Le diabète gestationnel (DG) est un trouble de la tolérance glucidique de gravité variable, survenant ou diagnostiqué pour la première fois pendant la grossesse, quel que soit le traitement nécessaire et son évolution après l’accouchement. Il est associé, à court et à long terme, à un ensemble de complications ou pathologies tant chez la mère que chez l’enfant. Nous avons étudié le rôle des cytokines, des adipokines, du statut anti-oxydant et des facteurs de croissance au cours du diabète gestationnel et de la macrosomie. Notre étude a montré que le diabète gestationnel et la macrosomie sont associés à une perturbation du métabolisme lipidique et une altération des statuts antioxydant et immunitaire. Le DG était lié à une diminution de l’adiponectine et des cytokines Th1 et une augmentation de la leptine et des cytokines inflammatoires alors que la macrosomie est associée à une augmentation des cytokines Th1 et une diminution de toutes ces hormones relatives à l’obésité (IL-6, TNF-α, leptine et adiponectine). Plusieurs altérations observées à la naissance dans le métabolisme des carbohydrates et des lipides chez les enfants issus de mères diabétiques persistent encore à l’âge adulte. Il semble que la programmation in utero au cours du diabète gestationnel crée une ‘‘mémoire métabolique’’ qui est responsable de l’obésité et des altérations chez les nouveau-nés macrosomiques. Selon les régressions linéaires multiples incrémentielles que nous avons établies, il semble que les facteurs de croissance qui influencent l’augmentation du poids fœtal sont : PDGF du côté maternel et FGF2 des deux côté maternel et fœtal. / Gestational diabetes mellitus (GDM) is defined as ‘carbohydrate intolerance of variable severity with onset or first recognition during pregnancy’, irrespective to necessary treatment and its evolution in the post partum. GDM is associated with a number of complications/ pathologies both in mother and in their newborns, with short and long-term. In this study, we investigated the role of cytokines, adipokines and antioxidant status during GDM and macrosomia. Our study has demonstrated that these pathologies are associated with a perturbation in lipid metabolism, and antioxidant and immune status. GDM is linked to the down-regulation of adiponectin along with Th1 cytokines and upregulation of leptin and inflammatory cytokines whereas macrosomia was associated with the up-regulation of Th1 cytokines and the down-regulation of the obesity-related agents (IL-6, TNF-α, leptin and adiponectin). Several alterations observed at birth in carbohydrates and lipids metabolism in the children born to diabetic mothers, still persist at the adulthood. It seems that in utero programming during diabetic pregnancy creates a ‘‘metabolic memory’’ which is responsible for the development of obesity and physiological anomalies in macrosomic offspring. According to multiple linear regressions incremental that we established, it appears that growth factors that influence the increase of foetal weight are: PDGF in mother's side and FGF2 in maternal and foetal side.

Abstract Background: Gestational diabetes is both physical and psychological for women. A lot of women is lacking knowledge about living with gestational diabetes. The incidence of gestational diabetes in the year of 2016 is 1,6 % of all pregnancies in Sweden and the incidence is increasing. Aim: To describe women´s experience of developed gestational diabetes and living with it. Method: A qualitative method with inductive approach and based on four individual interviews has been done. Data were analysed by latent content analysis. Findings: All women were satisfied about the care they have got. Lack of knowledge about the connection between pregnancy and gestational diabetes perceived from the midwife, but the nurse of diabetes perceived to have knowledge. The information of gestational diabetes was associated with shock, fear and shameless. Almost all women experience dietary changes and increased demands physical activity as demanding which meant a limitation for the women, but the lifestyle of changes led to a healthier life and it`s become estimated positive. To avoid insulin treatment during pregnancy was a goal which turned out to be a positive drift. Conclusion: The results of the study can contribute to increased knowledge about the woman's experience of developing gestational diabetes. Increased knowledge about gestational diabetes alleviates will relieves worry fort the woman and all the support from the surrounding people to the women and also the health professionals is very important for the women`s feel good during the pregnancy with gestational diabetes.

