Pathophysiology from preconception, during pregnancy, and beyond.

Gestational diabetes is the most common medical complication in pregnancy. Historically, gestational diabetes was considered a pregnancy complication involving treatment of rising glycaemia late in the second trimester. However, recent evidence challenges this view. Pre-pregnancy and pregnancy-specific factors influence gestational glycaemia, with open questions regarding roles of non-glycaemic factors in the aetiology and consequences of gestational diabetes. Varying patterns of insulin secretion and resistance in early and late pregnancy underlie a heterogeneity of gestational diabetes in the timing and pathophysiological subtypes with clinical implications: early gestational diabetes and insulin resistant gestational diabetes subtypes are associated with a higher risk of pregnancy complications. Metabolic perturbations of early gestational diabetes can affect early placental development, affecting maternal metabolism and fetal development. Fetal hyperinsulinaemia can affect the development of multiple fetal tissues, with short-term and long-term consequences. Pregnancy complications are prevented by managing glycaemia in early and late pregnancy in some, but not all women with gestational diabetes. A better understanding of the pathophysiology and heterogeneity of gestational diabetes will help to develop novel management approaches with focus on improved prevention of maternal and offspring short-term and long-term complications, from pre-conception, throughout pregnancy, and beyond.

Epidemiology and management of gestational diabetes.

Gestational diabetes is defined as hyperglycaemia first detected during pregnancy at glucose concentrations that are less than those of overt diabetes. Around 14% of pregnancies globally are affected by gestational diabetes; its prevalence varies with differences in risk factors and approaches to screening and diagnosis; and it is increasing in parallel with obesity and type 2 diabetes. Gestational diabetes direct costs are US$1·6 billion in the USA alone, largely due to complications including hypertensive disorders, preterm delivery, and neonatal metabolic and respiratory consequences. Between 30% and 70% of gestational diabetes is diagnosed in early pregnancy (ie, early gestational diabetes defined by hyperglycaemia before 20 weeks of gestation). Early gestational diabetes is associated with worse pregnancy outcomes compared with women diagnosed with late gestational diabetes (hyperglycaemia from 24 weeks to 28 weeks of gestation). Randomised controlled trials show benefits of treating gestational diabetes from 24 weeks to 28 weeks of gestation. The WHO 2013 recommendations for diagnosing gestational diabetes (one-step 75 gm 2-h oral glucose tolerance test at 24-28 weeks of gestation) are largely based on the Hyperglycemia and Adverse Pregnancy Outcomes Study, which confirmed the linear association between pregnancy complications and late-pregnancy maternal glycaemia: a phenomenon that has now also been shown in early pregnancy. Recently, the Treatment of Booking Gestational Diabetes Mellitus (TOBOGM) trial showed benefit in diagnosis and treatment of early gestational diabetes for women with risk factors. Given the diabesity epidemic, evidence for gestational diabetes heterogeneity by timing and subtype, and advances in technology, a life course precision medicine approach is urgently needed, using evidence-based prevention, diagnostic, and treatment strategies.

One-year postpartum weight retention and glucose intolerance in women with prediabetes after gestational diabetes.

AIMS: To determine risk factors for 1-year postpartum weight retention (PPWR) and glucose intolerance (prediabetes + diabetes) in women with a previous history of gestational diabetes (GDM) and prediabetes in early postpartum. METHODS: In this exploratory analysis of the MELINDA randomized controlled trial, we report data of 167 women with prediabetes at the 6-16 weeks (early) postpartum oral glucose tolerance test after a recent history of GDM. RESULTS: Of all participants, 45% (75) had PPWR >0 kg at 1-year postpartum. Compared to women without PPWR, women with PPWR had higher gestational weight gain [10.5 ± 6.4 vs. 6.5 ± 4.5 kg, p < 0.001], higher BMI (p < 0.01) and a worse metabolic profile (higher waist circumference, worse lipid profile and more insulin resistance) (all p < 0.05) both in early and late postpartum. Of all women with PPWR, 40.0% developed metabolic syndrome, compared to 18.9% of women without late PPWR (p = 0.003). The only independent predictor for late PPWR was weight retention in early postpartum (p < 0.001). Of all participants, 55.1% (92) had glucose intolerance (84 prediabetes, 8 diabetes) 1-year postpartum. Independent predictors for late postpartum glucose intolerance were lower gestational age at start insulin therapy in pregnancy and delivery by caesarean section (resp. p = 0.044 and 0.014). CONCLUSIONS: In women with a previous history of GDM and prediabetes in early postpartum, PPWR in early postpartum was a strong independent predictor for late PPWR, while earlier start of insulin therapy during pregnancy and delivery by caesarean section were independent predictors of glucose intolerance in late postpartum.

