CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / The preconception care for women with Pregestational Diabetes Mellitus (DM) is recognized for its benefits to the woman and the fetus in several countries, and must be guaranteed as a strategy to reduce maternal-fetal morbidity and mortality. We aimed to analyze the preconception care for women with pregestational DM assisted at SUS, aiming to describe the specific route of pregnant women with DM in the SUS health system in Fortaleza, know the clinical and reproductive profile, check the care received in preconception and identify the knowledge regarding maternal and fetal risks. Descriptive and exploratory qualitative study carried out in four reference units for high-risk pregnancies that compose the SUS-Fortaleza, CearÃ, Brazil. Data were collected from April to September 2012, involving 41 pregnant women with pregestational DM. We used the triangulation techniques of data collection: interviews, free observation with field notes and revision of the motherâs card and/or of the medical record. The data were organized in tables and received descriptive statistical treatment; the information learned in the field notes complemented the discussion of results. The project was approved by the Ethics Committee of the Universidade Federal do CearÃ, according to Protocol number 90/12 and one met the recommendations of Resolution 196/96. The average age of the group corresponded to 30.3  5.3, age of risk for developing DM type 2, the average of education level was 9.4  3.3 years, facilitator aspect for the practice of contraceptive care by women, 76.7% did not plan the current pregnancy, 26.7% were unaware of their type of DM. The prevalent time of diagnosis of DM was up to 10 years, comorbidities were reported by 33.4% of pregnant women; 56.7% of the respondents had between two and four pregnancies, with parity not over four births. The history of miscarriage and stillbirth was expected among women with pre-gestational DM who did not adopt preconceptional care and was present in 40%. About the preconception care needed for this group, the Ministry of Health recommends: glycemic control, replacement of oral hypoglycemic for insulin, control of comorbidities, monitoring of A1C, guidance on hypoglycemia and use of folic acid. Among these, the use of folic acid was being practiced by 10% of pregnant women and glucose monitoring for 6.6% of respondents. Out of these, 10% were receiving the necessary inputs to self-monitoring, when 100% should have it to recognize the best time to gestate. Regarding knowledge about maternal and fetal risks, 60% reported having gotten it in the current pregnancy. We suggest the managers of local public policies to restructure the municipal health system regarding the prenatal care of high-risk and to rescue the preconception attention in primary care. / O cuidado prÃ-concepcional de mulheres com Diabetes Mellitus (DM) prÃ-gestacional à reconhecido pelos benefÃcios à mulher e ao concepto em vÃrios paÃses, devendo ser garantido como estratÃgia para reduÃÃo da morbidade e mortalidade materno-fetal. Objetivamos analisar a atenÃÃo prÃ-concepcional de mulheres com DM prÃ-gestacional assistidas no Sistema Ãnico de SaÃde (SUS), tendo como objetivos especÃficos descrever o percurso de gestantes com DM na rede de saÃde do SUS-Fortaleza, conhecer o perfil clÃnico e reprodutivo, verificar os cuidados recebidos na prÃ-concepÃÃo e identificar o conhecimento quanto aos riscos maternos e fetais. Estudo descritivo e exploratÃrio qualitativo, realizado em quatro unidades de referÃncia para gestaÃÃo de alto risco que compÃe o SUS-Fortaleza, CearÃ, Brasil. Os dados foram coletados de abril a setembro de 2012, envolvendo 41 gestantes com DM prÃ-gestacional. Utilizamos a triangulaÃÃo de tÃcnicas de coleta de dados: entrevista, observaÃÃo livre com anotaÃÃes de campo e revisÃo do cartÃo da gestante e/ou do prontuÃrio. Os dados foram organizados em tabelas e receberem tratamento estatÃstico descritivo; as informaÃÃes apreendidas nas anotaÃÃes de campo complementaram a discussÃo dos resultados. O projeto foi aprovado pelo Comità de Ãtica em Pesquisa da Universidade Federal do CearÃ, conforme protocolo n 90/12 e foram atendidas as recomendaÃÃes da ResoluÃÃo 196/96. A mÃdia da idade do grupo correspondeu a 30,35,3, faixa etÃria de risco para o desenvolvimento do DM tipo 2; a mÃdia da escolaridade foi de 9,4Â3,3anos, aspecto facilitador a prÃtica dos cuidados prÃ-concepcionais pelas mulheres, 76,7% nÃo planejaram a gestaÃÃo atual; 26,7% desconheciam o tipo de DM. Predominou o tempo de diagnÃstico do DM atà 10 anos, as comorbidades foram referidas por 33,4% das gestantes; 56,7% das entrevistadas tinham entre duas e quatro gestaÃÃes, com paridade nÃo superior a quatro partos. O histÃrico de aborto e natimorto foi previsto entre mulheres com DM prÃ-gestacional que nÃo adotaram cuidados prÃ-concepcionais e estava presente em 40%. Sobre os cuidados prÃ-concepcionais necessÃrios a este grupo, o MinistÃrio da SaÃde preconiza: controle glicÃmico, substituiÃÃo do hipoglicemiante oral por insulina, controle das comorbidades, acompanhamento da A1C, orientaÃÃo sobre hipoglicemia e uso de Ãcido fÃlico. Entre estes, o uso de Ãcido fÃlico estava sendo praticado por 10% das gestantes e o monitoramento glicÃmico por 6,6% das entrevistadas. Destas, 10% recebiam os insumos necessÃrios ao auto monitoramento, quando 100% deveriam possuir para o reconhecimento do melhor momento de gestar. Quanto ao conhecimento sobre os riscos maternos e fetais, 60% referiu tÃ-lo adquirido na gestaÃÃo atual. Sugerimos aos gestores das polÃticas pÃblicas locais a reestruturaÃÃo da rede municipal de saÃde no que concerne à assistÃncia prÃ-natal de alto risco e ao resgate da atenÃÃo prÃ-concepcional pela atenÃÃo bÃsica.