In Sweden, there is currently no consensus addressing the screening, diagnostics and treatment of gestational diabetes mellitus (GDM). In addition, there is little knowledge on the impact of GDM on the daily life of pregnant women and the experiences of health care professionals providing maternal health care to women with GDM. Using different perspectives, this thesis examines the experiences of GDM and the performance of screening for GDM in a regional context in Sweden. The studies used qualitative and quantitative methods. In the qualitative studies, grounded theory was applied in two studies and qualitative content analysis in one study. In the quantitative study, a combination of questionnaire data and data from medical records of pregnancy and birth were processed. Surprisingly, screening for GDM was reduced despite local clinical guidelines stipulating the risk factors indicating an OGTT. Furthermore, the prevalence of the risk factors for GDM in the population investigated was almost doubled compared to previous Swedish studies. Pregnant women developing risk factors for GDM during pregnancy were found to be at substantially increased risk of giving birth to an infant with macrosomia. The experiences of pregnant women with GDM revealed that being diagnosed with and living with GDM during pregnancy might be understood as a process ‘from stun to gradual balance’. The experience comprised both negative and positive dimensions. Despite the challenges, the inconveniences and the changes involved, gradually adapting to an altered lifestyle and finding their balance in daily life was ‘the prize’ the women ‘were willing to pay’ to secure optimal maternal and foetal health. The experiences of midwives comprised managing conflicting demands providing antenatal care to pregnant women diagnosed with GDM. Most midwives felt the obligation to control and monitor the complicated pregnancy, to initiate and motivate the recommended changes in life style together with providing an empowering and caring relation with the women. These assignments disclosed complex conflicting situations and the midwives appeared to choose strategy for managing the situation depending on their perception of the circumstances. The experiences of the obstetricians were understood as ‘dealing with ambiguity’. The ambiguity permeated all aspects of working as an obstetrician within the maternal health care counselling women with GDM: the role of the obstetrician, the context of the organization, balancing the multifaceted interests of the maternal and foetal conditions and the lack of consensus, recommendations and evidence-based knowledge.   The studies revealed the complexity of the situation for the affected pregnant women as well as for the health care professionals providing antenatal care to women diagnosed with GDM. Furthermore, the performance of screening of GDM in pregnant women with risk factors for GDM was insufficient in the investigated region. The findings in this thesis may be useful to increase knowledge of the experiences of pregnant women living with or managing GDM. The findings may also be useful when planning for improvements of maternal health care directed to pregnant women diagnosed with GDM during pregnancy.

Introdução e objetivos – A finalidade prioritária no tratamento do diabetes mellitus gestacional (DMG) é alcançar níveis de glicemia materna tão próximos da normalidade quanto possível, a fim de reduzir os efeitos adversos associados à hiperglicemia na gestação. A auto verificação da glicemia capilar (perfil glicêmico) é o método mais usado para a monitorização do controle metabólico na gestação complicada por diabetes. Nosso objetivo foi analisar as associações entre os perfis glicêmicos maternos com os principais desfechos da gestação numa população de mulheres com DMG acompanhadas em ambulatório de pré-natal especializado em hospital universitário no sul do Brasil, Hospital de Clínicas de Porto Alegre (HCPA). Desenho e metodotologia – conduzimos um estudo de coorte prospectiva de gestantes referidas da rede de atenção primária de saúde pública para tratamento do DMG no HCPA, acompanhadas do diagnóstico ao parto. Pesquisamos associações entre os resultados dos perfis glicêmicos com o peso de nascimento e com o risco de recém-nascidos grandes para idade gestacional e de desfechos adversos perinatais. Resultados – acompanhamos 440 mulheres com DMG. A média do índice de massa corporal (IMC) foi 33.3kg/m2. 