Gestational diabetes mellitus is associated with in vivo platelet activation and platelet hyperreactivity.

BACKGROUND: Gestational diabetes mellitus is associated with obstetrical and long-term cardiovascular complications. Although platelet hyperresponsiveness in type-2 diabetes mellitus has been well characterized and has been shown to play a crucial role in cardiovascular complications, this aspect has been little studied in gestational diabetes mellitus. OBJECTIVE: We aimed to evaluate platelet reactivity, in vivo platelet activation, and endothelial function in gestational diabetes mellitus in comparison with normal pregnancy. STUDY DESIGN: This was a prospective, case-control study of 23 women with gestational diabetes mellitus and 23 healthy pregnant women who were studied at 26 to 28 and 34 to 36 weeks of gestation and at 8 weeks postpartum. Platelet reactivity and in vivo platelet activation, including light transmission aggregometry, PFA-100, platelet activation antigen expression, platelet adhesion under flow, platelet nitric oxide and reactive oxygen species production, and endothelial dysfunction markers, were assessed. RESULTS: The study of platelet function showed a condition of platelet hyperreactivity in cases with gestational diabetes mellitus when compared with healthy pregnant women at enrollment, which was further enhanced at the end of pregnancy and tended to decrease 2 months after delivery, although it still remained higher in gestational diabetes mellitus. In vivo platelet activation was also evident in gestational diabetes mellitus, especially at the end of pregnancy, in part persisting up to 8 weeks after delivery. Finally, women with gestational diabetes mellitus showed defective platelet nitric oxide production and endothelial dysfunction when compared with healthy pregnancies. CONCLUSION: Our data showed that gestational diabetes mellitus generates a condition of platelet hyperreactivity that in part persists up to 2 months after delivery. Impaired platelet sensitivity to nitric oxide and reduced platelet and endothelial nitric oxide production may contribute to the platelet hyperreactivity condition. Platelet hyperreactivity may play a role in the long-term cardiovascular complications of gestational diabetes mellitus women.

Reference intervals for glycated albumin during physiological pregnancy of Europid women: Evidences from a prospective observational study.

BACKGROUND AND AIMS: Glycated albumin (GA) may assess glycometabolic control over a short period of time respect to HbA1c, and its use to screen for gestational diabetes in pregnancy has been suggested. To this regard few data on reference intervals (RI) for GA on Europid women have been collected, only from cross-sectional investigations. Aim of this work has been to collect trimester-specific RI for GA in physiological pregnancies, following a longitudinal prospective study. METHODS: Forty-five healthy pregnant Europid women have been enrolled for whom a GDM screening test was scheduled at 24-28 weeks, in 5 different Italian centers. Only those negative to the OGTT were included. The women had 4 successive visits at 6-10 weeks of gestation, at 16-18 weeks, at 24-28 weeks and at the end of pregnancy. ALT, AST, total bilirubin, C-reactive protein, cholinesterase, creatinine, GGT, glycated albumin, iron, total serum proteins, transferrin were measured in duplicate on aliquots of serum samples by a central laboratory. RESULTS: The RI (2.5-97.5 percentiles) for GA were 11.1-14.8 % (I visit), 10.9-15.6 % (II visit), 10.6-14.1 % (III visit) and 10.7-14.3 % (IV visit). The RI of other biomarkers confirmed previously published data. The RI for serum cholinesterase we present are novel, and were 5049-9906 U/L (Iv), 4212-8965 U/L (IIv), 3518-8470 U/L (IIIv) and 3945-8727 U/L (IVv). CONCLUSIONS: Trimester-specific RI are important for using GA and serum cholinesterase in pregnancy. However, considering the high inter-individual variability of both markers, the use of longitudinal interpretations of the individual variations of both proteins during pregnancy should be preferred.

Screening of postpartum diabetes in women with gestational diabetes: high-risk subgroups and areas for improvements-the STRONG observational study.

