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Women with preeclampsia (PEC) and gestational hypertension (GH) exhibit insulin resistance during pregnancy, independent of obesity and glucose intolerance. Our aim was to determine whether women with PEC or GH during pregnancy have an increased risk of developing diabetes after pregnancy, and whether the presence of PEC/GH in addition to gestational diabetes (GDM) increases the risk of future (postpartum) diabetes. We performed a population-based, retrospective cohort study for 1,010,068 pregnant women who delivered in Ontario, Canada between April 1994 and March 2008. Women were categorized as having PEC alone (n=22,933), GH alone (n=27,605), GDM alone (n=30,852), GDM+PEC (n=1,476), GDM+GH (n=2,100), or none of these conditions (n=925,102). Our main outcome was a new diagnosis of diabetes postpartum in the following years, up until March 2011, based on new records in the Ontario Diabetes Database. The incidence rate of diabetes per 1,000 person-years was 6.47 for women with PEC and 5.26 for GH compared with 2.81 in women with neither of these conditions. In the multivariable analysis, both PEC alone (hazard ratio [HR]=2.08; 95% CI 1.97-2.19) and GH alone (HR=1.95; 95% CI 1.83-2.07) were risk factors for subsequent diabetes. Women with GDM alone were at elevated risk of developing diabetes postpartum (HR=12.77; 95% CI 12.44-13.10); however, the co-presence of PEC or GH in addition to GDM further elevated this risk (HR=15.75; 95% CI 14.52-17.07, and HR=18.49; 95% CI 17.12-19.96, respectively). Data on obesity were not available. Women with PEC/GH have a 2-fold increased risk of developing diabetes when followed up to 16.5 years after pregnancy, even in the absence of GDM. The presence of PEC/GH in the setting of GDM also raised the risk of diabetes significantly beyond that seen with GDM alone. A history of PEC/GH during pregnancy should alert clinicians to the need for preventative counseling and more vigilant screening for diabetes. Please see later in the article for the Editors' Summary.

ObjectiveThe study aims to assess the effect of intrauterine metformin exposure on offspring adiposity measures in childhood.DesignSystematic review and meta-analysis.Data sourcesMedline, Embase and Cochrane Central were searched from inception to 4 October 2024.Eligibility criteria for selecting studiesFollow-up studies of randomised-controlled trials and observational studies involving metformin use in pregnancy for any insulin-resistant maternal condition were included.Data extraction and synthesisTwo reviewers independently extracted data and completed risk-of-bias assessments using either Cochrane Risk-Of-Bias tool V.2 or Risk of Bias in Non-Randomised Studies of Exposure depending on study design. Meta-analyses were conducted using the generic inversed variance method in a random-effects model. Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess certainty of evidence.Results18 studies reporting on 7975 children with metformin exposure in utero and over 1 million children without metformin exposure were included. At the oldest age of follow-up reported (weighted mean age of 4.4 years), children with metformin exposure for any maternal indication had comparable body mass index (BMI) with their non-exposed peers (standardised mean difference (SMD) −0.02; 95% CI: −0.11, 0.07; low certainty). When stratified by age at follow-up, while metformin-exposed children had slightly higher BMI at 1–3 years of age (SMD 0.15; 95% CI: 0.04, 0.27; low certainty), no difference remained between the two groups by ages 3–6 and 6–11 years. When stratified by maternal diagnosis, no difference in BMI was found in the diabetes and obesity subgroups, while in the polycystic ovary syndrome subgroup metformin-exposed children were heavier than non-exposed peers (SMD 0.31; 95% CI: 0, 0.62; low certainty). No difference was seen in overweight, obesity or waist circumference.ConclusionsMetformin-exposed children did not differ in adiposity measures compared with their non-exposed peers in later childhood. This adds to the growing body of evidence supporting the long-term safety of metformin use in pregnancy.PROSPERO registration numberCRD42023394464.