351 bebês (79.8%) mostraram peso adequado à idade gestacional no nascimento. As médias de glicemia nos perfis pré e pósprandiais aumentaram com o avanço na categoria de peso nascimento. Três ou mais perfis glicêmicos anormais foram o fator de risco mais robusto para o nascimento de bebês grandes (OR 3.15 1.51-6.55) e para o desenvolvimento de desfechos adversos perinatais (OR 2.28 1.59-3.29). O ganho de peso materno durante o tratamento associou-se ao risco de recém-nascido grande para idade gestacional, assim como o IMC pré-gestacional, esse último também fator de risco independente para eventos perinatais adversos. Conclusão – perfis glicêmicos anormais em mais de 2 ocasiões foram o fator de risco mais relacionado ao nascimento de um bebê grande para a idade gestacional e para o desenvolvimento de complicações neonatais. Efeito benéfico do tratamento do DMG, guiado pelos perfis glicêmicos, foi a maioria de recém-nascidos com peso adequado à idade gestacional nessa coorte, apesar da incidência de desfechos perinatais adversos não ter sido diferente entre as categorias de peso fetal de nascimento. / Background and objective – a priority target in the treatment of gestational diabetes mellitus (GDM) is attaining maternal glucose levels as close as possible to euglycemia, in order to decrease the adverse outcomes linked to hyperglycemia. Self-performed capillary glucose (glycemic profile) is the most widely used method for metabolic monitoring in pregnancy complicated by diabetes. We intended to analyze the associations of maternal glycemic profile to main pregnancy outcomes in a population of GDM women treated in a specialized prenatal clinic at a university hospital in South Brazil, Hospital de Clínicas de Porto Alegre (HCPA). Research design and methodology – we conducted a prospective cohort study of pregnant women, referred from public primary health care for treatment of GDM at HCPA, between 2008 and 2015. We searched associations of glycemic profiles to birth weight, large for gestational age newborn and adverse neonatal outcomes. Results – we followed 440 GDM women from diagnosis to delivery. Mean prepregnancy body mass index (BMI) was 33.3kg/m2; 351 babies (79.8%) had appropriate birth weight for gestational age. Mean glucose in pre-prandial and postprandial profiles increased with raising birth weight category. Three or more abnormal glycemic profiles showed the strongest association to a large baby (OR 3.15 1.51-6.55) and to a composite of adverse neonatal outcomes (OR 2.28 1.59- 3.29). Gestational weight gain in the course of treatment was associated to large babies, as pre-pregnancy BMI, the latter also an independent risk factor for adverse neonatal outcome. Conclusion – abnormal maternal glycemic profiles in more than two occasions were the stronger risk factor for delivering a large baby and for developing neonatal complications. A beneficial effect of GDM treatment, guided by glycemic profiles, was that most of our newborns had birth weight appropriate for gestational age, although incidence of adverse neonatal outcomes had been no different across birth weight categories.

Introdução e objetivos – A finalidade prioritária no tratamento do diabetes mellitus gestacional (DMG) é alcançar níveis de glicemia materna tão próximos da normalidade quanto possível, a fim de reduzir os efeitos adversos associados à hiperglicemia na gestação. A auto verificação da glicemia capilar (perfil glicêmico) é o método mais usado para a monitorização do controle metabólico na gestação complicada por diabetes. Nosso objetivo foi analisar as associações entre os perfis glicêmicos maternos com os principais desfechos da gestação numa população de mulheres com DMG acompanhadas em ambulatório de pré-natal especializado em hospital universitário no sul do Brasil, Hospital de Clínicas de Porto Alegre (HCPA). Desenho e metodotologia – conduzimos um estudo de coorte prospectiva de gestantes referidas da rede de atenção primária de saúde pública para tratamento do DMG no HCPA, acompanhadas do diagnóstico ao parto. Pesquisamos associações entre os resultados dos perfis glicêmicos com o peso de nascimento e com o risco de recém-nascidos grandes para idade gestacional e de desfechos adversos perinatais. Resultados – acompanhamos 440 mulheres com DMG. A média do índice de massa corporal (IMC) foi 33.3kg/m2. 351 bebês (79.8%) mostraram peso adequado à idade gestacional no nascimento. As médias de glicemia nos perfis pré e pósprandiais aumentaram com o avanço na categoria de peso nascimento. Três ou mais perfis glicêmicos anormais foram o fator de risco mais robusto para o nascimento de bebês grandes (OR 3.15 1.51-6.55) e para o desenvolvimento de desfechos adversos perinatais (OR 2.28 1.59-3.29). O ganho de peso materno durante o tratamento associou-se ao risco de recém-nascido grande para idade gestacional, assim como o IMC pré-gestacional, esse último também fator de risco independente para eventos perinatais adversos. Conclusão – perfis glicêmicos anormais em mais de 2 ocasiões foram o fator de risco mais relacionado ao nascimento de um bebê grande para a idade gestacional e para o