Glucometabolic Alterations in Pregnant Women with Overweight or Obesity but without Gestational Diabetes Mellitus: An Observational Study.

INTRODUCTION: Maternal overweight is a risk factor for gestational diabetes mellitus (GDM). However, emerging evidence suggests that an increased maternal body mass index (BMI) promotes the development of perinatal complications even in women who do not develop GDM. This study aims to assess physiological glucometabolic changes associated with increased BMI. METHODS: Twenty-one women with overweight and 21 normal weight controls received a metabolic assessment at 13 weeks of gestation, including a 60-min frequently sampled intravenous glucose tolerance test. A further investigation was performed between 24 and 28 weeks in women who remained normal glucose tolerant. RESULTS: At baseline, mothers with overweight showed impaired insulin action, whereby the calculated insulin sensitivity index (CSI) was lower as compared to normal weight controls (3.5 vs. 6.7 10-4 min-1 [microU/mL]-1, p = 0.025). After excluding women who developed GDM, mothers with overweight showed higher average glucose during the oral glucose tolerance test (OGTT) at the third trimester. Moreover, early pregnancy insulin resistance and secretion were associated with increased placental weight in normal glucose-tolerant women. CONCLUSION: Mothers with overweight or obesity show an unfavorable metabolic environment already at the early stage of pregnancy, possibly associated with perinatal complications in women who remain normal glucose tolerant.

Effect of vaginal probiotics containing Lactobacillus casei rhamnosus (Lcr regenerans) on vaginal dysbiotic microbiota and pregnancy outcome, prospective, randomized study.

The intermediate bacterial microbiota is a heterogeneous group that varies in the severity of the dysbiosis, from minor deficiency to total absence of vaginal Lactobacillus spp. We treated women with this vaginal dysbiosis in the first trimester of pregnancy using a vaginally applied lactobacilli preparation to restore the normal microbiota in order to delay the preterm delivery rate. Pregnant women with intermediate microbiota of the vagina and a Nugent score of 4 were enrolled in two groups: intermediate vaginal microbiota and a Nugent score of 4 with lactobacilli (IMLN4) and intermediate vaginal microbiota and a Nugent score of 4 without lactobacilli (IM0N4), with and without vaginal lactobacilli at baseline, respectively. Half of the women in each group received the treatment. Among women without lactobacilli (the IM0N4 group), the Nugent sore decreased by 4 points only in the women who received treatment, and gestational age at delivery and neonatal birthweight were both significantly higher in the treated subgroup than in the untreated subgroup (p = 0.047 and p = 0.016, respectively). This small study found a trend toward a benefit of treatment with vaginal lactobacilli during pregnancy.

Prevalence of gestational diabetes mellitus in women with a family history of type 2 diabetes in first- and second-degree relatives.

AIMS: A family history of type 2 diabetes mellitus (T2DM) markedly increases an individual's lifetime risk of developing the disease. For gestational diabetes (GDM), this risk factor is less well characterized. This study aimed to investigate the relationship between family history of T2DM in first- and second-degree relatives in women with GDM and the differences in metabolic characteristics at early gestation. METHODS: This prospective cohort study included 1129 pregnant women. A broad risk evaluation was performed before 16 + 0 weeks of gestation, including a detailed family history of the different types of diabetes and a laboratory examination of glucometabolic parameters. Participants were followed up until delivery and GDM assessed according to the latest diagnosis criteria. RESULTS: We showed that pregnant women with first- (FHD1, 26.6%, OR 1.91, 95%CI 1.16 to 3.16, p = 0.005), second- (FHD2, 26.3%, OR 1.88, 95%CI 1.16 to 3.05, p = 0.005) or both first- and second-degree relatives with T2DM (FHD1 + D2, 33.3%, OR 2.64, 95%CI 1.41 to 4.94, p < 0.001) had a markedly increased risk of GDM compared to those with negative family history (FHN) (n = 100, 15.9%). The association was strongest if both parents were affected (OR 4.69, 95%CI 1.33 to 16.55, p = 0.009). Women with FHD1 and FHD1 + D2 had adverse glucometabolic profiles already in early pregnancy. CONCLUSIONS: Family history of T2DM is an important risk factor for GDM, also by applying the current diagnostic criteria. Furthermore, we showed that the degree of kinship plays an essential role in quantifying the risk already at early pregnancy.

Impact Of Prepregnancy Overweight And Obesity On Treatment Modality And Pregnancy Outcome In Women With Gestational Diabetes Mellitus.

