Real-World Evidence of Off-Label Use of Commercially Automated Insulin Delivery Systems Compared to Multiple Daily Insulin Injections in Pregnancies Complicated by Type 1 Diabetes.

Aims: To compare glycemic control and maternal-fetal outcomes of women with type 1 diabetes (T1D) using hybrid closed loop (HCL) versus multiple daily insulin injections (MDI) plus continuous glucose monitoring. Methods: Multicenter prospective cohort study of pregnant women with T1D in Spain. We evaluated HbA1c and time spent within (TIR), below (TBR), and above (TAR) the pregnancy-specific glucose range of 3.5-7.8 mmol/L. Adjusted models were performed for adverse pregnancy outcomes, including baseline maternal characteristics and center. Results: One hundred twelve women were included (HCL n = 59). Women in the HCL group had a longer duration of diabetes and higher rates of prepregnancy care. There was no between-group difference in HbA1c in any trimester. However, in the second trimester, MDI users had a greater decrease in HbA1c (-6.12 ± 9.06 vs. -2.16 ± 7.42 mmol/mol, P = 0.031). No difference in TIR (3.5-7.8 mmol/L) and TAR was observed between HCL and MDI users, but with a higher total insulin dose in the second trimester [+0.13 IU/kg·day)]. HCL therapy was associated with increased maternal weight gain during pregnancy (ßadjusted = 3.20 kg, 95% confidence interval [CI] 0.90-5.50). Regarding neonatal outcomes, newborns of HCL users were more likely to have higher birthweight (ßadjusted = 279.0 g, 95% CI 39.5-518.5) and macrosomia (ORadjusted = 3.18, 95% CI 1.05-9.67) compared to MDI users. These associations disappeared when maternal weight gain or third trimester HbA1c was included in the models. Conclusions: In a real-world setting, HCL users gained more weight during pregnancy and had larger newborns than MDI users, while achieving similar glycemic control in terms of HbA1c and TIR.

The PREDG study: A randomised controlled trial testing whether an educational intervention can prevent gestational weight gain in women with obesity.

OBJECTIVE: The PREDG trial was designed to study the influence of an educative program on gestational weight gain in women with pregestational obesity. METHODS: Randomized controlled clinical trial (https://www.isrctn.com/ISRCTN61793947) in 169 women with pregestational obesity (BMI ≥30 kg/m2). Women were randomized to participate in a group education program in nutrition and physical activity or conventional follow-up in a specialized Unit of Obesity and Pregnancy. The nutritional intervention was adjusted to prepregnancy BMI and to the physical activity intensity. Quality was based on the Mediterranean diet. Macronutrients were distributed as follows: 50% carbohydrates, 20% protein and 30% fat. Adequate gestational weight gain was defined between 5 and 9 kg (IOM 2009). Mean gestational weight gain was compared between groups by using the T Student test and frequencies of adequate gestational weight gain were compared by using ꓫ2. RESULTS: Gestational weight gain was lower in the intervention group: 8 (4-11) vs 9.2 (6-13) kg, p 0.026. Gestational weight gain was below 9 kg in 24 of 39 (61.5%) women of the intervention vs 10 of 41 (24.4%) of the control group (p 0.001). Regarding obstetric complications, there were 15 (8.3%) cases of gestational diabetes with no differences between the groups. There were 14 of 85 (18.2%) cases of gestational hypertension or preeclampsia in the intervention group compared with 26 of 84 (32.5%) in the control group (p 0.040). With reference to neonatal weight, there were 7 of 82 (8.5%) large for gestational age neonates in the intervention group compared with 15 of 79 (19.2%) in the control group (p 0.050). CONCLUSIONS: A group-based educative and structured intervention results in an adequate weight gain and lower rates of gestational hypertension, preeclampsia and large for gestational age neonates in pregnant women with obesity.

Predictors of postpartum glucose metabolism disorders in women with gestational diabetes mellitus.