desenvolvimento de complicações neonatais. Efeito benéfico do tratamento do DMG, guiado pelos perfis glicêmicos, foi a maioria de recém-nascidos com peso adequado à idade gestacional nessa coorte, apesar da incidência de desfechos perinatais adversos não ter sido diferente entre as categorias de peso fetal de nascimento. / Background and objective – a priority target in the treatment of gestational diabetes mellitus (GDM) is attaining maternal glucose levels as close as possible to euglycemia, in order to decrease the adverse outcomes linked to hyperglycemia. Self-performed capillary glucose (glycemic profile) is the most widely used method for metabolic monitoring in pregnancy complicated by diabetes. We intended to analyze the associations of maternal glycemic profile to main pregnancy outcomes in a population of GDM women treated in a specialized prenatal clinic at a university hospital in South Brazil, Hospital de Clínicas de Porto Alegre (HCPA). Research design and methodology – we conducted a prospective cohort study of pregnant women, referred from public primary health care for treatment of GDM at HCPA, between 2008 and 2015. We searched associations of glycemic profiles to birth weight, large for gestational age newborn and adverse neonatal outcomes. Results – we followed 440 GDM women from diagnosis to delivery. Mean prepregnancy body mass index (BMI) was 33.3kg/m2; 351 babies (79.8%) had appropriate birth weight for gestational age. Mean glucose in pre-prandial and postprandial profiles increased with raising birth weight category. Three or more abnormal glycemic profiles showed the strongest association to a large baby (OR 3.15 1.51-6.55) and to a composite of adverse neonatal outcomes (OR 2.28 1.59- 3.29). Gestational weight gain in the course of treatment was associated to large babies, as pre-pregnancy BMI, the latter also an independent risk factor for adverse neonatal outcome. Conclusion – abnormal maternal glycemic profiles in more than two occasions were the stronger risk factor for delivering a large baby and for developing neonatal complications. A beneficial effect of GDM treatment, guided by glycemic profiles, was that most of our newborns had birth weight appropriate for gestational age, although incidence of adverse neonatal outcomes had been no different across birth weight categories.

O diabetes mellitus tipo 1 (DM1) tem etiologia autoimune, enquanto o diabetes mellitus tipo 2 (DM2) e o diabetes mellitus gestacional (DMG) são considerados como distúrbios metabólicos. Neste trabalho, foi realizada análise do transcriptoma das células mononucleares do sangue periférico (do inglês, peripheral mononuclear blood cells - PBMCs), obtidas de pacientes com DM1, DM2 e DMG, realizando análises por module maps a fim de comparar características patogênicas e aspectos gerais do tratamento com anotações disponíveis de genes modulados, tais como: a) análises disponíveis a partir de estudos de associação em larga escala (do inglês genome-wide association studies GWAS); b) genes associados ao diabetes em estudos clássicos de ligação disponíveis em bancos de dados públicos; c) perfis de expressão de células imunológicas fornecidos pelo grupo ImmGen (Immunological Project). Foram feitos microarrays do transcriptoma total da plataforma Agilent (Whole genome onecolor Agilent 4x44k) para 56 pacientes (19 DM1, 20 DM2 e 17 DMG). Para a compreensão dos resultados foram aplicados filtros não-informativos e as listas de genes diferencialmente expressos foram obtidas por análise de partição e análise estatística não-paramétrica (rank products), respectivamente. Posteriormente, análises de enriquecimento funcional foram feitas pelo DAVID e os module maps construídos usando a ferramenta Genomica. As análises funcionais contribuíram para discriminar os pacientes a partir de genes envolvidos na inflamação, em especial DM1 e DMG. Os module maps de genes diferencialmente expressos revelaram: a) genes modulados exibiram perfis de transcrição típicos de macrófagos e células dendríticas, b) genes modulados foram associados com genes previamente descritos como genes de complicação ao diabetes a partir de estudos de ligação e de meta-análises; c) a duração da doença, obesidade, número de gestações, níveis de glicose sérica e uso de medicações, tais como metformina, influenciaram a expressão gênica em pelo menos um tipo de diabetes. Esse é o primeiro estudo de module maps mostrando a influência de padrões epidemiológicos, clínicos, laboratoriais, imunopatogênicos e de tratamento na modulação dos perfis transcricionais em pacientes com os três tipos clássicos de diabetes: DM1, DM2 e DMG. / Type 1 diabetes (T1D) is an autoimmune disease while type 2 (T2D) and gestational diabetes (GDM) are considered as metabolic disturbances. We performed a transcriptome analysis