoprenatalcareorreceiveonlyone ortwoprenatalvisits,theconceptofpreconceptioncareis a far- offgoalbutenvisaged as aninterventionthatcoulddramatically changematernal andneonatalhealth andoutcomes.Screening forconditionssuch asmalnutrition, anemia,overweight and obesity,hypertension,diabetes, andthyroiddysfunctionetc. mayhave a significantimpact.Forwomenwithdiabetes, preconceptioncareis alsocost-saving [15] andyetonlyhalfof thewomenwithdiabetesundergo appropriatepreconception glycemiccontrol [16]. DiscussiononpreconceptioncareinthecontextofGDM not onlyhasrelevanceintermsofrulingoutpre-existingdiabetes, but alsointermsofidentifyingwomenwho are atriskofGDM (asdescribedearlier) andinitiatingtreatment andpreventive care.Onlynormalizingbloodglucoselevelsinthepreconception period andinearlypregnancywillreducetherateofcongenital malformationsseenwithmarkedmaternalhyperglycemia. In thiscontext,postpartumcareofGDM womenispreconception carefor a subsequentpregnancy.Preconceptioncare as an opportunityforpredicting andpreventingnoncommunicable diseaseshasbeendescribedin a reviewbyHaderet al. [16] •FIGOcallsforpublichealthmeasurestoincrease awareness and acceptanceofpreconceptioncounseling andtoincrease affordability and accesstopreconception servicestowomenofreproductive age, asthisislikelyto havebothimmediate andlastingbenefitsformaternal and childhealth. References [1] CentersforDisease Control andPrevention. Recommendationstoimprove preconceptionhealth andhealthcare—UnitedStates: A Reportofthe CDC/ ATSDR Preconception CareWorkGroup andtheSelectPanelonPreconception Care.http://www.cdc.gov/MMWR/PDF/rr/rr5506.pdf.PublishedApril21, 2006. [2] Cox M,Whittle MJ,ByrneA,Kingdom JC, RyanG.Prepregnancycounselling: experiencefrom1,075cases.Br J ObstetGynaecol1992;99(11):873–6. [3] American CollegeofObstetricians andGynecologists.ACOG Committee Opinionnumber313,September2005.Theimportanceofpreconcep- tioncareinthecontinuumofwomen’shealthcare.ObstetGynecol 2005;106(3):665–6. [4] American CollegeofObstetricians andGynecologists.Guidelinesforwom- en’shealthcare.SecondEdition.Washington,DC: American Collegeof Obstetricians andGynecologists; 1996. [5] AmericanAcademyofPediatrics,American CollegeofObstetricians and Gynecologists.Guidelinesforperinatalcare.FifthEdition.ElkGroveVillage, IL: AmericanAcademyofPediatrics; 2002.Washington,DC: American CollegeofObstetricians andGynecologists; 2002. [6] Adams MM,BruceFC,ShulmanHB,Kendrick JS,BroganDJ.Pregnancyplan- ning andpre-conceptioncounseling.ThePRAMSWorkingGroup.Obstet Gynecol1993;82(6):955–9. [7] Kim C,Ferrara A, McEwenLN, MarreroDG,Gerzoff RB,HermanWH,et al. Preconceptioncareinmanagedcare: thetranslatingresearchinto actionfor diabetesstudy.Am J ObstetGynecol2005;192(1):227–32. [8] CommitteeonPerinatalHealth.Towardimprovingtheoutcomeofpregnancy (TOIP II): the90s andbeyond.WhitePlains,NY: MarchofDimes,National Foundation; 1993. [9] USDepartmentofHealth andHumanServices. Caringforourfuture: the contentofprenatalcare. ReportofthePublicHealthServiceExpertPanelon the ContentofPrenatal Care.Washington,DC: USDepartmentofHealth and HumanServices,PublicHealthService; 1989. [10] JackBW, CulpepperL.Preconceptioncare. Riskreduction andhealthpromo- tioninpreparationforpregnancy. JAMA1990;264(9):1147–9. [11] JackBW, CulpepperL.Preconceptioncare. J FamPract1991;32(3):306–15. [12] FreyKA.Preconceptioncarebythenonobstetricalprovider. Mayo ClinProc 2002;77(5):469–73. [13] Moos MK.Preconceptionalhealthpromotion: opportunities abound. Matern ChildHealth J 2002;6(2):71–3. [14] Moos MK.Preconceptionalwellness as a routineobjectiveforwomen’s healthcare: anintegrativestrategy. J ObstetGynecolNeonatalNurs 2003;32(4):550–6. [15] ReeceEA,Homko CJ.Prepregnancycare andthepreventionoffetalmal- formationsinthepregnancycomplicatedbydiabetes. ClinObstetGynecol 2007;50(4):990–7. [16] HaderE,AshwalE,Hod M.Thepreconceptionalperiod as anopportunityfor prediction andpreventionofnoncommunicabledisease.BestPract Res Clin ObstetGynaecol2015;29(1):54–62.