L’asthme est une maladie respiratoire chronique fréquente pendant la grossesse avec une prévalence de 8 %. Il a été démontré que l’asthme maternel augmente le risque de diabète gestationnel (DG), mais il y a peu d’évidences sur l’impact des médicaments antiasthmatiques d’entretien sur le risque de cette complication de grossesse. Un projet de recherche a été développé afin d’évaluer si le risque de DG est associé à la dose de corticostéroïdes inhalés (CSI) ou l’utilisation de β2-agonistes à longue durée d’action (BALA) chez les femmes enceintes asthmatiques. Pour ce faire, nous avons utilisé un devis cas-témoins niché dans une cohorte de grossesses de femmes asthmatiques qui ont accouché entre 1998 et 2010 reconstruite à partir de deux banques de données administratives de la province de Québec (Canada) : Maintenance et exploitation des données pour l’étude de la clientèle hospitalière (MED-ECHO) et Régie de l’assurance maladie du Québec (RAMQ). Le DG était défini par au moins un diagnostic de diabète gestationnel ou mellitus ou une ordonnance remplie d’un médicament antidiabétique après la 20e semaine de grossesse. Chaque cas était apparié à 30 témoins selon l’année calendrier et l’âge gestationnel. Des modèles d’équations d’estimation généralisées ont été utilisés pour estimer les rapports de cotes (aOR) et les intervalles de confiance à 95 % (IC 95 %) de DG ajustés pour la sévérité et la maîtrise de l’asthme et d’autres facteurs de risque de DG. L’association entre le DG et la dose de CSI a été estimé parmi les femmes non exposées aux BALA tandis que l’association avec les BALA a été estimée parmi les femmes exposées aux CSI à la date de survenue de l’issue pour les cas et à la date de sélection pour les témoins. Dans la cohorte de 12 587 grossesses de femmes asthmatiques, 1001 cas de DG (8 %) ont été identifiés. Nous n’avons observé aucun risque accru de DG avec une augmentation des doses de CSI parmi les non-utilisatrices de BALA avec des aOR (IC 95 %) de 0,95 (0,74-1,23) pour les faibles doses (<251 μg en équivalence de fluticasone), 1,14 (0,80-1,64) pour les moyennes doses (251 à 500 μg) et 1,13 (0,71-1,81 pour les hautes doses (>500 μg) de CSI. De plus, le risque de DG n’était pas plus élevé quand un BALA était ajouté à un CSI (aOR=0,99; IC 95 % : 0,69-1,44). Nos résultats ajoutent de l’évidence concernant l’innocuité des BALA et des doses de CSI pendant la grossesse, mais de plus amples études sont nécessaires pour examiner les associations potentielles entre les plus hautes doses de CSI et le risque de DG. / Asthma is a chronic respiratory disease that is frequent in pregnancy with a prevalence of 8%. Maternal asthma is known to increase the risk of gestational diabetes (GD), but the evidence is scarce regarding the impact of asthma controller medications on the risk of this pregnancy complication. A research study was developed to evaluate whether the risk of GD is associated with the dose of inhaled corticosteroids (ICS) or the use of long-acting β2-agonists (LABA) in pregnant women with asthma. To achieve our goals, we used a case-control design nested within a cohort of pregnancies from asthmatic women who delivered between 1998 and 2010 reconstructed from the linkage of two administrative databases from the province of Québec (Canada): Maintenance et exploitation des données pour l’étude de la clientèle hospitalière (MED-ECHO) and Régie de l’assurance maladie du Québec (RAMQ). GD was defined as at least one recorded diagnosis of gestational or chronic diabetes or a prescription for an antidiabetic medication filled after week 20 of gestation. Each case was matched to 30 controls according to calendar year and gestational age. Generalized estimating equation models were used to estimate odds ratios (aOR) and 95% confidence interval (95% CI) of GD adjusted for asthma severity and control and other risk factors of GD. The association between GD and ICS doses was estimated among women unexposed to LABA, while the association with LABA was estimated among women exposed to ICS at the date of the outcome for cases and the date of selection for controls. The cohort included 12 587 pregnancies from asthmatic woman and 1001 cases of GD (8.0%) were identified. The risk of GD showed no trend towards a higher risk with increasing dose of ICS among non-users of LABA with aOR (95% CI) of 0.95 (0.74 to 1.23) for low doses (<251 μg in fluticasone propionate equivalents), 1.14 (0.80 to 1.64) for medium doses (251 to 500 μg), and 1.13 (0.71 to 1.81) for high doses (>500 µg) of ICS. Moreover, the risk did not increase when LABA was added to an ICS (aOR=0.99; 95% CI: 0.69 to 1.44). Our results provide further evidence for the safety of LABA and ICS doses during pregnancy, but more studies are needed to examine the potential association between higher ICS doses and the risk of GD.

