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Increasing Incidence of Diabetes After Gestational Diabetes A long-term follow-up in a Danish population Jeannet Lauenborg , MD 1 , Torben Hansen , MD, PHD 2 , Dorte Møller Jensen , MD, PHD 3 , Henrik Vestergaard , MD, DMSC 4 , Lars Mølsted-Pedersen , MD, DMSC 5 , Peter Hornnes , MD, DMSC 1 , Henning Locht , MD 6 , Oluf Pedersen , MD, DMSC 2 and Peter Damm , MD, DMSC 1 1 Department of Obstetrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark 2 Steno Diabetes Center, Gentofte, Denmark 3 Department of Endocrinology, Odense University Hospital, Odense, Denmark 4 Department of Endocrinology, Herlev University Hospital, Herlev, Denmark 5 Department of Obstetrics, Glostrup University Hospital, Glostrup, Denmark 6 Department of Autoimmunology, Statens Serum Institut, Copenhagen, Denmark Address correspondence and reprint requests to Jeannet Lauenborg, MD, Department of Obstetrics, 4031, The Juliane Marie Centre Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: jeannet{at}lauenb.org Abstract OBJECTIVE —To study the incidence of diabetes among women with previous diet-treated gestational diabetes mellitus (GDM) in the light of the general increasing incidence of overweight and diabetes and to identify risk factors for the development of diabetes. RESEARCH DESIGN AND METHODS —Women with diet-treated GDM during 1978–1985 (old cohort, n = 241, also followed up around 1990) or 1987–1996 (new cohort, n = 512) were examined in 2000–2002. Women were classified by a 2-h, 75-g oral glucose tolerance test according to the World Health Organization criteria or an intravenous glucagon test supplemented by measurement of GAD antibodies. Historical data from index-pregnancy and anthropometrical measurements were collected. RESULTS —A total of 481 (63.9%) women were examined (median 9.8 years [interquartile range 6.4–17.2]) after index pregnancy. Diabetes and impaired glucose tolerance (IGT)/impaired fasting glucose were present in 40.0 and 27.0% of women, respectively. In the new cohort, 40.9% had diabetes compared with 18.3% in the old cohort at the 1990 follow-up ( P < 0.0005). Prepregnancy BMI was significantly higher in the new compared with the old cohort (26.0 [22.5–30.8] vs. 22.9 kg/m 2 [20.2–28.0], P < 0.0005). Among others, new-cohort membership, prepregnancy overweight (BMI ≥25 kg/m 2 ), and IGT postpartum were identified as independent predictors of diabetes by multiple logistic regression analyses. CONCLUSIONS —The incidence of diabetes among Danish women with previous diet-treated GDM was very high and had more than doubled over a 10-year period. This seems to be due to a substantial increase in BMI in women with GDM. GADA, GAD antibody GDM, gestational diabetes mellitus IFG, impaired fasting glucose IGT, impaired glucose tolerance OGTT, oral glucose tolerance test Footnotes Accepted February 16, 2004. Received October 30, 2003. DIABETES CARE

Background Women with prior gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes; however, this risk can be reduced by engaging in positive health behaviours e.g. healthy diet and regular physical activity. As such behaviours are difficult to obtain and maintain there is a need to develop sustainable behavioural interventions following GDM. We aimed to report the process of systematically developing a health promotion intervention to increase quality of life and reduce diabetes risk among women with prior GDM and their families. We distil general lessons about developing complex interventions through co-production and discuss our extensions to intervention development frameworks. Methods The development process draws on the Medical Research Council UK Development of complex interventions in primary care framework and an adaptation of a three-stage framework proposed by Hawkins et al. From May 2017 to May 2019, we iteratively developed the Face-it intervention in four stages: 1) Evidence review, qualitative research and stakeholder consultations; 2) Co-production of the intervention content; 3) Prototyping, feasibility- and pilot-testing and 4) Core outcome development. In all stages, we involved stakeholders from three study sites. Results During stage 1, we identified the target areas for health promotion in families where the mother had prior GDM, including applying a broad understanding of health and a multilevel and multi-determinant approach. We pinpointed municipal health visitors as deliverers and the potential of using digital technology. In stage 2, we tested intervention content and delivery methods. A health pedagogic dialogue tool and a digital health app were co-adapted as the main intervention components. In stage 3, the intervention content and delivery were further adapted in the local context of the three study sites. Suggestions for intervention manuals were refined to optimise flexibility, delivery, sequencing of activities and from this, specific training manuals were developed. Finally, at stage 4, all stakeholders were involved in developing realistic and relevant evaluation outcomes. Conclusions This comprehensive description of the development of the Face-it intervention provides an example of how to co-produce and prototype a complex intervention balancing evidence and local conditions. The thorough, four-stage development is expected to create ownership and feasibility among intervention participants, deliverers and local stakeholders. Trial registration ClinicalTrials.gov NCT03997773 , registered retrospectively on 25 June 2019.