  38. S204 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 10.Researchpriorities Pregnancyoffers a windowofopportunitytoprovidematernal careservicesinordertoreducetraditionalmaternal and perinatalmorbidity andmortalityindicators and alsoto address intergenerationalpreventionofnoncommunicablediseases,such asdiabetes,hypertension,cardiovasculardisease, andstroke.The relevanceofGDM as a priorityformaternalhealth anditsimpact onthefutureburdenofnoncommunicablediseasesisnolonger indoubt; buthowbesttodealwiththeissueremainsrelatively unclear asthere aremanyunansweredquestions.The available evidenceisoftennotdefinitive,thorough,orbasedonoptimum qualitydata.There aremanygapsinthisrealmofknowledge. However,thisshouldnotbe anexcuseforinaction. TheFIGO InitiativeonGDM isbasedoncurrent available evidence andbestpractice,expertopinion, andconsensus.FIGO acknowledgesthatthere aremajorgapsinknowledgeonhow besttoprevent,diagnose, andmanageGDM tooptimizecare and outcomes,before,during, and afterpregnancyfortheimmediate andlong-termhealthofboth a mother andheroffspring.These questionscanbestbe answeredonlythroughfurtherresearchin pregnancytoensurethatthewindowofopportunitymentioned aboveisfullyrealized.FIGOencourages allrelevantstakeholders to advocate,promote,support,carryout, andfundresearch to addressthemanyknowledgegaps andresearchpriorities identified anddescribedinAppendix3. •FIGOencourages allrelevantstakeholdersto advocate, promote,support,carryout, andfundresearchto address themanyknowledgegaps andresearchprioritiesinGDM.

  39. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S205 11.Appendices Appendix1. Current approachestoGDM diagnosisinselectedcountries Appendix 1a Why the diagnostic cut-off point of 2 hour 75 g ≥7.8 mmol/L (140 mg/dL)? Experience from India: The Diabetes in Pregnancy Study Group in India (DIPSI) test • DIPSI guidelineswereinitiatedbeforetheWHO accepted andendorsedthe IADPSGguideline andhavenowbeen ratifiedbythe MinistryofHealth andotherprofessional bodies.TheDIPSI guidelinefollowstheoldWHO2hourcut- offvalue. Astudytosupportthesinglenonfasting2-hour 75-g testwith a standardfasting 75-gOGTTwasdoneusing the ≥7.8mmol/L(140mg/dL)diagnosticcut-off, and demonstratednostatisticallysignificantdifferenceinthe glycemicprofile at2hoursbetweenthenonfasting and standardOGTTinthediagnosisofGDM [5,6]. Giventhepositiverelationshipofpoorpregnancyoutcomes withincreasingmaternalplasma glucosevaluesinshort Asian Indianwomenwith a relativelysmallpelvis, a cut-off valuebasedon a loweroddsratio(1.5ofHAPOdata)for macrosomia correspondingto a 2-hourvalueof 7.8mmol/L or140mg/dLoftheearlierWHOcriteria isconsideredmore appropriatetoidentifythose atriskformacrosomia-related birthcomplications. TreatmentofwomenwithGDM identifiedwith2-hour post-75gglucosecut-offvalues ≥7.8mmol/L(140mg/dL)is associatedwithreduced adversepregnancyoutcomes [7]. Asian Indians areconsideredtobe atthehighestriskof gestationaldiabetes.Basedonstudiesfrom India andkeepingin mindthe alreadyhighburden andrisingprevalenceofdiabetes andtherealitiesofresourceconstraintswithinthehealthsystem in India, aswell asthehighrateofdeliveries(27 millioneach year),theDiabetesinPregnancyStudyGroupin India (DIPSI) developedthefollowingguidelinefordiagnosisofGDM inthe community [1].Thisguidelinehasbeenendorsedbythe Ministry ofHealth,Governmentof India,theFederationofObstetrics and GynecologicalSocietiesof India (FOGSI), andtheAssociationof Physiciansof India (API). • • Who to test? The target population Allpregnantwomeninthecommunityshouldbetestedfor hyperglycemia duringpregnancy,i.e.thereshouldbeuniversal testing. • When to test? TestingforGDM isrecommendedtwiceduringprenatalcare. Thefirsttestingshouldbedoneduringfirstprenatalcontact asearly aspossibleinpregnancy.Thesecondtestingshouldbe doneideallyduring24−28weeksofpregnancyifthefirsttestis negative. Ifwomenpresentbeyond28weeksofpregnancy,only onetestistobedone atthefirstpointofcontact. Appendix 1b Experience from China: Using fasting plasma glucose values to reduce the number of OGTTs China isfacing a hugeburdenofdiabetes.Theoverall prevalenceofdiabetesinthe Chinese adultpopulationis estimatedtobe11.6%: 12.1% amongmen and11.0% amongwomen. Theprevalenceofpre-diabetesis50.1% in Chinese adults: 52.1% inmen and48.1% inwomen. In approximatelytwo-thirdsofthe cases,theconditionhadnotpreviouslybeendiagnosed [8].Of theparticipantswithundiagnoseddiabetes(44.1% ofmen and 50.2% ofwomen),46.6% haveisolatedincreased2-hourplasma glucoselevels after anOGTT and a fastingglucoselevel