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy December 2017. / Gestational diabetes mellitus (GDM) is characterized by high blood glucose levels that first develop during pregnancy. GDM has been linked with many adverse short and long term health outcomes for the developing foetus as well as for the mother. The Developmental Origins of Health and Disease (DOHaD) concept suggests that in the presence of adverse stimuli, the foetus will adapt, through epigenetic mechanisms, to ensure its immediate survival. For this reason, epigenetic modifications are emerging as mediators linking early environmental exposures during pregnancy with programmed changes in gene expression that alter offspring growth and development. The objective of this research study was to explore the role of altered gene expression and methylation in the development of GDM and determine whether these alterations are inherited by the exposed foetus. Transcriptome sequencing was performed on mRNA extracted from blood samples collected from six women with GDM and from six controls; as well as from exposed (N=6) and unexposed placenta (N=6). Genes that displayed significant (p<0.005) differential expression (log2 fold change >2 and <-2) between cases and controls were identified from the blood (N=60) and placenta (N=56) datasets. Gene ontology and enrichment was performed using DAVID and PANTHER with the aim to narrow down the candidate gene lists. The ten most likely candidate genes for differential gene expression from the blood dataset were G6PD, DCXR, TKT, ALDOA, PGLS, KCNQ1, C14orf80, KCNQ1, SLC25A22 and GSK3A. Gene enrichment revealed that five of these significantly under-expressed genes (G6PD, DCXR, TKT, ALDOA and PGLS) encode enzymes in the pentose phosphate pathway (PPP). In the placental dataset the top ten candidate genes were CXCR1, CXCR2, G6PD, TKT, IGFBP-1, IGFBP-2, IGFBP-6, GGT3P, MMP12 and GLT1D1. The direction and fold change of differential expression of all twenty genes were validated using TaqMan qPCR probes. Of these twenty genes, the five most promising biological candidates (G6PD, TKT, IGFBP-1, IGFBP-2 and IGFBP-6) were identified and the level of promoter region methylation was assessed using EpiTech Methyl II PCR Assays. The level of methylation in the promoter region of G6PD in both blood and placenta tissue was found to be significantly higher (p=1.90 x 10-5 and p=1.2 x 10-11 respectively) in the case groups, correlating with decreased mRNA expression levels. There was a significant negative correlation between G6PD mRNA expression in the blood and placenta with the level of maternal glucose at fasting (p=0.006 and p=0.001, respectively), 1-hr (p=0.016 and p=0.007, respectively) and 2-hr post OG (p=0.045 in placenta). We observed a significant positive correlation between G6PD promoter region methylation in both blood and placental tissues with maternal glucose levels at fasting (p=0.023 and p=0.001, respectively) and at 1-hr post OG (p=0.001 and p=0.004, respectively). IGFBP-1 was found to be significantly under-expressed in exposed placental tissue and hypermethylated (p=1.1 x 10-6) at the promoter region when compared to unexposed samples. There was a significant negative correlation between the expression of IGFBP-1 mRNA in the blood and placenta with foetal birth weight (p=0.005 and p=0.017, respectively). Our results suggest that high glucose levels, an important characteristic of GDM, result in the disturbance of the pentose phosphate pathway, a pathway linked closely to glycolysis, and the IGF-axis, which is important in foetal growth and development. In GDM there is suppression of G6PD mRNA expression in both the blood and placental tissue which influences the pentose phosphate pathway. We hypothesize that this is mediated through an epigenetic mechanism since it is correlated with increased methylation of the G6PD promoter region. Down regulation of G6PD would suppress the PPP and reduce the levels of NADPH production, which may in turn lead to an increase in oxidative stress and an adverse outcome in the mother and foetus. With regard to the IGF-axis, our results demonstrated that IGFBP-1 and IGFBP-2 mRNA expression in the placenta may be inhibited due to the presence of high glucose and insulin levels and this decrease in mRNA expression is likely implicated in the abnormal foetal growth which is often associated with GDM. This study has provided novel insights into gene expression and DNA methylation changes in the blood of women with GDM and the placenta of their female offspring that involve genes in the PPP and the IGF-axis. / LG2018

Objetivo: O presente estudo teve por objetivo comparar duas estratégias de acompanhamento nutricional em pacientes com Diabetes Mellitus Gestacional em relação à composição da dieta dessas pacientes. Método: Durante o período de Julho de 2012 a Fevereiro de 2014, foram acompanhadas 55 gestantes no setor de Endocrinopatias e Gestação da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP). Os critérios de inclusão foram: diagnóstico de DMG e idade gestacional inferior a 35 semanas na primeira avaliação nutricional. Foram excluídas as gestantes que não compareceram às consultas pré-estabelecidas (Grupo 1: duas avaliações; Grupo 2: quatro avaliações). As pacientes foram randomizadas em dois grupos: Grupo 1 (avaliação inicial e avaliação final) e Grupo 2 (avaliação inicial, orientação individualizada em mais dois encontros com intervalo de sete a quinze dias e avaliação final). Para avaliação do consumo inicial e final de nutrientes, bem como para nortear as orientação individualizadas (Grupo 2) utilizou-se o recordatório alimentar de 24h, seguido de análise no programa Nutrilife 8.0 ®. Na avaliação inicial, os dois grupos receberam orientação nutricional padrão. Para comparação entre os grupos, utilizou-se teste de qui-quadrado, exato de Fisher e teste de Mann-Whitney U. Resultados: Os dois grupos foram semelhantes em relação à ingestão de Macro e Micronutrientes na avaliação inicial. Na avaliação final, houve diferença estatisticamente significativa entre os grupos no que se refere ao consumo de carboidratos, lipídios e sódio. No Grupo 2, o consumo de