The increasing demand on healthcare from pregnancies complicated by gestational diabetes (GDM) and obesity is caused in large part by fetal macrosomia (FM). Alterations to the vasculature of the placenta leading to changes to nutrient flux may be more frequent when GDM and obesity occur concomitantly. However, the impact of obesity as an independent comorbidity is poorly understood. The current study sought to characterise structural and functional changes in placenta from pregnancies complicated by GDM and/or obesity and examine the involvement of miRs in this phenomenon, as the phenotype of vascular smooth muscle (VSM) has been documented to be influenced by microRNA (miR) expression. Patients were stratified according to the presence or absence of GDM and/or obesity, which resulted in four groups. Morphometric analysis of CD31 immuno-stained placentas showed that pregnancies complicated by GDM or obesity both had a higher mean sum ratio of the area of the lumen compared to the endothelium. No relationship was found with FM. The ratio increased with maternal body mass index (BMI) in all pregnancies. Immunohistochemistry with a panel of VSM markers suggested an altered phenotype of VSM in pregnancies complicated by GDM and/or obesity. RT-QPCR and immunoblotting showed a higher expression of smooth muscle myosin (SM-MHC), h-caldesmon (HC) and alpha smooth muscle actin (ASMA) in pregnancies complicated by obesity, consistent with a greater contractile capacity. This was most marked when obesity occurred without GDM.Studies were conducted on two miRs, miR-145, which is associated with VSM in many vascular tissues, and the snoRNA-derived species miR-664a-3p, which microarray studies had shown to be higher in placentas from pregnancies complicated by GDM. Dicer and dyskerin, components of the snoRNA-derived miR biogenesis pathway, were increased and reduced respectively in GDM placenta. However, studies in cultured placental villous explants suggested that neither miR species was regulated by glucose, insulin or IGF-I. Placental mesenchymal cells are the developmental precursors of VSM. In primary culture, these cells expressed both miRs. To determine the function of miR-664a-3p, a nucleofection protocol was developed in a fetal mesenchymal cell line, WI38, and applied to first-trimester placental mesenchymal cells. Preliminary proteomic analysis after nucleofection-mediated knockdown of miR-664a-3p suggested a series of novel candidate target proteins for this uncharacterised miR species. Blood vessel structure and VSM phenotype are both altered in pregnancies complicated by GDM and/or obesity. The significance of apparently higher level of contractile proteins with wider vessel lumens in obesity requires further investigation. Translational regulation by miRs including miR-145 and miR-664a-3p is implicated in these alterations. In future, targeted therapies that alter miR levels in the placenta may be useful in control of fetal overgrowth such as FM.

No description available.

