Use of GLP1 receptor agonists in early pregnancy and reproductive safety: a multicentre, observational, prospective cohort study based on the databases of six Teratology Information Services.

OBJECTIVES: Glucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the risks associated with GLP1-RA exposure during early pregnancy. DESIGN: This multicentre, observational prospective cohort study compared pregnancy outcomes in women exposed to GLP1-RA in early pregnancy either for diabetes or obesity treatment with those in two reference groups: (1) women with diabetes exposed to at least one non-GLP1-RA antidiabetic drug during the first trimester and (2) a reference group of overweight/obese women without diabetes, between 2009 and 2022. SETTING: Data were collected from the databases of six Teratology Information Services. PARTICIPANTS: This study included 168 pregnancies of women exposed to GLP1-RA during the first trimester, alongside a reference group of 156 pregnancies of women with diabetes and 163 pregnancies of overweight/obese women. RESULTS: Exposure to GLP1-RA in the first trimester was not associated with a risk of major birth defects when compared with diabetes (2.6% vs 2.3%; adjusted OR, 0.98 (95% CI, 0.16 to 5.82)) or to overweight/obese (2.6% vs 3.9%; adjusted OR 0.54 (0.11 to 2.75)). For the GLP1-RA group, cumulative incidence for live births, pregnancy losses and pregnancy terminations was 59%, 23% and 18%, respectively. In the diabetes reference group, corresponding estimates were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%, respectively. Cox proportional cause-specific hazard models indicated no increased risk of pregnancy losses in the GLP1-RA versus the diabetes and the overweight/obese reference groups, in both crude and adjusted analyses. CONCLUSIONS: This study offers reassurance in cases of inadvertent exposure to GLP1-RA during the first trimester of pregnancy. Due to the limited sample size, larger studies are required to validate these findings.

Continuous subcutaneous insulin infusion versus multiple daily injection therapy in pregnant women with type 1 diabetes.

INTRODUCTION: The study aimed to compare glycemic control and pregnancy outcomes in women with type 1 diabetes mellitus (T1DM) using multiple daily injection therapy (MDI) and continuous subcutaneous insulin infusion (CSII) and to compare outcomes of women treated with long-acting insulin or neutral protamine Hagedorn (NPH). METHODS: This multicenter prospective cohort study involved women with pregestational T1DM treated with MDI and CSII. Primary outcome was glycated hemoglobin (HbA1c) before and during pregnancy. Secondary outcomes included maternal and neonatal outcomes and quality of life. RESULTS: Of the 121 studied women, the average age was 28.48 years, and the average body mass index was 21.29 kg/m2 at conception and 26.32 kg/m2 at delivery. Of the studied women, 78.51% had planned pregnancy. Women treated with MDI and CSII had comparable HbA1c before pregnancy or in the first and second trimesters. In the third trimester, women on CSII therapy had significantly lower HbA1c (6.07 ± 0.62 vs 6.20 ± 0.88%, p = .017), higher HbA1c on-target rate (71.43% vs 64.62%, p = .030), and greater decline of HbA1c from preconception to the third trimester (-0.65 vs -0.30%, p = .047). Fewer daily insulin requirements were observed in those used CSII compared with MDI-treated women (0.60 ± 0.22 vs 0.73 ± 0.25 U/kg/day, p = .004). Newborns born of mothers treated with the CSII method were more likely to have neonatal jaundice (adjusted odds ratio [OR] 2.76, 95% confidence interval [CI] 1.16-6.57) and neonatal intensive care unit (adjusted OR 3.73, 95%CI 1.24-11.16), and women on CSII had lower scores in patient-reported quality of life (p = .045). In the MDI group, those receiving long-acting insulin had nonsignificant lower HbA1c and higher HbA1c on-target rate in the second and third trimesters, compared with those treated with NPH. CONCLUSIONS: Insulin pump users may achieve better glycemic control than multiple daily insulin injections, which did not substantially improve pregnancy outcome.

The IRELAnD study-investigating the role of early low-dose aspirin in diabetes mellitus: a double-blinded, placebo-controlled, randomized trial.