carboidratos foi maior, e o de sódio e lipídios foi menor em comparação ao Grupo 1. Conclusões: A orientação individualizada, mesmo que avaliada em curto período de tempo, foi capaz de promover modificações no comportamento alimentar das gestantes em relação ao consumo de carboidratos, lipídios e sódio / Objective: The current study aimed the comparison of two strategies of nutrition monitoring of patients with Gestational Diabetes Mellitus compared to the diet composition of these patients. Method: From July 2012 to February, 2014, 55 pregnant women were monitored at the Endocrinopathy and Pregnancy Sector of the Obstetrics Clinic at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP). The inclusion criterion was: GDM diagnosed and gestational age under 35 weeks at the first nutrition assessment. Pregnant women who attend the pre-established appointments (Group 1: two assessments; Group 2: four assessments) were removed. The patients were randomized into two groups: Group 1 (initial review and final review) and Group 2 (initial review, individual guidance in two appointments with a seven to fifteen day interval and final review). In order to assess the ideal initial and final consumption of nutrients, as well as to direct the individual guidance (Group 2), the 24h alimentary record was used, followed by the assessment on the Nutrilife 8.0® program. At the initial review, both groups received the standard nutritional guidance. In order to compare the two groups, a Chi-Square analysis, Fishers exact test and a Mann-Whitney U. test were performed. Results: the two groups were similar regarding the Macro and Micronutrients at the initial review. At the final review, there was a statistically significant difference between the groups with regards to the consumption of carbohydrates, lipids and sodium. In Group 2, there was a higher consumption of carbohydrates and the consumption of sodium and lipids was lower than in Group 1. Conclusions: The individual guidance, even if assessed in a short period of time, was capable of promoting changes in the alimentation behavior of the pregnant women with regards to the consumption of carbohydrates, lipids and sodium

Objetivo: O presente estudo teve por objetivo comparar duas estratégias de acompanhamento nutricional em pacientes com Diabetes Mellitus Gestacional em relação à composição da dieta dessas pacientes. Método: Durante o período de Julho de 2012 a Fevereiro de 2014, foram acompanhadas 55 gestantes no setor de Endocrinopatias e Gestação da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP). Os critérios de inclusão foram: diagnóstico de DMG e idade gestacional inferior a 35 semanas na primeira avaliação nutricional. Foram excluídas as gestantes que não compareceram às consultas pré-estabelecidas (Grupo 1: duas avaliações; Grupo 2: quatro avaliações). As pacientes foram randomizadas em dois grupos: Grupo 1 (avaliação inicial e avaliação final) e Grupo 2 (avaliação inicial, orientação individualizada em mais dois encontros com intervalo de sete a quinze dias e avaliação final). Para avaliação do consumo inicial e final de nutrientes, bem como para nortear as orientação individualizadas (Grupo 2) utilizou-se o recordatório alimentar de 24h, seguido de análise no programa Nutrilife 8.0 ®. Na avaliação inicial, os dois grupos receberam orientação nutricional padrão. Para comparação entre os grupos, utilizou-se teste de qui-quadrado, exato de Fisher e teste de Mann-Whitney U. Resultados: Os dois grupos foram semelhantes em relação à ingestão de Macro e Micronutrientes na avaliação inicial. Na avaliação final, houve diferença estatisticamente significativa entre os grupos no que se refere ao consumo de carboidratos, lipídios e sódio. No Grupo 2, o consumo de carboidratos foi maior, e o de sódio e lipídios foi menor em comparação ao Grupo 1. Conclusões: A orientação individualizada, mesmo que avaliada em curto período de tempo, foi capaz de promover modificações no comportamento alimentar das gestantes em relação ao consumo de carboidratos, lipídios e sódio / Objective: The current study aimed the comparison of two strategies of nutrition monitoring of patients with Gestational Diabetes Mellitus compared to the diet composition of these patients. Method: From July 2012 to February, 2014, 55 pregnant women were monitored at the Endocrinopathy and Pregnancy Sector of the Obstetrics Clinic at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP). The inclusion criterion was: GDM diagnosed and gestational age under 35 weeks at the first nutrition assessment. Pregnant women who attend the pre-established appointments (Group 1: two assessments; Group 2: four assessments) were removed. The patients were randomized into two groups: Group 1 (initial review and final review) and Group 2 (initial review, individual guidance in two appointments with a seven to fifteen day interval and final review). In order to assess the ideal initial and final consumption of nutrients, as well as to direct the individual guidance (Group 2), the 24h alimentary record was used, followed by the assessment on the Nutrilife 8.0® program. At the initial review, both groups received the standard nutritional guidance. In order to compare the two groups, a Chi-Square analysis, Fishers exact test and a Mann-Whitney U. test were performed. Results: the two groups were similar regarding the Macro and Micronutrients at the initial review. At the final review, there was a statistically significant difference between the groups with regards to the consumption of carbohydrates, lipids and sodium. In Group 2, there was a higher consumption of carbohydrates and the consumption of sodium and lipids was lower than in Group 1. Conclusions: The individual guidance, even if assessed in a short period of time, was capable of promoting changes in the alimentation behavior of the pregnant women with regards to the consumption of carbohydrates, lipids and sodium

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 73-81).

