Importance:Metformin and glyburide monotherapy are used as alternatives to insulin in managing gestational diabetes. Whether a sequential strategy of these oral agents results in noninferior perinatal outcomes compared with insulin alone is unknown. Objective:To test whether a treatment strategy of oral glucose-lowering agents is noninferior to insulin for prevention of large-for-gestational-age infants. Design, Setting, and Participants:Randomized, open-label noninferiority trial conducted at 25 Dutch centers from June 2016 to November 2022 with follow-up completed in May 2023. The study enrolled 820 individuals with gestational diabetes and singleton pregnancies between 16 and 34 weeks of gestation who had insufficient glycemic control after 2 weeks of dietary changes (defined as fasting glucose >95 mg/dL [>5.3 mmol/L], 1-hour postprandial glucose >140 mg/dL [>7.8 mmol/L], or 2-hour postprandial glucose >120 mg/dL [>6.7 mmol/L], measured by capillary glucose self-testing). Interventions:Participants were randomly assigned to receive metformin (initiated at a dose of 500 mg once daily and increased every 3 days to 1000 mg twice daily or highest level tolerated; n = 409) or insulin (prescribed according to local practice; n = 411). Glyburide was added to metformin, and then insulin substituted for glyburide, if needed, to achieve glucose targets. Main Outcomes and Measures:The primary outcome was the between-group difference in the percentage of infants born large for gestational age (birth weight >90th percentile based on gestational age and sex). Secondary outcomes included maternal hypoglycemia, cesarean delivery, pregnancy-induced hypertension, preeclampsia, maternal weight gain, preterm delivery, birth injury, neonatal hypoglycemia, neonatal hyperbilirubinemia, and neonatal intensive care unit admission. Results:Among 820 participants, the mean age was 33.2 (SD, 4.7) years). In participants randomized to oral agents, 79% (n = 320) maintained glycemic control without insulin. With oral agents, 23.9% of infants (n = 97) were large for gestational age vs 19.9% (n = 79) with insulin (absolute risk difference, 4.0%; 95% CI, -1.7% to 9.8%; P = .09 for noninferiority), with the confidence interval of the risk difference exceeding the absolute noninferiority margin of 8%. Maternal hypoglycemia was reported in 20.9% with oral glucose-lowering agents and 10.9% with insulin (absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%). All other secondary outcomes did not differ between groups. Conclusions and Relevance:Treatment of gestational diabetes with metformin and additional glyburide, if needed, did not meet criteria for noninferiority compared with insulin with respect to the proportion of infants born large for gestational age. Trial Registration:Netherlands Trial Registry Identifier: NTR6134.

IMPORTANCE Metformin and glyburide monotherapy are used as alternatives to insulin in managing gestational diabetes. Whether a sequential strategy of these oral agents results in noninferior perinatal outcomes compared with insulin alone is unknown. OBJECTIVE To test whether a treatment strategy of oral glucose-lowering agents is noninferior to insulin for prevention of large-for-gestational-age infants. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label noninferiority trial conducted at 25 Dutch centers from June 2016 to November 2022 with follow-up completed in May 2023. The study enrolled 820 individuals with gestational diabetes and singleton pregnancies between 16 and 34 weeks of gestation who had insufficient glycemic control after 2 weeks of dietary changes (defined as fasting glucose >95 mg/dL [>5.3 mmol/L], 1-hour postprandial glucose >140 mg/dL [>7.8 mmol/L], or 2-hour postprandial glucose >120 mg/dL [>6.7 mmol/L], measured by capillary glucose self-testing). INTERVENTIONS Participants were randomly assigned to receive metformin (initiated at a dose of 500 mg once daily and increased every 3 days to 1000 mg twice daily or highest level tolerated; n = 409) or insulin (prescribed according to local practice; n = 411). Glyburide was added to metformin, and then insulin substituted for glyburide, if needed, to achieve glucose targets. MAIN OUTCOMES AND MEASURES The primary outcome was the between-group difference in the percentage of infants born large for gestational age (birth weight >90th percentile based on gestational age and sex). Secondary outcomes included maternal hypoglycemia, cesarean delivery, pregnancy-induced hypertension, preeclampsia, maternal weight gain, preterm delivery, birth injury, neonatal hypoglycemia, neonatal hyperbilirubinemia, and neonatal intensive care unit admission. RESULTS Among 820 participants, the mean age was 33.2 (SD, 4.7) years). In participants randomized to oral agents, 79% (n = 320) maintained glycemic control without insulin. With oral agents, 23.9% of infants (n = 97) were large for gestational age vs 19.9% (n = 79) with insulin (absolute risk difference, 4.0%; 95% CI, -1.7% to 9.8%; P = .09 for noninferiority), with the confidence interval of the risk difference exceeding the absolute noninferiority margin of 8%. Maternal hypoglycemia was reported in 20.9% with oral glucose-lowering agents and 10.9% with insulin (absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%). All other secondary outcomes did not differ between groups. CONCLUSIONS AND RELEVANCE Treatment of gestational diabetes with metformin and additional glyburide, if needed, did not meet criteria for noninferiority compared with insulin with respect to the proportion of infants born large for gestational age.