BACKGROUND: Although aspirin therapy is being increasingly advocated with the intention of risk modification for a wide range of pregnancy complications, women with prepregnancy diabetes mellitus are commonly excluded from clinical trials. OBJECTIVE: The primary aim of this study was to examine the effect of aspirin therapy on a composite measure of adverse perinatal outcome in pregnancies complicated by pregestational diabetes mellitus. STUDY DESIGN: A double-blinded, placebo-controlled randomized trial was conducted at 6 university-affiliated perinatology centers. Women with type 1 diabetes mellitus or type 2 diabetes mellitus of at least 6 months' duration were randomly allocated to 150-mg daily aspirin or placebo from 11 to 14 weeks' gestation until 36 weeks. Established vascular complications of diabetes mellitus, including chronic hypertension or nephropathy, led to exclusion from the trial. The primary outcome was a composite measure of placental dysfunction (preeclampsia, fetal growth restriction, preterm birth <34 weeks' gestation, or perinatal mortality). The planned sample size was 566 participants to achieve a 35% reduction in the primary outcome, assuming 80% statistical power. Secondary end points included maternal and neonatal outcomes and determination of insulin requirements across gestation. Data were centrally managed using ClinInfo and analyzed using SAS 9.4. The 2 treatment groups were compared using t tests or chi-square tests, as required, and longitudinal data were compared using a repeated-measures analysis. RESULTS: From February 2020 to September 2022, 191 patients were deemed eligible, 134 of whom were enrolled (67 randomized to aspirin and 67 to placebo) with a retrospective power of 64%. A total of 101 (80%) women had type 1 diabetes mellitus and 25 (20%) had type 2 diabetes mellitus. Reaching the target sample size was limited by the impact of the COVID-19 pandemic. Baseline characteristics were similar between the aspirin and placebo groups. Treatment compliance was very high and similar between groups (97% for aspirin, 94% for placebo). The risk of the composite measure of placental dysfunction did not differ between groups (25% aspirin vs 21% placebo; P=.796). Women in the aspirin group had significantly lower insulin requirements throughout pregnancy compared with the placebo group. Insulin requirements in the aspirin group increased on average from 0.7 units/kg at baseline to 1.1 units/kg by 36 weeks' gestation (an average 83% within-patient increase), and increased from 0.7 units/kg to 1.3 units/kg (a 181% within-patient increase) in the placebo group, over the same gestational period (P=.002). Serial hemoglobin A1c levels were lower in the aspirin group than in the placebo group, although this trend did not reach statistical significance. CONCLUSION: In this multicenter, double-blinded, placebo-controlled randomized trial, aspirin did not reduce the risk of adverse perinatal outcome in pregnancies complicated by prepregnancy diabetes mellitus. Compared with the placebo group, aspirin-treated patients required significantly less insulin throughout pregnancy, indicating a beneficial effect of aspirin on glycemic control. Aspirin may exert a plausible placenta-mediated effect on pregestational diabetes mellitus that is not limited to its antithrombotic properties.

Performance of the Dexcom G7 Continuous Glucose Monitoring System in Pregnant Women with Diabetes.

Background: We evaluated accuracy and safety of a seventh-generation real-time continuous glucose monitoring (CGM) system during pregnancy. Materials and Methods: Evaluable data for accuracy analysis were obtained from 96 G7 sensors (Dexcom, Inc.) worn by 96 of 105 enrolled pregnant women with type 1 (n = 59), type 2 (n = 21), or gestational diabetes (n = 25). CGM values were compared with arterialized venous glucose values from the YSI comparator instrument during 6-h clinic sessions at different time points throughout the sensors' 10-day wear period. The primary endpoint was the proportion of CGM values in the 70-180 mg/dL range within 15% of comparator glucose values. Secondary endpoints included the proportion of CGM values within 20% or 20 mg/dL of comparator values ≥ or <100 mg/dL, respectively (the %20/20 agreement rate). Results: Of the 1739 pairs with CGM in the 70-180 mg/dL range, 83.2% were within 15% of comparator values. The lower bound of the 95% confidence interval was 79.8%. Of the 2102 pairs with CGM values in the 40-400 mg/dL range, the %20/20 agreement rate was 92.5%. Of the 1659 pairs with comparator values in the 63-140 mg/dL range, the %20/20 agreement rate was 92.3%. The %20/20 agreement rates on days 1, 4 and 7, and 10 were 78.6%, 96.3%, and 97.3%, respectively. Consensus error grid analysis showed 99.8% of pairs in the clinically acceptable A and B zones. There were no serious adverse events. The sensors' 10-day survival rate was 90.3%. Conclusion: The G7 system is accurate and safe during pregnancies complicated by diabetes and does not require confirmatory fingerstick testing. Clinical Trial Registration: clinicaltrials.gov NCT04905628.