alone wouldhavefailedtoidentifythesecases [9].As ageofonset ofdiabetesisdecreasing,theriskthatyoungwomenmayhave undiagnosedT2DM whentheybecomepregnantisquitereal as istheriskofGDM.GDM prevalencein China hasbeenreported tobe ashigh as17.5% [10]. The MinistryofHealthin China publisheditsrecommendations fortesting anddiagnosisofGDM in2011 [11].Accordingtothis, fastingplasma glucosemeasurementor 75-g2-hourOGTT shouldbetaken atfirstprenatalvisittoruleoutpre-existing diabetes.Fastingplasma glucose ≥7.0mmol/Lor ≥126mg/dL, or 75-g2-hourOGTT ≥11.1mmol/Lor ≥200mg/dL,orrandom plasma glucose ≥11.1mmol/Lor ≥200mg/dL areconsidered diagnosticofpre-existingdiabetes. ThediagnosisofGDM isbasedon a single-step 75-g2-hour OGTTdonebetween24 and28weeksofpregnancy.Thecut-off pointsfordiagnosisofGDM are0hour: 5.1mmol/Lor92mg/ dL; 1hour: 10mmol/Lor180mg/dL; and2hour: 8.5mmol/Lor 153mg/dL. ToreducethenumberofOGTTstobedone among allpregnant women at24 and28weeksofpregnancyithasbeensuggested thatthefastingplasma glucosetestmaybedonefirstusing a rulein/ruleout approach. Ifthefastingplasma glucosevalueis How to test? Testfordiagnosisshouldbesimple,economical, andfeasible bothwithintheresourcechallengedpublichealthsystem aswell astheequallyoverburdened andbusyprivatepractice. TheSingleStepTestmeasuresplasma glucose2hours after ingestionof 75gglucosedissolvedin approximately300mL waterirrespectiveofthelastmeal(fastingornonfasting). Inthe absenceof availablelaboratoryfacilities a plasma standardized glucometermaybeusedtoevaluatebloodglucose.Aglucose levelof ≤7.8mmol/Lor ≤140mg/dListaken asthecut-offfor diagnosisofGDM. Advantages of the DIPSI test • Singletest: Serves asbothscreening anddiagnostic procedure(universaltestingispossible).Fastingvalues alonefailtodetectmanywomenwithGDM particularlyin theAsiansetting. Convenient andfeasible: Mostwomendonotcomefasting fortheprenatalvisit [2].When askedtocomeback again inthefastingstateforthetest,thedropoutrateishigh [3,4] owingtotraveltime andcost; evenifwomendocome fasting,theirfastinggetsundulyprolongedbecauseofclinic schedules andhighpatientvolume,causingdiscomfort and inconvenience.Thenonfastingtestincreasesconvenience aswell asimplementationfeasibility.Usingtheglucometer provides anopportunitytocommunicateresultsinstantly andinitiatecounselingright away, avoidingtheneedforthe patienttoreturnfortestresult. •

  40. S206 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 lessthan4.4mmol/Lor80mg/dL,nofurthertestingisneeded [12].Forvalues above5.1mmol/Lor92mg/dLnofurthertesting isneeded andGDM canbediagnosedwithout anOGTT.Pregnant womenwithfastingglucosevaluesbetween4.4 and5.1mmol/L mustundergo a 75-g2-hourOGTTtofurtherconfirmorruleout GDM.Usingthisstrategy,onlyhalfofpregnantwomenwould require a formalOGTT [12]. Ifplasma-standardizedglucometers areused,womenrequiring anOGTTbasedontheresultsofthe fastingvaluemaybe administeredthe 75-gglucoseload and furthertestingcanbecontinuedinthesamesitting. Acomprehensivestudyfrom China [10] alsoshowedthatin Chinesewomen, a fastingplasma glucosevalue ≥5.1mmol/L or ≥92mg/dL atfirstprenatalvisitcannotbeusedtodiagnose GDM.Thestudyshowsthatlessthanone-thirdofwomenwith a fastingplasma glucosevalue >5.1mmol/Lor ≥92mg/dL at thefirstprenatalvisitshowed a fastingplasma glucosevalue >5.1mmol/Lor ≥92mg/dL at24–28weeksofpregnancy.Only 38.9% ofwomenwithfastingplasma glucosebetween5.1 and 6.09mmol/L(92−109mg/dL) atfirstprenatalvisitwenton todevelopGDM at24to28weeks; whereas abouttwo-thirds (66.2%)ofpregnantwomenwithfastingplasma glucosevalues between6.1 and 7.0mmol/L(110−125mg/dL) atfirstprenatalvisit developGDM at24to28weeks.Thestudyproposesthatwomen withfastingplasma glucosevalues ≥6.1mmol/L and <7.0mmol/L (110−125mg/dL) atfirstprenatalvisitmaybeconsideredtohave GDM andbetreatedwithdiet andexercise.Theymustundergo a 75-gOGTTbetween24 and28weeksofpregnancytoconfirm thediagnosisofGDM.Halfofthewomenwithfastingplasma glucosebetween5.6 and6.09mmol/L(92−109mg/dL)developed GDM andshouldthereforebeconsidered as a high-riskgroup forGDM.Proper attentionmustbepaidtotheirnutrition and exercise andtheymustundergo a formal 75-g2-hourOGTT between24 and28weeksofpregnancy. • Universalsingle-steptestingwith 75-gOGTT at 24–28weeksofpregnancyfor allpregnantwomennot previouslyknowntohaveprepregnancydiabetesor hyperglycemia inpregnancy. Womenwithriskfactorsforhyperglycemia inpregnancy shouldbetestedearlyinpregnancy.Someofthese riskfactorsinclude: prepregnancyBMI >30; previous macrosomia (babywithbirthweight >4500gor >90th centile); previoushyperglycemia