Closed-loop insulin delivery in pregnant women with type 1 diabetes (CRISTAL): a multicentre randomized controlled trial - study protocol.

BACKGROUND: Despite increasing use of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII, insulin pumps) in type 1 diabetes (T1D) in pregnancy, achieving recommended pregnancy glycaemic targets (3.5-7.8 mmol/L or 63-140 mg/dL) remains challenging. Consequently, the risk of adverse pregnancy outcomes remains high. Outside pregnancy, hybrid closed-loop (HCL) insulin delivery systems have led to a paradigm shift in the management of T1D, with 12% higher time in glucose target range (TIR) compared to conventional CSII. However, most commercially available HCL systems are currently not approved for use in pregnancy. This study aims to evaluate the efficacy, safety and cost-effectiveness of the MiniMed™ 780G HCL system (Medtronic) in T1D in pregnancy. METHODS: In this international, open-label, randomized controlled trial (RCT), we will compare the MiniMed™ 780G HCL system to standard of care (SoC) in T1D in pregnancy. Women aged 18-45 years with T1D diagnosis of at least one year, HbA1c ≤ 86 mmol/mol (≤ 10%), and confirmed singleton pregnancy up to 11 weeks 6 days will be eligible. After providing written informed consent, all participants will wear a similar CGM system (Guardian™ 3 or Guardian™ 4 CGM) during a 10-day run-in phase. After the run-in phase, participants will be randomised 1:1 to 780G HCL (intervention) or SoC [control, continuation of current T1D treatment with multiple daily injections (MDI) or CSII and any type of CGM] stratified according to centre, baseline HbA1c (< 53 vs. ≥ 53 mmol/mol or < 7 vs. ≥ 7%), and method of insulin delivery (MDI or CSII). The primary outcome will be the time spent within the pregnancy glucose target range, as measured by the CGM at four time points in pregnancy: 14-17, 20-23, 26-29, and 33-36 weeks. Prespecified secondary outcomes will be overnight TIR, time below range (TBR: <3.5 mmol/L or < 63 mg/dL), and overnight TBR. Other outcomes will be exploratory. The planned sample size is 92 participants. The study will end after postpartum discharge from hospital. Analyses will be performed according to intention-to-treat as well as per protocol. DISCUSSION: This large RCT will evaluate a widely used commercially available HCL system in T1D in pregnancy. Recruitment began in January 2021 and was completed in October 2022. Study completion is expected in May 2023. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04520971. Registration date: August 20, 2020. https://clinicaltrials.gov/ct2/show/NCT04520971.

Maternal factors during pregnancy influencing maternal, fetal, and childhood outcomes.

Enhancing pregnancy health is known to improve the mother's and offspring's life-long well-being. The maternal environment, encompassing genetic factors, impacts of social determinants, the nutritional/metabolic milieu, and infections and inflammation, have immediate consequences for the in utero development of the fetus and long-term programming into childhood and adulthood. Moreover, adverse pregnancy outcomes such as preterm birth or preeclampsia, often attributed to the maternal environmental factors listed above, have been associated with poor maternal cardiometabolic health after pregnancy. In this BMC Medicine article collection, we explore a broad spectrum of maternal characteristics across pregnancy and postnatal phenotypes, anticipating substantial cross-fertilization of new understanding and shared mechanisms around diverse outcomes. Advances in the ability to leverage 'omics across different platforms (genome, transcriptome, proteome, metabolome, microbiome, lipidome), large high-dimensional population databases, and unique cohorts are generating exciting new insights: The first articles in this collection highlight the role of placental biomarkers of preterm birth, metabolic influences on fetal and childhood growth, and the impact of common pre-existing maternal disorders, obesity and smoking on pregnancy outcomes, and the child's health. As the collection grows, we look forward to seeing the connections emerge across maternal, fetal, and childhood outcomes that will foster new insights and preventative strategies for women.

Reactive hypoglycaemia during the OGTT after gestational diabetes mellitus: Metabolic implications and evolution.