A Diabetes Pregnancy Technology Roadmap: The 2023 Norbert Freinkel Award Lecture.

Norbert Freinkel emphasized the need for "more aggressive therapy with exogenous insulin" during type 1 diabetes (T1D) pregnancy. Recent advances in diabetes technology, continuous glucose monitoring (CGM), and hybrid closed-loop (HCL) insulin delivery systems allow us to revisit Freinkel's observations from a contemporary perspective. The Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT) led to international recommendations that CGM be offered to all pregnant women with T1D to help them meet their pregnancy glucose targets and improve neonatal outcomes. However, despite CGM use, only 35% of trial participants reached the pregnancy glucose targets by 35 weeks' gestation, which is too late for optimal obstetric and neonatal outcomes. The constant vigilance to CGM data and insulin dose adjustment, with perpetual worry about the impact of hyperglycemia on the developing fetal structures, leave many pregnant women feeling overwhelmed. HCL systems that can adapt to marked gestational changes in insulin sensitivity and pharmacokinetics may help to bridge the gap between the nonpregnant time in range glycemic targets (70-180 mg/dL) and the substantially more stringent pregnancy-specific targets (TIRp) (63-140 mg/dL) required for optimal obstetric and neonatal outcomes. Use of HCL (CamAPS FX system) was associated with a 10.5% higher TIRp, 10.2% less hyperglycemia, and 12.3% higher overnight TIRp. Clinical benefits were accompanied by 3.7 kg (8 lb) less gestational weight gain and consistently achieved across a representative patient population of insulin pump or injection users, across trial sites, and across maternal HbA1c categories. Working collaboratively, women, HCL technology, and health care teams achieved improved glycemia with less worry, less work, and more positive pregnancy experiences.

Factors associated with maternal hyperglycaemia and neonatal hypoglycaemia after antenatal betamethasone administration in women with diabetes in pregnancy.

AIMS: Bespoke glycaemic control strategies following antenatal corticosteroids for women with diabetes in pregnancy (DIP) may mitigate hyperglycaemia. This study aims to identify predictive factors for the glycaemic response to betamethasone in a large cohort of women with DIP. METHODS: Evaluation of a prospective cohort study of 347 consecutive DIP pregnancies receiving two doses of 11.4 mg betamethasone 24 h apart between 2017 and 2021 and treated with the Pregnancy-IVI intravenous insulin protocol. Regression modelling identified factors associated with maternal glycaemic time-in-range (TIR) and maternal insulin requirements following betamethasone. Factors associated with neonatal hypoglycaemia (glucose <2.6 mmol/L) in infants born within 48 h of betamethasone administration (n = 144) were investigated. RESULTS: The mean maternal age was 31.9 ± 5.8 years, with gestational age at betamethasone of 33.5 ± 3.4 weeks. Gestational diabetes was present in 81% (12% type 1; 7% type 2). Pre-admission subcutaneous insulin was prescribed for 63%. On-infusion maternal glucose TIR (4.0-7.8 mmol/L) was 83% [IQR 77%-90%] and mean on-IVI glucose was 6.6 ± 0.5 mmol/L. Maternal hypoglycaemia (<3.8 mmol/L) was uncommon (0.47 h/100 on-IVI woman hours). Maternal glucose TIR was negatively associated with indicators of insulin resistance (type 2 diabetes, polycystic ovary syndrome), late-pregnancy complications (pre-eclampsia, chorioamnionitis) and the 1-h OGTT result. Intravenous insulin requirements were associated with type of diabetes, pre-eclampsia and intrauterine infection, the 1-h OGTT result and the timing of betamethasone administration. Neonatal hypoglycaemia was associated with pre-existing diabetes but not with measures of glycaemic control. CONCLUSION: An intravenous infusion protocol effectively controls maternal glucose after betamethasone. A risk-factor-based approach may allow individualisation of therapy.

