Diabetes gestacional: determinao de fatores de risco para diabetes mellitus

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ARTICLE IN PRESSG ModelRPEDM-43; No. of Pages 6ADmAMabcdefiHRAOPDDFKDGP1Rev Port Endocrinol Diabetes Metab. 2014;xxx(xx):xxxxxxRevista Portuguesade Endocrinologia, Diabetes e Metabolismowww.elsev ier .p t / rpedmrtigo originaliabetes gestacional: determinac o de fatores de risco para diabetesellitusna Maria Carvalho Ribeiroa, Cristina Nogueira-Silvab,c,d,, Gustavo Melo-Rochae,aria Lopes Pereira f e Afonso RochabUnidade de Sade Familiar de So Joo de Braga, Braga, PortugalServic o de Ginecologia e Obstetrcia, Hospital de Braga, Braga, PortugalInstituto de Cincias da Vida e da Sade (ICVS), Escola de Cincias da Sade, Universidade do Minho, Braga, PortugalICVS/3Bs - Laboratrio Associado do Governo Portugus, Braga/Guimares, PortugalServic o de Endocrinologia, Centro Hospitalar de Vila Nova de Gaia/ Espinho, Vila Nova de Gaia, PortugalServic o de Endocrinologia, Hospital de Braga, Braga, Portugalnformao sobre o artigoistorial do artigo:ecebido a 10 de fevereiro de 2014ceite a 28 de maio de 2014n-line a xxxalavras-chave:iabetes mellitusiabetes gestacionalatores preditivosr e s u m oObjetivos: Identificar fatores preditivos do desenvolvimento de diabetes mellitus (DM) em mulheres comantecedentes de diabetes gestacional (DG).Tipo de estudo: Estudo observacional, analtico, retrospetivo e de coorte.Local: Hospital de Braga.Populac o: Amostra aleatria de 300 mulheres, nascidas antes de 1995, com diagnstico de DG entre1 de janeiro de 2001 e 31 de dezembro de 2010 e seguimento da gravidez no Hospital de Braga.Mtodos: Os dados foram obtidos atravs da consulta de processos clnicos. A lista de doentes com DM,referente ao ano de 2011, foi utilizada para verificac o do desenvolvimento da doenc a no grupo seleci-onado. Foram analisados o perfil sociodemogrfico, os antecedentes pessoais, familiares e obsttricos eoutros fatores anteparto. Foi realizada uma anlise descritiva univariada e bivariada. Seguidamente foi cri-ado um modelo de regresso logstica binria para identificar potenciais preditores de desenvolvimentode DM tipo 2.Resultados: Trinta e dois vrgula sete por cento das mulheres desenvolveu DM. A probabilidade de desen-volvimento de DM aps DG aumentou 8,2 vezes quando idade gestacional menor que 24 semanas nomomento do diagnstico (OR = 8,19; p < 0,001), 3,4 vezes se necessidade de insulinoterapia (OR = 3,36;p < 0,001) e 3,1 vezes se ndice de massa corporal (IMC) prvio 26,4 kg/m2 (OR = 3,07; p = 0,003). Hist-ria familiar de DM tipo 2, 4 valores elevados na prova de tolerncia oral glicose, valor de glicemia emjejum, idade materna no momento do diagnstico e IMC ps-parto, apesar de apresentarem associac ocom desenvolvimento de DM no se revelaram seus preditores. No se verificou associac o entre gravidezprvia ou diagnstico prvio de DG com desenvolvimento de DM.Concluses: Em mulheres com DG, a idade gestacional menor que 24 semanas no momento do diagnstico,a necessidade de insulinoterapia e o IMC prvio 26,4 kg/m2 apresentaram-se como fatores de risco paradesenvolvimento de DM. 2014 Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Publicado por ElsevierEspaa, S.L.U. Todos os direitos reservados.Gestational diabetes: Determination of risk factors to diabetes mellitusComo citar este artigo: Carvalho Ribeiro AM, et al. Diabetes gestacional: determinac o de fatores de risco para diabetes mellitus. RevPort Endocrinol Diabetes Metab. 2014. http://dx.doi.org/10.1016/j.rpedm.2014.05.004eywords:iabetes mellitusestational diabetesredictive factorsa b s t r a c tAims: To identify predictive factors to diabetes mellitus (DM) development in women with history ofgestational diabetes (GD).Study design: An observational, analytic, cohort retrospective study. Autor para correspondncia.Correio eletrnico: cristinasilva@ecsaude.uminho.pt (C. Nogueira-Silva).http://dx.doi.org/10.1016/j.rpedm.2014.05.004646-3439/ 2014 Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Publicado por Elsevier Espaa, S.L.U. Todos os direitos reservados.dx.doi.org/10.1016/j.rpedm.2014.05.004dx.doi.org/10.1016/j.rpedm.2014.05.004www.elsevier.pt/rpedmmailto:cristinasilva@ecsaude.uminho.ptdx.doi.org/10.1016/j.rpedm.2014.05.004ARTICLE IN PRESSG ModelRPEDM-43; No. of Pages 62 A.M. Carvalho Ribeiro et al. / Rev Port Endocrinol Diabetes Metab. 