AIMS: Gestational diabetes (GDM) presents an increased cardio-metabolic risk and is diagnosed with an oral glucose tolerance test (OGTT). Reactive hypoglycaemia (RH) during the OGTT in pregnancy is associated with adverse outcomes. Although postpartum OGTT after GDM is recommended, the occurrence and implications of RH are unknown. We investigated the prevalence, metabolic implications and longitudinal evolution of RH at 6-8 weeks postpartum in women with a history of GDM. METHODS: Between 2011 and 2021, we consecutively followed 1237 women with previous GDM undergoing an OGTT at 6-8 weeks postpartum. RH was defined as 2-h glucose <3.9 mmoL/L after the OGTT. Metabolic outcomes were compared in women with and without RH (RH+/RH-). We also included a subcohort of 191 women with data on insulin sensitivity/secretion indices (MATSUDA, HOMA-IR, insulin-adjusted-secretion ISSI-2). RESULTS: The postpartum prevalence of RH was 12%. RH+ women had a more favourable metabolic profile including a 2-5-times lower prevalence of glucose intolerance and metabolic syndrome at 6-8 weeks postpartum compared to RH- (all p ≤ 0.034). In the subcohort, women with RH+ had higher insulin sensitivity, higher ISSI-2 and an earlier glucose peak after OGTT (p ≤ 0.049) compared to RH- women at the same time point. Insulin resistance increased and ISSI-2 decreased over the first year postpartum in both groups. These changes were associated with a 50% reduction in overall RH prevalence at 1-year postpartum. Some of the favourable profiles of RH+ persisted at 1-year postpartum, without group differences in the longitudinal metabolic changes. CONCLUSIONS: At 6-8 weeks postpartum, RH was frequent in women after GDM and associated with a better metabolic profile including increased insulin sensitivity and higher insulin-adjusted-secretory capacity. RH might be a marker of favourable metabolic prognosis in women with a history of GDM.

Risk for ketonaemia in type 1 diabetes pregnancies with sensor-augmented pump therapy with predictive low glucose suspend compared with low glucose suspend: a crossover RCT.

AIMS: To determine the frequency of ketonaemia in pregnant women with type 1 diabetes treated with a sensor-augmented pump (SAP) in predictive low glucose suspend (PLGS) mode compared with low glucose suspend (LGS) mode. METHODS: An open-label crossover pilot RCT in ten women with type 1 diabetes treated with a 640 Medtronic insulin pump, with inclusion between 12-30 weeks of pregnancy. Participants were 1/1 randomly assigned (allocation by statistician using a permuted block size of 2) to either 2 weeks with an SAP in PLGS mode or 2 weeks in LGS mode. After the first 2 weeks, participants were switched to the other mode. Ketones in the participants' serum were measured three times daily (fasting, midday and evening) during the 4 weeks. The primary endpoint was the frequency of blood ketones > 0.6 mmol/l. Participants and healthcare providers were not blinded to group assignment for assessment of outcomes. RESULTS: The median gestational week at inclusion was 12.5 weeks (12.0-15.0), participants had a median age of 31.5 years (24.0-33.0), BMI of 26.6 kg/m2 (24.5-31.8), baseline HbA1c of 41 mmol/mol (40-43; 5.9% [5.8-6.1]) and baseline time in range (TIR, 3.5-7.8 mmol/l) of 64.6% (55.6-68.7). Comparing the LGS mode with the PLGS mode, insulin suspension time per day was 2.0 h (1.3-2.3) vs 3.5 h (3.3-5.0; p = 0.002), ketonaemia > 0.6 mmol/l was 0% vs 0.5% (p = 1.000) and no participants had ketonaemia > 1 mmol/l. TIR on LGS was 64.7% (58.0-68.7) vs 61.1% (56.5-67.5) on PLGS (p = 0.492), time < 3.5 mmol/l was higher on LGS at 7.5% (4.6-8.3) vs 4.2% (2.4-6.9) on PLGS (p = 0.014). Treatment satisfaction and fear for hypoglycaemia were similar whether using LGS or PLGS mode. CONCLUSIONS/INTERPRETATION: Despite longer time periods with suspended insulin delivery, pregnant women using an SAP in PLGS mode were not at higher risk of developing ketonaemia compared with those in LGS mode. Women with an SAP in PLGS mode had similar TIR with less time in hypoglycaemia. TRIAL REGISTRATION: Clinical Trials NCT04292509 FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Cost-utility analysis of lifestyle interventions to prevent type 2 diabetes in women with prior gestational diabetes.