IntroductionGestational diabetes is a common metabolic disorder in pregnancy which identifies a substantial increased risk of future diabetes. Despite this risk, many individuals are not screened for dysglycaemia in the postpartum period. Continuous glucose monitoring (CGM) is an evolving technology that provides details of an individual’s glucose levels throughout the day; however, it has not yet been evaluated as a screening tool for postpartum dysglycaemia. To address this gap, this prospective cohort study will examine the use of CGM in the early postpartum period to predict the risk of maternal dysglycaemia after delivery.Methods and analysisThe Predicting Dysglycaemia in Individuals with Gestational Diabetes Immediately Postpartum using CGM (PREDISPOSE) study is a prospective cohort study designed to assess the ability of a CGM device (Freestyle Libre 2) worn in the postpartum period to detect persistent dysglycaemia in individuals with gestational diabetes. The study will recruit 240 individuals with gestational diabetes. Each participant will wear the CGM immediately postpartum and before attending routine postpartum diabetes screening, consisting of a 75-gram oral glucose tolerance test (OGTT) and related blood work (haemoglobin A1c (HbA1c), complete blood count and lipid profile). The primary outcome is the accuracy of the area under the curve for all glucose measurements from the first CGM wear to detect postpartum dysglycaemia. We will perform sensitivity and specificity analyses to determine optimal CGM cut-offs to diagnose diabetes or prediabetes. Secondary outcomes include the incidence of postpartum dysglycaemia (based on 75-gram OGTT and/or HbA1c), incidence of postpartum dyslipidaemia, patient acceptability of CGM testing, data variability from CGM and cardiometabolic health outcomes diagnosed in years one, two and five after delivery.Ethics and disseminationAll participating sites have received ethics approval of the current protocol and have started recruitment of participants to the study. The ethics boards that approved this study are the Biomedical Research Ethics Board at the University of Manitoba, the Conjoint Health Research Ethics Board at the University of Calgary, the Mount Sinai Hospital Research Ethics Board at Mount Sinai Hospital and the Comité d'éthique de la Recherche at Université Laval. Study results will be disseminated through conference presentations and publication in a peer-reviewed journal, regardless of study findings.Trial registration numberNCT04972955. Registration date: 28 June 2021.

Background Offspring of women with type 1 diabetes are at increased risk of fetal growth patterns which are associated with perinatal morbidity. Our aim was to compare rates of large- and small-for-gestational age (LGA; SGA) defined according to different criteria, using data from the Continuous Glucose Monitoring in Type 1 Diabetes Pregnancy Trial (CONCEPTT). Methods This was a pre-specified analysis of CONCEPTT involving 225 pregnant women and liveborn infants from 31 international centres ( ClinicalTrials.gov NCT01788527; registered 11/2/2013). Infants were weighed immediately at birth and GROW, INTERGROWTH and WHO centiles were calculated. Relative risk ratios, sensitivity and specificity were used to assess the different growth standards with respect to perinatal outcomes, including neonatal hypoglycaemia, hyperbilirubinaemia, respiratory distress, neonatal intensive care unit (NICU) admission and a composite neonatal outcome. Results Accelerated fetal growth was common, with mean birthweight percentiles of 82.1, 85.7 and 63.9 and LGA rates of 62, 67 and 30% using GROW, INTERGROWTH and WHO standards respectively. Corresponding rates of SGA were 2.2, 1.3 and 8.9% respectively. LGA defined according to GROW centiles showed stronger associations with preterm delivery, neonatal hypoglycaemia, hyperbilirubinaemia and NICU admission. Infants born > 97.7th centile were at highest risk of complications. SGA defined according to INTERGROWTH centiles showed slightly stronger associations with perinatal outcomes. Conclusions GROW and INTERGROWTH standards performed similarly and identified similar numbers of neonates with LGA and SGA. GROW-defined LGA and INTERGROWTH-defined SGA had slightly stronger associations with neonatal complications. WHO standards underestimated size in preterm infants and are less applicable for use in type 1 diabetes. Trial registration This trial is registered with ClinicalTrials.gov . number NCT01788527 . Trial registered 11/2/2013.