Background: Gestational Diabetes Mellitus (GDM) has been linked with later metabolic abnormalities in offspring due to subsequent overweight and obesity. In Sub-Saharan Africa, there is a paucity of data on the outcomes of children exposed to GDM in utero. Aims: The primary aim of this sub-study was to investigate the prevalence of overweight and obesity in 5 and 6-year-old children from GDM complicated pregnancies and macrosomia at birth in the same cohort. The secondary aim was to identify risk factors associated with overweight and obesity in these 5 and 6-year-old children. Outcome measures: The main outcome was the prevalence of overweight and obesity in these children as measured by their age-specific body mass index (BMI) and Z-scores. Additionally, the association between other risk factors, overweight and obesity was investigated. Methods: A cross-sectional sub-study design was employed nested within a larger study that is investigating the progression to type 2 diabetes in women managed for GDM during 2010 and 2011. Mothers who participated in the larger study were informed about the sub-study and invited to allow their children to participate in the sub-study. Written informed consent was obtained from the mothers for the sub-study. The following data were collected: anthropometric data at birth and pregnancy related information from the mothers’ hospital record, additional demographic, social and medical information by questionnaire from the mother and at the research center. In addition, the children were weighed and had their height measured using standardized methods. Anthropometry was standardized using WHO standards. Risk factors for overweight and obesity were tested using a BMI>1 Z-score cut-off, (as a binary variable) in a manual multivariate logistic regression model. Results: The sub-study recruited 176 participants; 78 boys (44.3%) and 98 girls (55.7%). The mean (SD) Z-scores for the children’s anthropometry at ages 5 to 6 years were 0.28 (1.40) for weight, 0.01 (1.07) for height and 0.37 (1.63) for BMI. The overall prevalence of macrosomia at birth (birth weight>4000 gm) was 12.3 % (95% CI 8.2-9.1). The overall prevalence of overweight in the 5 and 6-year-old children was 13.4% (95% CI 8.6-20.4), while the prevalence of obesity was 14.2% (95% CI 9.2-21.2). The combined prevalence of overweight and obesity was 27.6% (95% CI 20.6-35.9). The prevalence of macrosomia (P=0.53) or overweight/obesity proportions (P=0.37) at ages 5 to 6 years did not differ by gender. In multivariate logistic regression analysis, factors independently associated with the risk of overweight and obesity were: mothers’ oral glucose tolerance test 2-hour blood glucose level during pregnancy (AOR=2.06, 95% CI 1.14-3.74, P=0.02), birth weight (AOR=1.00, 95% CI 1.00-1.00, P=0.01), child’s age in years (AOR=0.03, 95% CI 0.002-0.29, P=0.004) and number of adults in the house (AOR=0.38, 95% CI 0.17-0.86, P=0.02). Conclusion: This is the first study to report the prevalence of overweight and obesity in children born from GDM complicated pregnancies, in the Western Cape, South Africa. The combined prevalence of overweight and obesity found in 5 and 6-year-old children exposed to GDM in the Western Cape is higher than overweight and obesity in children reported in other South African studies. This can imply a higher tendency towards overweight and obesity in children exposed to GDM which needs further exploration.

In this 15 year follow up study in a Chinese population, we confirmed that maternal gestational diabetic status significantly increased women’s future cardiometabolic risk. Glycaemic levels below the current criteria for a positive screening test for gestational diabetes and for the diagnosis of gestational diabetes still significantly predict women’s future risk. In utero hyperinsulinaemia, which caused by an intrauterine hyperglycaemic environment, was found to predict children’s AGT and adolescents’ overweight and MetS. The results had important implication that the current diagnostic criteria for gestational diabetes may not be discriminative in predicting both the mothers and their children’s future cardiometabolic risk. Although recent research has re-visited and emphasised on the diagnostic criteria of gestational diabetes which best predicted adverse pregnancy outcome, future study should also scrutinise on the optimal glycaemic threshold, either in screening or diagnostic test, that relate to the mothers’ and children offspring’s long term cardiometabolic risk. / Tam, Wing Hung. / Thesis (M.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 119-146). / Abstract also in Chinese. / LIST OF TABLES --- p.xxii / LIST OF FIGURES --- p.xxv / LIST OF ABBREVIATIONS --- p.xxvi / Chapter Chapter 1 --- Gestational diabetes & future cardiometabolic risk - an overview / Chapter 1.1 --- Historical background --- p.2 / Chapter 1.2 --- Pregnancy physiology vs. gestational diabetes --- p.5 / Chapter 1.3 --- Diabetes mellitus - a global epidemic --- p.6 / Chapter 1.4 --- History of gestational diabetes & progression to Type 2 DM --- p.7 / Chapter 1.5 --- History of gestational diabetes & cardiometabolic risk --- p.8 / Chapter 1.6 --- Type 2 DM among children and adolescents --- p.9 / Chapter 1.7 --- Type 2 DM among offspring of mothers with gestational diabetes --- p.10 / Chapter 1.8 --- Cardiometabolic risk in children exposed to maternal gestational diabetes --- p.12 / Chapter 1.9 --- Long term follow up on mothers & children cohort --- p.12 / Chapter Chapter 2 --- Research