MiniMedTM 780G Advanced Hybrid Closed-Loop System Study in Pregnant Women with Type 1 Diabetes.

Background: Evaluate the impact of the MiniMed™ 780G advanced hybrid closed-loop (AHCL) system on the glucose profile of pregnant women with type 1 diabetes (T1D) and maternal-neonatal complications. Methods: From April 2021 to September 2022, pregnant women with T1D treated with the AHCL system were included in an observational multicenter retrospective study. Continuous glucose monitoring parameters were analyzed monthly during pregnancy as well as maternal-neonatal complications. Results: Thirteen pregnant women, including a twin pregnancy (age: 33 ± 3 years, hemoglobin A1c [HbA1c]: 7.3% ± 0.7%, insulin doses: 0.72 ± 0.21 U/kg/day) were analyzed. At delivery, gestational age was 37 ± 2 weeks. During first 2 weeks of pregnancy, time in range (TIR, 63-140 mg/dL) was 46% (34-55) and increased to 54% (51-59) (P < 0.01), 64% (48-68) (P < 0.01), and 66% (60-70) (P < 0.001) during the first, second, and third trimester, respectively. During the night, TIR (63-140 mg/dL) was >70% throughout pregnancy. Time below the range <63 mg/dL increased from 0.5% (0-2) to 1.3% (0.7-2.2), 2% (1.2-3.5) (P < 0.05), and 1.3% (1.31-3) (P < 0.05) during the first, second, and third trimester, respectively. At delivery, insulin doses increased to 0.89 ± 0.35 IU/kg/day (P < 0.01), and HbA1c decreased to 6.4% ± 0.6% (P = 0.005). The reported carbohydrate amount increased from 167 ± 363 g/d during early pregnancy to 243 ± 106 g/d (P < 0.01) at delivery. The birthweight was 3134 ± 711 g, with 5/14 macrosomia and 2/14 neonatal hypoglycemia. Moreover, 5/13 patients had a preeclampsia and 9/13 a cesarean section, including three cases of scarred uterus. The Clinical Trial Registration number is: CE-2022-55. Conclusion: The AHCL system provided good glucose control during pregnancy and recommendation targets were reached during the nocturnal period only. The maternal and neonatal complications remained high.

Automated Insulin Delivery in Women with Pregnancy Complicated by Type 1 Diabetes.

BACKGROUND: Hybrid closed-loop insulin therapy has shown promise for management of type 1 diabetes during pregnancy; however, its efficacy is unclear. METHODS: In this multicenter, controlled trial, we randomly assigned pregnant women with type 1 diabetes and a glycated hemoglobin level of at least 6.5% at nine sites in the United Kingdom to receive standard insulin therapy or hybrid closed-loop therapy, with both groups using continuous glucose monitoring. The primary outcome was the percentage of time in the pregnancy-specific target glucose range (63 to 140 mg per deciliter [3.5 to 7.8 mmol per liter]) as measured by continuous glucose monitoring from 16 weeks' gestation until delivery. Analyses were performed according to the intention-to-treat principle. Key secondary outcomes were the percentage of time spent in a hyperglycemic state (glucose level >140 mg per deciliter), overnight time in the target range, the glycated hemoglobin level, and safety events. RESULTS: A total of 124 participants with a mean (±SD) age of 31.1±5.3 years and a mean baseline glycated hemoglobin level of 7.7±1.2% underwent randomization. The mean percentage of time that the maternal glucose level was in the target range was 68.2±10.5% in the closed-loop group and 55.6±12.5% in the standard-care group (mean adjusted difference, 10.5 percentage points; 95% confidence interval [CI], 7.0 to 14.0; P<0.001). Results for the secondary outcomes were consistent with those of the primary outcome; participants in the closed-loop group spent less time in a hyperglycemic state than those in the standard-care group (difference, -10.2 percentage points; 95% CI, -13.8 to -6.6); had more overnight time in the target range (difference, 12.3 percentage points; 95% CI, 8.3 to 16.2), and had lower glycated hemoglobin levels (difference, -0.31 percentage points; 95% CI, -0.50 to -0.12). Little time was spent in a hypoglycemic state. No unanticipated safety problems associated with the use of closed-loop therapy during pregnancy occurred (6 instances of severe hypoglycemia, vs. 5 in the standard-care group; 1 instance of diabetic ketoacidosis in each group; and 12 device-related adverse events in the closed-loop group, 7 related to closed-loop therapy). CONCLUSIONS: Hybrid closed-loop therapy significantly improved maternal glycemic control during pregnancy complicated by type 1 diabetes. (Funded by the Efficacy and Mechanism Evaluation Program; AiDAPT ISRCTN Registry number, ISRCTN56898625.).