Background: We aim to evaluate the impact of prepregnancy overweight on treatment modalities of Gestational Diabetes Mellitus (GDM). We assessed the association of increased pregravid Body Mass Index (BMI) with dosing of basal and rapid acting insulin as well as pregnancy outcome. Methods: We included 509 gestational diabetic women (normal weight: 200, overweight: 157, obese: 152), attending the pregnancy outpatient clinic at the Department of Obstetrics and Gynecology, Medical University of Vienna, in this retrospective study. We used a prospectively compiled database to assess patient characteristics, treatment approaches - particularly maximum doses of basal and rapid acting insulin or metformin - and pregnancy outcome. Results: Increased BMI was associated with the need of glucose lowering medication (odds ratio (OR): 1.08 for the increase of 1 kg/m² BMI, 95%CI 1.05-1.11, p<0.001). Mothers with pregestational obesity received the highest amount of insulin. Metformin was more often used in patients with obesity who also required higher daily doses. Maternal BMI was associated with increased risk of cesarean section (OR 1.04, 95%CI 1.01-1.07, p<0.001) and delivering large for gestational age offspring (OR 1.09, 95%CI 1.04-1.13, p<0.001). Birthweight percentiles were highest in patients with obesity who required glucose lowering therapy. Conclusions: Treatment modalities and outcome in GDM pregnancies are closely related to the extent of maternal BMI. Patients with obesity required glucose lowering medication more often and were at higher risk of adverse pregnancy outcomes. It is crucial to further explore the underlying pathophysiologic mechanisms to optimize clinical management and individual treatment approaches.

Fatty liver indices and their association with glucose metabolism in pregnancy - An observational cohort study.

AIMS: Non-invasive hepatic steatosis indices can be used to assess the risk for metabolic (dysfunction) associated fatty liver disease (MAFLD). This may be helpful to detect metabolic disorders in pregnancy, specifically gestational diabetes (GDM). We aimto examine the association of these indices with parameters of glucose metabolism. METHODS: 109 women underwent a metabolic characterization at 16 weeks of gestation andwere classified according to the fatty-liver index (FLI) andhepatic-steatosis index (HSI) into low (G1), intermediate (G2) and high risk (G3). At 26 weeks, participants received an oral glucose tolerance test (OGTT) to assess insulin action, ß-cell function and GDM status. RESULTS: Both MAFLD indices wereassociated with impaired insulin sensitivityand compensatory increase of insulin release. G3 groups showedimpaired insulin action. The higher circulating insulin concentrations were not able to compensate for insulin resistance in women with higher MAFLD scores, resulting in an increased risk of GDM(OR: 1.05, 95% CI 1.03 to 1.08, p < 0.001 for FLI). MAFLD scores were associated with fetal overgrowth. CONCLUSIONS: Maternal MAFLD represents a high-risk obstetric condition. Hepatic steatosis indices are associated with impaired glucose regulation and may provide a useful tool for early risk assessment for impaired glucose metabolism.

Recurrence of Gestational Diabetes Mellitus: To Assess Glucose Metabolism and Clinical Risk Factors at the Beginning of a Subsequent Pregnancy.

Women with a history of gestational diabetes mellitus (GDM) are at high risk of developing hyperglycemia in a subsequent pregnancy. This study aimed to assess parameters of glucose metabolism at the beginning of a subsequent pregnancy in women with a history of GDM. This prospective cohort study included 706 women who had at least one previous pregnancy (120 with prior GDM and 586 without GDM history). All study participants received a broad risk evaluation and laboratory testing at the beginning of a subsequent pregnancy and were followed up until delivery to assess GDM status, risk factors for GDM recurrence, and pregnancy outcomes. Women with a history of GDM exhibited lower insulin sensitivity and subtle impairments in ß-cell function associated with subclinical hyperglycemia already at the beginning of a subsequent pregnancy compared to women without GDM history. This was associated with a markedly increased risk for the later development of GDM (OR: 6.59, 95% CI 4.34 to 10.09, p < 0.001). Early gestational fasting glucose and HbA1c were identified as the most important predictors. Mothers with a history of GDM showed marked alterations in glucose metabolism at the beginning of a subsequent pregnancy, which explains the high prevalence of GDM recurrence in these women.

Performance of early risk assessment tools to predict the later development of gestational diabetes.