Early identification of gestational diabetes mellitus (GDM) aims to reduce the risk of adverse maternal and perinatal outcomes. Currently, no circulating biomarker has proven clinically useful for accurate prediction of GDM. In this study, we tested if a panel of small non-coding circulating RNAs could improve early prediction of GDM. We performed a nested case-control study of participants from the European multicenter ‘Vitamin D and lifestyle intervention for GDM prevention (DALI)’ trial using serum samples from obese pregnant women (BMI ≥ 29 kg/m2) entailing 82 GDM cases (early- and late- GDM), and 41 age- and BMI-matched women with normal glucose tolerance (NGT) throughout pregnancy (controls). Anthropometric, clinical and biochemical characteristics were obtained at baseline (<20 weeks of gestation) and throughout gestation. Baseline serum microRNAs (miRNAs) were measured using quantitative real time PCR (qPCR). Elevated miR-16-5p, -29a-3p, and -134-5p levels were observed in women, who were NGT at baseline and later developed GDM, compared with controls who remained NGT. A combination of the three miRNAs could distinguish later GDM from NGT cases (AUC 0.717, p = 0.001, compared with fasting plasma glucose (AUC 0.687, p = 0.004)) as evaluated by area under the curves (AUCs) using Receiver Operator Characteristics (ROC) analysis. Elevated levels of individual miRNAs or a combination hereof were associated with higher odds ratios of GDM. Conclusively, circulating miRNAs early in pregnancy could serve as valuable predictive biomarkers of GDM.

Background Gestational diabetes mellitus (GDM) is associated with an increased risk of future diabetes in both mother, father and offspring. More knowledge is needed about how to effectively reduce the risk of diabetes through sustained behavioural interventions in these families. The Face-it intervention is a complex health promotion intervention embedded in multi-level supportive environments. The aim of the intervention is to reduce type 2 diabetes risk and increase quality of life among families in the first year following a GDM-affected pregnancy by promoting physical activity, healthy dietary behaviours and breastfeeding through a focus on social support, motivation, self-efficacy, risk perception and health literacy. Methods This national multicentre study is a two-arm randomised controlled trial including 460 women with GDM in a ratio of 2 (intervention):1 (usual care). The Face-it intervention consists of three main components: 1) additional visits from municipal health visitors, 2) digital health coaching tailored to family needs and 3) a structured cross-sectoral communication system in the health care system. The intervention runs from 3 to 12 months after delivery. The primary outcome is maternal body mass index at 12 months after delivery as a proxy for diabetes risk. The women will be examined at baseline and at follow-up, and this examination will include blood tests, oral glucose tolerance test (OGTT), anthropometrics, blood pressure, self-reported diet and physical activity, breastfeeding, quality of life, health literacy, physical and mental health status, risk perception and social support. Aside from those data collected for OGTT and breastfeeding and offspring parameters, the same data will be collected for partners. Data on offspring anthropometry will also be collected. Information on pregnancy- and birth-related outcomes will be derived from the medical records of the woman and child. Discussion This randomised controlled trial seeks to demonstrate whether the Face-it intervention, addressing the individual, family and health care system levels, is superior to usual care in reducing diabetes risk for mothers and their families. Coupled with a process evaluation and an economic analysis, the study will provide evidence for policymakers and health services about health promotion among families affected by GDM and the potential for reducing risk of type 2 diabetes and associated conditions. Trial registration ClinicalTrials.gov NCT03997773 . Registered June 25, 2019 – Retrospectively registered.

