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.

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.

Gestational Weight Gain Following Metabolic Bariatric Surgery: A Scoping Review.

Metabolic bariatric surgery remains the most effective and durable treatment for severe obesity. Women of reproductive age represent the largest demographic group undergoing these procedures. Metabolic bariatric surgery can have both beneficial and adverse effects on pregnancy outcomes. One of the most common adverse effects is fetal growth restriction. To mitigate these adverse effects, it is crucial to explore lifestyle modifications aimed at promoting a healthy pregnancy. Modifiable factors during pregnancy after metabolic bariatric surgery include the amount of gestational weight gain. The aim of this comprehensive review is to provide an overview of what is known about gestational weight gain in pregnancy after bariatric metabolic surgery. This review is focused on the two most performed procedures: sleeve gastrectomy and Roux-en-Y gastric bypass.

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.

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.

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.

The 2024 Flemish consensus on screening for gestational diabetes mellitus early and later in pregnancy.

BACKGROUND: Screening for gestational diabetes mellitus (GDM) is important to improve pregnancy outcomes and to prevent type 2 diabetes after pregnancy. Due to a lack of evidence, the 2019 Flemish consensus did not recommend screening for GDM in early pregnancy. Recently, a large randomized controlled trial (TOBOGM) demonstrated that screening for GDM before 20 weeks reduces the risk of neonatal complications in women with risk factors when using higher cut-offs to define GDM compared to the criteria used later in pregnancy. METHODS: Based on this new evidence, members of the Diabetes Liga, the Flemish associations of general physicians (Domus Medica), obstetricians (VVOG), midwives (VBOV), diabetes nurse educators (BVVDV), dieticians (VBVD) and clinical chemists (RBSLM) have adapted the Flemish consensus on screening for GDM. BACKGROUND: Recommendations: As in 2019, this new consensus recommends universal screening for overt diabetes in early pregnancy preferably by measuring fasting plasma glucose by using the same diagnostic criteria as in the non-pregnant state. Based on the new evidence, women with fasting plasma glucose 95-125 mg/dL (5.3-6.9 mmol/L) before 20 weeks gestation should be diagnosed as early GDM. In addition, in women with obesity and/or a history of GDM, it is advised to perform already a 75 g oral glucose tolerance test (OGTT) between 6 and 20 weeks gestation using higher cut-offs to diagnose early GDM [fasting ≥95 mg/dL (5.3 mmol/L), 1 hour ≥ 19 mg/dL (10.6 mmol/L) and/or 2 hour ≥ 162 mg/dL (9.0 mmol/L))]. The recommendation concerning screening for GDM between 24 and 28 weeks remains unchanged with a diagnosis of GDM based on the 75 g OGTT and IADPSG criteria [fasting ≥ 92 mg/dL (5.1 mmol/L), 1 hour ≥ 180 mg/dL (10.0 mmol/L) and/or 2 hour ≥ 153 mg/dL (8.5 mmol/L)].

Fetal size monitoring in women with gestational diabetes and normal glucose tolerance.

AIMS: To monitor fetal size and identify predictors for birthweight in women with gestational diabetes (GDM) and normal glucose tolerance (NGT). METHODS: Cohort study of 1843 women universally screened for GDM, with routine ultrasounds each trimester. Women with GDM and NGT were categorized in subgroups by birthweight centile. RESULTS: Of the total cohort, 231 (12.5%) women were diagnosed with GDM. Fetal size, incidence of large-for-gestational age (LGA: 12.3% of GDM vs. 12.9% of NGT, p = 0.822) and small-for-gestational age (SGA) neonates (4.8% of GDM vs. 5.1% of NGT, p = 0.886) were similar between GDM and NGT. GDM women with LGA neonates were more insulin resistant at baseline and had more often estimated fetal weight (EFW) ≥ P90 on the 28-33 weeks ultrasound (p = 0.033) than those with AGA (appropriate-for-gestational age) neonates. Compared to NGT women with AGA neonates, those with LGA neonates were more often obese and multiparous, had higher fasting glycemia, a worse lipid profile, and higher insulin resistance between 24 -28 weeks, with more often excessive gestational weight gain. On the 28-33 weeks ultrasound, abdominal circumference ≥ P95 had a high positive predictive value for LGA neonates in GDM (100%), whereas, in both GDM and NGT, EFW ≥ P90 and ≤ P10 had a high negative predictive value for LGA and SGA neonates (> 88%), respectively. CONCLUSIONS: There were no differences in fetal size throughout pregnancy nor in LGA incidence between GDM and NGT women. EFW centile at 28-33 weeks correlated well with birthweight. This indicates that GDM treatment is effective and targeted ultrasound follow-up is useful. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02036619. Registration date: January 15, 2014. https://clinicaltrials.gov/ct2/show/NCT02036619 .

Impact of breastfeeding on risk of glucose intolerance in early postpartum after gestational diabetes.

Aims: To determine the impact of breastfeeding on the risk of postpartum glucose intolerance in women with gestational diabetes. Methods: Sub-analysis of two multi-centric prospective cohort studies (BEDIP-N and MELINDA) in 1008 women with gestational diabetes. Data were collected during pregnancy and at a mean of 12 weeks postpartum. Multivariate logistic regression was used to estimate the effect of breastfeeding on glucose intolerance, with adjustment for ethnicity, education, income, professional activity and BMI. Results: Of all participants, 56.3% (567) breastfed exclusively, 10.1% (102) gave mixed milk feeding and 33.6% (339) did not breastfeed. Mean breastfeeding duration was 3.8 ± 2.4 and 3.7 ± 2.1 months in the breastfeeding and mixed milk feeding groups (p=0.496). The rate of glucose intolerance was lower in both the breastfeeding [22.3% (126)] and mixed milk feeding [25.5% (26)] groups compared to the no breastfeeding group [29.5% (100)], with an adjusted OR of 0.7 (95% CI 0.5-1.0) for glucose intolerance in the breastfeeding group compared to no breastfeeding group and an adjusted OR of 0.7 (95% CI 0.4-1.2) for the mixed milk feeding group compared to the no breastfeeding group. Postpartum, breastfeeding women had a lower BMI, less often postpartum weight retention, lower fasting triglycerides, less insulin resistance and a higher insulin secretion-sensitivity index-2 than the mixed milk feeding and no breastfeeding group. The mixed milk feeding group was more often from an non-White background, had a lower blood pressure and lower fasting triglycerides compared to the no breastfeeding group. Conclusions: Breastfeeding (exclusive and mixed milk feeding) is associated with less glucose intolerance and a better metabolic profile in early postpartum in women with gestational diabetes.