inpregnancy; age ≥40years; Asian, Indiansubcontinent,Aboriginal,Torres Strait Islander,Pacific Islander, Maori, MiddleEastern, non-whiteAfricanethnicbackground; familyhistoryoffirst degreerelativewithdiabetesor a sisterwithhyperglycemia inpregnancy; PCOSetc.Themethodoftestingmustbe basedonclinicaljudgment,localhealthcarepolicy, and possibleriskstratification. TheuseofWHO2013recommendationsforthe classification anddiagnosisofhyperglycemia firstdetected at anytimeduringpregnancy. • • Appendix 1e National Institute for Health and Care Excellence (NICE) Guideline 3 (UK) NICEpublished anupdatetoits2008guidanceonDiabetesin PregnancyonFebruary25,2015 [18].Bythetimethisdocument became availablepublicallytheFIGOGDM Initiativewriting grouphadfinalizeditsdocument andrecommendations, anddid nothavetimetofullyreviewthisdocument. ThekeyfeaturesoftheNICE Recommendations arethe following: • NICEguidancedoesnotrecommenduniversaltestingfor GDM. • NICEguidancerecommendsearlytesting(assoon as possible afterbooking,whetherinthefirstorsecond trimester)with a 75-g2-hourOGTTonlyforwomenwith historyofGDM in a previouspregnancy andforwomen withglycosuria of2+ or aboveon1occasionorof1+ or aboveon2ormoreoccasionsdetectedbyreagentstrip duringroutineprenatalcareincurrentpregnancy. • NICEguidancerecommendstestingforGDM with a 75-g 2-hourOGTTbetween24 and28weeksofpregnancyonly forwomenwiththefollowingriskfactors: – BMI >30 – Previousmacrosomicbabyweighing4.5kgor above – PreviousGDM – Familyhistoryofdiabetes(first-degreerelativewith diabetes) – Minorityethnicfamilyoriginwith a highprevalenceof diabetes • Cut-offvaluesfordiagnosingGDM are: – Fastingplasma glucose ≥5.6mmol/Lor ≥100mg/d – 2-hourplasma glucose ≥7.8mmol/Lor ≥140mg/dL • Indecidingontherecommendationforriskfactorbased testingversusuniversaltesting andthecut-offvalues,the NICEguidance, apartfromother availableevidence, also reliedonthecost-effectivenessofdifferenttestingoptions (universalversusriskfactorbased) andcut-offvalues primarilyusingdata fromtheHyperglycemia andAdverse PregnancyOutcomes(HAPO)studycentersintheUK and Australia—representingthepopulationoftheUK. • NICEguidancedoesnotdistinguishbetweendiabetes firstdiagnosedduringpregnancy andGDM.Anylevelof glycemia abovethecut-offlevelsdiagnosedforthefirst timeduringtheindexpregnancyisconsideredGDM. Appendix 1c Latin American practice Atthetimeofbooking/firsttrimester, a fastingplasma glucosetestisdonetoruleoutovertdiabetes(≥7 mmol/Lor >126mg/dL). • Valuesunder5.6mmol/Lor100mg/dL areconsidered normal and a 75-g2-hourOGTTisdonebetween24 and 28weeksofpregnancy. • Valuesbetween5.6 and6.9mmol/Lor100 and125mg/dL areconsidereddiagnosticforGDM. Cut-offvaluefor a 75-g2-hourOGTT at24to28weeks: • ≥7.8mmol/Lor ≥140mg/dLisconsideredGDM. • <140mg/dLisnormal.However,ifthepatienthasrisk factors,thetestisrepeatedbetween31 and33weeks. Thecut-offpoint 7.8mmol/Lor >140mg/dLissupported bytheACHOIStrial [13] andtheBrazilianGestationalDiabetes StudyGroupdata [14] andotherstudies [15,16]. Preliminarydata analysisfrom anongoingmulticenterstudy comparingmaternal andneonataloutcomesin4000pregnant womeninLatinAmerica showsthattheincidenceofmacrosomia amongtheoffspringofmotherswithfastingplasma glucose between92 and99mg/dL andnotreceiving anytreatmentis similartothatofthewholepopulation. Appendix 1d ADIPS consensus guidelines for the testing and diagnosis of hyperglycemia in pregnancy in Australia and New Zealand TheADIPSconsensusguidelines [17] recommend:

  41. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S207 Appendix 1f Criteria for gestational diabetes in Europe at 24-28 weeks of pregnancy Gestational diabetes: Situation in middle-eastern countries Inthebeliefthatuseof a uniform2-hour 75-gOGTTin pregnancywiththesamediagnosticcriteria acrossEuropewill leadtosimplification andfacilitateresearchonGDM within Europe,EBCOGhasproposedtheuseofthe 75-gOGTT andWHO 2013diagnosticcriteria forGDM at24−28weeksofpregnancy. However,owingtolackofconsensus,noclearrecommendation hasbeenmadeonwhetheruniversalone-step,two-step,or a selectiveriskfactor-basedscreening approachshouldbeused. TheregionalofficeoftheWHOin Cairolists21countriesin theEastern Mediterranean Region.Theyincludecountriesthat: (1) are affluent(e.g.SaudiArabia, Qatar,UAE,SaudiArabia, Oman,Kuwait); (2)have averageincome(Tunisia,Egypt,Syria, Lebanon, Morocco); and(3)havelowincome(Sudan,Somalia). Theprevalenceofdiabetes(andgestationaldiabetes)inthe sixrichestcountriesintheEastern Mediterranean Regionis amongthehighestintheworld, at