BACKGROUND AND AIMS: Postpartum glucose metabolism disorders are a common problem in women with gestational diabetes mellitus (GDM). They are often underdiagnosed since many patients do not attend the postpartum screening. This study aims to assess predictors of postpartum glucose metabolism disorders and type 2 diabetes mellitus (T2DM) after GDM. MATERIAL AND METHODS: Retrospective study in women with GMD who underwent postpartum screening for glucose metabolism disorders (n = 2688). Logistic regression was used in the statistical analysis. RESULTS: 24.6% of women had postpartum glucose metabolism disorder. In multivariate analysis, pre-pregnancy body mass index (BMI) 25-30 kg/m2 (OR 1.46, 95%CI 1.05 to 2.02) or BMI ≥30 kg/m2 (OR 2.62, 95%CI 1.72 to 3.96), diagnosis of GDM before 20 weeks of pregnancy (OR 2.33, 95%CI 1.57 to 3.46), fasting plasma glucose after diagnosis of GDM ≥90 mg/dl (OR 2.12, 95%CI 1.50 to 2.98), postprandial glucose ≥100 mg/dl (OR 1.47, 95%CI 1.09 to 2.99), and HbA1c in the third trimester of pregnancy ≥5.3% (2.04, 95%CI, 1.52 to 2.75) were independent predictors for any postpartum glucose metabolism disorder. CONCLUSION: postpartum screening for T2DM should be performed in all women with GDM, and it is especially important not to lose follow-up in those with one or more predictive factors.

Efficacy of continuous glucose monitoring on maternal and neonatal outcomes in gestational diabetes mellitus: a systematic review and meta-analysis of randomized clinical trials.

AIMS: This systematic review aims to evaluate the effect of continuous glucose monitoring (CGM) on maternal and neonatal outcomes in gestational diabetes mellitus (GDM). METHODS: Two authors conducted a systematic search using PubMed, Embase, CENTRAL, CINAHL, Scopus, Web of Science, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The inclusion criteria for the systematic review were randomized clinical trials that compared the effects of CGM and blood glucose monitoring (BGM) in women with GDM. A restricted maximum likelihood random-effects model was used for the meta-analysis. The measures of effect were risk ratios for categorical data and mean differences for continuous data. RESULTS: Of the 457 studies reviewed, six randomized clinical trials met the inclusion criteria. A total of 482 patients were included in the meta-analysis. The use of CGM was associated with lower HbA1c levels at the end of pregnancy (mean difference: -0.22; 95%CI -0.42 to -0.03) compared to BGM. Women using CGM also had less gestational weight gain (mean difference: -1.17, 95%CI -2.15 to -0.19), and their children had lower birth weight (mean difference: -116.26, 95%CI -224.70 to -7.81). No differences were observed in the other outcomes evaluated. CONCLUSION: Women with GDM using CGM may achieve lower average blood glucose levels, lower maternal weight gain and infant birth weight than women using BGM. Nevertheless, current evidence is limited by the low number of studies and the small sample sizes of these studies. Larger clinical trials are needed to better understand the effects of CGM in GDM. REGISTRATION: PROSPERO registration ID CRD42021225651.

Identification of Resistance to Exogenous Thyroxine in Humans.