Context: Time-restricted eating (TRE), which consists of restricting the eating window to typically 4 to 8 hours (while fasting for the remaining hours of the day), has been proposed as a nonpharmacological strategy with cardiometabolic benefits but little is known about its metabolic effect on type 2 diabetes mellitus (T2DM). Objective: We evaluated whether TRE can improve pancreatic [beta]-cell function and metabolic status in overweight individuals with early T2DM. Methods: In a randomized, crossover trial, 39 participants (mean 2.9 years of diabetes duration, baseline glycated hemoglobin [A.sub.1c] [[HbA.sub.1c]] 6.6% [+ or -] 0.7% and body mass index [BMI] 32.4 [+ or -] 5.7) were randomly assigned to either an initial intervention consisting of 6 weeks of TRE (20 h-fasting/4 h-eating) or standard lifestyle. The primary outcome of [beta]-cell function was assessed by the Insulin Secretion-Sensitivity Index-2 (ISSI-2) derived from an oral glucose tolerance test. Results: As compared to standard lifestyle, TRE induced a 14% increase in ISSI-2 (+14.0 [+ or -] 39.2%; P =.03) accompanied by a 14% reduction of hepatic insulin resistance as evaluated by HOMA-IR (-11.6% [-49.3 to 21.9]; P =.03). Fasting glucose did not differ between interventions, but TRE yielded a statistically significant reduction in [HbA.sub.1c] (-0.32 [+ or -] 0.48%; P <.001). These metabolic improvements were coupled with a reduction of body weight of 3.86% (-3.86 [+ or -] 3.1%; P <.001) and waist circumference of 3.8 cm (-3.8 [+ or -] 7.5 cm; P =.003). Conclusion: TRE improved [beta]-cell function and insulin resistance in overweight patients with early diabetes, accompanied by beneficial effects on adiposity. Key Words: intermittent fasting, time-restricted eating, type 2 diabetes, [beta]-cell function, insulin resistance, metabolic health, body weight, abdominal obesity

Time-restricted eating (TRE), which consists of restricting the eating window to typically 4 to 8 hours (while fasting for the remaining hours of the day), has been proposed as a nonpharmacological strategy with cardiometabolic benefits but little is known about its metabolic effect on type 2 diabetes mellitus (T2DM). We evaluated whether TRE can improve pancreatic β-cell function and metabolic status in overweight individuals with early T2DM. In a randomized, crossover trial, 39 participants (mean 2.9 years of diabetes duration, baseline glycated hemoglobin A1c [HbA1c] 6.6% ± 0.7% and body mass index [BMI] 32.4 ± 5.7) were randomly assigned to either an initial intervention consisting of 6 weeks of TRE (20 h-fasting/4 h-eating) or standard lifestyle. The primary outcome of β-cell function was assessed by the Insulin Secretion-Sensitivity Index-2 (ISSI-2) derived from an oral glucose tolerance test. As compared to standard lifestyle, TRE induced a 14% increase in ISSI-2 (+14.0 ± 39.2%; P = .03) accompanied by a 14% reduction of hepatic insulin resistance as evaluated by HOMA-IR (-11.6% [-49.3 to 21.9]; P = .03). Fasting glucose did not differ between interventions, but TRE yielded a statistically significant reduction in HbA1c (-0.32 ± 0.48%; P < .001). These metabolic improvements were coupled with a reduction of body weight of 3.86% (-3.86 ± 3.1%; P < .001) and waist circumference of 3.8 cm (-3.8 ± 7.5 cm; P = .003). TRE improved β-cell function and insulin resistance in overweight patients with early diabetes, accompanied by beneficial effects on adiposity.