approximately20% [19].The overallprevalenceofGDM in allEastern Mediterraneancountries is14.5% (3.5%−26.2%)usingtheWHO1999criteria.Thefollow- up afterdeliverythatcouldpotentiallyreducetheepidemicof diabetesmellitusinthesehigh-riskpopulationsispoor. Ingeneral,information aboutGDM guidelines andcriteria fordiagnosis aresketchy and,whenpresent,outdated.Among thewebsitesofthecountriesexamined,none—includingthe WHOregionalofficein Cairo [20]—mentionedthe International AssociationofDiabetesinPregnancyStudyGroups(IADPSG)/ WHO2013criteria. A2012physiciansurvey [21] assessedthecurrentregional practicesofscreening,diagnosis, andfollow-upofGDM and knowledgeofHAPO and IADPSGwithinsevenhospitalsinUAE andoneinOman.Physiciansused a multitudeofcriteria forGDM: NationalDiabetesData Group(NDDG1979),AmericanDiabetes Association(ADA2010),WHO1999,AustralasianDiabetesin PregnancySociety(ADIPS1998), andtheNewZealandSociety forStudyofDiabetes(NZSSD2011).Therewasnoconsistency within andbetweenhospitals.Approximately60% physicians were awareofHAPOor IADPSG. More awareness andeducation ofcaregiverswouldmakethediscordant approachtoGDM (within andbetweenhospitals)moreharmonious. Postpartum screening strategy for glucose intolerance in women with a history of GDM ThecurrentEBCOGproposalistoscreenwomenwith a history ofGDM at6−12weekspostpartumusingthe2-hour 75-gOGTT withnonpregnancydiagnosticcriteria.Womenwith a history ofGDM shouldhavelifelongscreeningforthedevelopmentof diabetesorprediabetes, atleastevery3years.Ascurrentlythere isinsufficientevidencetorecommendonetestovertheother; HbA1C,FPG,or 75-g2-hourOGTT are allconsidered appropriate totestfordiabetes andprediabetesinthepostpartumperiod. Womenwith a historyofGDM foundtohaveprediabetesshould receivespecificlifestyleinterventionswithorwithoutmetformin topreventdiabetes.EBCOGhas alsodevelopedstandardsofcare forobesewomen [23] andrecommendsthesebetakeninto accountwhenprovidingpostpartumcare. References [1] SeshiahV,BalajiV,ShahSN, JoshiS,DasAK,SahayBK,et al.Diagnosisof gestationaldiabetesmellitusinthecommunity. J AssocPhysicians India 2012;60:15–7. [2] SeshiahV,BalajiV,Balaji MS,Sanjeevi CB,GreenA.Gestationaldiabetesmel- litusin India. J AssocPhysicians India 2004;52:707–11. [3] DivakarH, Manyonda IT.Battlingtherisingprevalenceofgestationaldiabe- tesin India: Arecliniciansontherighttrack? JournalofNeonatal−Perinatal Medicine2012;5(3). [4] InternationalAssociationofDiabetes andPregnancyStudyGroups ConsensusPanel, MetzgerBE,GabbeSG,PerssonB,BuchananTA, Catalano PA,et al. International associationofdiabetes andpregnancystudygroups recommendationsonthediagnosis andclassificationofhyperglycemia in pregnancy.Diabetes Care2010;33(3):676–82. [5] Anjalakshi C,BalajiV,Balaji MS,Ashalata S,SuganthiS,ArthiT,et al.Asin- gletestproceduretodiagnosegestationaldiabetesmellitus.Acta Diabetol 2009;46(1):51–4. [6] BalajiV,Balaji M,Anjalakshi C, Cynthia A,ArthiT,SeshiahV.Diagnosisofges- tationaldiabetesmellitusinAsian-Indianwomen. Indian J Endocrinol Metab 2011;15(3):187–90. [7] Crowther CA,Hiller JE, Moss JR, McPheeAJ, JeffriesWS, Robinson JS,et al. Effectoftreatmentofgestationaldiabetesmellitusonpregnancyoutcomes. NEngl J Med2005;352(24):2477–86. [8] XuY,WangL,He J,BiY,Li M,WangT,et al.Prevalence andcontrolofdiabetes in Chinese adults. JAMA2013;310(9):948–59. [9] YangW,Lu J,Weng J, Jia W, JiL, Xiao J,et al.Prevalenceofdiabetes among men andwomenin China.NEngl J Med2010;362(12):1090–101. [10] ZhuWW,FanL,YangHX,KongLY,SuSP,WangZL,et al.Fastingplasma glu- cose at24-28weekstoscreenforgestationaldiabetesmellitus: newevi- dencefrom China.Diabetes Care2013;36(7):2038–40. [11] YangHX.Diagnosticcriteria forgestationaldiabetesmellitus(WS331-2011). Chin Med J (Engl)2012;125(7):1212–3. [12] ZhuWW,YangHX,WeiYM,Yan J,WangZL,Li XL,et al.Evaluationofthe valueoffastingplasma glucoseinthefirstprenatalvisittodiagnosegesta- tionaldiabetesmellitusinchina.Diabetes Care2013;36(3):586–90. [13] Crowther CA,Hiller JE, Moss JR, McPheeAJ, JeffriesWS, Robinson JS.Effectof treatmentofgestationaldiabetesmellitusonpregnancyoutcomes.NEngl J Med2005;352(24):2477–86. [14] Schmidt MI,DuncanBB, ReicheltAJ,BranchteinL, Matos MC, Costa eForti A,et al.Gestationaldiabetesmellitusdiagnosedwith a 2-h 75-goralglu- cosetolerancetest and adversepregnancyoutcomes.Diabetes Care 2001;24(7):1151–5. [15] WendlandEM,Torloni MR,Falavigna M,Trujillo J,Dode MA, Campos MA, et al.Gestationaldiabetes andpregnancyoutcomes--a systematicreview oftheWorldHealthOrganization(WHO) andthe InternationalAssociation Appendix 1g The European