Continuous Subcutaneous Infusion Versus Multiple Daily Injections of Insulin for Pregestational Diabetes in Pregnancy: A Systematic Review and Meta-Analysis.

BACKGROUND: The use of continuous subcutaneous insulin infusion (CSII) therapy in pregnancies affected by pregestational diabetes mellitus (DM) has generated mixed outcome data worthy of further investigation. This systematic review and meta-analysis aims to evaluate clinical outcomes associated with CSII versus multiple daily injections (MDIs) in pregnant persons with pregestational DM. METHODS: A predefined, systematic, librarian-assisted search of MEDLINE (PubMed), Embase, Cochrane Library, Scopus, ClinicalTrials.gov, and World Health Organization International Clinical Trial Registry Platform (published from 2010 to 2022) yielded 3003 studies describing pregnancy outcomes associated with CSII and/or MDI for pregestational DM. The primary exposure was mode of insulin administration, with cesarean delivery and neonatal hypoglycemia as the primary maternal and neonatal outcomes, respectively. Secondary outcomes included hypertensive disorders of pregnancy, first and third-trimester glycemic control, large-for-gestational age (LGA) neonate, preterm birth, neonatal intensive care unit admission, need for respiratory support, hyperbilirubinemia, 5-minute Apgar <7, shoulder dystocia, and perinatal mortality. We calculated pooled odds ratios (OR) with 95% confidence intervals (CI) using random-effects models. RESULTS: Among 39 eligible studies, 39% of the 5518 pregnancies included were exposed to CSII. Odds of cesarean delivery were higher with CSII (20 studies: 63% vs 56%, odds ratio [OR] 1.3 [95% confidence interval (CI) 1.2-1.5]), but we did not identify a difference in the odds of neonatal hypoglycemia (23 studies: 31% vs 34%, OR 1.1 [95% CI 0.9-1.5]). Among secondary outcomes, only the odds of LGA (20 studies: 47% vs 38%, OR 1.4 [95% CI 1.2-1.6]) were higher in individuals using CSII versus MDI. CONCLUSIONS: Use of CSII (vs MDI) for pregestational DM in pregnancy is associated with higher odds of cesarean delivery and delivery of an LGA neonate. Further evaluation of how CSII use may influence neonatal size and delivery route is warranted.

Post Antenatal Late Preterm Steroids trial: interrupted time series analysis of respiratory outcomes in twin and pregestational diabetes.