2014;xxx(xx):xxxxxxLocal: Hospital of Braga.Population: A random sample of 300 women, born before 1995, with GD diagnosed since January 1, 2001to December 31, 2010 and pregnancy surveillance in a public Hospital of Braga.Methods: Data was collected by consultation of medical records. The DM patients list of 2011 was used toverification of the disease development in the selected group. Sociodemographic profile, personal, familyand obstetric history, and other antepartum factors were analyzed. A univariate descriptive analysis anda bivariate analysis were performed. A binary logistic regression model was created to identify potentialpredictors of type 2 DM development.Results: 32.7% of women developed DM. The probability of DM development after GD was increased8.2 times when gestational age at diagnosis was less than 24 weeks (OR = 8.19; p < 0.001), 3.4 times withthe need of insulin therapy (OR = 3.36; p < 0.001) and 3.1 times with previous pregnancy body mass index(BMI) 26.4 kg/m2 (OR = 3.07; p = 0.003). Although family history of type 2 DM, maternal age at diagnosis,postpartum BMI, 4 abnormal values in the diagnostic oral glucose tolerance test and fasting glucose levelhad presented association with DM development, did not present as its predictors. It was not verifiedassociation between previous pregnancy or previous GD diagnosis and DM development.Conclusions: In women with GD, gestational age at diagnosis less than 24 weeks, need of insulin therapyand previous pregnancy BMI 26.4 kg/m2 were presented as risk factors to DM development. 2014 Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Published by Elsevier Espaa,S.L.U. All rights reserved.Iptm1iEmp(pmorceatPdcfDMvpa3pfm1loTabela 1Critrios de incluso e exclusoCritrios de incluso Critrios de exclusoSer residente no concelho de Braga Mulheres em que a informac oclnica se apresentava incompletaAno de nascimento prvio a 1995 Mulheres cujo parto no ocorreuno Hospital de Braga e em que ainformac o clnica se apresentavaindisponvelVigilncia da gravidez no Hospital glucose (PTOG)b, necessidade de insulinoterapia, nvel sanguneode glucose).b Em Portugal, at janeiro de 2011, a PTGO com 100 g de glucose foi o teste apro-vado para fazer o diagnstico de DG. Este teste era feito aps um resultado positivono teste de rastreio (teste de OSullivan). O teste de rastreio era realizado imediata-mente aps o diagnstico de gravidez nas mulheres com alto risco de DG e entre as24-28 semanas de gestac o nas restantes grvidas. Era considerado um teste posi-tivo, quando uma hora aps a ingesto de 50 g de glucose existia um nvel de glucoseno sangue igual ou superior a 140 mg/dL. Se fosse obtido um resultado negativo oteste deveria ser repetido s 32 semanas. A PTGO consistia na medic o de 4 valo-ntroduc oA prevalncia de diabetes mellitus (DM) tem aumentadorogressivamente1. Alis, mais de 382 milhes de pessoas emodo o mundo tm diabetes, o que corresponde a 8,3% da populac oundial2. Atualmente, em Portugal, a prevalncia de DM atinge os2,9%2.A diabetes gestacional (DG) definida como qualquer grau dentolerncia glicose com incio ou detec o durante a gravidez3.m Portugal a prevalncia de DG, em 2009 (ainda utilizando otodo de rastreio antigo), foi de 3,9% e atualmente estima-se umarevalncia de 4,8%, valor semelhante ao apresentado pelos EUAaproximadamente 4%)2,4,5. A DG um conhecido fator de riscoara DM6,7. Na ltima dcada, o risco de desenvolver DM aps DGais do que duplicou8. Em comparac o com a populac o em geral, grupo de mulheres com antecedentes de DG apresenta tambmisco aumentado de desenvolvimento de complicac es associadas DM9,10.De forma a estratificar o risco de desenvolvimento de DM e,onsequentemente, reduzir a morbimortalidade associada, vriosstudos procuraram estabelecer os fatores de risco que aumentam probabilidade de desenvolver DM em mulheres com anteceden-es de DG11. No entanto, existem ainda muitas controvrsias e, emortugal, no esto disponveis dados relativos nossa populac o.Assim, o presente estudo pretende contribuir para a definic oestes fatores de risco e apresenta como principais objetivosaracterizar o perfil sociodemogrfico, os antecedentes pessoais,amiliares e obsttricos e outros fatores anteparto de mulheres comG, e determinar os fatores preditores de DM.todosEstudo observacional, analtico, de coorte e retrospetivo. O uni-erso constitudo por mulheres com antecedentes de DG e aopulac o consiste nas mulheres, nascidas antes de 1995, comntecedentes de DG diagnosticada entre 1 de janeiro de 2001 e1 de dezembro de 2010, e com vigilncia da gravidez num hos-ital pblico da regio norte de Portugal (Hospital de Braga). Deorma a evitar a incluso de adolescentes e apresentar uma amostraComo citar este artigo: Carvalho Ribeiro AM, et al. Diabetes gestacionPort Endocrinol Diabetes Metab. 