Board and College of Obstetrics and Gynaecology (EBCOG) proposal on screening for gestational diabetes and on the management for obesity Developing a consensusonscreeningforGDM inEurope ischallengingowingtodiversityofethnicpopulations and healthcaredeliverysystems acrossEurope.AftertheWHO 2013recommendationswerereleased,manynationalsocieties withinEuropehaveeitherrevisedor areconsideringrevising theirguidelines.However,mostnationalsocietiesinEuropedo notrecommend a universalone-stepscreeningstrategywith an OGTT,inpartbecauseofthe associatedworkload andcosts. Asteeringcommittee, appointedbyEBCOG,hasdeveloped a proposalfortheuseofuniformdiagnosticcriteria forGDM in Europe [22]. Screening for overt diabetes in early pregnancy Sincethefrequencyofobesity andT2DM inyoung adultsis increasinginEurope and astheuseof a simplescreeningtestwill leadtomorewomenbeingtimelydiagnosedwithovertdiabetes, thesteeringgrouprecommendsscreeningforovertdiabetes at preconceptionor atfirstprenatalcontact,especiallyinhigh-risk groupsusingthecut-offvaluesfordiabetesoutsidepregnancy. Duetothelackofclearevidenceonwhichwomenwould benefitmostfromscreening andtreatmentofGDM inearly pregnancy andwhichscreeningstrategyforGDM shouldbeused, thesteeringgrouphasnotmade anyrecommendationsonwhich diagnosticcriteria forGDM shouldbeusedinearlypregnancy.

  42. S208 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 ofDiabetesinPregnancyStudyGroups(IADPSG)diagnosticcriteria.BMC Pregnancy Childbirth2012;12:23. [16] deSereday MS,Damiano MM,González CD,BennettPH.Diagnosticcrite- ria forgestationaldiabetesinrelationtopregnancyoutcome. J Diabetes Complications2003;17(3):115–9. [17] NankervisA, McIntyreHD, Moses R, RossGP, CallawayL,Porter C,et al.ADIPS ConsensusGuidelinesfortheTesting andDiagnosisofHyperglycaemia in PregnancyinAustralia andNewZealand.http://adips.org/downloads/2014 ADIPSGDMGuidelinesV18.11.2014_000.pdf. ModifiedNovember,2014. [18] National Collaborating CentreforWomen’s and Children’sHealth.Diabetes inpregnancy. Managementofdiabetes anditscomplicationsfromprecon- ceptiontothepostnatalperiod.NICEGuideline3. Methods,evidence and recommendations. http://www.nice.org.uk/guidance/ng3/evidence/full- guideline-3784285.PublishedFebruary25th,2015.Accessedon March12, 2015. [19] InternationalDiabetesFederation. IDFAtlas.SixthEdition.Brussels,Belgium: InternationalDiabetesFederation; 2013. [20] KhatibOM.Guidelinesfortheprevention,management andcareofdia- betesmellitus.WorldHealthOrganization RegionalOfficefortheEastern Mediterranean.EMROTechnicalPublicationsSeries(2006).http://applica- tions.emro.who.int/dsaf/dsa664.pdf.Published2006. [21] Agarwal MM,ShahSM,AlKaabi J,SaquibS,OthmanY.Gestationaldiabetes mellitus: Confusion amongmedicaldoctorscausedbymultipleinternational criteria. J ObstetGynaecol Res2015;41(6):861−9. [22] Benhalima K, Mathieu C,DammP,VanAsscheA,Devlieger R,DesoyeG,et al. Aproposalfortheuseofuniformdiagnosticcriteria forGestationalDiabetes inEurope: anopinionpaperbytheEuropeanBoardAnd CollegeofObstetrics & Gynaecology(EBCOG).2015 [Epub aheadofprint] [23] EuropeanBoard and CollegeofObstetrics andGynaecology.Obstetric andNeonatalServices2014.Standard9. CareofObesePregnantWomen. November2014:34.http://www.ebcog.eu/doc/obstetric.pdf

  43. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S209 Appendix2.GestationalDiabetesFormulasfor Cost-Effectiveness(GeDiForCE) TheGeDiForCE(NovoNordisk,Denmark)modelis an Excel-based(Microsoft, Redmond,USA)mathematicalmodel developedtoestimatethecost andhealthimpactofvarious GDM screening andmanagementchoices [1].Themodel aims toinformpolicymakersregardingGDM screeningstrategies andguidelines.GeDiForCEcancompare alternativescreening algorithms,prenatalinterventions, andpostpartumpreventive lifestyleinterventions. Itestimatesthecostperyearofscreening andinterventions,perinatalcomplications, andcasesofT2DM. It alsocalculates averteddisability-adjustedlife-years(DALYs). Themodelisstructuredusing a decisiontreeflowingfrom testing,toprenatalinterventions andperinataloutcomes,to postpartuminterventions andlong-termT2DM outcomes.Key inputsincludetestsensitivity andspecificity,healthoutcome risks, andinterventionefficacyinreducingthoserisks—all derivedfromliterature.Apreviouslydevelopeddiabetesmodel, the COREmodel [2],isusedto assessthecosts andhealtheffects relatedtoT2DM thatoccur afterpregnancyinthemother and heroffspring. Foreveryuse,theGeDiForCEmodelwillbepopulatedwith setting-specificdata onGDM prevalence andcostofGDM screening andmanagement.Themodelhasbeenpilotedinfive