BACKGROUND: To compare estimated costs and health outcomes of lifestyle interventions for the prevention of type 2 diabetes mellitus in women who had gestational diabetes. METHODS: An age-specific Markov model was applied comparing costs and quality-adjusted life years (QALYs) of three alternatives: 'doing nothing'; an annual reminder system (ARS) with an awareness campaign ('ARS-awareness'); and an ARS with an intensive lifestyle intervention ('ARS-ILS'). A healthcare payer perspective was adopted, the time horizon was 30 years and the setting was Flanders (Belgium). Sensitivity analyses were performed. RESULTS: 'ARS-awareness' was extendedly dominated. Per 10 000 participants, 'ARS-ILS' cost €13 210 256 more and gained 496 QALYs compared with 'doing nothing' (26 632 €/QALY), with a 63% probability of being cost effective, given a cost effectiveness threshold of 35 000 €/QALY. A scenario analysis showed that 'ARS-ILS' for 15 years only offered to women with prediabetes (compared with 'doing nothing') has an 89.5% likelihood of being dominant. CONCLUSIONS: 'ARS-ILS' may be the preferred intervention. However, the probability of being cost effective was low. Based on further scenario analyses, we recommend healthcare decision makers to consider the application of a more intensive alternative, focused on the highest risk profiles and with a shorter intervention duration.

Characteristics and pregnancy outcomes across gestational diabetes mellitus subtypes based on insulin resistance.

AIMS/HYPOTHESIS: This study aimed to determine the characteristics and pregnancy outcomes across different subtypes of gestational diabetes mellitus (GDM) based on insulin resistance. METHODS: GDM subtypes were defined in 1813 pregnant women from a multicentre prospective cohort study, stratified according to insulin resistance, based on Matsuda index below the 50th percentile of women with normal glucose tolerance (NGT), during a 75 g OGTT at 24-28 weeks' gestation. GDM was diagnosed in 12.4% (n = 228) of all participants based on the 2013 WHO criteria. RESULTS: Compared with women with NGT (1113 [61.4%] of the total cohort) and insulin-sensitive women with GDM (39 [17.1%] women with GDM), women with GDM and high insulin resistance (189 [82.9%] women with GDM) had a significantly higher BMI, systolic BP, fasting plasma glucose (FPG), fasting total cholesterol, LDL-cholesterol and triacylglycerol levels in early pregnancy. Compared with women with NGT, insulin-sensitive women with GDM had a significantly lower BMI but similar BP, FPG and fasting lipid levels in early pregnancy. Compared with women with NGT, women with GDM and high insulin resistance had higher rates of preterm delivery (8.5% vs 4.7%, p = 0.030), labour induction (42.7% vs 28.1%, p < 0.001), Caesarean section (total Caesarean sections: 28.7% vs 19.4%, p = 0.004; emergency Caesarean sections: 16.0% vs 9.7%, p = 0.010), neonatal hypoglycaemia (15.4% vs 3.5%, p < 0.001) and neonatal intensive care unit admissions (16.0% vs 8.9%, p = 0.003). In multivariable logistic regression analyses using different models to adjust for demographics, BMI, FPG, HbA1c, lipid levels and gestational weight gain in early pregnancy, preterm delivery (OR 2.41 [95% CI 1.08, 5.38]) and neonatal hypoglycaemia (OR 4.86 [95% CI 2.04, 11.53]) remained significantly higher in women with GDM and high insulin resistance compared with women with NGT. Insulin-sensitive women with GDM had similar pregnancy outcomes as women with NGT. The need for insulin treatment during pregnancy and the rate of glucose intolerance in the early postpartum period were not significantly different among the GDM subtypes. CONCLUSIONS/INTERPRETATION: GDM with high insulin resistance represents a more adverse metabolic profile with a greater risk of adverse pregnancy outcomes.

The need for appropriate registration of pregnancy outcomes under newer oral glucose-lowering therapies.

Because of the increase in type 2 diabetes (T2DM) in young adults, women of childbearing age are frequently treated with newer glucose-lowering therapies, and an increase in unintentional exposure to therapies unapproved for use during pregnancy is expected. The clinician is left with the dilemma of deciding between discontinuation of a novel agent that is providing excellent glycaemic control, while switching to other agents may cause deterioration of glycaemia, and continued use of novel agents that may have uncertain effects on the unborn child. For T2DM, pregnancy data are collected only via spontaneous reporting systems. Therefore, we evaluated the available data on pregnancy outcomes under newer glucose-lowering agents in pharmaceutical safety databases. We found that data on pregnancy outcomes with new glucose-lowering agents in T2DM are scarce, with a high risk of bias towards negative outcomes, limiting their usefulness in robustly assessing safety. Because of the lack of information at present, these agents are not recommended for use during pregnancy or when planning pregnancy. To better guide clinical practice, structured systems of assessing pregnancy outcomes in women receiving these novel agents are urgently needed.