BACKGROUND: The Antenatal Late Preterm Steroids trial found that corticosteroid administration decreased respiratory complications by 20% among late preterm singleton deliveries. After the Antenatal Late Preterm Steroids trial, corticosteroid administration increased by 76% among twin pregnancies and 113% among singleton pregnancies complicated by pregestational diabetes mellitus compared with expected rates based on the pre-Antenatal Late Preterm Steroids trial trend. However, the effect of corticosteroids on twin pregnancies and pregnancies complicated by pregestational diabetes mellitus is not well studied, as the Antenatal Late Preterm Steroids trial excluded twin pregnancies and pregnancies complicated by pregestational diabetes mellitus. OBJECTIVE: This study aimed to examine the change in the incidence rate of immediate assisted ventilation use and ventilation use for more than 6 hours among 2 populations after the dissemination of the Antenatal Late Preterm Steroids trial at the population level. STUDY DESIGN: This study was a retrospective analysis of publicly available US birth certificate data. The study period was from August 1, 2014, to April 30, 2018. The dissemination period of the Antenatal Late Preterm Steroids trial was from February 2016 to October 2016. Population-based interrupted time series analyses were performed for 2 target populations: (1) twin pregnancies not complicated by pregestational diabetes mellitus and (2) singleton pregnancies complicated by pregestational diabetes mellitus. For both target populations, analyses were limited to individuals who delivered nonanomalous live neonates between 34 0/7 and 36 6/7 weeks of gestation (vaginal or cesarean delivery). As a sensitivity analysis, a total of 23 placebo tests were conducted before (5 tests) and after (18 tests) the dissemination period. RESULTS: For the analysis of late preterm twin deliveries, 191,374 individuals without pregestational diabetes mellitus were identified. For the analysis of late preterm singleton pregnancy with pregestational diabetes mellitus, 21,395 individuals were identified. After the dissemination period, the incidence rate of immediate assisted ventilation use for late preterm twin deliveries was significantly lower than the expected value based on the pre-Antenatal Late Preterm Steroids trial trend (11.6% observed vs 13.0% expected; adjusted incidence rate ratio, 0.87; 95% confidence interval, 0.78-0.97). The incidence rate of ventilation use for more than 6 hours among late preterm twin deliveries did not change significantly after the dissemination of the Antenatal Late Preterm Steroids trial. A significant increase in the incidence rate of immediate assisted ventilation use and ventilation use for more than 6 hours was found among singleton pregnancies with pregestational diabetes mellitus. However, the results of placebo tests suggested that the increase in incidence was not necessarily due to the dissemination period of the Antenatal Late Preterm Steroids trial. CONCLUSION: The dissemination of the Antenatal Late Preterm Steroids trial was associated with decreased incidence of immediate assisted ventilation use, but no change in ventilation use for more than 6 hours, among late preterm twin deliveries in the United States. In contrast, the incidence of neonatal respiratory outcomes among singleton deliveries with pregestational diabetes mellitus did not decrease after the dissemination of the Antenatal Late Preterm Steroids trial.

Maternal-fetal outcomes of pregnant women with type 1 diabetes treated with continuous subcutaneous insulin infusion or multiple daily injections during pregnancy - A Brazilian health care referral center cohort study.

Objective: Pregnant women with type 1 diabetes (T1D) have an increased risk of maternal-fetal complications. Regarding treatment, continuous subcutaneous insulin infusion (CSII) has advantages compared to multiple daily injections (MDI), but data about the best option during pregnancy are limited. This study's aim was to compare maternal-fetal outcomes among T1D patients treated with CSII or MDI during pregnancy. Subjects and methods: This study evaluated 174 pregnancies of T1D patients. Variables of interest were compared between the groups (CSII versus MDI), and logistic regression analysis was performed (p < 0.05). Results: Of the 174 included pregnancies, CSII was used in 21.3% (37) and MDI were used in 78.7% (137). HbA1c values improved throughout gestation in both groups, with no difference in the first and third trimesters. The frequency of cesarean section was significantly higher in the CSII group [94.1 vs. 75.4%, p = 0.017], but there was no significant difference in the frequency of other complications, such as miscarriage, premature delivery and preeclampsia. The mean birth weight and occurrence of neonatal complications were also similar, except for the proportion of congenital malformations, which was significantly lower in the CSII group [2.9 vs. 15.6%, p = 0.048]. In regression analysis, the association of CSII with cesarean section and malformations lost significance after adjusting for HbA1c and other covariates of interest. Conclusion: In this study, we observed a higher frequency of cesarean section and a lower occurrence of congenital malformations in the CSII group, but the adjusted results might indicate that these associations are influenced by glycemic control.

Use of metformin and insulin among pregnant women with gestation diabetes in the United Kingdom: A population-based cohort study.

AIMS: The contemporary prescription patterns of antidiabetic drugs following guideline changes recommending metformin as first-line gestational diabetes (GDM) pharmacotherapy is underexplored. We aimed to examined use of metformin and insulin during pregnancy among women with GDM over 20 years in the United Kingdom. METHODS: We conducted a population-based cohort study using linked data from the Clinical Practice Research Datalink, its pregnancy register and Hospital Episode Statistics from 1998 to 2017. We included pregnancies of women without prior diabetes history who received GDM diagnosis or initiated an antidiabetic drug after 20 weeks gestation. Patient-level and practice-level characteristics were compared between metformin initiators and insulin initiators. We described trends of initiating metformin as first-line treatment and described time to initiation of rescue insulin overall, and by body mass index among metformin initiators. RESULTS: Our cohort included 5633 pregnancies from 5393 women with GDM, of whom 38.9% initiated pharmacotherapy (41% insulin, 59% metformin). Metformin prescriptions (as opposed to insulin) increased substantially, from <5% of pregnancies before 2007 to 42.5% in 2008. Over 85% of pregnancies that were prescribed pharmacotherapy were prescribed metformin as first-line treatment in 2015. Among metformin initiators, 16% initiated rescue insulin, typically occurring within 40 days of metformin initiation. Choice of GDM pharmacotherapy varied by characteristics, including smoking, obesity, race/ethnicity and general practice regions. CONCLUSIONS: Metformin was the most prescribed medication for GDM, with large increases over the past 2 decades. The increasing use of oral-antidiabetic drugs during pregnancy, consistent with other regions, highlights the need for future studies examining effectiveness and safety of antidiabetic drug use during pregnancy.