It is generally appreciated that gestational diabetes is a risk factor for type 2 diabetes. However, the precise relation between these 2 conditions remains unknown. We sought to determine the incidence of diabetes mellitus after diagnosis of gestational diabetes. We used a population-based database to identify all deliveries in the province of Ontario over the 7-year period from Apr. 1, 1995, to Mar. 31, 2002. We linked these births to mothers who had been given a diagnosis of gestational diabetes through another administrative database that records people with diabetes on the basis of either physician service claims or hospital admission records. We examined database records for these women from the time of delivery until Mar. 31, 2004, a total of 9 years. We determined the presence of diabetes mellitus according to a validated administrative database definition for this condition. We identified 659 164 pregnant women who had no pre-existing diabetes. Of these, 21 823 women (3.3%) had a diagnosis of gestational diabetes. The incidence of gestational diabetes rose significantly over the 9-year study period, from 3.2% in 1995 to 3.6% in 2001 (p < 0.001). The probability of diabetes developing after gestational diabetes was 3.7% at 9 months after delivery and 18.9% at 9 years after delivery. After adjustment for age, urban or rural residence, neighbourhood income quintile, whether the woman had a previous pregnancy, whether the woman had hypertension after the index delivery, and primary care level before the index delivery, the most significant risk factor for diabetes was having had gestational diabetes during the index pregnancy (hazard ratio 37.28, 95% confidence interval 34.99-40.88; p < 0.001). Age, urban residence and lower income were also important factors. When analyzed by year of delivery, the rate of development of diabetes was higher among the latest subcohort of women with gestational diabetes (delivery during 1999-2001) than among the earliest subcohort (delivery during 1995 or 1996) (16% by 4.7 years after delivery v. 16% by 9.0 years). In this large population-based study, the rate of development of diabetes after gestational diabetes increased over time and was almost 20% by 9 years. This estimate should be used by clinicians to assist in their counselling of pregnant women and by policy-makers to target these women for screening and prevention.

Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse pregnancy outcomes in the setting of poor glycemic control. The initial management for GDM includes intensive lifestyle modification, which often requires behavioral and nutritional changes to optimize glycemic control. Pharmacotherapy for GDM is initiated when glycemic targets are not met. The rapid-acting bolus analogues aspart and lispro achieve postprandial targets with less hypoglycemia compared to regular insulin, with similar fetal outcomes. The long-acting insulin analogues glargine and detemir appear safe with similar maternal/fetal outcomes compared to NPH. While insulin has been the mainstay therapy for women with GDM to improve glycemic control when lifestyle modifications are insufficient, certain oral antihyperglycemic drugs (OADs) can be considered as alternative treatment options for GDM but continue to be controversial for use as first-line treatment options compared to insulin by many professional bodies. Metformin has good efficacy and short-term safety data but it freely crosses the placenta and long-term safety data are lacking. Glyburide has good efficacy and short-term data but it also crosses the placenta and may be associated with increased rates of large-for-gestational-age (LGA) infants and neonatal hypoglycaemia when compared with insulin. This review aims to give an overview of the pharmacological treatment for women with GDM including some of the known safety profiles of current therapeutic options.

Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. In this multicentre, open-label, randomised controlled trial, we recruited women aged 18–40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference −0·19%; 95% CI −0·34 to −0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research.

Background Extracellular vesicles are membrane vesicles that are released into the extracellular environment and accumulate in the circulation in vascular disease. We aimed to quantify circulating extracellular vesicles in pregnant women with type 1 diabetes and to examine associations between extracellular vesicle levels, continuous glucose measures, and pregnancy outcomes. Methods We used plasma samples from the Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial study and quantified circulating extracellular vesicles by flow cytometry ( n  = 163). Relationships with clinical variables were assessed by repeated measures correlation. Logistic regression was used to assess associations between elevated extracellular vesicle levels and pregnancy outcomes. Results Platelet extracellular vesicle levels were inversely associated with glucose time above range and glycaemic variability measures ( P  < 0.05). A weak positive association was observed between endothelial extracellular vesicles and mean amplitude of glycemic excursion ( P  < 0.05). In a univariate logistic regression model, high baseline endothelial extracellular vesicles was associated with increased risk of neonatal intensive care unit (NICU) admission (OR: 2.06, 1.03–4.10), and respiratory distress requiring ventilation (OR: 4.98, 1.04–23.92). After adjusting for HbA1c and blood pressure the relationship for NICU admission persisted and an association with hyperbilirubinemia was seen (OR: 2.56, 1.10–5.94). Elevated platelet extracellular vesicles were associated with an increased risk of NICU admission (OR: 2.18, 1.04–4.57), and hyperbilirubinemia (OR: 2.61, 1.11–6.12) after adjusting for HbA1c and blood pressure. Conclusions High levels of extracellular vesicles in early pregnancy were associated with adverse neonatal outcomes. Assessment of extracellular vesicles may represent a novel approach to personalized care in type 1 diabetes pregnancy.