methodology / Chapter 2.1 --- Subjects --- p.16 / Chapter 2.2 --- Obstetric and neonatal information --- p.18 / Chapter 2.2.1 --- Maternal glycaemic indices at pregnancy --- p.18 / Chapter 2.2.2 --- Umbilical cord blood C-peptide & insulin levels --- p.18 / Chapter 2.2.3 --- Definition of antenatal variables --- p.19 / Chapter 2.3 --- Follow up assessment of the mothers --- p.19 / Chapter 2.4 --- Follow up assessment of the children and adolescents --- p.22 / Chapter 2.5 --- Definition of abnormal glucose tolerance and metabolic syndrome --- p.24 / Chapter 2.5.1 --- Definition of abnormal glucose tolerance --- p.24 / Chapter 2.5.2 --- Definition of metabolic syndrome in adult --- p.24 / Chapter 2.5.3 --- Definition of metabolic syndrome in adolescent --- p.25 / Chapter 2.6 --- Determination of insulin resistance and pancreatic beta cell function --- p.26 / Chapter 2.6.1 --- Definition of insulin resistance --- p.26 / Chapter 2.6.2 --- Definition of pancreatic beta cell function --- p.26 / Chapter 2.6.3 --- Measurement of insulin resistance and pancreatic β-cell function --- p.27 / Chapter 2.7 --- Statistical analysis --- p.31 / Chapter 2.7.1 --- Statistical programme --- p.31 / Chapter 2.7.2 --- Comparison between group differences --- p.31 / Chapter 2.7.3 --- General Linear Model --- p.32 / Chapter 2.7.4 --- Multivariate logistic regression --- p.33 / Chapter 2.7.5 --- Receiver operating characteristic analysis --- p.37 / Chapter 2.8 --- Ethics approval --- p.41 / Chapter 2.9 --- Funding --- p.42 / Chapter Chapter 3 --- History of gestational diabetes and women’s future cardiometabolic risk / Chapter 3.1 --- Maternal clinical parameters at the index pregnancy --- p.44 / Chapter 3.2 --- Maternal cardiometabolic status at 8 years post-delivery --- p.45 / Chapter 3.3 --- Maternal cardiometabolic status at 15 years post-delivery --- p.49 / Chapter 3.4 --- Prediction of cardiometabolic risk by maternal gestational diabetic status --- p.50 / Chapter 3.4.1 --- Abnormal glucose tolerance and metabolic syndrome at 8 years by maternal gestational diabetic status --- p.52 / Chapter 3.4.2 --- Abnormal glucose tolerance, DM, hypertension and metabolic syndrome at 15 years by maternal gestational diabetic status --- p.52 / Chapter 3.5 --- The role of insulin resistance in predicting women’s DM and metabolic syndrome --- p.55 / Chapter 3.6 --- Discussion --- p.57 / Chapter 3.7 --- Conclusion --- p.62 / Chapter Chapter 4 --- Glycaemic variables measured at mid-gestation of the index pregnancy predict women’s future cardiometabolic risk / Chapter 4.1 --- Glycaemic levels in pregnancy and perinatal outcome --- p.64 / Chapter 4.2 --- Glycaemic levels in pregnancy and women’s future cardiometabolic risk --- p.65 / Chapter 4.2.1 --- Prediction of women’s cardiometabolic risk at 8 and 15-year --- p.66 / Chapter 4.2.2 --- Optimal cut-off levels in predicting women’s future cardio- metabolic risk --- p.69 / Chapter 4.3 --- Discussion --- p.75 / Chapter 4.4 --- Conclusion --- p.78 / Chapter Chapter 5 --- Maternal gestational diabetes and offspring’s cardiometabolic risk / Chapter 5.1 --- Offspring’s cardiometabolic risk at 8 years age --- p.80 / Chapter 5.1.1 --- Baseline characteristics at pregnancy and delivery --- p.80 / Chapter 5.1.2 --- Children’s clinical and biochemical parameters at 8 years age --- p.82 / Chapter 5.2 --- Offspring’s cardiometabolic risk at 15 years age --- p.84 / Chapter 5.2.1 --- Adolescents’ clinical and biochemical parameters at 15 years age --- p.84 / Chapter 5.2.2 --- Clinical parameters of adolescents with abnormal glucose tolerance --- p.84 / Chapter 5.3 --- Discussion --- p.88 / Chapter 5.4 --- Conclusion --- p.90 / Chapter Chapter 6 --- In utero hyperinsulinaemia and offspring’s cardiometabolic risk / Chapter 6.1 --- Umbilical cord blood insulin and C-peptide --- p.92 / Chapter 6.1.1 --- Umbilical cord insulin and C-peptide concentrations in the original cohort --- p.92 / Chapter 6.1.2 --- Determination of in utero hyperinsulinaemia by umbilical cord insulin and C-peptide levels --- p.95 / Chapter 6.2 --- The effect of in utero hyperinsulinaemia on children’s abnormal glucose tolerance at 8 years of age --- p.98 / Chapter 6.2.1 --- Receiver operating characteristic analysis --- p.98 / Chapter 6.2.2 --- Logistic regression analysis --- p.98 / Chapter 6.3 --- The effect of in utero hyperinsulinaemia on adolescents’ cardio- metabolic risk at 15years of age --- p.102 / Chapter 6.3.1 --- Logistic regression analysis --- p.102 / Chapter 6.4 --- Discussion --- p.105 / Chapter 6.5 --- Conclusion --- p.108 / Chapter Chapter 7 --- Summary and conclusion / Chapter 7.1 --- Summary of the thesis --- p.110 / Chapter 7.1.1 --- Women’s long term cardiometabolic risk after a pregnancy with gestational diabetes --- p.110 / Chapter 7.1.2 --- The long term cardiometabolic risk of children born to mothers who had gestational diabetes --- p.111 / Chapter 7.1.3 --- New findings from the studies and their implications --- p.111 / Chapter 7.2 --- Strength and weakness in the study --- p.113 / Chapter 7.2.1 --- Unique cohort from universal screening --- p.113 / Chapter 7.2.2 --- Study design --- p.113 / Chapter 7.2.3 --- Response rate and loss to follow up --- p.114 / Chapter 7.2.4 --- Treatment effect of gestational diabetes --- p.115 / Chapter 7.3 --- Issues of future research --- p.115 / Chapter 7.3.1 --- Follow up study on the HAPO cohort --- p.115 / Chapter 7.3.2 --- Opportunity for international collaboration --- p.117 / Chapter 7.4 --- Conclusion --- p.118 / REFERENCES --- p.119