Abstract Introduction Gestational diabetes mellitus (GDM), or hyperglycemia first diagnosed in pregnancy, affects 7–10% of all pregnancies worldwide. Perinatal risk rises with increasing glycemia at oral glucose tolerance test (OGTT). The new (2013) WHO criteria recommend a lower fasting, and a higher post-load threshold for GDM diagnosis in comparison to the old (1999) WHO criteria. To date, however, outcomes of GDM treatment for those affected by the altered diagnostic criteria, has not been well investigated. We hypothesized that intensive GDM treatment according to the new (2013) GDM criteria would result in a reduction in infants with birth weight > 90th centile (large for gestational age, LGA), in comparison to treatment according to the old criteria (1999). Methods The TANGO-DM trial is an open label, multicenter randomized controlled trial. Participants are pregnant with a gestational age between 16 + 0 and 32 + 0 weeks, who underwent a 1-step venous 2- or 3-point 75-gram oral OGTT, were eligible if they had glucose concentrations discordant between the old (1999) and the new (2013) criteria. After informed consent, women are randomized to either intensive GDM treatment, consisting of dietary advice and glucose monitoring and, if euglycemia is not reached, antihyperglycemic agents, or normal obstetric care without GDM treatment. The primary outcome is large-for-gestational-age infants (birth weight > 90th percentile). Secondary outcome measures include maternal complications, obstetric complications, neonatal complications, obstetric interventions, quality of life, and healthcare and societal costs. Outcomes will be analyzed according to the intention-to-treat principle. The study is powered to detect a reduction in LGA from 16% in the untreated to 10% in the treated group, which requires 1032 participants (516 per arm; alpha-error 5% for 80% power). Discussion The TANGO-DM trial will provide high-level evidence to support or refute the use of the new 2013 WHO diagnostic criteria in terms of their ability to lower the number of large for gestational age infants and/or improve maternal and perinatal outcomes and/or costs in women with gestational diabetes. Trial registration Central Committee on Research Involving Human Subjects (CCMO) (NL63013.018.18). Registered on 22 September 2018.