Risk factors for large-for-gestational age infants in pregnant women with type 1 diabetes.

BACKGROUND: The rate of neonatal overweight remains generally high in type 1 diabetes (T1DM). Since glycemic control has improved over time other contributors need to be identified. Our aim is to evaluate the risk factors for large-for-gestational age infants (LGA) in women with T1DM and to evaluate whether the rate of LGA decreased over time. METHODS: Retrospective analysis of the medical files of pregnant women with T1DM attending our university hospital form 01-01-1992 till 31-07-2014. The generalized mixed model was used to adjust for several pregnancies over time in the same women. A multivariable model was used to evaluate independent risk factors for LGA. RESULTS: Over a 22-year period, 259 pregnancies in 180 T1DM women were identified. Mean diabetes duration of women was 13.7 ± 7.1 years, with a mean age of 29.5 ± 5.2 years. Macrosomia (>4Kg) was present in 16.2 % of deliveries, LGA was present in 45.2 % and these numbers did not change over time (resp. p = 0.19 and p = 0.70). Over time, significant more women were overweight (23.3 % vs. 39.3 %, p = 0.009) and more women had excessive weight gain during pregnancy (21.3 % vs. 37.7 %, p = 0.019). Compared to women with a non-LGA baby, women with a LGA baby had a higher weight at delivery (84.1 ± 11.1 vs. 80.4 ± 10.8, p = 0.016), had more often excessive weight gain (45.3 % vs. 25.2 %, p = 0.003) and had less strict glycaemic control in the first and third trimester [HbA1c of resp. 49 ± 10 mmol/mol (6.7 % ±0.9) vs. 47 ± 8 mmol/mol (6.5 % ±0.8), p = 0.01 and 44 ± 5 mmol/mol (6.2 % ±0.5) vs. 42 ± 6 mmol/mol (6.0 % ±0.6), p = 0.01]. In the forward multivariable analysis, excessive weight gain [OR 1.95 (1.08-3.53), p = 0.027], HbA1c level in early [OR 1.43 (1.05-1.95), p = 0.023] and late pregnancy [OR 1.70 (1.07-2.71), p = 0.026] remained independent predictors for LGA. CONCLUSIONS: LGA remains a frequent complication in T1DM. Excessive weight gain and HbA1c in early and late pregnancy are important risk factors for LGA in our population. These findings highlight the importance of strict maternal glycemic control and simultaneous striving to appropriate gestational weight gain to minimize the risk of fetal overgrowth in T1DM pregnancies.

A proposal for the use of uniform diagnostic criteria for gestational diabetes in Europe: an opinion paper by the European Board & College of Obstetrics and Gynaecology (EBCOG).

Screening and diagnostic criteria for gestational diabetes (GDM) are inconsistent across Europe, and the development of a uniform GDM screening strategy is necessary. Such a strategy would create opportunities for more women to receive timely treatment for GDM. Developing a consensus on screening for GDM in Europe is challenging, as populations are diverse and healthcare delivery systems also differ. The European Board & College of Obstetrics and Gynaecology (EBCOG) has responded to this challenge by appointing a steering committee, including members of the EBCOG and the Diabetic Pregnancy Study Group (DPSG) associated with the EASD, to develop a proposal for the use of uniform diagnostic criteria for GDM in Europe. A proposal has been developed and has now been approved by the Council of the EBCOG. The current proposal is to screen for overt diabetes at the first prenatal contact using cut-off values for diabetes outside pregnancy, with particular efforts made to screen high-risk groups. When screening for GDM is performed at 24 weeks' gestation or later, the proposal is now to use the 75 g OGTT with the new WHO diagnostic criteria for GDM. However, more research is necessary to evaluate the best GDM screening strategy for different populations in Europe. Therefore, no clear recommendation has been made on whether a universal one-step, two-step or a risk-factor-based screening approach should be used. The use of the same WHO diagnostic GDM criteria across Europe will be an important step towards uniformity.

Differences in pregnancy outcomes and characteristics between insulin- and diet-treated women with gestational diabetes.