AIMS: To assess the proportion of women with gestational diabetes (GDM) by performing postpartum Oral Glucose Tolerance Test (OGTT) and to identify GDM phenotypes at high-risk of postpartum dysglycemia (PPD). METHODS: Observational, retrospective, multicenter study involving consecutive GDM women. Recursive partitioning (RECPAM) analysis was used to identify distinct and homogeneous subgroups of women at different PPD risk. RESULTS: From a sample of 2,736 women, OGTT was performed in 941 (34.4%) women, of whom 217 (23.0%) developed PPD. Insulin-treated women having family history of diabetes represented the subgroup with the highest PPD risk (OR 5.57, 95% CI 3.60-8.63) compared to the reference class (women on diet with pre-pregnancy BMI < = 28.1 kg/m2). Insulin-treated women without family diabetes history and women on diet with pre-pregnancy BMI > 28.1 kg/m2 showed a two-fold PPD risk. Previous GDM and socioeconomic status represent additional predictors. Fasting more than post-prandial glycemia plays a predictive role, with values of 81-87 mg/dl (4.5-4.8 mmol/l) (lower than the current diagnostic GDM threshold) being associated with PPD risk. CONCLUSIONS: Increasing compliance to postpartum OGTT to prevent/delay PPD is a priority. Easily available characteristics identify subgroups of women more likely to benefit from preventive strategies. Fasting BG values during pregnancy lower than those usually considered deserve attention.

Gestational diabetes: A link between OGTT, maternal-fetal outcomes and maternal glucose tolerance after childbirth.

BACKGROUND AND AIM: The relationship among distribution of pathological values at the Oral Glucose Tolerance Test (OGTT), metabolic risk factors and pregnancy outcomes in women with Gestational Diabetes (GDM), has not been clearly identified. We retrospectively compared metabolic and therapeutic parameters, maternal-fetal outcomes and post-partum OGTTs, with respect to the number and distribution of altered values of diagnostic OGTT in pregnancy. Secondly, we assessed whether insulin therapy predictive factors were identifiable. METHODS AND RESULTS: This analysis included 602 pregnant women with GDM, followed in Diabetes and Pregnancy Unit of Perugia Hospital from diagnosis to childbirth. All women were diagnosed diabetic upon 75g OGTT, according IADPSG criteria. Women were divided into 3 groups, respect to distribution of diagnostic blood glucose (BG) values at OGTT: Group 1: only fasting BG (OGTT0h); Group 2: 1 and/or 2h (OGTT1-2h); Group 3: both fasting and 1 h and/or 2h (OGTT0+1-2h) BG. Pregnant women with fasting hyperglycemia at OGTT (Groups 1 and 3) had similar metabolic characteristics (weight, prevalence of obesity, gestational weight gain, HbA1c), a greater need for insulin therapy, and a higher risk of impaired glucose tolerance persistence after childbirth, as compared to Group 2. No significant differences were observed in terms of maternal and neonatal outcomes (p > 0.05), except for a greater prevalence of caesarean sections in Group 3. CONCLUSION: The metabolic characteristics of GDM women are mirrored by OGTT values at diagnosis, but are not associated with adverse pregnancy outcomes. Intensive management and a tailored treatment of GDM improve maternal-neonatal outcomes, regardless of diagnostic values distribution and pre-gestational metabolic characteristics.

Italian recommendations for the diagnosis of gestational diabetes during COVID-19 pandemic: Position statement of the Italian Association of Clinical Diabetologists (AMD) and the Italian Diabetes Society (SID), diabetes, and pregnancy study group.