AimsThe impact of maternal metformin use during pregnancy on fetal, infant, childhood and adolescent growth, development, and health remains unclear. Our objective was to systematically review the available evidence from animal experiments on the effects of intrauterine metformin exposure on offspring's anthropometric, cardiovascular and metabolic outcomes.MethodsA systematic search was conducted in PUBMED and EMBASE from inception (searched on 12th April 2023). We extracted original, controlled animal studies that investigated the effects of maternal metformin use during pregnancy on offspring anthropometric, cardiovascular and metabolic measurements. Subsequently, risk of bias was assessed and meta-analyses using the standardized mean difference and a random effects model were conducted for all outcomes containing data from 3 or more studies. Subgroup analyses were planned for species, strain, sex and type of model in the case of 10 comparisons or more per subgroup.ResultsWe included 37 articles (n = 3133 offspring from n = 716 litters, containing n = 51 comparisons) in this review, mostly (95%) on rodent models and 5% pig models. Follow-up of offspring ranged from birth to 2 years of age. Thirty four of the included articles could be included in the meta-analysis. No significant effects in the overall meta-analysis of metformin on any of the anthropometric, cardiovascular and metabolic offspring outcome measures were identified. Between-studies heterogeneity was high, and risk of bias was unclear in most studies as a consequence of poor reporting of essential methodological details.ConclusionThis systematic review was unable to establish effects of metformin treatment during pregnancy on anthropometric, cardiovascular and metabolic outcomes in non-human offspring. Heterogeneity between studies was high and reporting of methodological details often limited. This highlights a need for additional high-quality research both in humans and model systems to allow firm conclusions to be established. Future research should include focus on the effects of metformin in older offspring age groups, and on outcomes which have gone uninvestigated to date.

Objective: The WHO 2013 guidelines recommend screening for gestational diabetes mellitus (GDM) by 3-point oral glucose tolerance test (OGTT). The objective of this retrospective cohort study was to evaluate GDM diagnosed by an isolated high glucose. Study design: We included pregnant women deemed at risk for GDM were offered GDM screening. We examined the records of 1939 consecutively screened pregnancies at two teaching hospitals in Amsterdam during 2016 -2020. Using the WHO 2013 diagnostic criteria, we calculated the proportion of GDM cases diagnosed by isolated abnormal glucose values. Results: Among those screened in our high risk cohort, GDM incidence was 31.5%. Of the GDM diagnoses, 57.0% were based on an isolated fasting glucose value, 30.9% based on multiple raised glucose measurements, 7.4% on an isolated raised 2-hour glucose and 4.7% on an isolated raised 1-hour glucose. For 1-hour glucose, the number needed to screen was 67 persons for one additional GDM case. Conclusion: The 1-hour glucose in the 3 point OGTT, as suggested by the WHO 2013 guidelines for GDM, contributes only small numbers of GDM cases and a high number needed to screen (67 for 1 additional case in a selective high risk GDM screening strategy), and is likely even less effective in universally screened populations.

Aim: To investigate the association between continuous glucose monitoring (CGM) metrics and perinatal outcomes in insulin-treated diabetes mellitus in pregnancy.Materials and Methods: In a post-hoc analysis of the GlucoMOMS randomized controlled trial, we investigated the association between the metrics of an offline, intermittent CGM, glycated haemoglobin (HbA1c) and perinatal outcomes per trimester in different types of diabetes (type 1, 2 or insulin-treated gestational diabetes mellitus [GDM]). Data were analysed using multivariable binary logistic regression. Outcomes of interest were neonatal hypoglycaemia, pre-eclampsia, preterm birth, large for gestational age (LGA) and Neonatal Intensive Care Unit (NICU) admission. The glucose target range was defined as 3.5-7.8 mmol/L (63-140 mg/dL).Results: Of the 147 participants (N = 50 type 1 diabetes, N = 94 type 2 diabetes/insulin-treated GDM) randomized to the CGM group of the GlucoMOMS trial, 115 participants had CGM metrics available and were included in the current study. We found that, in pregnancies with type 1 diabetes, a higher second trimester mean glucose was associated with LGA (odds ratio 2.6 [95% confidence interval 1.1-6.2]). In type 2 and insulin-treated gestational diabetes, an increased area under the curve above limit was associated with LGA (odds ratio 10.0 [95% confidence interval 1.4-72.8]). None of the CGM metrics were associated with neonatal hypoglycaemia, pre-eclampsia, shoulder dystocia, preterm birth and NICU admission rates for pregnancies complicated by any type of diabetes.Conclusion: In this study, in type 2 diabetes or insulin-treated GDM, the glucose increased area under the curve above limit was associated with increased LGA. In type 1 diabetes, the mean glucose was the major determinant of LGA. Our study found no evidence that other CGM metrics determined adverse pregnancy outcomes.