Background: Thyroxine (T4) to triiodothyronine (T3) deiodination in the hypothalamus/pituitary is mediated by deiodinase type-2 (D2) activity. Dio2(-/-) mice show central resistance to exogenous T4. Patients with resistance to exogenous thyroxine (RETH) have not been described. The aim of this study was to identify hypothyroid patients with thyrotropin (TSH) unresponsiveness to levothyroxine (LT4) and to characterize the clinical, hormonal, and genetic features of human RETH. Methods: We investigated hypothyroid patients with elevated TSH under LT4 treatment at doses leading to clinical and/or biochemical hyperthyroidism. TSH and free T4 (fT4) were determined by chemiluminescence, and total T4, T3, and reverse T3 (rT3) by radioimmunoassay. TSH/fT4 ratio at inclusion and T3/T4, rT3/T4, and T3/rT3 ratios at follow-up were compared with those from patients with resistance to thyroid hormone (RTH) due to thyroid hormone receptor-ß (THRB) mutations. DIO2, including the Ala92-D2 polymorphism, selenocysteine binding protein 2 (SECISBP2), and THRB were fully sequenced. Results: Eighteen hypothyroid patients (nine of each sex, 3-59 years) treated with LT4 showed elevated TSH (15.5 ± 4.7 mU/L; reference range [RR]: 0.4-4.5), fT4 (20.8 ± 2.4 pM; RR: 9-20.6), and TSH/fT4 ratio (0.74 ± 0.25; RR: 0.03-0.13). Despite increasing LT4 doses from 1.7 ± 1.0 to 2.4 ± 1.7 µg/kg/day, TSH remained elevated (6.9 ± 2.7 mU/L). Due to hyperthyroid symptoms, LT4 doses were reduced, and TSH increased again to 7.9 ± 3.2 mU/L. In the euthyroid/hyperthyrotropinemic state, T3/T4 and T3/rT3 ratios were decreased (9.2 ± 2.4, RR: 11.3-15.3 and 2.5 ± 1.4, RR: 7.5-8.5, respectively) whereas rT3/T4 was increased (0.6 ± 0.2; RR: 0.43-0.49), suggesting reduced T4 to T3 and increased T4 to rT3 conversion. These ratios were serum T4-independent and were not observed in RTH patients. Genetic testing was normal. The Ala92-D2 polymorphism was present in 7 of 18 patients, but the allele dose did not correlate with RETH. Conclusions: Human RETH is characterized by iatrogenic thyrotoxicosis and elevated TSH/fT4 ratio. In the euthyroid/hyperthyrotropinemic state, it is confirmed by decreased T3/T4 and T3/rT3 ratios, and elevated rT3/T4 ratio. This phenotype may guide clinicians to consider combined T4+T3 therapy in a targeted fashion. The absence of germline DIO2 mutations suggests that aberrant post-translational D2 modifications in pituitary/hypothalamus or defects in other genes regulating the T4 to T3 conversion pathway could be involved in RETH.

Increased risk of neonatal complications or death among neonates born small for gestational age to mothers with gestational diabetes.

AIMS: To evaluate if neonatal complications or death were poorer for neonates born small for gestational age (SGA) than for those born with adequate weight or large for gestation age (LGA) to women with gestational diabetes mellitus (GDM). METHODS: Retrospective analysis of the clinical outcomes of neonates born to 3413 women with GDM. The prevalence of neonatal hypoglycaemia, hypocalcaemia, hyperbilirubinemia, polycythaemia, and death was compared among three birthweight groups: SGA, adequate, and LGA. A two-sided chi-squared or Fisher's exact test was used for between-group comparisons. A forward multiple logistic regression was performed to determine the odds ratio (OR) associated with SGA. RESULTS: Neonatal complications were more frequent in the SGA group (20.1%) than in the adequate (9.9%) or LGA (15.2%) groups. There were four deaths (1.6%) in the SGA group compared to one in the LGA (0.4%) and six in the adequate (0.2%) groups (P = 0.002). SGA was a risk factor for neonatal complications or death (OR. 2.122; 95% confidence interval, 1.552-2.899), independent of maternal age, weight gain, fasting glucose, glycaemic control, gestational hypertension, pre-eclampsia, smoking, or neonatal prematurity. CONCLUSION: SGA birthweight is an important risk factor for neonatal complications or death among neonates born to mothers with GDM.

Gestational diabetes mellitus: glycemic control during pregnancy and neonatal outcomes of twin and singleton pregnancies. / Diabetes mellitus gestacional: control glucémico durante el embarazo y su relación con los resultados neonatales en embarazos gemelares y de feto único.