AIM: In response to the COVID-19 pandemic, there is a need for substantial changes in the procedures for accessing healthcare services. Even in the current pandemic, we should not reduce our attention towards the diagnosis and treatment of GDM. The purpose of this document is to provide a temporary guide for GDM screening, replacing the current guidelines when it is not possible to implement standard GDM screening because of an unfavorable risk/benefit ratio for pregnant women or when usual laboratory facilities are not available. DATA SYNTHESIS: At the first visit during pregnancy, we must exclude the presence of "Overt diabetes" in all women. The criteria for the diagnosis of overt diabetes are either fasting plasma glucose ≥126 mg/dL, or random plasma glucose ≥200 mg/dL, or glycated hemoglobin ≥6.5%. When the screening procedure (OGTT) cannot be safely performed, the diagnosis of GDM is acceptable if fasting plasma glucose is ≥ 92 mg/dL. In order to consider the impaired fasting glucose as an acceptable surrogate for the diagnosis of GDM, the fasting glucose measurement should be performed within the recommended time windows for the risk level (high or medium risk). CONCLUSIONS: The changes to the screening procedure for GDM reported below are specifically produced in response to the health emergency of the COVID-19 pandemic. Therefore, these recommended changes should cease to be in effect and should be replaced by current national guidelines when the healthcare authorities declare the end of this emergency.

Awareness about diabetes and pregnancy among diabetes specialists and fellows: The YoSID diabetes and pregnancy project.

BACKGROUND AND AIMS: Despite evidence that pregnancy planning improves outcomes, in Italy, as in many other countries worldwide, <50% of women with diabetes prepare their pregnancy. The aim of this study was to document training and knowledge on diabetes and pregnancy (D&P) among diabetes professionals. METHODS AND RESULTS: We administered an anonymous online questionnaire, focused on diabetes and pregnancy planning, to diabetes team members. Between Nov-2017 and Jul-2018, n = 395 professionals (60% diabetes/endocrinology/internal medicine specialists, 28% fellows) completed the survey. Fifty-nine percent of the specialists, mainly (78%) those completing their fellowship after 2006, reported having received training on D&P during fellowship. Considering specialists reporting training, 43% correctly identified fetal risks of inadequate preconceptional glucose control and 55% maternal risks, 38% identified risks associated with overweight/obesity, and 39% would prescribe hormonal contraception to women with diabetes only if glucose control is good. CONCLUSIONS: The results of our survey suggest the need to improve training and awareness of professionals in the area of diabetes and pregnancy.

Recommendations and management of hyperglycaemia in pregnancy during COVID-19 pandemic in Italy.

Many specialists use the remote management of people with chronic disease as diabetes, but structured management protocols have not been developed yet. The COVID-19 pandemic has given a big boost to the use of telemedicine, as it allows to maintain the physical distance, essential to the containment of contagion having regular health contact. Encouraging results related to the use of telemedicine in women with hyperglycaemia in pregnancy, have been recently published. It is well known that hyperglycaemia alters the immune response to infections, that inflammation, in turn, worsens glycaemic control and that any form of hyperglycaemia in pregnancy (HIP) has effects not only on the mother but also on development of the foetus. Therefore, the Italian Diabetes and Pregnancy Study Group, together with a group of experts, developed these recommendations in order to guide physicians in the management of HIP, providing specific diagnostic, therapeutic and assistance pathways (PDTAs) for the COVID-19 emergency. Three detailed PDTAs were developed, for type 1, type 2 and gestational diabetes.

Nutrition and Metabolic Adaptations in Physiological and Complicated Pregnancy: Focus on Obesity and Gestational Diabetes.

Pregnancy offers a window of opportunity to program the future health of both mothers and offspring. During gestation, women experience a series of physical and metabolic modifications and adaptations, which aim to protect the fetus development and are closely related to both pre-gestational nutritional status and gestational weight gain. Moreover, pre-gestational obesity represents a challenge of treatment, and nowadays there are new evidence as regard its management, especially the adequate weight gain. Recent evidence has highlighted the determinant role of nutritional status and maternal diet on both pregnancy outcomes and long-term risk of chronic diseases, through a transgenerational flow, conceptualized by the Development Origin of Health and Diseases (Dohad) theory. In this review we will analyse the physiological and endocrine adaptation in pregnancy, and the metabolic complications, thus the focal points for nutritional and therapeutic strategies that we must early implement, virtually before conception, to safeguard the health of both mother and progeny. We will summarize the current nutritional recommendations and the use of nutraceuticals in pregnancy, with a focus on the management of pregnancy complicated by obesity and hyperglycemia, assessing the most recent evidence about the effects of ante-natal nutrition on the long-term, on either maternal health or metabolic risk of the offspring.