(Acta Obstet Gynecol Scand. 2021;100:941–948) The average age of women in the Netherlands delivering their first child has significantly increased over the last 50 years (31.2 in 2017, 24.3 in 1970). Advanced maternal age (AMA) carries increased likelihood of adverse maternal and perinatal outcomes. This study aimed to understand the association between adverse maternal and perinatal outcomes and AMA by comparing parturients ages 25 to 29 with pregnant women aged 40 and up.

BACKGROUND Implementation of new diagnostic criteria for gestational diabetes mellitus (GDM) are still a subject of debate, mostly due to concerns regarding the effects on the number of women diagnosed with GDM and the risk profile of the women newly diagnosed. AIM To estimate the impact of the World Health Organization (WHO) 2013 criteria compared with the WHO 1999 criteria on the incidence of gestational diabetes mellitus as well as to determine the diagnostic accuracy for detecting adverse pregnancy outcomes. METHODS We retrospectively analyzed a single center Dutch cohort of 3338 women undergoing a 75 g oral glucose tolerance test where the WHO 1999 criteria to diagnose GDM were clinically applied. Women were categorized into four groups: non-GDM by both criteria, GDM by WHO 1999 only (excluded from GDM), GDM by WHO 2013 only (newly diagnosed) and GDM by both criteria. We compared maternal characteristics, pregnancy outcomes and likelihood ratios for adverse pregnancy outcomes. RESULTS Retrospectively applying the WHO 2013 criteria increased the cohort incidence by 13.1%, from 19.3% to 32.4%. Discordant diagnoses occurred in 21.3%; 4.1% would no longer be labelled as GDM, and 17.2% were newly diagnosed. Compared to the non-GDM group, women newly diagnosed were older, had higher rates of obesity, higher diastolic blood pressure and higher rates of caesarean deliveries. Their infants were more often delivered preterm, large-for-gestational-age and were at higher risk of a 5 min Apgar score < 7. Women excluded from GDM were older and had similar pregnancy outcomes compared to the non-GDM group, except for higher rates of shoulder dystocia (4.3% vs 1.3%, P = 0.015). Positive likelihood ratios for adverse outcomes in all groups were generally low, ranging from 0.54 to 2.95. CONCLUSION Applying the WHO 2013 criteria would result in a substantial increase in GDM diagnoses. Newly diagnosed women are at increased risk for pregnancy adverse outcomes. This risk, however, seems to be lower than those identified by the WHO 1999 criteria. This could potentially influence the treatment effect that can be achieved in this group. Evidence on treatment effects in newly diagnosed women is urgently needed.

The age at which women give birth is rising steadily in the western world. Advanced maternal age has been associated with adverse pregnancy outcomes. We assessed the association between advanced maternal age and the risk of adverse maternal and perinatal outcome in primigravid and multigravid women. The study was a population-based cohort study and included women giving birth between January 2000 and December 2018 using data from the Dutch perinatal registration of Perined. Women were divided into age groups. We compared outcomes between women of 40-44, 45-49, and over 50 years old (the study groups) with women of 25-29 years old (reference group), stratified for parity. We employed multivariable regression to correct for possible confounders including methods of conception, multiple pregnancies, ethnicity, and socio-economic status. Our primary outcomes were maternal and perinatal mortality. Secondary outcomes included common maternal and perinatal complications, as well as cesarean section rate. A cohort of 3 700 326 women gave birth during the study period. Of these women, 3.2% were above 40 years of age. Maternal mortality was rare in all groups, but significantly higher in multigravid women over 50 years old. Perinatal mortality was significantly higher in all pregnancies of women over 40 years old, but not for primigravida over 50 years old. The most notable results with the steepest increase were in maternal complications. Both primigravida and multigravida over 40 years old were at a two times higher risk of perinatal mortality, cesarean section, gestational diabetes, hypertensive disorders, and a low Apgar score after 5 minutes. The risk for women over 45 was almost tripled for perinatal mortality and gestational diabetes and six times higher for cesarean section. Women over 50 years old had a seven times higher risk of cesarean section, a four times higher risk of gestational diabetes, postpartum hemorrhage, and neonatal intensive care unit admission, and a 10 times higher risk of hypertensive disorders. The risk of adverse maternal and perinatal outcomes for women over 40 years old surges as age increases. A novel aspect was the consistent increased risks not only for primigravid women but also for multigravida.