2014. http://dx.doi.org/10.1016/j.rpeais homognea, foram selecionadas mulheres nascidas antes de995. Os critrios de incluso e excluso so apresentados em deta-he na tabela 1. Durante o perodo de tempo a que se reportou estudo foram diagnosticados 986 casos de DG. Obedecendo aosde Bragacritrios de incluso e excluso, obteve-se um valor final de 897mulheres com antecedentes de DG. O tamanho da amostra (n = 300)foi estimado de acordo com Pedhazur12 e tendo em considerac oque o teste estatstico escolhido foi a regresso logstica binria. Deseguida, a determinac o da amostra de 300 elementos foi realizadapor selec o aleatria simples, atravs de um software (randomi-zer.org).O desenho do estudo e protocolo foram aprovados pelaComisso de tica do referido hospital. Utilizando como fontede informac o os processos clnicos individuais, foi recolhidainformac o relativa ao perfil sociodemogrfico (idade atual [em2011], escolaridade e situac o laboral), aos antecedentes pessoais,familiares (ndice de massa corporal [IMC] prvio, IMC ps-parto,histria familiar de DM tipo 2) e obsttricos, e outros fatores ante-parto (gravidez prvia, idade materna no momento do diagnstico,idade gestacional no diagnstico, valores da prova de tolerncia oralal: determinac o de fatores de risco para diabetes mellitus. Revdm.2014.05.004res de glucose no sangue: em jejum, uma hora, 2 horas e 3 horas aps a ingestode 100 g desse ac car. Valores anormais eram respetivamente iguais ou superio-res a 95 mg/dL, 180 mg/dL, 155 mg/dL e 140 mg/dL. O diagnstico era confirmadona presenc a de 2 ou mais valores anormais. Se no fosse confirmado, a prova erarepetida no trimestre seguinte.dx.doi.org/10.1016/j.rpedm.2014.05.004 IN PRESSG ModelRocrinol Diabetes Metab. 2014;xxx(xx):xxxxxx 3f2tirA-PdasanqbdqcfiutARCmeitepdTabela 2Caracterizac o sociodemogrficaCaractersticas sociodemogrficas % (n)Habilitac es literrias1. ciclo 7,3 (22)2. ciclo 30,3 (91)3. ciclo 21,7 (65)Ensino secundrio 20,3 (61)Ensino superior 20,3 (61)Situac o laboralTrabalhador ativo 33,3 (100)Trabalhador inativo* 66,7 (200)ARTICLEPEDM-43; No. of Pages 6A.M. Carvalho Ribeiro et al. / Rev Port EndNo que respeita ao diagnstico de DM, as informac es obtidasoram recolhidas a partir da lista de doentes com DM referente a011, aps solicitac o e obtenc o de autorizac o. Esta lista per-ence ao Agrupamento de Centros de Sade (ACES) de Braga (quenclui todos os centros de cuidados de sade primrios da rea deeferncia do Hospital de Braga).nlise estatsticaOs dados quantitativos so apresentados como mdia desvio-padro. A anlise estatstica foi realizada utilizando o Statisticalackage for the Social Sciences (SPSS, verso22.0). Uma anliseescritiva univariada foi obtida atravs do clculo das frequnciasbsolutas e relativas, medidas de tendncia central e de disper-o, em consonncia com as variveis em estudo. Para estabelecerssociac o entre o desenvolvimento de DM e algumas variveisominais foi realizada uma anlise bivariada usando o teste deui-quadradro (2). Quanto s variveis quantitativas, para esta-elecer diferenc as estatisticamente significativas entre o grupo queesenvolveu DM e o grupo sem a doenc a foi usado o teste t (uma vezue as variveis apresentavam distribuic o normal, com valores deurtose entre 0,132-4,643 e de assimetria entre 0,124-1,147). Paranalizar, foi conduzida uma anlise multivariada com a criac o dem modelo de regresso logstica binria, com o intuito de iden-ificar potenciais preditores de desenvolvimento de DM aps DG. significncia estatstica foi confirmada se p < 0,05.esultadosaraterizaco sociodemogrficaA idade atual da amostra foi de 38 5,1 anos, com uma idadenima de 22 e mxima de 50 anos. Comparando os 2 grupos (com sem desenvolvimento de DM, respetivamente), no que respeita dade atual no se verificaram diferenc a estatisticamente significa-Como citar este artigo: Carvalho Ribeiro AM, et al. Diabetes gestacionPort Endocrinol Diabetes Metab. 2014. http://dx.doi.org/10.1016/j.rpeiva entre as mulheres que desenvolveram a doenc a (39 4,9 anos) as que no desenvolveram (38 5,2 anos) (t [202, 278] = 1,528; = 0,128) (fig. 1). A escolaridade e situac o laboral encontram-seescritas na tabela 2. No momento do diagnstico 30,3% da amostra7% 3%33%42%56%60%[20:30] [30:40] [40:50]Idade (anos)0%20.0%40.0%60.0%Percentagem de mulheresSem DM Com DMFigura 1. Distribuic o da idade atual nos grupos com e sem DM.