of peripheral mononuclear blood cells obtained from T1D, T2D and GDM patients, and we took advantage of the module map approach to compare pathogenic and treatment features of our patient series with available annotation of modulated genes from i) genome-wide association studies; ii) genes provided by diabetes meta-analysis in public databases, iii) immune cell gene expression profiles provided by the ImmGen project. Whole genome one-color Agilent 4x44k microarray was performed for 56 (19 T1D, 20 T2D, 17 GDM) patients. Noninformative filtered and differentially expressed genes were obtained by partitioning and rank product analysis, respectively. Functional analyses were carried out using the DAVID software and module maps were constructed using the Genomica tool. Functional analyses contributed to discriminate patients on the basis of genes involved in inflammation, primarily for T1D and GDM. Module maps of differentially expressed genes revealed that: i) modulated genes exhibited transcription profiles typical of macrophage and dendritic cells, ii) modulated genes were associated with previously reported diabetes complication genes disclosed by association and meta-analysis studies, iii) disease duration, obesity, number of gestations, glucose serum levels and the use of medications, such as metformin, influenced gene expression profiles in at least one type of diabetes. This is the first module map study to show the influence of epidemiological, clinical, laboratory, immunopathogenic and treatment features on the modulation of the transcription profiles of T1D, T2D and GDM patients.

O diabetes mellitus (DM) é definido como doença metabólica, caracterizado pela hiperglicemia, causada pela disfunção da secreção de insulina, atividade da insulina ou ambas. É classificado em quatro classes clínicas i) diabetes mellitus tipo 1 (DM1), ii) diabetes mellitus tipo 2 (DM2), iii) diabetes mellitus gestacional (DMG), iv) outros tipos específicos. Dentre os genes conhecidos por influenciarem o mecanismo de produção e liberação de insulina no organismo humano, o gene da insulina (INS) é o mais bem caracterizado nas classes clínicas do DM. A região promotora do gene INS tem sido alvo de estudo em diversas amostras populacionais do mundo, devido a sua capacidade de modular os níveis de expressão de insulina no timo e no pâncreas, de acordo, com a classe alélica que compõe o genótipo do indivíduo. Localizada a 596pb acima do sítio de transcrição do gene da insulina, é estruturada em alelos minissatélites distribuídos in tandem (ACAGGGGTGTGGGG). O alelo classe I (30 - 60 repetições) tem sido associado com predisposição ao DM1, enquanto o alelo classe III (120 - 170 repetições) tem efeito de proteção ao DM1, no entanto, esse alelo tem apresentado correlação ao DM2, à obesidade em crianças e jovens e, aumento de riscos cardiovasculares. O presente trabalho tem como objetivo analisar o polimorfismo da região promotora do gene da insulina sobre os fenótipos do DM e a possível influência desse em características demográficas, clínicas e laboratoriais desses pacientes. Foram analisados 189 pacientes com DM1, 116 pacientes com DM2, 68 pacientes com DMG e 339 indivíduos controle da região de Ribeirão Preto, SP. O DNA genômico foi extraído por salting-out, seguido da amplificação e digestão enzimática do fragmento referente a região promotora do gene INS, o qual contém na sequência downstream, o polimorfismo -23HphI, cujo desequilíbrio de ligação (r2 1) com o polimorfismo INSVNTR, permite inferir os genótipos por intermédio da análise do polimorfismo -23HphI. Observamos que o alelo classe I e o genótipo classe I : classe I estão relacionados à predisposição ao DM1, enquanto o alelo classe III, predominantemente em homozigose, está associado à proteção ao DM1. Em relação ao DM2, o genótipo classe I : classe III foi associado à susceptibilidade a doença e, nenhum genótipo foi correlacionado ao DMG. De acordo com os dados demográficos, clínicos e laboratoriais, variáveis como gênero e pigmentação da pele têm influenciado na frequência do polimorfismo INSVNTR em pacientes com DM1, como por exemplo, a maior frequência de homens com genótipo classe I : classe I no conjunto DM1. Em contrapartida, nesse mesmo grupo de pacientes, o genótipo classe III : classe III evidenciou maior susceptibilidade ao desenvolvimento de retinopatia (p=0,0020; OR= 0,05333; 95% I.C. 0,007839 - 0,3629). Em pacientes com DM2, a comparação entre gêneros evidenciou maior frequência do genótipo classe III : classe III em mulheres. E, em relação ao DMG, os genótipos de classe I : classe I e classe I : classe III estavam associados ao menor nível de glicose no plasma sanguíneo em relação as pacientes que exibiam o genótipo classe III : classe III. Esse é o primeiro estudo de associação do