O Diabetes melito gestacional (DMG) está relacionado ao crescimento fetal exagerado. Entender a influência do controle glicêmico no padrão do crescimento fetal auxilia na identificação dos fetos com maior risco de desvios da normalidade. Objetivo: comparar o crescimento fetal em pacientes com DMG segundo o controle glicêmico. Método: estudo retrospectivo com 89 gestantes da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo no período de maio de 2005 a junho de 2011. Foram incluídas apenas pacientes com gestações únicas e com DMG diagnosticado pelo teste de tolerância oral à glicose de 100 gramas ou 75 gramas, sem doenças maternas que interferem no ganho de peso fetal, sem malformações fetais ou tabagismo. Todas as gestantes realizaram retornos semanais no pré-natal especializado, dieta para diabetes, controle glicêmico diário e uso de insulina quando necessário. Foi introduzida insulina quando 30% ou mais das glicemias capilares aferidas em uma semana eram superiores a: jejum> 95 mg/dl, 1hora pós-prandial> 140 mg/dl ou 2 horas pós-prandial> 120 mg/dl. As gestantes foram divididas para análise dos dados em dois grupos: se apresentassem menos de 30% de hiperglicemias em todas as glicemias capilares aferidas eram alocadas no grupo 1 (n= 65), e caso contrário no grupo 2 (n=24). Elas realizaram três ultrassonografias (USG): USG 0 (entre 18 a 24 semanas), USG 1 (início do tratamento do DMG) e USG 2 (final do tratamento). Foram analisadas as médias dos percentis do peso e da circunferência abdominal fetal para avaliação do padrão do crescimento fetal, e o ganho de peso fetal entre os USG. Resultados: Não houve diferenças quanto à: idade materna e índice de massa corpórea pré-gestacional; ganho de peso materno no pré-natal; idade gestacional do diagnóstico do DMG e do início do tratamento; idade gestacional da realização das USG. As médias glicêmicas foram de 98,7 mg/dl no grupo 1 e de 111,9 mg/dl no grupo 2 (p<0,001). O uso de insulina foi de 16,9% vs. 87,5%; p<0, 001 nos grupos 1 e 2, respectivamente. O valor da hemoglobina glicada no diagnóstico de DMG foi maior no grupo 2 (5,52% vs. 5,93%; p<0,001). Os percentis do peso fetal foram semelhantes entre os grupos no USG 0 e no USG 1, porém significativamente maiores no grupo 2 no USG 2 (p=0,02). Os percentis da circunferência abdominal fetal foram significativamente maiores no grupo 2 no USG 1 e USG 2. O grupo 2 apresentou um maior ganho de peso fetal (27,53 gramas/dia vs. 33,43gramas/dia; p=0,001) e um maior peso ao nascer (3247g. vs. 3499g.; p=0,025). Conclusões: O controle glicêmico influenciou no peso fetal, as gestantes que apresentaram mais de 30% de hiperglicemia durante o pré-natal apresentaram maior velocidade de ganho de peso fetal durante o tratamento e recém-nascidos com maior peso ao nascer. O percentil da circunferência abdominal fetal parece modificar antes que o percentil do peso fetal e seria um marcador mais sensível de alterações no potencial de crescimento fetal. / Gestational diabetes (GDM) is related to overgrowth fetal. Objective: To evaluate fetal growth in patients with gestational diabetes (GD) according to glycemic control. Methods: Eighty-nine pregnant women seen at the Obstetric Clinic of the University Hospital, University of São Paulo School of Medicine, between May 2005 and June 2011 were studied retrospectively. The study included non-smoking women with singleton pregnancies and GD diagnosed by the 100- or 75-g oral glucose tolerance test. The patients had no maternal disease interfering with fetal weight gain and there were no fetal malformations. All women attended weekly specialized prenatal care, consumed a diabetes diet, performed daily glycemic control, and used insulin when necessary. Insulin was introduced when >=30% of the capillary glucose measurements obtained in one week were >95 mg/dl (fasting), >140 mg/dl (1 h postprandial), or >120 mg/dl (2 h postprandial). The women were divided into two groups according to the frequency of hyperglycemic episodes in all capillary glucose measurements obtained during treatment: group 1 (n = 65, <=30%), and group 2 (n = 24, >30%). Ultrasound (US) was performed at three time points for the comparison of mean fetal weight and abdominal circumference percentiles and fetal weight gain (g/day): US0 (18 to 24 weeks), US1 (at the beginning of treatment of GD), and US2 (at the end of treatment) Results: The two groups did not differ in terms of maternal age, pregestational BMI, prenatal maternal weight gain, gestational age at the diagnosis of GD, time of onset of treatment, or gestational age at US. Mean glycemia was 98.7 mg/dl in group 1 and 111.9 mg/dl in group 2 (p<0.001). Insulin was used by 16.9% of the patients of group 1 vs. 87.5% of group 2 (p<0.001). HbA1c at diagnosis of GD was higher in group 2 (5.52% vs. 5.93%; p<0.001). Fetal weight percentiles were similar in the two groups at US0 and US1, but significantly higher in group 2 at US2 (p=0.02). Abdominal circumference percentiles were significantly higher in group 2 at US1 and US2. Fetal weight gain (27.5 vs. 33.4 g/day; p=0.001) and birthweight (3247 vs. 3499 g; p=0.025) were higher in group 2. Conclusions: The pattern of fetal growth in patients with GD varies according to glycemic control. The fetal growth velocity and newborn birthweight were higher in women who presented >30% of hyperglycemic episodes during treatment of GD. The abdominal circumference percentile seems to change before the weight percentile and would be a more sensitive marker of altered fetal growth.