Pregnancy induces maternal metabolic adaptations including mild glucose intolerance and weight gain in order to support fetal development and lactation. Adipose tissue (AT) function in gestation is featured by reduced insulin sensitivity and fat mass accrual which partly accounts for the weight gain in pregnant women and adaptation of glucose metabolism. A common metabolic pregnancy complication is gestational diabetes mellitus (GDM), a disease characterized by impaired glucose tolerance with onset in gestation. However, the relationship between AT expandability and glucose metabolism in gestation is not well understood. The goal of this thesis was to investigate the adaptations of human AT expansion induced by pregnancy, how these changes are reflected in pregnancies complicated with GDM and characterize a mouse model to study the mechanisms underlying this disease. This dissertation illustrates that pregnancy promotes AT expandability by a signaling mechanism between placental pregnancy-associated plasma protein-A (PAPP-A) and AT- insulin-like growth factor binding protein-5 (IGFBP5). In addition, gravidas with GDM showed impaired AT expansion. Studies investigating the relationship between PAPP-A and glycemic state demonstrated that low levels of PAPP-A in the 1sttrimester are highly associated with the development of GDM. Moreover, PAPP-A knockout mice exhibit reduced insulin sensitivity and impaired AT growth exclusively in gestation. These results expand the knowledge of AT biology in gestation and have the potential to improve maternal care by proposing PAPP-A as an early biomarker and possible therapeutic for GDM. It also introduces a new mouse model to study the etiology of gestational diabetes.

Adipositas und die damit verbundenen Begleiterkrankungen zeigen einen deutlichen Anstieg der Prävalenz in der Bevölkerung. Auch für die Schwangerschaft gilt starkes Übergewicht als Risikofaktor für metabolische und vaskuläre Komplikationen wie Gestationsdiabetes mellitus (GDM) und Präeklampsie (PE). In den letzten 20 Jahren wurde eindrücklich nachgewiesen, dass eine Dysregulation von Fettzell-sezernierten Proteinen, sogenannten Adipokinen, ursächlich zu GDM und PE beitragen könnte. Zu Beginn der Dissertation lagen jedoch nur unzureichende Daten über die Regulation des Insulinresistenz-induzierenden, anti-adipogenen und anti-angiogenen Adipokins Preadipocyte factor-1 (Pref-1) bei GDM und PE vor. Die vorliegende Arbeit untersucht daher die Regulation von zirkulierendem Pref-1 bei GDM und PE sowie seine Expression in der Plazenta. Bei 74 Patientinnen mit GDM konnte kein signifikanter Unterschied der Pref-1 Konzentrationen (0.40 µg/l) verglichen zu 74 Gesunden (0.42 µg/l) (p = 0.655) festgestellt werden (Wurst U et al., Cytokine 2015; 71: 161–164). Es zeigte sich in der Kohorte eine unabhängige Assoziation zwischen Pref-1 und Schwangerschaftsalter bei der Blutentnahme, Triglyzeriden, Kreatinin, Body Mass Index und C reaktivem Protein (p < 0.05). In einer Studienkohorte von 51 Schwangeren mit PE wurden signifikant niedrigere Serumspiegel von Pref-1 (0.49 µg/l) im Vergleich zu 51 gesunden Schwangeren (0.68 µg/l) (p < 0.001) gemessen (Schrey S, Wurst U, et al., Cytokine 2015; 75: 338–343). In der multiplen Regressionsanalyse waren PE, Schwangerschaftsalter zum Zeitpunkt der Blutentnahme sowie zirkulierendes Leptin unabhängige Prädiktoren für Pref-1. Im peripartalen Zeitraum zeigte sich ein akuter und deutlicher Abfall von zirkulierendem Pref-1 im mütterlichen Blut und das Adipokin wurde immunhistochemisch im Plazentagewebe nachgewiesen. Die Daten dieser Studien sind vereinbar mit den Hypothesen, dass Pref-1 mit fortschreitender Schwangerschaft zunehmend produziert wird, die Plazenta zur Sekretion des Adipokins aktiv beiträgt sowie das Adipokin bei PE dysreguliert ist. Weiterführende Untersuchungen im Tiermodell sowie prospektive Studien sind notwendig, um die Signifikanz von Pref-1 bei GDM und PE näher zu untersuchen.

