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.

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.

Management of type 1 diabetes in pregnancy: update on lifestyle, pharmacological treatment, and novel technologies for achieving glycaemic targets.

Glucose concentrations within target, appropriate gestational weight gain, adequate lifestyle, and, if necessary, antihypertensive treatment and low-dose aspirin reduces the risk of pre-eclampsia, preterm delivery, and other adverse pregnancy and neonatal outcomes in pregnancies complicated by type 1 diabetes. Despite the increasing use of diabetes technology (ie, continuous glucose monitoring and insulin pumps), the target of more than 70% time in range in pregnancy (TIRp 3·5-7·8 mmol/L) is often reached only in the final weeks of pregnancy, which is too late for beneficial effects on pregnancy outcomes. Hybrid closed-loop (HCL) insulin delivery systems are emerging as promising treatment options in pregnancy. In this Review, we discuss the latest evidence on pre-pregnancy care, management of diabetes-related complications, lifestyle recommendations, gestational weight gain, antihypertensive treatment, aspirin prophylaxis, and the use of novel technologies for achieving and maintaining glycaemic targets during pregnancy in women with type 1 diabetes. In addition, the importance of effective clinical and psychosocial support for pregnant women with type 1 diabetes is also highlighted. We also discuss the contemporary studies examining HCL systems in type 1 diabetes during pregnancies.

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.

Type 1 diabetes-related autoimmune antibodies in women with gestational diabetes mellitus and the long-term risk for glucose intolerance.

Aims: To characterize women with gestational diabetes mellitus (GDM) positive for type 1 diabetes-related autoimmune antibodies (T1D-related autoantibodies) in pregnancy and to evaluate their risk for long-term glucose intolerance. Methods: In a multi-centric prospective cohort study with 1843 women receiving universal screening for GDM with a 75 g oral glucose tolerance test (OGTT), autoantibodies were measured in women with GDM: insulin autoantibodies (IAA), islet cell antibodies (ICA), insulinoma-associated protein-2 antibodies (IA-2A) and glutamic acid decarboxylase antibodies (GADA). Long-term follow-up ( ± 4.6 years after delivery) with a 75 g OGTT and re-measurement of autoantibodies was done in women with a history of GDM and autoantibody positivity in pregnancy. Results: Of all women with GDM (231), 80.5% (186) received autoantibody measurement at a mean of 26.2 weeks in pregnancy, of which 8.1% (15) had one positive antibody (seven with IAA, two with ICA, four with IA-2A and two with GADA). Characteristics in pregnancy were similar but compared to women without autoantibodies, women with autoantibodies had more often gestational hypertension [33.3% (5) vs. 1.7% (3), p<0.001] and more often neonatal hypoglycemia [40.0% (6) vs. 12.5% (19), p=0.012]. Among 14 of the 15 autoantibody positive women with an early postpartum OGTT, two had impaired fasting glucose (IFG). Of the 12 women with long-term follow-up data, four tested again positive for T1D-related autoantibodies (three positive for IA-2A and one positive for ICA and IAA). Five women were glucose intolerant at the long-term follow-up of which two had IA-2A (one had IFG and one had T1D) and three without autoantibodies. There were no significant differences in long-term characteristics between women with and without autoantibodies postpartum. Conclusions: Systematic screening for T1D-related autoantibodies in GDM does not seem warranted since the low positivity rate for autoantibodies in pregnancy and postpartum. At 4.6 years postpartum, five out of 12 women were glucose intolerant but only two still had autoantibodies. In women with clinically significant increased autoantibody levels during pregnancy, postpartum autoantibody re-measurement seems useful since the high risk for further increase of autoantibody levels.

Fasting plasma glucose level to guide the need for an OGTT to screen for gestational diabetes mellitus.