BACKGROUND: Several prognostic models for gestational diabetes mellitus (GDM) are provided in the literature; however, their clinical significance has not been thoroughly evaluated, especially with regard to application at early gestation and in accordance with the most recent diagnostic criteria. This external validation study aimed to assess the predictive accuracy of published risk estimation models for the later development of GDM at early pregnancy. METHODS: In this cohort study, we prospectively included 1132 pregnant women. Risk evaluation was performed before 16 + 0 weeks of gestation including a routine laboratory examination. Study participants were followed-up until delivery to assess GDM status according to the IADPSG 2010 diagnostic criteria. Fifteen clinical prediction models were calculated according to the published literature. RESULTS: Gestational diabetes mellitus was diagnosed in 239 women, that is 21.1% of the study participants. Discrimination was assessed by the area under the ROC curve and ranged between 60.7% and 76.9%, corresponding to an acceptable accuracy. With some exceptions, calibration performance was poor as most models were developed based on older diagnostic criteria with lower prevalence and therefore tended to underestimate the risk of GDM. The highest variable importance scores were observed for history of GDM and routine laboratory parameters. CONCLUSIONS: Most prediction models showed acceptable accuracy in terms of discrimination but lacked in calibration, which was strongly dependent on study settings. Simple biochemical variables such as fasting glucose, HbA1c and triglycerides can improve risk prediction. One model consisting of clinical and laboratory parameters showed satisfactory accuracy and could be used for further investigations.

Characteristics of gestational diabetes subtypes classified by oral glucose tolerance test values.

BACKGROUND: In clinical practice, gestational diabetes mellitus (GDM) is treated as a homogenous disease but emerging evidence suggests that the diagnosis of GDM possibly comprises different metabolic entities. In this study, we aimed to assess early pregnancy characteristics of gestational diabetes mellitus entities classified according to the presence of fasting and/or post-load hyperglycaemia in the diagnostic oral glucose tolerance test performed at mid-gestation. METHODS: In this prospective cohort study, 1087 pregnant women received a broad risk evaluation and laboratory examination at early gestation and were later classified as normal glucose tolerant (NGT), as having isolated fasting hyperglycaemia (GDM-IFH), isolated post-load hyperglycaemia (GDM-IPH) or combined hyperglycaemia (GDM-CH) according to oral glucose tolerance test results. Participants were followed up until delivery to assess data on pharmacotherapy and pregnancy outcomes. RESULTS: Women affected by elevated fasting and post-load glucose concentrations (GDM-CH) showed adverse metabolic profiles already at beginning of pregnancy including a higher degree of insulin resistance as compared to women with normal glucose tolerance and those with isolated defects (especially GDM-IPH). The GDM-IPH subgroup had lower body mass index at early gestation and required glucose-lowering medications less often (28.9%) as compared to GDM-IFH (47.8%, P = .019) and GDM-CH (54.5%, P = .005). No differences were observed in pregnancy outcome data. CONCLUSIONS: Women with fasting hyperglycaemia, especially those with combined hyperglycaemia, showed an unfavourable metabolic phenotype already at early gestation. Therefore, categorization based on abnormal oral glucose tolerance test values provides a practicable basis for clinical risk stratification.

Association between maternal triglycerides and disturbed glucose metabolism in pregnancy.

AIMS: Dyslipidemia in pregnancy is associated with adverse pregnancy outcomes as elevated triglycerides might be considered as a risk factor for hyperglycemia and gestational diabetes. As only a few studies have addressed the association between maternal triglycerides and glucose metabolism, we aimed to explore the pathophysiologic associations of moderate hypertriglyceridemia and maternal glucose metabolism in pregnancy. METHODS: Sixty-seven pregnant women received a detailed metabolic characterization at 12+0-22+6 weeks of gestation by an extended 2h-75g OGTT (oral glucose tolerance test); with measurements of glucose, insulin and C-peptide at fasting and every 30 min after ingestion and assessment of triglycerides at fasting state. All examinations were repeated at 24+0-27+6 weeks of gestation. RESULTS: Elevated triglycerides in early gestation were associated with insulin resistance and ß-cell dysfunction. Mean glucose concentrations during the OGTT in early pregnancy were already higher in women with hypertriglyceridemia as compared to women with triglycerides in the normal range. A higher degree of insulin resistance and increased OGTT glucose levels were also observed when metabolic assessments were repeated between 24 and 28 weeks of gestation. Of note, elevated triglycerides at early gestation were associated with development of gestational diabetes by logistic regression (odds ratio: 1.16, 95%CI: 1.03-1.34, p=0.022 for an increase of 10 mg/dl). CONCLUSIONS: Hypertriglyceridemia at the start of pregnancy is closely related to impaired insulin action and ß-cell function. Women with hypertriglyceridemia have higher mean glucose levels in early- and mid-gestation. Pregnant women with elevated triglycerides in early pregnancy are at increased risk of developing gestational diabetes.

Maternal Overweight vs. Polycystic Ovary Syndrome: Disentangling Their Impact on Insulin Action in Pregnancy-A Prospective Study.