BACKGROUND: Our aim was to evaluate the difference in pregnancy outcomes and characteristics between insulin- and diet-treated women with gestational diabetes (GDM). METHODS: Retrospective analysis of the medical files from 2010-2013 of women with GDM diagnosed with the Carpenter & Coustan criteria attending two clinics, one in a university and another in a non-university hospital. Characteristics associated with insulin use were analyzed. Multivariable logistic regression was used to adjust for confounders. For women attending the university hospital, indices of insulin sensitivity such as the reciprocal of the homeostasis model assessment of insulin resistance (1/HOMA-IR) and an index of beta-cell function, the Insulin Secretion-Sensitivity Index-2 (ISSI-2) were calculated. RESULTS: Over a 4 year period, 601 women were identified with GDM of whom 22.9% were obese at first prenatal visit. 24.2% needed insulin. Insulin did not prevent adverse outcomes, as women on insulin had higher rates of large-for-gestational age infants (LGA) (28.5% vs. 13.1 %, p < 0.0001) and more cesarean sections (44.1% vs. 27.0%, p = 0.001), remaining significant after adjustment for confounders. Compared to diet-treated women, women on insulin more often had an ethnic minority background (33.3 % vs. 21.6%, p = 0.004), more often had a history of GDM (21.5% vs. 10.4%, p = 0.002), were more often multiparous (59.3% vs. 47.6%, p = 0.044) and were diagnosed with GDM earlier in pregnancy (weeks 25.3 ± 4.9 vs. 27.1 ± 3.7, p < 0.0001). When undergoing an oral glucose tolerance test, women treated with insulin had a higher fasting glycaemia (97.6 ± 18.8 vs.87.7 ± 10.3, p < 0.0001), a higher 1-hour glycaemia (197.7 ± 30.1 vs.184.5 ± 25.8, p < 0.0001), a higher 2-hour glycaemia (185.2 ± 28.5 vs. 175.0 ± 22.8, p < 0.0001), more often 3 and 4 abnormal values (58.1% vs. 37.8%, p < 0.0001 and 24.8% vs. 7.7%, p < 0.0001) and higher HbA1c levels (5.5 ± 0.6 vs 5.2 ± 0.5, p < 0.0001). ISSI-2 (1.3 ± 0.5 vs. 1.7 ± 0.5, p < 0.0001) and 1/HOMA-IR [0.01 (0.001-0.002) vs. 0.02 (0.01-0.03), p = 0.027] were lower in women on insulin. Women on insulin more often received corticoids in preparation of preterm delivery (11.0% vs. 2.4%, p < 0.0001). CONCLUSION: Compared to diet-treated women with GDM, women treated with insulin have a higher risk profile, impaired beta-cell function and lower insulin sensitivity. Rates of LGA and cesarean sections were higher in insulin-treated women.

The Belgian Diabetes in Pregnancy Study (BEDIP-N), a multi-centric prospective cohort study on screening for diabetes in pregnancy and gestational diabetes: methodology and design.

BACKGROUND: The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommends universal screening with a 75 g oral glucose tolerance test (OGTT) using stricter criteria for gestational diabetes (GDM). This may lead to important increases in the prevalence of GDM and associated costs, whereas the gain in health is unclear. The goal of 'The Belgian Diabetes in Pregnancy Study' (BEDIP-N) is to evaluate the best screening strategy for pregestational diabetes in early pregnancy and GDM in an ethnically diverse western European population. The IADPSG screening strategy will be followed, but in addition risk questionnaires and a 50 g glucose challenge test (GCT) will be performed, in order to define the most practical and most cost effective screening strategy in this population. METHODS: BEDIP-N is a prospective observational cohort study in 6 centers in Belgium. The aim is to enroll 2563 pregnant women in the first trimester with a singleton pregnancy, aged 18-45 years, without known diabetes and without history of bariatric surgery. Women are universally screened for overt diabetes and GDM in the first trimester with a fasting plasma glucose and for GDM between 24-28 weeks using the 50 g GCT and independently of the result of the GCT, all women will receive a 75 g OGTT using the IADPSG criteria. Diabetes and GDM will be treated according to a standardized routine care protocol. Women with GDM, will be reevaluated three months postpartum with a 75 g OGTT. At each visit blood samples are collected, anthropometric measurements are obtained and self-administered questionnaires are completed. Recruitment began in April 2014. DISCUSSION: This is the first large, prospective cohort study rigorously assessing the prevalence of diabetes in early pregnancy and comparing the impact of different screening strategies with the IADPSG criteria on the detection of GDM later in pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02036619. Registered 14-1-2014.

Automated Insulin Delivery for Pregnant Women With Type 1 Diabetes: Where do we stand?