AIM:We assessed the association between ethnicity and the risk of gestational diabetes mellitus (GDM) in the Netherlands. METHODS:A cohort of 7815 women with known GDM status and ethnicity, including women of Sub-Saharan African ethnicity who are currently not identified as high-risk in guidelines. We compared GDM rates among participants of ethnicity to those of ethnic Dutch participants. We employed multivariable regression to correct for possible confounders, including maternal age, pre-pregnancy body mass index (BMI), and education. GDM prevalence and odds ratios based on ethnicity were the main outcome measures. RESULTS:The prevalence rates of GDM according to ethnicity were: Dutch 0.6%, South-Asian Surinamese 6.9%, African-Surinamese 3.5%, Antillean 1.0%, Turkish 1.0%, Moroccan 1.4%, Ghanaian 6.8%, Sub-Saharan African 3.5%, other Western 0.5% and other non-Western 2.8%. After adjustment for age, pre-pregnancy BMI, and education duration, compared with the reference Dutch-ethnicity population, adjusted odds ratios (aOR) for GDM were statistically significantly higher in South-Asian Surinamese (aOR 10.9; 95% Confidence Interval (CI), 4.7-25.0), African-Surinamese (4.3; 2.0-9.2), Ghanaian (6.5; 3.0-14.5), Sub-Saharan African (5.7; 2.0-16.0), and other non-Western women (4.5; 2.2-9.0). GDM was not significantly increased among Antillean (1.4; 0.2-10.3), Turkish (1.4; 0.4-4.2), Moroccan (1.8; 0.8-4.0), and other Western women (0.8; 0.3-2.2). CONCLUSIONS:This study shows for the first time in the Netherlands that women of Ghanaian or other Sub-Saharan African ethnicity have an increased risk of developing GDM than the Dutch. This calls for adaptation of the Dutch guidelines of screening high-risk groups for GDM and more awareness amongst obstetric caregivers.

Introduction: The age at which women give birth is rising steadily in the western world. Advanced maternal age has been associated with adverse pregnancy outcomes. We assessed the association between advanced maternal age and the risk of adverse maternal and perinatal outcome in primigravid and multigravid women. Material and methods: The study was a population-based cohort study and included women giving birth between January 2000 and December 2018 using data from the Dutch perinatal registration of Perined. Women were divided into age groups. We compared outcomes between women of 40-44, 45-49, and over 50 years old (the study groups) with women of 25-29 years old (reference group), stratified for parity. We employed multivariable regression to correct for possible confounders including methods of conception, multiple pregnancies, ethnicity, and socio-economic status. Our primary outcomes were maternal and perinatal mortality. Secondary outcomes included common maternal and perinatal complications, as well as cesarean section rate. Results: A cohort of 3 700 326 women gave birth during the study period. Of these women, 3.2% were above 40 years of age. Maternal mortality was rare in all groups, but significantly higher in multigravid women over 50 years old. Perinatal mortality was significantly higher in all pregnancies of women over 40 years old, but not for primigravida over 50 years old. The most notable results with the steepest increase were in maternal complications. Both primigravida and multigravida over 40 years old were at a two times higher risk of perinatal mortality, cesarean section, gestational diabetes, hypertensive disorders, and a low Apgar score after 5 minutes. The risk for women over 45 was almost tripled for perinatal mortality and gestational diabetes and six times higher for cesarean section. Women over 50 years old had a seven times higher risk of cesarean section, a four times higher risk of gestational diabetes, postpartum hemorrhage, and neonatal intensive care unit admission, and a 10 times higher risk of hypertensive disorders. Conclusions: The risk of adverse maternal and perinatal outcomes for women over 40 years old surges as age increases. A novel aspect was the consistent increased risks not only for primigravid women but also for multigravida.