"MySweetGestation": A novel smartphone application for women with or at risk of diabetes during pregnancy.

Mobile health (mHealth) applications (apps) have been recently introduced as an easily accessible tool for providing information to pregnant women with diabetes. Despite the growing number of apps on the topic "diabetes & pregnancy", a smartphone app offering comprehensive and individualized information to both women (before and during gestation) and their healthcare professionals was still missing. To overcome this lack, the Italian Diabetes and Pregnancy Study Group conceived and realized in 2016 a novel mobile app called "MySweetGestation". It is designed to be an interactive educational tool for both patients and physicians not expert in the field. Through an interactive way of learning, it provides validated information to the user, focusing on different area of interest: from prevention and risk factors for developing diabetes during pregnancy to treatment and follow-up strategies after gestation. Three years since its publication, MySweetGestation has been downloaded in different western and eastern countries worldwide, suggesting a widespread social impact. Easily accessible personalized information made available via mHealth technology may be of great importance to spread controlled information among the pregnant population. MySweetGestation, being an interactive educational device for both patients and healthcare professionals, may contribute to improve the management of pregnant women with diabetes.

Guidelines for the screening and diagnosis of gestational diabetes in Italy from 2010 to 2019: critical issues and the potential for improvement.

AIMS: In 2010, Italian health professionals rapidly implemented the one-step screening for gestational diabetes mellitus (GDM) based on a 75 g OGTT, to comply with the diagnostic criteria proposed by the International Association of Diabetes and Pregnancy Study Groups (IADPSG). The change was promoted by the two main Italian scientific societies of diabetology, Associazione Medici Diabetologi (AMD) and Società Italiana di Diabetologia (SID), and it took just a few months for the Istituto Superiore di Sanità, together with several scientific societies, to revise the criteria and include them in the National Guidelines System. Over the last 9 years, the implementation of these guidelines has shown some benefits and some drawbacks. METHODS: In order to evaluate the critical issues arisen from the implementation of the current Italian guidelines for the diagnosis of GDM, the studies published on this topic have been reviewed. The search was performed using the following keywords: "gestational diabetes" AND "diagnostic criteria" OR screening AND Ital*. The study is an expert opinion paper, based on the relevant scientific literature published between 2010 and 2019. The databases screened for the literature review included PubMed, MEDLINE, and Scopus. RESULTS: The implementation of the Guidelines for Screening and Diagnosis of GDM in Italy present some strengths and some weaknesses. One of the positive aspects is that high-risk women are required to perform an OGTT early in pregnancy. By contrast, there are several aspects in need of improvement: (1) In spite of the current indications, only a minority of high-risk women perform OGTT early in pregnancy; (2) several low-risk women are screened for GDM; (3) in some low-risk women affected by GDM, the diagnosis might be missed with the application of the current guidelines; (4) there is a lack of homogeneity in the risk assessment data from different regions. CONCLUSIONS: In order to improve the current Italian GDM guidelines, some practical solutions have been suggested.

Renal Consequences of Gestational Diabetes Mellitus in Term Neonates: A Multidisciplinary Approach to the DOHaD Perspective in the Prevention and Early Recognition of Neonates of GDM Mothers at Risk of Hypertension and Chronic Renal Diseases in Later Life.