MicroRNA (miRNA) are short non-coding RNA molecules that regulate gene expression at the post-transcriptional level. Many miRNAs are involved in the pathogenesis of cardiovascular diseases, which is associated with altered gene expression. This work compares miRNA gene expression profiles among various biological sources - whole peripheral venous blood (whole PB), plasma and plasma exosomes. For all tested groups combined, the expression levels of miRNA were maximal in whole PB and lowered in plasma and plasma exosomes, and the expression levels of miRNA were higher in plasma than in plasma exosomes, except miR-126-3p, which had a higher level detected in plasma exosomes compared to plasma. This work also compares expression levels of cardiovascular miRNA between women with anamnesis of gestational diabetes mellitus (GDM) and physiological gravidity 3-11 years postpartum in whole PB, plasma and plasma exosomes. In whole PB, 12 of 29 tested miRNAs were up-regulated in women with prior exposure to GDM. MiR-181a-5p was up-regulated in plasma exosomes and miR-499a-5p in plasma in women with prior exposure to GDM. The changes in whole peripheral venous blood seem to reflect the complex systemic response to the changes that occurred during the onset of GDM. Women with aberrant epigenetic profiles may...

La dépression affecte environ 20 % des femmes en âge de procréer et environ 5 % à 15 % des femmes enceintes. Les troubles anxieux, souvent concomitants de la dépression maternelle sont de l’ordre de 15 % durant la grossesse. Au cours des dernières années, l’utilisation gestationnelle des antidépresseurs s’est accrue, malgré les risques associés pour la mère et l’enfant rapportés dans la littérature. Les risques maternels tels que le risque de diabète gestationnel et de dépression postpartum ont été peu étudiés avec des résultats souvent contradictoires. De plus, les données sur l’évolution dans le temps de la prévalence de la dépression/anxiété et de l’utilisation des antidépresseurs durant la grossesse sont très peu disponibles dans la littérature. La Cohorte des Grossesses du Québec (CGQ) a été utilisée pour cette recherche et la thèse a été organisée en trois volets. Dans un premier volet, nous avons réalisé une étude descriptive pour étudier la prévalence et les tendances d’utilisation des antidépresseurs et de la dépression maternelle/anxiété durant la grossesse, sur la période allant de 1998 à 2015. La prévalence d’utilisation des antidépresseurs durant la grossesse a triplé, allant de 2,2 % en 1998 à 6,2 % en 2015, alors que la prévalence de dépression maternelle/anxiété a été multipliée par 1,3 (de 5 % en 1998 à 7 % en 2015). Le deuxième volet consistait à réaliser une étude utilisant le devis cas-témoins niché dans une cohorte pour évaluer si l’utilisation gestationnelle des antidépresseurs était associée à une augmentation du risque du diabète gestationnel. Nous avons trouvé que l’utilisation des antidépresseurs est associée à une augmentation du risque de diabète gestationnel (aOR = 1,19, IC 95% : 1,08-1,30) et particulièrement pour la venlafaxine (aOR = 1,27, IC 95% :1,09-1,49) et l’amitriptyline (aOR = 1,52, IC 95% :1,25-1,84). Le troisième volet consistait en une analyse de survie pour déterminer si différentes trajectoires d’utilisation d’antidépresseurs durant la grossesse, chez des femmes déprimées avant la grossesse pouvaient affecter le risque de dépression postpartum. Nos résultats montrent que les femmes exposées en continu durant la grossesse (aHR=1,69; IC à 95 % : 1,01-2,84), celles exposées au deuxième/troisième trimestre (aHR=2,56; 95 % CI : 1,33-4,90), et celles avec une exposition intermittente (aHR=2,41; 95 % CI : 1,59-3,66) ont un risque plus élevé de dépression postpartum que les femmes enceintes déprimées, non exposées pendant la gestation. A contrario, celles exposées uniquement au premier trimestre (aHR=1,35; IC à 95 % : 0,81-2,25) étaient moins à risque de dépression postpartum par rapport aux femmes non exposées. En conclusion, les antidépresseurs sont de plus en plus utilisés en grossesse et nous avons observé une augmentation modérée du risque de diabète gestationnel associé à leur utilisation, principalement pour la venlafaxine et l’amitriptyline. En ce qui concerne leur efficacité en vie réelle dans la prévention de la dépression postpartum, nous n’avons pas trouvé de diminution du risque pour les utilisatrices au sein d’une cohorte de femmes avec une dépression prénatale. Néanmoins, malgré