IntroductionRoux-en-Y gastric bypass (RYGB) increases the risk of postprandial hypoglycemia, whereas pregnancy decreases insulin sensitivity, which could be expected to counteract hypoglycemia. We examined if RYGB performed prior to pregnancy altered the postprandial glucose metabolism and enteropancreatic hormone responses to a mixed meal test (MMT).Research design and methodsTwenty-three women with RYGB and 23 women matched on prepregnancy body mass index and parity underwent a 4-hour MMT in the first and third trimester of pregnancy with measurement of circulating levels of glucose, insulin, C-peptide, glucose-dependent insulin peptide (GIP), glucagon-like peptide 1 (GLP-1), glucagon, free fatty acids, and lactate. Biochemical hypoglycemia was defined as plasma glucose <3.5 mmol/L.ResultsWomen with RYGB had earlier and higher peak glucose, lower nadir glucose levels, and a higher frequency of biochemical hypoglycemia compared with women without RYGB in both the first and third trimester. The lower glucose levels were preceded by markedly elevated total GLP-1 and insulin levels in women with RYGB, whereas total GIP levels were unaltered. The glucagon levels were lower in women with RYGB. In the first trimester MMT, peak and area under the curve of total plasma GLP-1 and serum insulin levels were negatively associated with nadir plasma glucose, while the early postmeal response of plasma glucagon was positively associated with nadir plasma glucose in the third trimester.ConclusionsThese results provide novel insights into the combined effects of RYGB and pregnancy on postmeal glucose metabolism and enteropancreatic hormone responses during pregnancy, and how these changes associate with an increased risk of postprandial hypoglycemia.Trial registration numberNCT03713060.

Introduction The aim of this study was to validate type 1 diabetes in women giving live birth in the Danish national registries against a clinical cohort of confirmed cases (the Danish Diabetes Birth Registry [DDBR] cohort). Methods National registries including diagnosis codes, redeemed prescriptions and background data were combined. Three main algorithms were constructed to define type 1 diabetes in women giving live birth: (1) Any diabetes diagnosis registered before delivery and before age of 30, (2) a specific type 1 diabetes diagnosis registered before delivery regardless of maternal age and (3) a ‘preexisting type 1 diabetes in pregnancy’ diagnosis registered before delivery. In additional sub‐algorithms, we added information on anti‐diabetic medicine and gestational diabetes diagnosis. We calculated positive predictive value (PPV) and completeness using the DDBR cohort as gold standard. Since DDBR included between 75 and 93% of women with confirmed type 1 diabetes giving live birth, we used quantitative bias analysis to assess the potential impact of missing data on PPV and completeness. Results Main algorithm 2 had the highest PPV (77.4%) and shared the highest completeness (92.4%) with main algorithm 1. Information on anti‐diabetic medicine and gestational diabetes increased PPV, on expense of completeness. All algorithms varied with PPV between 65.7 and 87.6% and completeness between 73.6 and 92.4%. The quantitative bias analysis indicated that PPV was underestimated, and completeness overestimated for all algorithms. For algorithm 2, corrected PPV was between 82.1 and 94.6% and corrected completeness between 84.7 and 91.2%. Conclusions The Danish national registries can identify type 1 diabetes in women giving live birth with a reasonably high accuracy. The registries are a valuable source for future comparative outcome studies and may also be suitable for monitoring prevalence and incidence of type 1 diabetes in women giving live birth. The aim of this study was to validate type 1 diabetes live births in the Danish national registries against a clinical cohort of confirmed cases.The study concludes that algorithms can reliably identify type 1 diabetes in pregnancy in health registries, with a PPV above 90% and completeness around 80%. The algorithms are well‐suited for future comparative outcome studies.

Background Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of mortality and morbidity. VTE may occur asymptomatic or subclinical. Fluid retention during intensive re-nutrition or rapid weight changes are well-known phenomena in anorexia nervosa (AN) and may represent a significant risk factor for VTE. Objective The incidence of VTE in patients with AN is unknown, and the conditions may be overlooked in a complex clinical picture. Method This study report four cases of VTE in women with severe AN (age range 19–41 years, BMI range 10.6–13.1) admitted to a specialized unit for medical stabilization. Results DVT or PE was diagnosed in all four patients. The patients were admitted for intensive re-nutrition according to conventional conservative guidelines with slow increase in energy supply (start low and advance slow). Due to suspected VTE, thromboprophylaxis was given during hospitalization, three of whom were undergoing re-nutrition. Conclusion The four presented cases suggest that VTE during re-nutrition in AN may be an overlooked risk which may not be sufficiently addressed in the literature. General recommendations should not be issued on the basis of case reports; however, we want to raise awareness and call for studies to identify the VTE risk and appropriate thromboprophylaxis in AN patients.