differenthealthcarefacilitiesin India and Israel.An analysis ofthecost-effectivenessofGDM screeninginurban China waspresented attheDiabetesinPregnancy(DIP)Symposium inBerlin,April2015,concludingthatGDM screening and interventions arecost-savingin anurban Chinesesettingby IADPSGstandards [3]. Development of GeDiForCE Themodelwasdevelopedbyhealtheconomicexperts andtheoveralldesignofthemodelwasreviewedby a group ofinternationalexpertsinmathematicalmodelling,health economics,gestationaldiabetesrisk andmanagement, and publichealth,inStockholm,September2010, and atworkshops held attheDiabetesinPregnancy(DIP)symposia in2011 and 2013.Themodelwassubsequentlymodified accordingtothe inputsreceived. ThedevelopmentoftheGeDiForCEmodelwasfundedbyNovo NordiskA/S.Themodelismade availableforusefreeofcharge andcanbedownloaded at: www.changingdiabetesaccess.com References [1] LohseN, MarseilleE,Kahn JG.Developmentof a modelto assessthecost- effectivenessofgestationaldiabetesmellitusscreening andlifestyle changeforthepreventionoftype2diabetesmellitus. Int J GynecolObstet 2011;115(Suppl1):S20–5. [2] PalmerAJ, RozeS,ValentineWJ, Minshall ME,FoosV,LuratiFM,et al.The COREDiabetes Model: Projectinglong-termclinicaloutcomes,costs and cost-effectivenessofinterventionsindiabetesmellitus(types1 and2)to supportclinical andreimbursementdecision-making. Curr Med ResOpin. 2004;20(Suppl1):S5–26. [3] ZhangL. Cost-effectiveness analysisofgestationaldiabetesmellitusscreen- ingin Chinesesetting.Paperpresented at: The8th InternationalDIP Symposium: Diabetes,Hypertension, MetabolicSyndrome & Pregnancy; April15-18,2015; Berlin,Germany.

  44. S210 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 Appendix3. Researchprioritiesingestationaldiabetes measurementsoffetal abdominalcircumference). Research isrequiredtoseeifthisis a viableoptionindifferentresource settings andpopulations, andwhatothertoolscanbeusedin the absenceofultrasoundservices.Similarly,inthe absenceof a nonstresstest andbiophysicalprofile,whatothermeasures,such askickcounts,canbeusedto assessfetalwell-being? Needs, capacity, and resource assessment Itis acknowledgedthattheincreasedprevalenceof hyperglycemia inpregnancy,evenwithpotentialrevisedmodels ofcare,willhaveresourceimplications.FIGOcallsfor actionby national associationsincollaborationwithotherstakeholders tosupport andundertakecomprehensivenationalreviewof capacity,trainingneeds, andobstetric andneonatalresource allocationsrelatingtohyperglycemia inpregnancy. Prediction and early testing Hyperglycemia inpregnancyisgenerallydiagnosedinthelate secondorearlythirdtrimester.Prepregnancypredictionmay help addressprevention andearlydetection, andtreatmentmay potentiallyimproveoutcomes.However,thereisnoorlimited evidenceinthis area.Well-designedstudiestodetermine themost appropriatemeansofprepregnancyprediction and testingforgestationaldiabetesinearlypregnancy andexploring outcomesofearlytreatmentinterventions areneeded. Options for risk stratification Not allcitedriskfactorsforhyperglycemia inpregnancy are likelytobeofequivalentpredictivevalue andfurtherresearch isrequiredtodeterminewhethersomeriskfactorscouldbe designated “high.” The ability and accuracyofobstetriccare providerstoconductearlypregnancytestingforhyperglycemia inpregnancybasedonthepotentialstratificationofriskfactors willrequireevaluation andwillbeinfluencedbythefrequency of abnormalglucosetoleranceinthelocalpopulation. Long-term observational cohort studies Whilethere arestudiestoshowthatmaternalGDM or diabetesinpregnancyis associatedwithhigherriskofobesity, earlyonsetT2DM, andmetabolicsyndromeintheoffspring, thereiscurrentlylimitedornoevidencetoshowthatgood glycemiccontrolduringpregnancyresultsinreducedriskto offspring.Similarly,itiswellknownthatGDM increasestherisk ofprogressiontoT2DM butthere arenostudiestoshowwhether thequalityofmetaboliccontrolduringpregnancyinfluencesthe levelofriskorspeedofprogressiontoT2DM inmotherswith GDM. Point of care testing and alternatives to glucose tolerance tests (GTT) Givenconstraintsof access,resources andcapacity, andthe needfortravel,time, andcostsoflaboratory-basedtestingfor GDM inmanypartsoftheworld,thecurrentstrategies are unlikelyto achievetheobjectiveofuniversaltestingforGDM. Thereis a pressingneedtodevelop alternativeconvenient, reliable,quick,lowcost,nonfastingtestingstrategiestodetect GDM atthepointofcareorclosetohome,e.g.moreevidenceon theuseofhandheldglucometersthatcanbeusedbycommunity healthworkers,ornoninvasiveglucosetesting,oruseofglycated serumproteins