polimorfismo INS-VNTR comparando as três principais classes clínicas de DM oriundas de uma mesma amostra geográfica, sendo evidenciado um perfil genotípico padrão de susceptibilidade de acordo com o tipo de DM. / Diabetes mellitus (DM) is defined as a metabolic disorder characterized by hyperglycemia caused by impaired insulin secretion, insulin activity or both. It is classified into four clinical classes i) type 1 diabetes mellitus (T1DM), ii) type 2 diabetes mellitus (T2DM), iii) gestational diabetes mellitus (GDM), iv) other specific types. Among the genes known to influence the mechanism of production and release of insulin, the insulin gene (INS) has been well characterized in disease susceptibility. The INS promoter has been studied in different worldwide populations due to its ability to modulate expression levels of insulin in the thymus and pancreas, in accordance with the type of diabetes. The major polymorphic site is located 596bp upstream from the translation initiation site of the INS gene and it is structured into minisatellite alleles (ACAGGGGTGTGGGG). The shorter class I alleles (30 60 repeats) confers predisposition to DM1 and the longer class III (120 170 repeats) confers protection to DM1; however, the latter allele has also shown to be correlated with DM2, obesity in children and juvenile individuals, and increased cardiovascular risks. This study aims to analyze the association of a polymorphic site at promoter region of the INS gene with diabetes phenotypes, with the purpose of evaluating this region as a possible genetic marker of the disease, and the possible influence on demographic, clinical and laboratory features in a sample of the urban Brazilian population. We analyzed 189 T1DM patients, 116 T2DM patients, 68 GDM patients and 339 healthy individuals from the region of Ribeirão Preto, SP. DNA extraction was performed using a salting-out procedure, followed by amplification and restriction enzyme digestion of the fragment relating to INS gene promoter, which contains another polymorphism, -23HphI, which is in perfect linkage disequilibrium (r2 1) with the INS-VNTR, making it an useful genetic marker. We observed that the class I allele and class I : class I genotype are associated with predisposition to T1DM, whereas, class III allele, predominantly in homozygosity, is associated to T1DM protection. In relation to T2DM, the class I : class III genotype has been associated with susceptibility to disease. Finally, no genotype was correlated with GDM. Data stratification according to demographical, clinical and laboratory variables, indicated that gender, skin color seemed to influence the frequency of the INS-VNTR polymorphism; i. e., the class I : class I genotype was more frequent in male T1DM patients. On the other hand, the presence of the class III : class III genotype was associated with susceptibility the development of retinopathy (p=0,0020; OR= 0,05333; 95% I.C. 0,007839 - 0,3629). In T2DM patients, a trend association was observed between the class III : class III genotype with female diabetic patients. In relation to GDM, the genotypes class I : class I and class I : class III were associated with decreased glucose levels in relation to patients exhibiting the class III : class III genotype. This is the first study of the INS-VNTR polymorphism encompassing the major types if DM patients from the same geographical region, which showed a differential pattern of susceptibility according to the underlying type of DM.

Gestational diabetes (GDM) is a disorder of glucose metabolism arising for the first time in pregnancy and spontaneously receding after birth. The issue of GDM is very topical since, according to the latest update of diagnostic criteria, up to 17% of pregnant women is threatened by this disorder. The incidence of GDM correlates with the increasing prevalence of overweight/obesity and metabolic syndrome. It is proved that women who have had gestational diabetes have an enormously increased risk of developing type 2 diabetes mellitus (DM2T). The risk accosiated with a gestational diabetes pregnancy stretches beyond the host, and can affect the fetus both directly (e. g. macrosomia development), and epigenetically (increases susceptibility to obesity, DM2T development or cardiovascular disease). Significant influence on the development of GDM (or DM2T) is a body composition that is directly related to lifestyle (nutritional intake and physical activity) and genetic role i salso involved. Early intervention may help delay the risk of developing DM2T and other metabolic complications. In this diploma thesis we monitored metabolic profiles of glucose and lipids and body composition based on anthropometric examination and questionnaires of nutritional income and physical activity. For the complex...