Fetal exposure to gestational diabetes mellitus (GDM) seems to stimulate a negative impact on the kidneys. Renal volumes and urinary biomarkers of renal function and tubular impairment and injury were evaluated in 30⁻40-day old newborns of GDM mothers (n = 139) who needed insulin therapy during pregnancy. We found that neonates of mothers who maintained strict control over normoglycemia (n = 65) during pregnancy and fulfilled the other criteria of the GDM management program showed no differences compared to control (n = 55). Conversely, those (n = 74), whose mothers did not maintain glycemic control and were not compliant to the management program, exhibited significantly lower levels of renal volumes and higher activity of N-acetyl-ß-D-glucosaminidase and cathepsin B. Differences due to maternal pre-gestational and gestational body mass index (BMI) as well as to maternal weight gain were demonstrated. Our findings indicate that a multidisciplinary approach, which involves an appropriate management of GDM, prevents the negative effects of GDM on the kidneys at 30⁻40 days of postnatal age, indicating the fundamental role of glycemic control, as well as of an adequate range of maternal weight gain. Total renal volume, cortical volume, and urinary activity of N-acetyl-ß-D-glucosaminidase and cathepsin B may be suggested as indicators for the early recognition of GDM neonates at long-term risk of hypertension and kidney disease.

Gender-Disparities in Adults with Type 1 Diabetes: More Than a Quality of Care Issue. A Cross-Sectional Observational Study from the AMD Annals Initiative.

We evaluated gender-differences in quality of type 1 diabetes (T1DM) care. Starting from electronic medical records of 300 centers, 5 process indicators, 3 favorable and 6 unfavorable intermediate outcomes, 6 treatment intensity/appropriateness measures and an overall quality score were measured. The likelihood of women vs. men (reference class) to be monitored, to reach outcomes, or to be treated has been investigated through multilevel logistic regression analyses; results are expressed as Odd Ratios (ORs) and 95% confidence intervals (95%CIs). The inter-center variability in the achievement of the unfavorable outcomes was also investigated. Overall, 28,802 subjects were analyzed (45.5% women). Women and men had similar age (44.5±16.0 vs. 45.0±17.0 years) and diabetes duration (18.3±13.0 vs. 18.8±13.0 years). No between-gender differences were found in process indicators. As for intermediate outcomes, women showed 33% higher likelihood of having HbA1c ≥8.0% (OR = 1.33; 95%CI: 1.25-1.43), 29% lower risk of blood pressure ≥140/90 mmHg (OR = 0.71; 95%CI: 0.65-0.77) and 27% lower risk of micro/macroalbuminuria (OR = 0.73; 95%CI: 0.65-0.81) than men, while BMI, LDL-c and GFR did not significantly differ; treatment intensity/appropriateness was not systematically different between genders; overall quality score was similar in men and women. Consistently across centers a larger proportion of women than men had HbA1c ≥8.0%, while a smaller proportion had BP ≥140/90 mmHg. No gender-disparities were found in process measures and improvements are required in both genders. The systematic worse metabolic control in women and worse blood pressure in men suggest that pathophysiologic differences rather than the care provided might explain these differences.

Functional Profiles of Human Umbilical Cord-Derived Adult Mesenchymal Stem Cells in Obese/Diabetic Versus Healthy Women.

BACKGROUND: Adult human mesenchymal stem cells retrieved, from the post-partum human umbilical cord Wharton jelly (hUCMS), have recently gained growing interest due to their morphological and functional properties. OBJECTIVE: The main purpose of our work was to examine morphology and functional properties of hUCMS retrieved from healthy women as compared to those with obesity, or gestational or type 2 diabetes mellitus, under fair metabolic control. Possible differences between groups could shed light into the potential use of these cells for the cell therapy of a variety of diseases, regardless of the obesity/diabetes status of the donor mothers. Additionally, information on how the maternal disease may affect the cord-derived stem cells, hence possibly newborn children would be important. METHOD: We have studied obese/diabetic or normal donor post-partum umbilical cord-derived hUCMS, either in basal or during differentiation protocols into several cell phenotypes and the definitive endoderm. Immunomodulatory properties of these cells, in terms of inhibition of activated lymphocyte proliferation, also was examined. RESULTS: According to our preliminary results, there are functional differences, as assessed by cell and molecular assays, in terms of both, differentiation and immunomodulatory potential, between the cells derived from normal as compared to obese/diabetic mothers. CONCLUSION: The findings seemingly indicate that the uterine environment of obese/diabetic mothers is quite distant from normal, regardless of metabolic control. Hence hUCMS extracted from obese/diabetic mothers do not appear to be suitable for cell therapy clinical protocols but more studies are required.