AIMS: To determine the fasting plasma glucose (FPG) level at which an oral glucose tolerance test (OGTT) could be avoided to screen for gestational diabetes (GDM) and to evaluate the characteristics of women across this FPG threshold. METHODS: A multi-centric prospective cohort study with 1843 women receiving universal screening for GDM with a 75 g OGTT. RESULTS: In the total population, GDM prevalence was 12.5% (231). A FPG < 78 mg/dL was the cut-off with best trade-off to limit the number of missed GDM cases [44 (19.0%)] with a negative predictive value of 97.3% (95% CI 96.5-98.0) for GDM, while avoiding 52.2% OGTTs. Compared to GDM with FPG ≥ 78 mg/dL [187 (81.0%)], GDM women with FPG < 78 mg/dL had a significantly lower BMI (27.1 ± 4.5 vs. 29.6 ± 5.2 kg/m2, p = 0.003), less insulin resistance [Matsuda: 0.4 (0.4-0.7) vs. 0.3 (0.2-0.5), p < 0.001] and better ß-cell function [ISSI-2: 0.13 (0.08-0.25) vs. 0.09 (0.04-0.15), p = 0.004]. Compared to NGT women (1612) with FPG ≥ 78 mg/dL [846 (52.5%)], NGT with FPG < 78 mg/dL [766 (47.5%)] had a significantly lower BMI (26.0 ± 3.9 vs. 27.8 ± 4.7 kg/m2, p < 0.001), less insulin resistance [Matsuda: 0.7 (0.5-0.9) vs. 0.5 (0.4-0.7), p < 0.001], better ß-cell function [ISSI-2: 0.17 (0.10-0.30) vs. 0.12 (0.07-0.21), p < 0.001], and less often large-for-gestational age infants [9.2 (70) vs. 16.2% (136), p < 0.001]. CONCLUSIONS: FPG < 78 mg/dL can be used to limit the number of OGTTs when screening for GDM. Women with FPG < 78 mg/dL had a better metabolic profile and in NGT women also less fetal overgrowth.

An Update on Screening Strategies for Gestational Diabetes Mellitus: A Narrative Review.

Gestational diabetes mellitus (GDM) is a frequent medical complication during pregnancy. Screening and diagnostic practices for GDM are inconsistent across the world. This narrative review includes data from 87 observational studies and randomized controlled trials (RCTs), and aims to give an overview of the current evidence on screening strategies and diagnostic criteria for GDM. Screening in early pregnancy remains controversial and studies show conflicting results on the benefit of screening and treatment of GDM in early pregnancy. Implementing the one-step "International Association of Diabetes and Pregnancy Study Groups" (IADPSG) screening strategy at 24-28 weeks often leads to a substantial increase in the prevalence of GDM, without conclusive evidence regarding the benefits on pregnancy outcomes compared to a two-step screening strategy with a glucose challenge test (GCT). In addition, RCTs are needed to investigate the impact of treatment of GDM diagnosed with IADPSG criteria on long-term maternal and childhood outcomes. Selective screening using a risk-factor-based approach could be helpful in simplifying the screening algorithm but carries the risk of missing significant proportions of GDM cases. A two-step screening method with a 50g GCT and subsequently a 75g oral glucose tolerance test (OGTT) with IADPSG could be an alternative to reduce the need for an OGTT. However, to have an acceptable sensitivity to screen for GDM with the IADPSG criteria, the threshold of the GCT should be lowered from 7.8 to 7.2 mmol/L. A pragmatic approach to screen for GDM can be implemented during the COVID-19 pandemic, using fasting plasma glucose (FPG), HbA1c or even random plasma glucose (RPG) to reduce the number of OGTTs needed. However, usual guidelines and care should be resumed as soon as the COVID pandemic is controlled.

Screening for Gestational Diabetes Mellitus in Early Pregnancy: What Is the Evidence?

The incidence of gestational diabetes mellitus (GDM) is increasing worldwide. This has a significant effect on the health of the mother and offspring. There is no doubt that screening for GDM between 24 and 28 weeks is important to reduce the risk of adverse pregnancy outcomes. However, there is no consensus about diagnosis and treatment of GDM in early pregnancy. In this narrative review on the current evidence on screening for GDM in early pregnancy, we included 37 cohort studies and eight randomized controlled trials (RCTs). Observational studies have shown that a high proportion (15-70%) of women with GDM can be detected early in pregnancy depending on the setting, criteria used and screening strategy. Data from observational studies on the potential benefit of screening and treatment of GDM in early pregnancy show conflicting results. In addition, there is substantial heterogeneity in age and BMI across the different study populations. Smaller RCTs could not show benefit but several large RCTs are ongoing. RCTs are also necessary to determine the appropriate cut-off for HbA1c in pregnancy as there is limited evidence showing that an HbA1c ≥6.5% has a low sensitivity to detect overt diabetes in early pregnancy.