Automated insulin delivery (AID) systems mimic an artificial pancreas via a predictive algorithm integrated with continuous glucose monitoring (CGM) and an insulin pump, thereby providing AID. Outside of pregnancy, AID has led to a paradigm shift in the management of people with type 1 diabetes (T1D), leading to improvements in glycemic control with lower risk for hypoglycemia and improved quality of life. As the use of AID in clinical practice is increasing, the number of women of reproductive age becoming pregnant while using AID is also expected to increase. The requirement for lower glucose targets than outside of pregnancy and for frequent adjustments of insulin doses during pregnancy may impact the effectiveness and safety of AID when using algorithms for non-pregnant populations with T1D. Currently, the CamAPS® FX is the only AID approved for use in pregnancy. A recent randomized controlled trial (RCT) with CamAPS® FX demonstrated a 10% increase in time in range in a pregnant population with T1D and a baseline glycated hemoglobin (HbA1c) ≥ 48 mmol/mol (6.5%). Off-label use of AID not approved for pregnancy are currently also being evaluated in ongoing RCTs. More evidence is needed on the impact of AID on maternal and neonatal outcomes. We review the current evidence on the use of AID in pregnancy and provide an overview of the completed and ongoing RCTs evaluating AID in pregnancy. In addition, we discuss the advantages and challenges of the use of current AID in pregnancy and future directions for research.

Prospective associations between breast feeding, metabolic health, inflammation and bone density in women with prior gestational diabetes mellitus.

INTRODUCTION: The aim of the study is to investigate prospective associations between breastfeeding and metabolic outcomes, inflammation, and bone density in women with prior gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: We prospectively included 171 women with GDM from the MySweetheart trial. Women were followed during pregnancy (from 24 up to 32 weeks' gestational age) up to 1 year postpartum. Outcomes included weight, weight retention, body composition, insulin resistance and secretion indices, C reactive protein (CRP), and bone density. We compared differences in the associations between breastfeeding and health outcomes between women who breast fed <6 months vs ≥6 months. Analyses were adjusted for potential medical and sociodemographic confounders. RESULTS: Breastfeeding initiation was 94.2% (n=161) and mean breastfeeding duration was 6.6 months. Breastfeeding duration was independently associated with lower weight, weight retention, body fat, visceral adipose tissue, lean mass, CRP, insulin resistance (Homeostatic Model Assessment for Insulin Resistance), and insulin secretion (Homeostatic Model Assessment of ß-cell index) at 1 year postpartum (all p≤0.04) after adjusting for confounders. Breastfeeding was associated with higher insulin resistance-adjusted insulin secretion (Insulin Secretion-Sensitivity Index-2) in the unadjusted analyses only. There was no association between breastfeeding duration and bone density. Compared with <6 months, breastfeeding duration ≥6 months was associated with lower weight, weight retention, body fat, fat-free mass as well as lower CRP at 1 year postpartum (all p<0.05) after adjusting for confounders. CONCLUSIONS: Longer breastfeeding duration among women with prior GDM was associated with lower insulin resistance, weight, weight retention, body fat and inflammation, but not lower bone density at 1 year postpartum. Breastfeeding for ≥6 months after GDM can help to improve cardiometabolic health outcomes 1 year after delivery.

Comparing advanced hybrid closed loop therapy and standard insulin therapy in pregnant women with type 1 diabetes (CRISTAL): a parallel-group, open-label, randomised controlled trial.