assurrogatemarkerforhyperglycemia. How to improve postpartum follow-up and preventive care ThebiggesteconomicbenefitofGDM diagnosis andcare emergesfromthe abilitytopreventfuturediabetes andmetabolic syndromeinbothmother andchildthroughpostpartumfollow- up andpreventivecare.Unfortunately, 75%−80% ofwomen are losttofollow-up.Operationalresearchis advocatedto ascertain ifthefollow-upcanbelinkedtothechild’svaccinationprogram andwell-babyclinicsbyidentifyingthemother andchildhigh- riskpairformoreintensivecounselling andfollow-up. Prospective observational studies in low-resource countries to estimate the impact of universal GDM testing, diagnosis, and care on pregnancy outcomes and maternal and perinatal morbidity and mortality DespitethatGDM isoneofthemostcommonmedical disordersofpregnancythatincreasestheriskforother pregnancy-associatedmedicaldisorders,such aspregnancy- inducedhypertension,pre-eclampsia,etc—allcontributing topooroutcomes—screeningforGDM inmostlow-resource countriesis anexceptionratherthantherule. Itsoverall negativeimpactonmaternaloutcomesisthereforeperhaps underestimated. Studieslooking atpregnancyoutcomesincentersinlow- resourcecountrieswithsimilarclinicalsettingsrandomized toeitherimplement a universalGDM testing,diagnosis, and standardtreatmentprotocol,orthecurrentstatus-quo approach, wouldhelpdeterminethetruedirect andindirectimpactof hyperglycemia inpregnancyonpoorpregnancyoutcomes.These studieswillhelp advocateformoreresources andbuildevidence for action. Cost-effectiveness studies Existingpublishedcost/benefit analysesbasedonmodelling suggestedthattestingwomenforGDM andprovidingcare are cost-effectiveinimprovingpregnancyoutcomes andlonger-term maternalhealth.However,nolarge-scalelong-termprospective cohortstudiesweredoneusing actualcosts andoutcomesto assesscost-effectivenessofthedifferenttesting,treatment, and follow-upregimens. Inthe absenceofsuchstudiesitmaybe usefultouselocalinputcostsdata topopulate availablemodels such asGeDiForCEtodevelopcost-effectivenessestimatesfor differentcountries andregions. Treatment targets Metabolomics, microbiome, and micro RNAs Well-designedinterventionstudiesfordeterminingoptimal glucosecontrolforbesttreatmentoutcomes. Studiestosearchformetabolomicsignaturesinwomen withGDM andtheirnewbornscanhelpbetterunderstandthe mechanismsofmanycongenital abnormalities aswell ashelp developdiagnostic andprognosticteststodetectthesechanges andtakepreventive andcorrective actions. Theroleofgutmicrobiomeininfluencinghostmetabolismis onlystartingtoberevealednow.Earlystudiesshowthatchanges Fetal well-being and growth assessment Intensityoftherapyis adjusteddependingontheresults ofultrasonographic assessmentoffetalgrowth(inparticular

  45. M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S211 ingutmicrobialecologycancausemetabolic abnormalities leadingtoobesity anddiabetes.Studiesontheeffectof pregnancyongutmicrobes anditsimpactonmetabolismleading togestationaldiabetes andhypertensioncouldoffersolutions forprevention andmanagementoftheseconditions.Similarly, theinfluenceofmaternalgutmicrobiomeonthecolonizationof theoffspring’sgut anditsconsequentlong-termimpactontheir metabolismis an area forstudythatmayopenupopportunities forprevention. Theevidenceimplicatingmicro RNAs(miRNAs)inthepatho- physiologyofhumandiseaseshastriggeredgreatinterestin developingdiagnostictests aswell asmodalitiestoinhibitor restoremiRNAfunction.TherecognitionthatspecificmiRNAs areinducedbyhypoxia and arecommonlydysregulatedin pre-eclampsia raisesthepossibilitythatsuchmiRNAsmediate the adverseeffectsofplacentalhypoxia inpre-eclampsia.The connectionbetweenmiRNAs, adiposetissue, andinsulinresistance mayhave a roleinGDM pathophysiology aswell.ThesemiRNAs presentinmaternalbloodmayhavethepotentialtobeused as biomarkers, asthey arerelativelystable andtissuespecific.

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  48. Volume 131 Supplement 3 October 2015 ISSN 0020-7292 The International Federation of Gynecology and Obstetrics (FIGO) Initiative on Gestational Diabetes Mellitus: A Pragmatic Guide for Diagnosis, Management, and Care Publication of this Supplement was supported by funding from an unrestricted educational grant provided by Novo Nordisk. The International Federation of Gynecology and Obstetrics (FIGO) Initiative on Gestational Diabetes Mellitus: A Pragmatic Guide for Diagnosis, Management, and Care Ofcial publication of FIGO The International Federation of Gynecology and Obstetrics

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