Pregnancy-related complications such as gestational hypertension, preeclampsia, fetal growth restriction, gestational diabetes mellitus, spontaneous preterm birth, and preterm premature rupture of membranes may have severe consequences for both the mother and the child. The development of reliable early screening methods for pregnancy-related complications has therefore been a long-term goal of obstetrics. New possibilities for prenatal diagnostics have opened with the discovery of circulating microRNAs in maternal plasma. MicroRNAs are short, noncoding, 21 to 23 nucleotides long, single-strand RNAs whose main function is to regulate gene expression. During pregnancy, both common and unique miRNAs are expressed by the placenta, amongst them the miRNAs of the C19MC cluster. Several C19MC miRNAs have been shown to display a different expression profile associated with certain pregnancy-related complications. This thesis identifies the plasma exosomal profiles of six C19MC miRNAs (miR-516-5p, miR-517-5p, miR-518b, miR-520a-5p, miR-520h, and miR-525-5p) in patients in their first trimester of gestation who later developed pregnancy-related complications, and compares them with profiles in patients with normal pregnancies.

Objectifs : L’objectif principal de cette étude est d’établir si la santé parodontale des femmes enceintes ayant un DG est moindre que celle des femmes enceintes sans DG. L’objectif secondaire est d’évaluer l’association entre la fréquence et l’intensité du ronflement avec la santé parodontale chez les femmes enceintes ayant un DG. Méthodologie : Une étude de type cas-contrôle a été conduite parmi des femmes enceintes suivies au CHU Sainte-Justine. Le diagnostic de DG a été recueilli dans le dossier médical des participantes. Le volet 1 de l’étude incluait des mesures autorapportées par des questionnaires. Un sous-groupe de femmes enceintes était ensuite invité au volet 2 qui incluait un examen buccal permettant d’évaluer la santé parodontale des participantes. Les associations entre le DG et le ronflement, l’apnée obstructive du sommeil (AOS) et les maladies parodontales ont été évaluées à l’aide d’analyses bivariées. Résultats : Douze femmes enceintes avec DG et 85 femmes enceintes sans DG ont rempli les questionnaires du volet 1. De ces femmes, trois avec DG et sept sans DG ont participé au volet 2. Les femmes enceintes avec le DG étaient moins nombreuses à travailler à temps plein (p=0.032), avaient un revenu individuel (p=0.039) et familial (p=0.050) plus faible, faisaient moins d’activité physique (p=0.004) et allaient moins chez le dentiste (p=0.002) que les femmes enceintes sans DG. Il n’y avait pas de différence statistiquement significative entre les deux groupes pour le ronflement, l’AOS et les maladies parodontales. Conclusions : Les résultats préliminaires de l’étude n’ont pas établi si la santé parodontale des femmes enceintes avec DG est moindre ni démontré une association avec les troubles respiratoires obstructifs du sommeil. Pour atteindre les objectifs de l’étude, l’augmentation de la taille d’échantillon prévue à n=200 est requise. / Introduction Gestational diabetes mellitus (GDM) affects one in six pregnancies worldwide. Several short- and long-term complications affecting the mother and child can result from GDM. A few studies have shown a positive association between periodontal disease and GDM. Periodontal disease is also associated with adverse effects on pregnancy. In addition to potentially affecting fetal health and maternal insulin resistance, periodontal diseases are associated with obstructive sleep-disordered breathing. However, the relationship between these two entities in the context of GDM has not yet been studied. Objectives: The primary objective of this study is to establish whether the periodontal health of pregnant women with GDM is less than the one of pregnant women without GDM. The secondary objective is to assess the association between snoring frequency and intensity with periodontal health in pregnant women with GDM. Methodology: A case-control study was conducted among pregnant women followed at Sainte-Justine Hospital. The diagnosis of GDM was collected from the participants' medical records. The first phase of the study included self-reported measures by questionnaires. A subgroup of pregnant women was then invited to a second clinical phase. This included an oral examination to assess the participants' periodontal health. The associations between GDM and snoring, obstructive sleep apnea (OSA), and periodontal disease were evaluated using bivariate analyses. Results: Twelve pregnant women with GDM and 85 pregnant women without GDM completed the questionnaires in the first phase of the study. Of these women, three with GDM and seven without GDM participated in the second phase. Pregnant women with GDM worked less full-time (p=0.032), had lower individual (p=0.039) and family (p=0.050) income, engaged in less physical activity (p=0.004), and went to the dentist less often (p=0.002) than pregnant women without GDM. There was no statistically significant difference between the two groups for snoring, OSA and periodontal disease. Conclusions: Preliminary results of the study did not establish whether periodontal health in pregnant women with GDM is poorer, nor did they demonstrate an association with obstructive sleep-disordered breathing. To achieve the study objectives, the increase in sample size to n=200 is required.