BACKGROUND: To investigate insulin sensitivity and glucose metabolism in pregnant lean and overweight polycystic ovary syndrome (PCOS) patients vs. lean and overweight controls without PCOS. METHODS: Prospective cohort study on 67 pregnant women (31 with PCOS and 36 controls, subdivided into overweight or obese and normal weight). All women underwent a 2h-OGTT including glucose, insulin, and C-peptide in early- and mid-gestation and were followed-up until delivery. RESULTS: Insulin sensitivity and glucometabolic parameters were comparable between PCOS patients and controls, whereas marked differences were observed between overweight/obese and lean mothers. Impaired whole-body insulin sensitivity at early pregnancy is mainly a consequence of higher BMI (body mass index; p < 0.001) compared to PCOS (p = 0.216), whereby no interaction between overweight/obesity and PCOS was observed (p = 0.194). Moreover, overweight was significantly associated with gestational diabetes (p = 0.0003), whereas there were no differences between women with and without PCOS (p = 0.51). Birth weight was inversely related to whole-body insulin sensitivity (rho = -0.33, p = 0.014) and positively associated with higher pregestational BMI (rho = 0.33, p = 0.012), whereas there was no association with PCOS. CONCLUSIONS: Impaired insulin action was mainly a consequence of overweight rather than PCOS. Our data suggest that overweight is more relevant than PCOS for the effects on insulin sensitivity and impaired glucose metabolism.

Effectiveness of real-time continuous glucose monitoring to improve glycaemic control and pregnancy outcome in patients with gestational diabetes mellitus: a study protocol for a randomised controlled trial.

INTRODUCTION: Real-time continuous glucose monitoring (rt-CGM) informs users about current interstitial glucose levels and allows early detection of glycaemic excursions and timely adaptation by behavioural change or pharmacological intervention. Randomised controlled studies adequately powered to evaluate the impact of long-term application of rt-CGM systems on the reduction of adverse obstetric outcomes in women with gestational diabetes (GDM) are missing. We aim to assess differences in the proportion of large for gestational age newborns in women using rt-CGM as compared with women with self-monitored blood glucose (primary outcome). Rates of neonatal hypoglycaemia, caesarean section and shoulder dystocia are secondary outcomes. A comparison of glucose metabolism and quality of life during and after pregnancy completes the scope of this study. METHODS AND ANALYSIS: Open-label multicentre randomised controlled trial with two parallel groups including 372 female patients with a recent diagnosis of GDM (between 24+0 until 31+6 weeks of gestation): 186 with rt-CGM (Dexcom G6) and 186 with self-monitored blood glucose (SMBG). Women with GDM will be consecutively recruited and randomised to rt-CGM or control (SMBG) group after a run-in period of 6-8 days. The third visit will be scheduled 8-10 days later and then every 2 weeks. At every visit, glucose measurements will be evaluated and all patients will be treated according to the standard care. The control group will receive a blinded CGM for 10 days between the second and third visit and between week 36+0 and 38+6. Cord blood will be sampled immediately after delivery. 48 hours after delivery neonatal biometry and maternal glycosylated haemoglobin A1c (HbA1c) will be assessed, and between weeks 8 and 16 after delivery all patients receive a re-examination of glucose metabolism including blinded CGM for 8-10 days. ETHICS AND DISSEMINATION: This study received ethical approval from the main ethic committee in Vienna. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03981328; Pre-results.

Oral probiotics to reduce vaginal group B streptococcal colonization in late pregnancy.

This study aimed to evaluate the potential of oral probiotics to eradicate vaginal GBS colonization during the third trimester of pregnancy. We screened 1058 women for GBS colonization at 33-37 gestational weeks using a combination of vaginal-to-rectal swab and culture-based methods. Women who tested GBS positive were randomized to either the verum group, receiving a dietary probiotic supplement of four viable strains of Lactobacillus twice-daily for 14 days, or to the placebo group. Women underwent follow-up smears, whereat GBS colonization upon follow-up was considered the primary endpoint. We found that 215 women (20.3%) were positive for GBS upon screening, of which 82 (38.1%) were eligible for study inclusion; 41 (50%) of these were randomized to the verum and placebo groups each. After treatment, 21/33 (63.6%) members of the verum group, and 21/27 (77.8%) of the placebo group were still GBS positive (p = 0.24). Four (9.8%) women in the verum group and one (2.4%) in the placebo group experienced preterm birth (p = 0.20); smokers showed significantly higher rates of preterm birth (p = 0.03). Hence, the findings did not support the hypothesis that oral probiotics can eradicate GBS during pregnancy, although we observed a trend toward reduced GBS persistence after probiotic intake.