OBJECTIVE: To assess the impact of glycemic control in gestational on neonatal weight and metabolic complications of twin and singleton pregnancies. METHODS: An observational, retrospective study to monitor 120 twin and 240 singleton pregnancies in women with GDM. Maternal glycemic parameters during pregnancy (oral glucose tolerance test results, treatment, insulinization rate, mean HbA1c in the third trimester), and neonatal complications and weight were recorded. RESULTS: A higher infant birth weight ratio (IBWR 1.02±0.12 vs. 0.88±0.12, P<.001) and a lower rate of newborns small for gestational age (severe SGA 2.5% vs. 8.3%, P=.012) were seen after singleton pregnancies as compared to twin pregnancies. The rates of newborns large for gestational age (LGA 12.6% vs. 12.5%, P=.989); macrosomic (6.7% vs. 7.5%, P=.777); or small for gestational age (SGA 6.7% vs. 10.8%, P=.175) were similar in both groups. Neonates from twin pregnancies had a higher risk of hypoglycemia (adjusted OR 4.71; 1.38-16.07, P=.013) and polycythemia (adjusted OR 10.05; 1.82-55.42, P=0.008). A linear relationship was seen between third trimester HbA1c levels and IBWR in singleton (r=.199, P=.003), but not in twin pregnancies (r=0.049, P=0.610). CONCLUSIONS: Risk of severe SGA, hypoglycemia, and polycythemia was significantly higher in twin pregnancies of women with GDM. Neonatal weight outcomes and metabolic complications in twin pregnancies of women with GDM were not related to glycemic control. Moreover, in our study population, fasting glucose at diagnosis and mean HbA1c in the third trimester showed a linear relationship with higher birth weights in singleton, but not in twin pregnancies.

Optimal Gestational Weight Gain for Women with Gestational Diabetes and Morbid Obesity.

OBJECTIVES: Our aim was to investigate the greatest gestational weight gain (GWG) without adverse pregnancy complications in women with gestational diabetes mellitus (GDM) and morbid obesity. METHODS: An observational retrospective study including 3284 patients with single pregnancies and GDM was completed. Of the patients, 131 (4.0%) were classified as having pre-pregnancy morbid obesity (BMI ≥ 35 kg/m2). Perinatal complications were compared among BMI groups. In the group with morbid obesity, GWG threshold values to predict outcomes were examined based on sensitivity and specificity values under the receiver operating characteristic curve. RESULTS: GWG was higher in mothers with morbid obesity and macrosomic neonates: 11.3 (4.4-15.7) versus 4.8 (1.5-8.2) kg (p = 0.033). The GWG and neonatal ponderal index were positively correlated (r = 0.305, p = 0.001). The GWG was 7.0 (2.9-11.6) kg in women with hypertensive disorder versus 4.5 (1.0-7.5) kg in normotensive women (p = 0.017). A GWG above 5 kg was a risk factor for macrosomia (87.8% sensitivity, 54.7% specificity) and hypertensive disorder (70.0% sensitivity, 48.4% specificity). GWG associations were maintained after controlling for glycemic control, maternal and gestational age, parity, smoking and neonatal sex. CONCLUSIONS FOR PRACTICE: A GWG below 5 kg is recommended for women with GDM and morbid obesity. In these women, adequate GWG may prevent macrosomia, fetal overgrowth and hypertensive disorder.

HbA1c and Gestational Weight Gain Are Factors that Influence Neonatal Outcome in Mothers with Gestational Diabetes.

BACKGROUND: Maternal glucose and weight gain are related to neonatal outcome in women with gestational diabetes mellitus (GDM). The aim of this study was to explore the influence of average third-trimester HbA1c and excess gestational weight gain on GDM neonatal complications. MATERIALS AND METHODS: This observational study included 2037 Spanish singleton pregnant women with GDM followed in our Diabetes and Pregnancy Unit. The maternal HbA1c level was measured monthly from GDM diagnosis to delivery. Women were compared by average HbA1c level and weight gain categorized into ≤ or > the current Institute of Medicine (IOM) recommendations for body mass index. The differential effects of these factors on large-for-gestational-age birth weight and a composite of neonatal complications were assessed. RESULTS: Women with an average third-trimester HbA1c ≥5.0% (n = 1319) gave birth to 7.3% versus 3.8% (p = 0.005) of large-for-gestational-age neonates and 22.0% versus 16.0% (p = 0.006) of neonates with complications. Women with excess gestational weight gain (n = 299) delivered 12.5% versus 5.2% (p < 0.001) of large-for-gestational-age neonates and 24.7% versus 19.0% (p = 0.022) of neonates with complications. In an adjusted multiple logistic regression analysis among mothers exposed to the respective risk factors, ∼47% and 52% of large-for-gestational-age neonates and 32% and 37% of neonatal complications were potentially preventable by attaining an average third-trimester HbA1c level <5.0% and optimizing gestational weight gain. CONCLUSIONS: Average third-trimester HbA1c level ≥5% and gestational weight gain above the IOM recommendation are relevant risk factors for neonatal complications in mothers with gestational diabetes.