* Situac es laborais de trabalhador inativo englobam o desemprego e o trabalhodomstico sem remunerac o. %: frequncia relativa; n: frequncia absoluta.tinha completado 6 anos de escolaridade e a maioria das mulheres(66,7%) eram trabalhadoras inativas.Antecedentes pessoais, familiares e obsttricos e outros fatoresantepartoUm IMC prvio 26,4 kg/m2 estava presente em 34% (n = 102)das mulheres e o IMC ps-parto da amostra era de 29,5 4,6 kg/m2(mnimo 20,4 e mximo 48,9 kg/m2). Considerando ahistria familiar, 50% (n = 150) das mulheres com DG tm antece-dentes familiares de DM tipo 2. Relativamente aos antecedentesobsttricos e outros fatores anteparto, 69% (n = 207) das mulherestiveram pelo menos uma gravidez anterior e aproximadamente8% apresentaram diagnstico prvio de DG. A idade materna nomomento do diagnstico era 34 4,8 anos. Doze vrgula setepor cento das mulheres apresentaram idade gestacional menorque 24 semanas no momento do diagnstico. A presenc a de 4valores elevados na PTGO foi verificada em 15% e a necessidadede insulinoterapia em 31%. O valor mdio de glicose em jejum foi85 13,5 mg/dL (tabela 3).Determinac o de fatores preditivos do desenvolvimento dediabetes mellitus em mulheres com antecedentes de diabetesgestacionalDo total de 300 mulheres da amostra, 32,7% (n = 98) desenvolveuDM aps DG. Associac es possveis entre DM e variveis nominaisindependentes foram analisadas (tabela 4). Tal como apresentadona tabela 4, existe relac o estatisticamente significativa entre odesenvolvimento de DM e as variveis IMC prvio 26,4 kg/m2,histria familiar de DM tipo 2, idade gestacional menor que24 semanas no momento do diagnstico, 4 valores elevados naPTGO e necessidade de insulinoterapia. Estas variveis foram maisfrequentes nas mulheres que desenvolveram DM (p < 0,05). Gravi-dez prvia e diagnstico prvio de DG no apresentaram relac oestatisticamente significativa com o desenvolvimento de DM.As possveis associac es entre desenvolvimento de DM eas variveis independentes quantitativas so apresentadas natabela 5. As mulheres que desenvolveram DM apresentavam idadematerna no momento do diagnstico, IMC ps-parto e valor de gli-cemia em jejum superiores de forma estatisticamente significativa(p < 0,05).De forma a identificar potenciais preditores do desenvolvimentode DM em mulheres com antecedentes de DG, foi realizada umaanlise multivariada atravs de um modelo de regresso logs-tica binria. O modelo obtido foi estatisticamente significativo(G2 = 87,49; p < 0,001) e ajustado de forma tambm estatistica-al: determinac o de fatores de risco para diabetes mellitus. Revdm.2014.05.004mente significativa (2HL = 9,55; p = 0,298). A idade gestacionalmenor que 24 semanas no momento do diagnstico aumentou8,2 vezes a probabilidade de desenvolver DM aps DG (oddsratio [OR] = 8,191; 95% IC = 3,295-20,360; p < 0,001), enquanto adx.doi.org/10.1016/j.rpedm.2014.05.004Como citar este artigo: Carvalho Ribeiro AM, et al. Diabetes gestacional: determinac o de fatores de risco para diabetes mellitus. RevPort Endocrinol Diabetes Metab. 2014. http://dx.doi.org/10.1016/j.rpedm.2014.05.004ARTICLE IN PRESSG ModelRPEDM-43; No. of Pages 64 A.M. Carvalho Ribeiro et al. / Rev Port Endocrinol Diabetes Metab. 2014;xxx(xx):xxxxxxTabela 3Antecedentes obsttricos e outros fatores pr-parto da amostraAntecedentes obsttricos e fatoresanteparto% (n) M DP Mediana Moda Max MinGravidez prvia 69,0 (207) NA NA NA NA NA NADiagnstico prvio de DG 7,7 (23) NA NA NA NA NA NAIdade materna no momentodo diagnsticoNA 34 4,8 33 33 44 19Idade gestacional menor que24 semanas no momentodo diagnstico12,7 (38) NA NA NA NA NA NA4 valores alterados na PTOG 15,0 (45) NA NA NA NA NA NAInsulinoterapia 31,0 (93) NA NA NA NA NA NAValor de glicemia em jejum NA 85 13,5 83 87 156 45%: frequncia relativa; DG: diabetes gestacional; DP: desvio-padro; M: mdia; Max: mximo; Min: mnimo; n: frequncia absoluta; NA: no aplicvel; PTOG: prova detolerncia oral glicose.Tabela 4Associaco entre a varivel dependente diabetes mellitus e as variveis independentes nominaisSem DM (n = 202) Com DM (n = 98) X 2cc (df) p% (n) % (n)IMC pr-gravidez 26,4 kg/m2 24,3 (49) 54,1 (53) 24,84 (1) ***Histria familiar de DM tipo 2 46,0 (93) 58,2 (57) 3,88 (1) *Gravidez prvia 67,3 (136) 72,4 (71) 0,59 (1) 0,443Diagnstico prvio de DG 6,9 (14) 9,2 (9) 0,21 (1) 0,648Idade gestacional < 24 semanas no momentodo diagnstico4,0 (8) 30,6 (30) 39,99 (1) ***4 valores alterados na PTOG 9,9 (20) 25,5 (25) 11,42 (1) **Necessidade de insulinoterapia 19,8 (40) 54,1 (53) 34,67 (1) ***%: frequncia relativa; df: graus de liberdade; DG: diabetes gestacional; DM: diabetes mellitus; IMC: ndice de massa corporal; n: frequncia absoluta; PTOG: prova detolerncia oral glicose.