O Diabetes melito gestacional (DMG) está relacionado ao crescimento fetal exagerado. Entender a influência do controle glicêmico no padrão do crescimento fetal auxilia na identificação dos fetos com maior risco de desvios da normalidade. Objetivo: comparar o crescimento fetal em pacientes com DMG segundo o controle glicêmico. Método: estudo retrospectivo com 89 gestantes da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo no período de maio de 2005 a junho de 2011. Foram incluídas apenas pacientes com gestações únicas e com DMG diagnosticado pelo teste de tolerância oral à glicose de 100 gramas ou 75 gramas, sem doenças maternas que interferem no ganho de peso fetal, sem malformações fetais ou tabagismo. Todas as gestantes realizaram retornos semanais no pré-natal especializado, dieta para diabetes, controle glicêmico diário e uso de insulina quando necessário. Foi introduzida insulina quando 30% ou mais das glicemias capilares aferidas em uma semana eram superiores a: jejum> 95 mg/dl, 1hora pós-prandial> 140 mg/dl ou 2 horas pós-prandial> 120 mg/dl. As gestantes foram divididas para análise dos dados em dois grupos: se apresentassem menos de 30% de hiperglicemias em todas as glicemias capilares aferidas eram alocadas no grupo 1 (n= 65), e caso contrário no grupo 2 (n=24). Elas realizaram três ultrassonografias (USG): USG 0 (entre 18 a 24 semanas), USG 1 (início do tratamento do DMG) e USG 2 (final do tratamento). Foram analisadas as médias dos percentis do peso e da circunferência abdominal fetal para avaliação do padrão do crescimento fetal, e o ganho de peso fetal entre os USG. Resultados: Não houve diferenças quanto à: idade materna e índice de massa corpórea pré-gestacional; ganho de peso materno no pré-natal; idade gestacional do diagnóstico do DMG e do início do tratamento; idade gestacional da realização das USG. As médias glicêmicas foram de 98,7 mg/dl no grupo 1 e de 111,9 mg/dl no grupo 2 (p<0,001). O uso de insulina foi de 16,9% vs. 87,5%; p<0, 001 nos grupos 1 e 2, respectivamente. O valor da hemoglobina glicada no diagnóstico de DMG foi maior no grupo 2 (5,52% vs. 5,93%; p<0,001). Os percentis do peso fetal foram semelhantes entre os grupos no USG 0 e no USG 1, porém significativamente maiores no grupo 2 no USG 2 (p=0,02). Os percentis da circunferência abdominal fetal foram significativamente maiores no grupo 2 no USG 1 e USG 2. O grupo 2 apresentou um maior ganho de peso fetal (27,53 gramas/dia vs. 33,43gramas/dia; p=0,001) e um maior peso ao nascer (3247g. vs. 3499g.; p=0,025). Conclusões: O controle glicêmico influenciou no peso fetal, as gestantes que apresentaram mais de 30% de hiperglicemia durante o pré-natal apresentaram maior velocidade de ganho de peso fetal durante o tratamento e recém-nascidos com maior peso ao nascer. O percentil da circunferência abdominal fetal parece modificar antes que o percentil do peso fetal e seria um marcador mais sensível de alterações no potencial de crescimento fetal. / Gestational diabetes (GDM) is related to overgrowth fetal. Objective: To evaluate fetal growth in patients with gestational diabetes (GD) according to glycemic control. Methods: Eighty-nine pregnant women seen at the Obstetric Clinic of the University Hospital, University of São Paulo School of Medicine, between May 2005 and June 2011 were studied retrospectively. The study included non-smoking women with singleton pregnancies and GD diagnosed by the 100- or 75-g oral glucose tolerance test. The patients had no maternal disease interfering with fetal weight gain and there were no fetal malformations. All women attended weekly specialized prenatal care, consumed a diabetes diet, performed daily glycemic control, and used insulin when necessary. Insulin was introduced when >=30% of the capillary glucose measurements obtained in one week were >95 mg/dl (fasting), >140 mg/dl (1 h postprandial), or >120 mg/dl (2 h postprandial). The women were divided into two groups according to the frequency of hyperglycemic episodes in all capillary glucose measurements obtained during treatment: group 1 (n = 65, <=30%), and group 2 (n = 24, >30%). Ultrasound (US) was performed at three time points for the comparison of mean fetal weight and abdominal circumference percentiles and fetal weight gain (g/day): US0 (18 to 24 weeks), US1 (at the beginning of treatment of GD), and US2 (at the end of treatment) Results: The two groups did not differ in terms of maternal age, pregestational BMI, prenatal maternal weight gain, gestational age at the diagnosis of GD, time of onset of treatment, or gestational age at US. Mean glycemia was 98.7 mg/dl in group 1 and 111.9 mg/dl in group 2 (p<0.001). Insulin was used by 16.9% of the patients of group 1 vs. 87.5% of group 2 (p<0.001). HbA1c at diagnosis of GD was higher in group 2 (5.52% vs. 5.93%; p<0.001). Fetal weight percentiles were similar in the two groups at US0 and US1, but significantly higher in group 2 at US2 (p=0.02). Abdominal circumference percentiles were significantly higher in group 2 at US1 and US2. Fetal weight gain (27.5 vs. 33.4 g/day; p=0.001) and birthweight (3247 vs. 3499 g; p=0.025) were higher in group 2. Conclusions: The pattern of fetal growth in patients with GD varies according to glycemic control. The fetal growth velocity and newborn birthweight were higher in women who presented >30% of hyperglycemic episodes during treatment of GD. The abdominal circumference percentile seems to change before the weight percentile and would be a more sensitive marker of altered fetal growth.