Studies on the relationship between vitamin D (VitD) and glucose homeostasis usually consider either total VitD or 25OHD3 but not 25OHD2 and epimers. We aimed to evaluate the cross-sectional association of VitD compounds with glucose homeostasis measurements in pregnant women with overweight/obesity participating in the Vitamin D And Lifestyle Intervention for Gestational Diabetes Mellitus Prevention study. Methods: The analysis included 912 women. Inclusion criteria: <20 weeks gestation, body mass index ≥29 kg/m2 and information on exposure and outcome variables at baseline. Measurements: A 75 g OGTT at <20, 24–28 and 35–37 weeks gestation (except if previous diabetes diagnosis). Exposure variables: 25OHD2, 25OHD3 and C3-epimer. Outcome variables: fasting and post-challenge insulin sensitivity and secretion indices, corresponding disposition indices (DI), plasma glucose at fasting and 1 and 2 h, hyperglycemia in pregnancy (HiP). Statistics: Multivariate regression analyses with adjustment. Results: Baseline VitD sufficiency was 66.3%. Overall, VitD compounds did not show strong associations with any glucose homeostasis measures. 25OHD3 showed direct significant associations with: FPG at <20 and 24–28 weeks (standardized β coefficient (β) 0.124, p = 0.030 and 0.111, p = 0.026 respectively), 2 h plasma glucose at 24–28 weeks (β 0.120, p = 0.018), and insulin sensitivity (1/HOMA-IR, β 0.127, p = 0.027) at 35–37 weeks; it showed an inverse association with fasting DI (QUCKI*HOMA-β) at <20 and 24–28 weeks (β −0.124, p = 0.045 and β −0.148, p = 0.004 respectively). 25OHD2 showed direct associations with post-challenge insulin sensitivity (Matsuda, β 0.149, p = 0.048) at 24–28 weeks) and post-challenge DI (Matsuda*Stumvoll phase 1) at 24–28 and 35–37 weeks (β 0.168, p = 0.030, β 0.239, p = 0.006). No significant association with C3-epimer was observed at any time period. Conclusions: In these women with average baseline VitD in sufficiency range, VitD compounds did not show clear beneficial associations with glucose homeostasis measures.

Circulating non-coding microRNAs (miRNAs) are important for placentation, but their expression profiles across gestation in pregnancies, which are complicated by gestational diabetes mellitus (GDM), have not been fully established. Investigating a single time point is insufficient, as pregnancy is dynamic, involving several processes, including placenta development, trophoblast proliferation and differentiation and oxygen sensing. Thus, the aim of this study was to compare the temporal expression of serum miRNAs in pregnant women with and without GDM. This is a nested case-control study of longitudinal data obtained from a multicentric European study (the ‘DALI’ study). All women (n = 82) were overweight/obese (BMI ≥ 29 kg/m2) and were normal glucose tolerant (NGT) at baseline (before 20 weeks of gestation). We selected women (n = 41) who were diagnosed with GDM at 24–28 weeks, according to the IADPSG/WHO2013 criteria. They were matched with 41 women who remained NGT in their pregnancy. miRNA (miR-16-5p, -29a-3p, -103-3p, -134-5p, -122-5p, -223-3p, -330-3p and miR-433-3p) were selected based on their suggested importance for placentation, and measurements were performed at baseline and at 24–28 and 35–37 weeks of gestation. Women with GDM presented with overall miRNA levels above those observed for women remaining NGT. In both groups, levels of miR-29a-3p and miR-134-5p increased consistently with progressing gestation. The change over time only differed for miR-29a-3p when comparing women with GDM with those remaining NGT (p = 0.044). Our findings indicate that among overweight/obese women who later develop GDM, miRNA levels are already elevated early in pregnancy and remain above those of women who remain NGT during their pregnancy. Maternal circulating miRNAs may provide further insight into placentation and the cross talk between the maternal and fetal compartments.

Aims. To compare metabolic profiles and the long-term risk of metabolic dysfunction between women with previous gestational diabetes mellitus (pGDM) and women without pGDM (non-GDM) matched on age, prepregnancy body mass index (BMI), and parity. Methods. In total, 128 women with pGDM (median follow-up: 7.8 years) and 70 non-GDM controls (median follow-up: 10.0 years) completed a 2 h oral glucose tolerance test (OGTT) with assessment of glucose, C-peptide, insulin, and other metabolic measures. Additionally, anthropometrics, fat mass, and blood pressure were assessed and indices of insulin sensitivity and beta cell function were calculated. Results. The prevalence of type 2 diabetes mellitus (T2DM) was significantly higher in the pGDM group compared to the non-GDM group (26% vs. 0%). For women with pGDM, the prevalence of prediabetes (38%) and the metabolic syndrome (MetS) (59%) were approximately 3-fold higher than in non-GDM women (p’s<0.001). Both insulin sensitivity and beta cell function were significantly reduced in pGDM women compared to non-GDM women. Conclusion. Despite similar BMI, women with pGDM had a substantially higher risk of developing T2DM, prediabetes, and the MetS compared to controls. Both beta cell dysfunction and reduced insulin sensitivity seem to contribute to this increased risk.