Novel Indices of Glucose Homeostasis Derived from Principal Component Analysis: Application for Metabolic Assessment in Pregnancy.

AIMS: This study is aimed at assessing the association of previously developed indices of glucose homeostasis derived from principal component analysis (PCA) with parameters of insulin action, secretion, and beta cell function during pregnancy. METHODS: In this prospective longitudinal study, an oral glucose tolerance test was performed in sixty-seven pregnant women at two prepartum (12+0 to 22+6 and 24+0 to 28+6) and one postpartum (2 to 11 months) visits. Three principal component scores (PCS) were calculated based on measurements of glucose, insulin, C-peptide, age, and BMI to assess their association with fasting and dynamic indices of insulin action, secretion, and ß-cell function. RESULTS: PCS1 was positively associated with fasting and dynamic parameters of insulin sensitivity (Matsuda index: r = 0.93, p < 0.001), whereas a strong negative association was observed for early, late, and total insulin response. PCS2 was associated with higher mean glucose but negatively related to parameters of insulin secretion. PCS3 was significantly associated with fasting indices of insulin sensitivity. PCS1 to 3 assessed at early pregnancy were also associated with development of GDM, whereby random forest analysis revealed the highest variable importance for PCS1. PCS1 to 3 were significantly related to the oral disposition index explaining 49.0% of its variance. CONCLUSIONS: PCS1 to 3 behaved similarly as compared to previous observations in nonpregnant women and were furthermore associated with the development of GDM. These findings support our hypothesis that PCS1 to 3 could be used as novel indices of glucose disposal during pregnancy.

Effects of gum chewing on glycaemic control in women with gestational diabetes mellitus: A randomized controlled trial. Impact of chewing on hyperglycaemia in women with GDM.

BACKGROUND: The amount of chewing might be relevant in reducing hyperglycaemia in diabetic patients. The study assessed the impact of enhanced chewing on glycaemic control in women with gestational diabetes mellitus (GDM). METHODS: As an open-label, mono-centre randomized controlled trial, 59 women with recent diagnosis of GDM were included. They received either routine care or additional chewing gum intervention. SMBG was performed for five days. RESULTS: No significant impact on mean values of postprandial glucose levels were observed. The estimated mean differences (intervention vs. control group) were: 4.9 mg/dl, 98.4 %CI -7.2-17.1 (breakfast); -4.5 mg/dl, 98.4 %CI -15.1-6.0 (lunch); -3.8 mg/dl, 98.4 %CI -15.9 to 8.4 (dinner). OGTT levels at 60 and 120 min. were associated with glucose levels after breakfast. CONCLUSION: In conclusion, no significant differences in blood glucose levels were observed between the groups and therefore major effects of chewing on hyperglycaemia in women with GDM could be excluded. TRIAL REGISTRATION: ClinicalTrials.gov; NCT03961542, Date of registration: 20.01.2019. Retrospectively registered.

Early Assessment of the Risk for Gestational Diabetes Mellitus: Can Fasting Parameters of Glucose Metabolism Contribute to Risk Prediction?

BACKGROUND: An early identification of the risk groups might be beneficial in reducing morbidities in patients with gestational diabetes mellitus (GDM). Therefore, this study aimed to assess the biochemical predictors of glycemic conditions, in addition to fasting indices of glucose disposal, to predict the development of GDM in later stage and the need of glucose-lowering medication. METHODS: A total of 574 pregnant females (103 with GDM and 471 with normal glucose tolerance [NGT]) were included. A metabolic characterization was performed before 15⁺6 weeks of gestation by assessing fasting plasma glucose (FPG), fasting insulin (FI), fasting C-peptide (FCP), and glycosylated hemoglobin (HbA1c). Thereafter, the patients were followed-up until the delivery. RESULTS: Females with NGT had lower levels of FPG, FI, FCP, or HbA1c at the early stage of pregnancy, and therefore, showed an improved insulin action as compared to that in females who developed GDM. Higher fasting levels of FPG and FCP were associated with a higher risk of developing GDM. Moreover, the predictive accuracy of this metabolic profiling was also good to distinguish the patients who required glucose-lowering medications. Indices of glucose disposal based on C-peptide improved the predictive accuracy compared to that based on insulin. A modified quantitative insulin sensitivity check index (QUICKIc) showed the best differentiation in terms of predicting GDM (area under the receiver operating characteristics curve [ROC-AUC], 72.1%) or need for pharmacotherapy (ROC-AUC, 83.7%). CONCLUSION: Fasting measurements of glucose and C-peptide as well as the surrogate indices of glycemic condition could be used for stratifying pregnant females with higher risk of GDM at the beginning of pregnancy.