certaines limites méthodologiques, ces résultats renforcent la nécessité d’une approche de traitement personnalisée pour chaque femme enceinte souffrant de dépression, afin de faire les meilleurs choix pour sa santé et celle de l’enfant à naitre. / Depression affects about 20% of women of childbearing age and about 5% to 15% of pregnant women. Anxiety disorders, often concomitant with maternal depression, are in the order of 15% during pregnancy. In recent years, gestational use of antidepressants has increased, despite the associated risks to mother and child reported in the literature. Maternal risks such as the risk of gestational diabetes and postpartum depression have been little studied with often contradictory results. In addition, data on the evolution over time of the prevalence of depression / anxiety and the use of antidepressants during pregnancy are very limited in the literature. The Quebec Pregnancy Cohort (QPC) was used for this research and the thesis was organized in three parts. In a first part, we carried out a descriptive study to determine the prevalence and the trends of use of antidepressants and maternal depression / anxiety during pregnancy. over the period from 1998 to 2015. We observed that the prevalence of antidepressants use during pregnancy has tripled, ranging from 2.2% in 1998 to 6.2% in 2015, while the prevalence of maternal depression / anxiety has increased by 1.3 (from 5% in 1998 to 7% in 2015). The second part consisted of carrying out a study using the nested case-control design to assess whether the gestational use of antidepressants was associated with an increased risk of gestational diabetes. We have found that the use of antidepressants is associated with an increased risk of gestational diabetes (aOR = 1.19, 95% CI: 1.08-1.30) and particularly for venlafaxine (aOR = 1.27, 95% CI: 1.09-1.49) and amitriptyline (aOR = 1.52, 95% CI: 1.25-1.84). The third part consisted of a survival analysis to determine whether different trajectories of antidepressant use during pregnancy in women depressed before pregnancy could affect the risk of postpartum depression. Our results show that women exposed continuously during pregnancy (aHR = 1.69; 95% CI: 1.01-2.84), those exposed in the second / third trimester (aHR = 2.56; 95% CI: 1.33-4.90), and those with intermittent exposure (aHR = 2.41; 95% CI: 1.59-3.66) have a higher risk of postpartum depression than depressed pregnant women, not exposed during gestation. Conversely, those exposed only in the first trimester (aHR = 1.35; 95% CI: 0.81-2.25) were less at risk of postpartum depression compared to unexposed women. In conclusion, antidepressants are increasingly used in pregnancy and we have observed a moderate increase in the risk of gestational diabetes associated with their use, mainly for venlafaxine and amitriptyline. Regarding their real-life efficacy in preventing postpartum depression, we found no decreased risk for users in a cohort of women with prenatal depression. Nonetheless, despite some methodological limitations, these results reinforce the need for a personalized treatment approach for each pregnant woman with depression, in order to make the best choices for her health and that of the unborn child.

Gestational diabetes mellitus (GDM), a pregnancy-induced metabolic disorder that affects 2-10% of pregnancies poses future risk for diabetes mellitus (DM) and cardiovascular disease in mother and child. However, few prospective studies have examined the effect of GDM on altered maternal and cord blood lipids, specifically HDL, LDL, triglycerides, and total cholesterol, both during and after pregnancy. We have evaluated the association between GDM and lipid metabolism in pregnant mothers and their infants using data from a prospective cohort study conducted at Baystate Medical Center’s Wesson Women and Infant’s Unit. GDM was assessed prenatally by 3-hr GTT blood samples and was confirmed by obstetrician review. Lipids were assessed via fasting and non-fasting blood samples obtained during 3-hr GTTs performed at 24-28 weeks of gestation and 6-8 weeks post-partum. Data for covariates were collected via an interview form administered at the time of recruitment. We used multivariable linear regression to evaluate the association between GDM status and maternal lipids during and after pregnancy as well as cord lipids. These study results inform future research on GDM as a risk factor for future metabolic disorders in mother and child.