* p < 0,05.** p < 0,01.*** p < 0,001.Tabela 5Associaco entre a varivel dependente diabetes mellitus e as variveis independentes quantitativasSem DM (n = 202) Com DM (n = 98) t(df) pM DP M DPIdade materna no momento do diagnstico 33,0 4,8 34 4,6 1,718 (298) *IMC ps-parto 29,0 4,2 30,6 5,2 2,745 (158,51) **Glicemia em jejum 83,0 12,8 88,0 14,3 3,156 (298) **df: graus de liberdade; DM: diabetes mellitus; DP: desvio-padro; IMC: ndice de massa corporal; M: mdia; n: frequncia absoluta.* p < 0,05.** p < 0,01.Tabela 6Determinac o de fatores preditores do desenvolvimento de diabetes mellitus: regresso logstica binriaVariveis independentes Coeficiente deregressoErro-padro Wald df p OR IC 95% ORLimite inferior Limite superiorIMC pr-gravidez 26,4 kg/m2 1,123 0,385 8,531 1 ** 3,074 1,447 6,532Histria familiar de DM tipo 2 0,261 0,298 0,766 1 0,382 1,298 0,724 2,329Idade gestacional < 24 semanasno momento do diagnstico2,103 0,465 20,493 1 *** 8,191 3,295 20,3604 valores alterados na PTOG 0,767 0,415 3,408 1 0,065 2,153 0,954 4,861Necessidade de insulinoterapia 1,211 0,314 14,874 1 *** 3,358 1,814 6,216Idade materna no momento do diagnstico 0,011 0,031 0,141 1 0,707 1,012 0,953 1,074IMC ps-parto 0,012 0,039 0,096 1 0,756 0,988 0,916 1,066Glicemia em jejum 0,006 0,011 0,272 1 0,602 1,006 0,984 1,028Df: graus de liberdade; DM: diabetes mellitus; IC: intervalo de confianc a; IMC: ndice de massa corporal; OR: odds ratio; PTOG: prova de tolerncia oral glicose.** p < 0,01.*** p < 0,001.dx.doi.org/10.1016/j.rpedm.2014.05.004ARTICLE ING ModelRPEDM-43; No. of Pages 6A.M. Carvalho Ribeiro et al. / Rev Port EndocrinoCurva ROC0.0 0.2 0.4 0.6 0.8 1.00.00.20.40.60.81.0SensibilidadeFnvdCnrjacodRo(DDldqlpefapDtDmetacCaetffi1 - especificidadeigura 2. Sensibilidade e especificidade do modelo de regresso logstica binria.ecessidade de insulinoterapia aumentou essa probabilidade 3,4ezes (OR = 3,358; 95% IC = 1,814-6,216; p < 0,001) e a presenc ae IMC prvio 26,4 kg/m2 aumentou 3,1 vezes (OR = 3,074; 95%I = 1,447-6,532; p = 0,003) (tabela 6). As variveis idade maternao momento do diagnstico, 4 valores elevados na PTGO, hist-ia familiar de DM tipo 2, IMC ps-parto e valor de glicose emejum no influenciaram, de forma estatisticamente significativa, probabilidade de desenvolvimento de DM (tabela 6).O modelo proposto permitiu que 74,7% das mulheres fossemlassificadas corretamente no que se refere ao desenvolvimentou no de DM. A sensibilidade foi de 75,5% e a especificidadee 74,3% (com um ponto de corte de 0,3%). A rea sob a curvaOC foi significativamente maior que 0,5 (c = 0,819; p < 0,001), que indica um modelo com boa capacidade discriminatriafig. 2).iscussoNuma tentativa de diminuir a morbimortalidade associada M, foram estudados os fatores de risco que aumentam a probabi-idade de desenvolvimento de DM em mulheres com antecedentese DG. O presente estudo demostra que a idade gestacional menorue 24 semanas no momento do diagnstico, a necessidade de insu-inoterapia e IMC prvio gravidez 26,4 kg/m2 so fatores de riscoara desenvolvimento de DM.A idade um fator de risco conhecido para DM tipo 2. Nestestudo, a idade atual das mulheres que desenvolveram DM nooi significativamente diferente das mulheres sem DM. Portanto, idade atual no influenciou a determinac o de fatores preditivosara o desenvolvimento de DM.Relativamente aos fatores de risco para desenvolvimento deM aps DG, os resultados foram maioritariamente consisten-es com a literatura. Gravidez prvia e diagnstico prvio deG no apresentaram relac o significativa com o desenvolvi-ento de DM. Existem alguns estudos que verificaram associac ontre a paridade e o desenvolvimento de DM aps DG13,14. Con-udo, um nmero superior de trabalhos no encontrou a referidassociac o1518. A controvrsia destes resultados pode estar rela-ionada com a heterogeneidade tnica das diferentes amostras.ontrovrsia semelhante est presente na literatura relativamenteo diagnstico prvio de DG. De facto, existe associac o com DMm alguns estudos13,19, mas esta relac o desaparece em outrosComo citar este artigo: Carvalho Ribeiro AM, et al. Diabetes gestacionPort Endocrinol Diabetes Metab. 