Body mass index associated to rs2021966 ENPP1 polymorphism increases the risk for gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a condition of impaired glucose tolerance occurring in 1-14% of all pregnancies. This wide range reflects pathological involvement of single nucleotide polymorphisms (SNPs) and maternal weight as risk factors. This study evaluated the association of genetic component and maternal factors to identify women with higher risk of developing GDM. About 240 pregnant women characterized by negative Oral Glucose Tolerance Test (-OGTT) and 38 with positive OGGT (+OGTT) were enrolled. SNPs for ENPP1, NRF1, VEGFA, CEBPA, and PIK3R1 were analyzed by SNP genotyping. An association study was performed and differences in genotype and allele frequencies between cases and controls were analyzed by χ(2) test. +OGTT was associated to high values of pre-gestational body mass index (BMI) and age. SNP for ENPP1 gene was associated to +OGTT, while genetic variants for other genes did not correlate to GDM. ENPP1 homozygous for A allele and heterozygous showed altered frequencies in +OGTT when compared with -OGTT. Association of both pre-gestational BMI and age with AA homozygous genotype increased significantly the risk to +OGTT. Our results demonstrate that correlation of age and pre-gestational BMI with homozygous for A allele increased significantly the risk of impaired glucose tolerance and GDM.

Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.

To assess if anti-mullerian hormone (AMH) concentrations decrease during the third trimester of pregnancy and puerperium and whether this is correlated to gestational diabetes mellitus (GDM). AMH serum concentrations were determined by ELISA, with lowest detection limit of 0.08 ng/ml, during the third trimester of pregnancy and puerperium in 34 patients with GDM and in 32 healthy control pregnant women. Three blood samples were collected at 28-32, 34-36 weeks' gestation and 40 days after delivery, respectively. No differences in AMH concentration between GDM and healthy pregnant women were found at any follow-up time. On the contrary, significant differences in delta AMH values between the first and the second sample (p < 0.0001), the second and the third sample (p < 0.0001), and the first and the third sample (p = 0.004) were found in both groups. The multivariate analysis showed that maternal age was not correlated to delta AMH variations. The analysis of AMH concentrations did not show a significant relationship with body mass index-variation, newborn and placental weight, and GDM, while only maternal age was significantly correlated with AMH concentrations in all blood samples. A significant decrease in AMH values was observed during the third trimester of pregnancy and this was independent on maternal age. GDM does not seem to influence the AMH concentrations during pregnancy and after delivery.

Insulin analogs and pregnancy: an update.

It is well known that good metabolic control maintained throughout pregnancy reduces maternal and fetal complications in diabetes. Before conception and throughout pregnancy, insulin therapy needs to be optimized and, in this context, the insulin analogs currently available in the market may help to achieve good metabolic control. We therefore review here what is known about the potential benefits and risks related to the use of these new insulins in pregnancy. Clinical and experimental data on insulin aspart and lispro strongly suggest that they have no adverse maternal or fetal effects during pregnancy in women with pregestational and gestational diabetes, and that their use results in improved glycemic control, fewer hypoglycemic episodes, and improved patient satisfaction. At present there are no published data on the use of glulisine in pregnancy. Insulin glargine during pregnancy is not recommended but, in the last years, larger surveys (retrospective and case-control studies) have been published on this field and, to date, results of about 335 pregnancies with type 1 diabetes are available showing an incidence of congenital malformation similar to that obtained with human insulin. There are no published data concerning the use of detemir in pregnancy but the results of a prospective study are expected in 2010.