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O diabetes mellitus gestacional (DMG) à uma das sÃndromes metabÃlicas mais freqÃentes, e muitas vezes exige internaÃÃo. O exercÃcio profissional dedicado ao cuidado das gestantes com DMG mostrou problemas sociais e psicolÃgicos acarretados pelo diagnÃstico e a obrigatoriedade da internaÃÃo hospitalar, dando origem ao seguinte pressuposto: o diagnÃstico de DG inesperado e a internaÃÃo prolongada trazem sentimentos de medo de nÃo conseguir chegar ao termo da gravidez e ter um bebà saudÃvel. Esses momentos tambÃm sÃo permeados de preocupaÃÃes com relaÃÃo ao afastamento dos filhos que ficaram em casa. As experiÃncias compartilhadas com essas mulheres incentivaram o desenvolvimento da presente investigaÃÃo, que se propÃs a compreender o significado do diagnÃstico e da internaÃÃo hospitalar na perspectiva de um grupo de grÃvidas com DMG. Estudo fenomenolÃgico, realizado na clÃnica obstÃtrica da Maternidade Escola Assis Chateaubriand, Universidade Federal do CearÃ, localizada no municÃpio de Fortaleza. Participaram da investigaÃÃo 12 gestantes hospitalizadas pela primeira vez durante a gravidez. As informaÃÃes obtidas no perÃodo de abril a outubro de 2007 foram extraÃdas de prontuÃrios, de entrevistas semi-estruturadas, de prÃticas de arte-terapia e de anotaÃÃes de diÃrio de campo. Foram ainda organizadas à luz do mÃtodo de Colaizzi e analisadas com base nos estudiosos da fenomenologia existencial, da arte-terapia e do diabetes gestacional. O estudo evidenciou que ter diabetes gestacional significa: 1. vivenciar experiÃncias que trazem felicidade, bem-estar e mudanÃas de atitude como o sentimento prazeroso de gestar e ser mÃe; o sentimento de felicidade devido Ãs chances de tratamento, controle e atà cura da doenÃa, e a oportunidade de ser-com-o-outro durante a hospitalizaÃÃo e 2. vivenciar experiÃncias de sofrimento decorrentes do diagnÃstico e da internaÃÃo hospitalar, como o medo da morte, desespero, tristeza, angÃstia, inseguranÃa e depressÃo. A compreensÃo do fenÃmeno em questÃo confirmou o pressuposto formulado e acrescentou outras facetas ao fenÃmeno, revelando a necessidade de um novo olhar para o cuidado Ãs gestantes internadas com diabetes mellitus gestacional, que priorize a utilizaÃÃo de recursos lÃdicos e expressivos; a permissÃo para que filhos menores possam visitar as mÃes durante a hospitalizaÃÃo; e a implementaÃÃo de aÃÃes educativas no interior das unidades de internaÃÃo. A partir dos discursos das gestantes apreendeu-se que tais estratÃgias tornam o perÃodo de hospitalizaÃÃo mais tranqÃilo e acolhedor, o que ajudarà essas mulheres a se perceberem como Seres Humanos de mÃltiplas possibilidades. / Gestational Diabetes Mellitus is one of the most frequent metabolic syndromes and often requires hospitalization.The professional exercise dedicated to the care of pregnant women with DMG showed social and psycological problems caused by diagnosis and obligation of hospitalization, leading to the following assumption: the diagnosis of DG unexpected and prolonged hospitalization bring feelings of fear of not reaching the end of pregnancy and have a healthy baby. These moments are also permeated of concerns regarding to the absence of the children who stayed at home. The experiences shared with these women encouraged the development of this research, which is proposed to understand the meaning of the diagnosis and hospitalization in the perspective of a group of pregnant women with GDM.The phenomenological study was conducted in the obstetrical clinic of Maternidade Escola Assis Chateaubriand, Federal University of CearÃ, in Fortaleza/CearÃ. Twelve women hospitalized for the first time during pregnancy participated in the research. Information obtained between April and October, 2007, were extracted from medical records, semi-structured interviews, practice of art-therapy and daily notes from a field diary. Such information was also organized on the method of Colaizzi and analyzed based on the scholars of existential phenomenology, art-therapy and gestational diabetes. The study showed that to have gestational diabetes means: 1. living experiences that bring happiness, welfare and changes in attitude, as the pleasant feeling of pregnancy and be a mother; the sense of happiness due the chances of treatment, control and even cure of the disease, and the opportunity to be with each other during hospitalization and 2. living experiences of suffering emerged from the impact of diagnosis, as the fear of death, despair, sadness, anxiety, distress, insecurity and depression. The comprehension of the phenomenon confirmed the assumption formulated and added other facets to the same phenomenon, revealing the need for a new look to the care of pregnant women hospitalized with gestational diabetes mellitus which prioritize the use of entertainment and expressive resources; the permission for the children to visit their mothers during hospitalization; and implementation of educational activities within the units of hospitalization. From the speeches of the women it was observed that such strategies make the period of hospitalization more quiet and receptive, which would help these women to realize themselves as Human Beings with multiple possibilities.