L'intégration du traitement et de la prévention des maladies chroniques non transmissibles (MNT) au sein des soins de santé primaires représente le principal défi à venir pour la santé publique et les systèmes de santé dans les pays à faible et moyen revenu comme l’Afrique du Sud. Il constitue le principal objectif de cette thèse. L’expérience de l'intégration de la prévention de la transmission du VIH de la mère à l'enfant (PTME) dans les soins de santé primaires (SSP) peut apporter des leçons importantes pour l'intégration de la prévention du diabète chez les femmes souffrant de diabète gestationnel récent (DSG) dans les SSP. Il a été estimé que le DSG touche plus de 9,1 % des grossesses en 2018 en Afrique du Sud. Le DSG augmente le risque de développer ultérieurement du diabète de type 2 (DT2). Le DSG multiplie par plus de 7 le risque de développer un DT2 ainsi que les risques de troubles métaboliques pour les bébés des femmes qui en sont atteintes. Cette thèse explore comment appliquer les leçons tirées de l’intégration de la PTME pour intégrer le dépistage du DSG et les initiatives de prévention du DT2 dans les soins de santé primaires de routine en Afrique du Sud. Le cadre conceptuel adapté pour cette thèse permet ainsi de comprendre les aspects de l’intégration au niveau du patient et du système de santé, englobant les contextes, les mécanismes et la mise en œuvre de l’intégration d’interventions préventives dans les services existants. L'étude s'inscrit dans le cadre du projet IINDIAGO, « Intervention intégrée du système de santé visant à réduire les risques de diabète de type 2 chez les femmes défavorisées après un diabète gestationnel en Afrique du Sud ». La thèse présente d’abord une revue narrative de l’impact de la PTME sur les services et les systèmes de soins de santé en Afrique subsaharienne (Article 1). Les résultats de cette revue montrent que la PTME a eu l’impact positif et négatif sur d’autres services de soins de santé et que son intégration dans les systèmes de santé est de plus en plus privilégiée. L’article 2 est une étude qualitative analysant l’histoire et l’expérience locales de l’intégration de la PTME dans les SSP de routine en Afrique du Sud de différents points de vue. Bien qu’elle ait constaté un fort soutien en faveur de l’intégration parmi tous les répondants, cette étude a fait état de multiples obstacles à la pleine intégration de la PTME dans les SSP, le post-partum en particulier. Les articles 3 et 4 ont utilisé les méthodes mixtes et révélé que l’intégration des services dans les SSP de routine, à base communautaire, pour dépister universellement le DSG et pour prévenir ou retarder le DT2 après le DSG, était perçue comme faisable, acceptable et nécessaire de toute urgence en Afrique du Sud. L’article 6 (dont le protocole est l’article 5) présentait une revue systématique et une méta-analyse sur la prise en charge intégrée du DSG et du DT2 dans le contexte de la multimorbidité en Afrique. Les 13 études incluses dans cette étude ont montré que la gestion intégrée du DSG et du DT2 dans le cadre de la multimorbidité était mise en œuvre avec succès, mais qu’elle nécessitait une formation et une supervision adéquates des infirmières, et la fourniture d’équipements et de médicaments additionnels au sein des systèmes de santé nationaux en Afrique. Les conclusions de cette thèse suggèrent que, bien qu’elle n’ait pas toujours été retenue, en raison de défis structurels et opérationnels, l’intégration complète plutôt que partielle des services de santé est considérée comme souhaitable et réalisable par les femmes, les travailleurs de la santé, les gestionnaires et les experts. L’intégration complète pourrait être idéale pour dépister, diagnostiquer et soigner les maladies chroniques, y compris le DSG et le DT2, au sein des SSP de routine et selon l’approche de la PTME dont les leçons d’intégration n’ont pas été adaptées à ce prochain défi de santé publique. / Integrating chronic, non-communicable diseases (NCDs) and their prevention into primary health care is the next major challenge for public health and health systems in low and middle-income countries like South Africa and is the primary focus of this thesis. The experience of integration of Prevention of Mother-to-Child Transmission (PMTCT) of HIV into primary health care (PHC) may have important lessons for integrating prevention of diabetes among women with recent gestational diabetes (GDM) into PHC. GDM was estimated to affect more than 9.1% of pregnancies in 2018 in South Africa. GDM increases the risk of developing subsequent type 2 diabetes (T2DM) more than 7-fold as well as increasing the risks of metabolic disorders for the babies of women who had GDM. This thesis conducted a systematised narrative synthesis, a systematic review and a convergent mixed methods study using primarily qualitative methods in South Africa (focus on Cape Town, Western Cape) to explore how to apply lessons from PMTCT integration in order to integrate GDM screening and T2DM prevention initiatives into routine PHC in South Africa. The adapted conceptual framework for this thesis enables to understand both patient-level and health system-level aspects of integration and encompassing the contexts, mechanisms and implementation for integrating preventive interventions in the existing services. The study was nested in the IINDIAGO project, “Integrated health system intervention aimed at reducing type 2 diabetes risks in disadvantaged women after gestational diabetes in South Africa”. The thesis first presents a narrative review of the impact of PMTCT on health care services and systems in sub-Saharan Africa (Paper 1). This review findings show that PMTCT has had positive and negative impacts on other health care services and that its integration into health systems is increasingly favored. Paper 2 qualitatively documented the local history and experience of PMTCT integration into routine PHC in South Africa from different perspectives. Though it found strong support for integration among all respondents (N=20), this study reported multiple barriers for the full integration of PMTCT into PHC, especially in postpartum. Papers 3 and 4 used mixed methods and highlighted that integrating services within routine, community-based PHC to universally screen GDM and to prevent or delay of T2DM after GDM, was perceived as feasible, acceptable and urgently needed in South Africa – but that it is not currently occurring at a satisfactory level, despite international and national guidelines. The fifth article is a published protocol for Paper 6, a systematic review and meta-analysis on the integrated management of GDM and T2DM in the context of multimorbidity in Africa. This was a study in which all 13 included studies showed that integrated management of GDM and T2DM within multimorbidity was successfully implemented but it required adequate training and supervision of nurses, provision of additional equipment and drugs to the existing resources within national health systems in Africa. This thesis concludes that although not always opted for, due to structural and operational challenges, the full instead of partial integration of health services to screen, diagnose and care for chronic diseases including GDM and T2DM into routine PHC, following the PMTCT approach, was seen as both desirable and feasible by women, health workers, managers, and experts. However, the lessons learned through the history of PMTCT and its integration have not been adapted to this next public health challenge.

Identification of biomarkers involved in the pathophysiology of gestational diabetes mellitus ABSTRACT Gestational diabetes mellitus is a disorder of glucose metabolism that occurs in pregnancy and resolves after delivery. Increasing production of pregnancy-related hormones leads to insulin resistance which is not adequately compensated by increased insulin secretion. Since obesity is an important risk factor for gestational diabetes and is also associated with adipose tissue dysfunction and increased peripheral insulin resistance, the question arises as to what extent is the adipose tissue involved in the development of gestational diabetes. The first part of the thesis focuses on the identification of changes in plasma concentration and mRNA expression of adipokines fetuin A, fetuin B and FGF21. In our study we did not show that the presence of gestational diabetes significantly influenced the plasma concentration of fetuin A, fetuin B and FGF21 during pregnancy. An important finding was that women who had pregnancy complicated with gestational diabetes had a significantly higher concentration of FGF21 several months after delivery in comparison to healthy pregnant women. We have been able to demonstrate the production of fetuin A in the placenta and fetuin B in perineal and subcutaneous tissue. However,...