2014. http://dx.doi.org/10.1016/j.rperabalhos15,20.Em consonncia com relatos anteriores, a existncia de histriaamiliar de DM tipo 2 apresentou relac o estatisticamente signi-cativa com o desenvolvimento posterior de DM, no entanto, este PRESSl Diabetes Metab. 2014;xxx(xx):xxxxxx 5fator no foi um dos preditores do desenvolvimento da doenc a apsDG1417;1922. Resultados similares foram obtidos para 4 valoreselevados na PTGO. Porm, estes resultados contradizem a litera-tura existente, que salienta os valores da PTGO como preditores dodesenvolvimento de DM20,23.Mulheres que desenvolvem DM apresentam valores superioresde idade materna no momento do diagnstico, IMC ps-parto eglicose em jejum. Nenhuma das 3 variveis se apresentou comopreditor para desenvolvimento de DM. No que respeita idadematerna no momento do diagnstico e o IMC ps-parto, os resulta-dos obtidos esto de acordo com a literatura1322;24,25. No entanto,os resultados do valor de glicose em jejum contrariam o que j foipublicado1323;26.IMC prvio 26,4 kg/m2 aumentou 3,1 vezes a probabilidade dedesenvolvimento de DM aps DG. A maioria dos estudos prviosconfirma a existncia desta associac o17,18,20,21,24,27, com apenasuma minoria a no verificar a associac o14,18. A necessidade deinsulinoterapia aumentou 3,4 vezes a probabilidade de desenvolvi-mento de DM. A associac o entre estas 2 variveis alvo de debate.De facto, enquanto alguns estudos apoiam a associac o16,21, outrosno13,20,22. Esta controvrsia pode estar associada com o facto daprogresso para insulinoterapia depender do sucesso das medidasde modificac o de estilos de vida, que tambm podem prevenir ouatrasar a progresso para uma DM3.Idade gestacional menor que 24 semanas no momento do diag-nstico aumentou 8,2 vezes a probabilidade de desenvolvimentode DM aps DG. A bibliografia algo controversa no que res-peita referida associac o: alguns estudos suportam-na15,20,21,24,26enquanto outros no encontram evidncia da sua existncia14,16,18. possvel que a justificac o para esta contradic o seja secund-ria utilizac o de diferentes protocolos para o rastreio de DGnos diferentes estudos3. No presente estudo, os resultados dosparmetros que avaliam os valores anormais da glicose (4 valoreselevados na PTGO e valor de glicose em jejum) no se apre-sentaram como fatores preditores de desenvolvimento de DM,o que aparentemente contaria a literatura. Contudo, uma revi-so sistmica conduzida por Baptist-Roberts et al. demostrouque as medidas antropomtricas de obesidade, insulinoterapiae idade gestacional no momento do diagnstico so os fato-res de risco com maior evidncia para o desenvolvimento deDM aps DG. De facto, esta reviso sistmica defende que osestudos que existem so heterogneos no que respeita etniados elementos das diferentes amostras, aos fatores de riscoavaliados e aos mtodos estatsticos utilizados. Portanto, existefraca evidncia para obter concluses firmes sobre outros fato-res de risco28. Mais, uma reviso sistmica restrita anlise dasalterac es da glicemia na PTGO como preditores de desenvolvi-mento de DM aps DG mostrou que se tratavam de preditoresconsistentes. No entanto, a qualidade desta reviso sistmicafoi limitada por importantes perdas durante o follow-up e curtadurac o23.O presente estudo apresenta algumas limitac es. Apesar de umaamostra aleatria diminuir a possibilidade de um vis de selec o,assim como de variveis de confuso, a amostra constituda pormulheres com diagnstico de DG efetuado durante um perodo detempo compreendido entre 1-10 anos. Portanto, as mulheres compartos mais recentes podem no ter desenvolvido DM ainda. Almdisso, alguns elementos podem ter falecido durante o tempo decor-rido entre o diagnstico de DG e 2011 ou podem ter mudado deACES durante esse perodo. Isto pode conduzir a uma percentagemde participantes com DM inferior real. Contudo, a percentagem demulheres que desenvolveu DM foi similar descrita na literatura4.al: determinac o de fatores de risco para diabetes mellitus. Revdm.2014.05.004De facto, neste estudo 32,7% das mulheres desenvolveu a doenc a.Na literatura tm sido descritas percentagens de desenvolvimentode DM que variam entre 2,6-70%, desde as 6 semanas at 28 anosaps o parto3.dx.doi.org/10.1016/j.rpedm.2014.05.004 ING ModelR6 ocrinodugdndmpGopzepdprqpEdpmddedaarccfCB111111111122222222223ARTICLEPEDM-43; No. of Pages 6 A.M. Carvalho Ribeiro et al. / Rev Port EndDe referir que, neste trabalho, apesar de um novo mtodoe rastreio de DG ter sido implementado em Portugal em 2011,tilizaram-se mulheres com diagnstico de DG