IntroductionIn women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM.MethodsThe SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle.Ethics and disseminationThe study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals.Trial registration numberNTR6134; Pre-results.

Introduction There are assertions that vaginal mode may be the preferred approach of minimally invasive hysterectomy, yet rates of laparoscopic hysterectomy (LH) continue to rise while vaginal hysterectomy (VH) rate remains relatively unchanged. The aim of this study is to compare the perioperative outcomes of LH vs VH. Material and methods We identified women who underwent either LH or VH for benign indications between 2009 and 2015 at a large academic institution. A propensity score-matched analysis was used to adjust for differences between women undergoing VH vs LH. Outcome parameters were perioperative complications (both intraoperative and postoperative), operative time, blood loss, hospital length of stay, conversion and readmission. Results A total of 1921 patients underwent either LH or VH during the study period. In all, 155 patients from each group were successfully matched using propensity score match analysis. While most intra- and postoperative characteristics did not differ between groups, LH was associated with lower blood loss during surgery (102.8 +/- 166.5 mL vs 185.0 +/- 179.0 mL, P < 0.001) and shorter hospital stay (0.9 +/- 1 days vs 1.2 +/- 0.9 days, P < 0.0001). Concomitant adnexal surgery was performed more frequently during LH (47.7% vs 12.3%, P < 0.0001), and concomitant prolapse surgery was performed more frequently at the time of VH (14.2% vs 68.4%, P < 0.0001). Conclusions Both VH and LH have overall favorable perioperative outcomes; however, LH is associated with lower blood loss and a shorter hospital stay. The results support the trend toward increasing rates of laparoscopic approach to hysterectomy when appropriate.

STUDY OBJECTIVE:To evaluate perioperative outcomes and symptom resolution in women undergoing removal of the Essure device for device-attributed symptoms. DESIGN:Retrospective case series and follow-up patient survey (Canadian Task Force classification III). SETTING:Large academic medical center. PATIENTS:Fifty-two women who underwent laparoscopic or hysteroscopic Essure removal between 2012 and 2016. INTERVENTIONS:Women underwent one of four procedures: laparoscopic hysterectomy (LH) and bilateral salpingectomy (BS), laparoscopic BS and cornuectomy, laparoscopic Essure removal and BS, or hysteroscopic Essure removal and laparoscopic BS. MEASUREMENTS AND MAIN RESULTS:Fifty-two women who underwent Essure removal were asked to complete a survey regarding symptom resolution and quality of life following the procedure. Thirty-two women (61.5%) responded to the survey. Seventy-five percent (24/32) reported almost total or total improvement in quality of life, 56.3% (18/32) for sex life, 53.1% (17/32) for pelvic pain, and 65.6% (21/32) for daily activities. The majority of women reported some degree of improvement in all four domains queried (87.5%, 28/32). When asked about their symptoms in general, 31.3% (10/32) of women reported ongoing or worse symptoms after Essure removal. All procedures took approximately one hour (mean 65 min, SD 33 min), were associated with minimal blood loss (mean 31 mL, SD 17), and had no perioperative complications. CONCLUSION:Essure removal is a procedure that may be effective for treating most women with symptoms attributed to the device. Patients should be counseled that some symptoms may persist or even worsen following surgery.