Effect of Continuous Positive Airway Pressure on Glycemic Control in Patients with Obstructive Sleep Apnea and Type 2 Diabetes. A Randomized Clinical Trial.

RATIONALE: Obstructive sleep apnea (OSA) is a risk factor for type 2 diabetes that adversely impacts glycemic control. However, there is little evidence about the effect of continuous positive airway pressure (CPAP) on glycemic control in patients with diabetes. OBJECTIVES: To assess the effect of CPAP on glycated hemoglobin (HbA1c) levels in patients with suboptimally controlled type 2 diabetes and OSA, and to identify its determinants. METHODS: In a 6-month, open-label, parallel, and randomized clinical trial, 50 patients with OSA and type 2 diabetes and two HbA1c levels equal to or exceeding 6.5% were randomized to CPAP (n = 26) or no CPAP (control; n = 24), while their usual medication for diabetes remained unchanged. MEASUREMENTS AND MAIN RESULTS: HbA1c levels, Homeostasis Model Assessment and Qualitative Insulin Sensitivity Check Index scores, systemic biomarkers, and health-related quality of life were measured at 3 and 6 months. After 6 months, the CPAP group achieved a greater decrease in HbA1c levels compared with the control group. Insulin resistance and sensitivity measurements (in noninsulin users) and serum levels of IL-1ß, IL-6, and adiponectin also improved in the CPAP group compared with the control group after 6 months. In patients treated with CPAP, mean nocturnal oxygen saturation and baseline IL-1ß were independently related to the 6-month change in HbA1c levels (r(2) = 0.510, P = 0.002). CONCLUSIONS: Among patients with suboptimally controlled type 2 diabetes and OSA, CPAP treatment for 6 months resulted in improved glycemic control and insulin resistance compared with results for a control group. Clinical trial registered with www.clinicaltrials.gov (NCT01801150).

Prepregnancy body mass index and prenatal fasting glucose are effective predictors of early postpartum metabolic syndrome in Spanish mothers with gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) may be an expression of early metabolic syndrome. It is unknown whether weight and/or glucose parameters assessed at GDM pregnancies predict the risk of metabolic syndrome at the early postpartum period. METHODS: A group of women with GDM (N=1512) was evaluated at 3-11 months postpartum. Incident cases of diabetes were excluded. Antenatal measurements of GDM severity, third-trimester average glycated hemoglobin levels, prepregnancy body mass index (BMI), and increased gestational weight gain were considered. The predictive capability of these factors for postpartum metabolic syndrome was estimated. RESULTS: The prevalence of postpartum metabolic syndrome was 10.9%. The three most common features of metabolic syndrome were low levels of high-density lipoprotein cholesterol (31.2%), high fasting glucose values (23.5%), and a high waist circumference (22.8%). The main predictors of metabolic syndrome were overweight or obesity prepregnancy and high antenatal fasting glycemia. This analysis was adjusted for family history of diabetes, prior GDM, dyslipidemia before pregnancy, chronic arterial hypertension, age, and smoking. The model area 95% confidence interval under the receiver operating characteristic curve was 0.87 (0.84-0.90) for metabolic syndrome presence. The risk for metabolic syndrome was progressively increased as risk factors were added (P<0.001 for trend). When obesity and high fasting glycemia were combined, a multiplied effect ensued. CONCLUSIONS: Women having GDM are at threat of early postpartum metabolic syndrome. This risk can be easily identified by assessing prepregnancy BMI and antenatal fasting glycemia in the first pregnancy visit.

Paucisymptomatic retroperitoneal fibrosis unmasked soon after a colonoscopy: a prompt resolution.

A 60-year-old man was diagnosed with retroperitoneal fibrosis. Curiously, his back pain became intense immediately after the performance of a colonoscopy. The fibrotic mass was seen on computed tomography (CT) of the abdomen. The patient developed obstructive nephropathy secondary to bilateral encasing of the ureters. Early diagnosis and combined therapy with corticosteroids and ureteral stents led to clinical and radiological remission of the disease.