baseado nos anti-os critrios. De facto, essencial conhecer a populac o em risco deesenvolvimento de DM e s poderamos avaliar as mulheres diag-osticadas de acordo com os novos critrios, pelo menos 10 anosepois da sua implementac o. Para alm disso, de referir que estaodificac o nos critrios de diagnstico e classificac o da DG, pro-ostos pela International Association of Diabetes in Pregnancy Studyroups (IADPSG) e baseados nos resultados do estudo observaci-nal HAPO (Hyperglycemia and Adverse Pregnancy Outcome study),ermanece controversa29,30. Na verdade, faltam estudos randomi-ados controlados que suportem a alterac o dos referidos critrios,stimando-se tambm que a prevalncia de DG aumente de 2-5%ara mais de 16%30. Tal poder ter implicac es futuras ao nvela relac o custo-efetividade, uma vez que inicialmente os custosodem aumentar bastante face necessidade, destas pacientes emisco, de um seguimento mais apertado.31 De salientar, no entanto,ue alguns destes custos podem ser compensados a longo prazoelos ganhos na identificac o precoce destes indivduos em risco31.m suma, mantm-se a necessidade de confirmar a efetividadeos critrios propostos pela IADPSG na melhoria das complicac eserinatais30.Em concluso, este estudo demonstrou que a idade gestacionalenor que 24 semanas no momento do diagnstico, a necessi-ade de insulinoterapia e o IMC prvio 26,4 kg/m2 so fatorese risco para desenvolvimento de DM. Os autores acreditam questes resultados sero vlidos mesmo no sendo os critrios deiagnstico de DG atualmente os mesmos, pois nenhuma dessasssociac es est na dependncia desses novos critrios. Em ltimanlise, este estudo contribuiu para a literatura existente, necess-ia para a estratificac o do risco e prevenc o de DM em mulheresom antecedentes de DG.Autoria/colaboradoresOs autores Ana Maria Carvalho Ribeiro e Cristina Nogueira-Silvaontriburam igualmente para o manuscrito (partilhando destaorma o lugar de 1 autor).onflito de interessesOs autores declaram no haver conflito de interesses.ibliografia1. Cheung NW, Byth K. Population health significance of gestational diabetes. Dia-betes Care. 2003;26:20059.2. Sociedade Portuguesa de Diabetologia. Observatrio Nacional da Diabetes:Diabetes: Factos e Nmeros 2013. Relatrio Anual do Observatrio Nacionalda Diabetes. [consultado 31 Mar 2014]. Disponvel em: http://spd.pt/images/prova final od2013.pdf3. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2diabetes: A systematic review. Diabetes Care. 2002;25:18628.4. Sociedade Portuguesa de Diabetologia. Observatrio Nacional da Diabetes: Dia-betes: Factos e Nmeros 2010. Relatrio Anual do Observatrio Nacional daDiabetes. [consultado 5 Mar 2013]. Disponvel em: http://www.spd.pt/images/relatorioanualdiabetes%20fev%202011.pdf5. Bell DS, Barger BO, Go RC, Goldenberg RL, Perkins LL, Vanichanan CJ, et al.Risk factors for gestational diabetes in black population. Diabetes Care.Como citar este artigo: Carvalho Ribeiro AM, et al. Diabetes gestacionPort Endocrinol Diabetes Metab. 2014. http://dx.doi.org/10.1016/j.rpe1990;13:1196201.6. Nolan CJ. Controversies in gestational diabetes. Best Pract Res Clin Obstet Gyna-ecol. 2011;25:3749.7. Strehlow SL, Mestman JH. Prevention of T2DM in women with a previous historyof GDM. Curr Diab Rep. 2005;5:2727.3 PRESSl Diabetes Metab. 2014;xxx(xx):xxxxxx8. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estima-tes for the year 2000 and projections for 2030. Diabetes Care. 2004;27:104753.9. Swan WE, Liaw ST, Dunning T, Pallant JF, Kilmartin G. Diabetes risk reductionbehaviours of rural postpartum women with a recent history of gestationaldiabetes. Rural Remote Health. 2010;10:1461.0. Kim C. Managing women with gestational diabetes mellitus in the postnatalperiod. Diabetes Obes Metab. 2010;12:205.1. Bennett WL, Bolen S, Wilson LM, Bass EB, Nicholson WK. Performance charac-teristics of postpartum screening tests for type 2 diabetes mellitus in womenwith a history of gestational diabetes mellitus: A systematic review. J WomensHealth (Larchmt). 2009;18:97987.2. Pedhazur EJ. Multiple Regression in Behavioral Research: Explanation and Pre-diction United States of America. 3a ed. California: Harcourt Brace CollegePublishers; 1997.3. Steinhart JR, Sugarman JR, Connell FA. Gestational diabetes is a herald of NIDDMin Navajo women: High rate of abnormal glucose tolerance after GDM. DiabetesCare. 1997;20:9437.4. Damm P, Khl C, Bertelsen A, Mlsted-Pedersen L. Predictive factors for thedevelopment of diabetes in women with previous gestational diabetes mellitus.Am J ObstetGynecol. 