BACKGROUND: Advanced hybrid closed loop (AHCL) therapy can improve glycaemic control in pregnant women with type 1 diabetes. However, data are needed on the efficacy and safety of AHCL systems as these systems, such as the MiniMed 780G, are not currently approved for use in pregnant women. We aimed to investigate whether the MiniMed 780G can improve glycaemic control with less hypoglycaemia in pregnant women with type 1 diabetes. METHODS: CRISTAL was a double-arm, parallel-group, open-label, randomised controlled trial conducted in secondary and tertiary care specialist endocrinology centres at 12 hospitals (11 in Belgium and one in the Netherlands). Pregnant women aged 18-45 years with type 1 diabetes were randomly assigned (1:1) to AHCL therapy (MiniMed 780G) or standard insulin therapy (standard of care) at a median of 10·1 (IQR 8·6-11·6) weeks of gestation. Randomisation was done centrally with minimisation dependent on baseline HbA1c, insulin administration method, and centre. Participants and study teams were not masked to group allocation. The primary outcome was proportion of time spent in the pregnancy-specific target glucose range (3·5-7·8 mmol/L), measured by continuous glucose monitoring (CGM) at 14-17 weeks, 20-23 weeks, 26-29 weeks, and 33-36 weeks. Key secondary outcomes were overnight time in target range, and time below glucose range (<3·5 mmol/L) overall and overnight. Analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT04520971). FINDINGS: Between Jan 15, 2021 and Sept 30, 2022, 101 participants were screened, and 95 were randomly assigned to AHCL therapy (n=46) or standard insulin therapy (n=49). 43 patients assigned to AHCL therapy and 46 assigned to standard insulin therapy completed the study. At baseline, 91 (95·8%) participants used insulin pumps, and the mean HbA1c was 6·5% (SD 0·6). The mean proportion of time spent in the target range (averaged over four time periods) was 66·5% (SD 10·0) in the AHCL therapy group compared with 63·2% (12·4) in the standard insulin therapy group (adjusted mean difference 1·88 percentage points [95% CI -0·82 to 4·58], p=0·17). Overnight time in the target range was higher (adjusted mean difference 6·58 percentage points [95% CI 2·31 to 10·85], p=0·0026), and time below range overall (adjusted mean difference -1·34 percentage points [95% CI, -2·19 to -0·49], p=0·0020) and overnight (adjusted mean difference -1·86 percentage points [95% CI -2·90 to -0·81], p=0·0005) were lower with AHCL therapy than with standard insulin therapy. Participants assigned to AHCL therapy reported higher treatment satisfaction. No unanticipated safety events occurred with AHCL therapy. INTERPRETATION: In pregnant women starting with tighter glycaemic control, AHCL therapy did not improve overall time in target range but improved overnight time in target range, reduced time below range, and improved treatment satisfaction. These data suggest that the MiniMed 780G can be safely used in pregnancy and provides some additional benefits compared with standard insulin therapy; however, it will be important to refine the algorithm to better align with pregnancy requirements. FUNDING: Diabetes Liga Research Fund and Medtronic.

Effectiveness of a blended mobile-based lifestyle intervention in women with glucose intolerance after a recent history of gestational diabetes (MELINDA): a 1-year, prospective, multicentre, randomised controlled trial.

Background: Women with glucose intolerance after gestational diabetes mellitus (GDM) are at high risk to develop type 2 diabetes. Traditional lifestyle interventions in early postpartum have limited impact. We investigated the efficacy of a blended mobile-based lifestyle intervention in women with glucose intolerance after a recent history of GDM. Methods: Prospective, double-arm, non-masked, multicentre randomised controlled trial (RCT) in which women with glucose intolerance, diagnosed 6-16 weeks after a GDM-complicated pregnancy, were assigned 1:1 to a one-year blended-care, telephone- and mobile-based lifestyle program (intervention) or usual care (control). Primary endpoint was the proportion of women able to achieve their weight goal (≥5% weight loss if prepregnancy BMI ≥ 25 kg/m2 or return to prepregnancy weight if prepregnancy BMI < 25 kg/m2) in the intention-to-treat sample. Key secondary outcomes were frequency of glucose intolerance, diabetes and metabolic syndrome, and lifestyle-related outcomes assessed with self-administered questionnaires. The study was registered in ClinicalTrials.gov (NCT03559621). Findings: Between April 10th 2019 and May 13th 2022, 240 participants were assigned to the intervention (n = 121) or control group (n = 119), of which 167 (n = 82 in intervention and n = 85 in control group) completed the study. Primary outcome was achieved by 46.3% (56) of intervention participants compared to 43.3% (52) in the control group [odds ratio (OR) 1.13, 95% confidence interval (CI) 0.63-2.03, p = 0.680; risk ratio 1.07, 95% CI (0.78-1.48)]. Women in the intervention group developed significantly less often metabolic syndrome compared to the control group [7.3% (6) vs. 16.5% (14), OR 0.40, CI (0.22-0.72), p = 0.002], reported less sedentary behaviour and higher motivation for continuing healthy behaviours. In the intervention group, 84.1% (69) attended at least eight telephone sessions and 70.7% (58) used the app at least once weekly. Interpretation: A blended, mobile-based lifestyle intervention was not effective in achieving weight goals, but reduced the risk to develop metabolic syndrome. Funding: Research fund of University Hospitals Leuven, Novo Nordisk, Sanofi, AstraZeneca, Boehringer-Ingelheim, Lilly.