1992;167:60716.5. Kjos SL, Peters RK, Xiang A, Henry OA, Montoro M, Buchanan TA. Predictingfuture diabetes in Latino women with gestational diabetes. Utility of early post-partum glucose tolerance testing. Diabetes. 1995;44:58691.6. Lam KS, Li DF, Lauder IJ, Lee CP, Kung AW, Ma JT. Prediction of persistent car-bohydrate intolerance in patients with gestational diabetes. Diabetes Res ClinPract. 1991;12:1816.7. Metzger BE, Cho NH, Roston SM, Radvany R. Prepregnancy weight and ante-partum insulin secretion predict glucose tolerance five years after gestationaldiabetes mellitus. Diabetes Care. 1993;16:1598605.8. Kaufmann RC, Schleyhahn FT, Huffman DG, Amankwah KS. Gestational diabe-tes diagnostic criteria: Long-term maternal follow up. Am J Obstet Gynecol.1995;172:6215.9. Grant PT, Oats JN, Beischer NA. The long-term follow-up of women with gesta-tional diabetes. Aust N Z J Obstet Gynaecol. 1986;26:1722.0. Albareda M, Caballero A, Badell G, Piquer S, Ortiz A, de Leiva A, et al. Diabetesand abnormal glucose tolerance in women with previous gestational diabetes.Diabetes Care. 2003;26:1199205.1. Catalano PM, Vargo KM, Bernstein IM, Amini SB. Incidence and risk factors asso-ciated with abnormal postpartum glucose tolerance in women with gestationaldiabetes. Am J ObstetGynecol. 1991;165:9149.2. Coustan DR, Carpenter MW, OSullivan PS, Carr SR. Gestational diabetes: Pre-dictors of subsequent disordered glucose metabolism. Am J Obstet Gynecol.1993;168:113945.3. Golden SH, Bennett WL, Baptist-Roberts K, Wilson LM, Barone B, Gary TL, et al.Antepartum glucose tolerance test results as predictors of type 2 diabetes mel-litus in women with a history of gestational diabetes mellitus: A systematicreview. Gend Med. 2009;6:10922.4. Persson B, Hanson U, Hartling SG, Binder C. Follow-up of women with previousGDM. Insulin, C-peptide, and proinsulin responses to oral glucose load. Diabetes.1991;40:13641.5. Buchanan TA, Xiang AH, Kjos SL, Trigo E, Lee WP, Peters RK. Antepartum predic-tors of the development of type 2 diabetes in Latino women 11-26 months afterpregnancies complicated by gestational diabetes. Diabetes. 1999;48:24306.6. Kjos SL, Buchanan TA, Greenspoon JS, Montoro M, Bernstein GS, MestmanJH. Gestational diabetes mellitus: The prevalence of glucose intolerance anddiabetes mellitus in the first two months postpartum. Am J Obstet Gynecol.1990;163:938.7. Sociedade Portuguesa de Diabetologia. Grupo de Estudo Diabetes e Gravi-dez: Atividades do Grupo de estudos de diabetes e gravidez da SociedadePortuguesa de Diabetologia. [consultado 5 Mar 2013]. Disponvel em:http://www.spd.pt/images/gruposestudo/5-Actividades ja realizadas2.pdf8. Baptiste-Roberts K, Barone BB, Gary TL, Golden SH, Wilson LM, Bass EB, et al.Risk factors for type 2 diabetes among women with gestational diabetes:A systematic review. Am J Med. 2009;122:20714.9. Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, et al. Inter-national association of diabetes and pregnancy study groups recommendationson the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care.2010;33:67682.0. Werner EF, Pettker CM, Zuckerwise L, Reel M, Funai EF, Valk HW, et al. Screeningfor gestational diabetes mellitus: Are the criteria proposed by the internationalal: determinac o de fatores de risco para diabetes mellitus. Revdm.2014.05.004association of the diabetes and pregnancy study groups cost-effective? DiabetesCare. 2012;35:52935.1. Ikenoue S, Miyakoshi K, Saisho Y, Sakai K, Kasuga Y, Fukutake M, et al. Clini-cal impact of women with gestational diabetes mellitus by the new consensuscriteria: Two year experience in a single institution in Japan. Endocr J. 2014:16.dx.doi.org/10.1016/j.rpedm.2014.05.004http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0005http://spd.pt/images/prova_final_od2013.pdfhttp://spd.pt/images/prova_final_od2013.pdfhttp://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://refhub.elsevier.com/S1646-3439(14)00018-2/sbref0015http://www.spd.pt/images/relatorioanualdiabetes 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gestacional: determinao de fatores de risco para diabetes mellitusIntroduoMtodosAnlise estatsticaResultadosCaraterizao sociodemogrficaAntecedentes pessoais, familiares e obsttricos e outros fatores antepartoDeterminao de fatores preditivos do desenvolvimento de diabetes mellitus em mulheres com antecedentes de diabetes gestac...DiscussoConflito de interessesBibliografia