Comprehensive Management of Type 2 Diabetes During Pregnancy.

This JAMA Insights Clinical Update discusses a comprehensive approach to treating pregnant patients with type 2 diabetes to reduce adverse perinatal and neonatal outcomes.

Hypertensive disorders of pregnancy pre- and postaspirin guideline publication in individuals with pregestational diabetes mellitus.

BACKGROUND: The US Preventive Services Taskforce published guidelines in 2014 recommending that low-dose aspirin be initiated between 12 and 28 weeks of gestation among high-risk patients for preeclampsia prophylaxis. Moreover, low-dose aspirin is recommended by some clinicians for the prevention of preterm birth. OBJECTIVE: This study aimed to evaluate whether there is an association between the US Preventive Services Taskforce aspirin guideline hypertensive disorders of pregnancy and the rates of hypertensive disorders of pregnancy and preterm birth in individuals with pregestational diabetes mellitus. STUDY DESIGN: This was a repeated cross-sectional analysis of individuals with pregestational diabetes mellitus and at least 1 singleton delivery at >20 weeks of gestation with records available in the National Vital Statistics System between 2010 and 2018. The primary outcome was hypertensive disorders of pregnancy, and the secondary outcome was preterm birth. Demographics and clinical characteristics among individuals in the pre-US Preventive Services Taskforce guideline cohort (2010-2013) were compared with that of individuals in the post-US Preventive Services Taskforce guideline cohort (2015-2018). Multivariable regression estimated the odds ratios and 95% confidence intervals for the association between guideline publication and the selected endpoints. Effect modification was assessed for access to prenatal care using the Kotelchuck Index (<80% vs ≥80%). Furthermore, a sensitivity analysis limited to nulliparas was performed. RESULTS: Overall, 224,065 individuals were included. Individuals in the post-US Preventive Services Taskforce guideline cohort were more likely to be older, be obese, and have a history of preterm birth. In unadjusted and adjusted modeling, delivery in the post-US Preventive Services Taskforce guideline cohort was associated with hypertensive disorders of pregnancy (adjusted odds ratio, 1.25; 95% confidence interval, 1.22-1.28) and preterm birth (adjusted odds ratio, 1.10; 95% confidence interval, 1.08-1.12). The adjusted odds ratios for hypertensive disorders of pregnancy and preterm birth were more pronounced among those with less than adequate access to care. The findings were similar in the sensitivity analysis of only nulliparas. CONCLUSION: Delivery after US Preventive Services Taskforce aspirin guideline publication was associated with higher rates of hypertensive disorders of pregnancy and preterm birth in a population of individuals with diabetes mellitus. It is unknown whether patient or practitioner factors, or other changes in obstetrical care, contributed to these findings.

Glycosylated haemoglobin as an indicator of diabetes control in pregnancy: A 10-year review of the relationship between HbA1c trends and delivery outcome in type I and type II diabetes.

BACKGROUND: Pregestational diabetes mellitus (PGDM) confers an increased risk of adverse maternal and neonatal outcomes [1,2]. Glycaemic control in the medium and long term is commonly evaluated by examining glycosylated haemoglobin (HbA1c) levels. However, the value of HbA1c in pregnancy may be diminished by increased level of red cell turnover characteristic of pregnancy [3,4]. We sought to examine the impact of HbA1c in the first trimester and pre-delivery, and the within-patient change throughout gestation on mode of delivery and birthweight in pregnancies complicated by a pre-pregnancy diagnosis of type I or type II diabetes. METHODS: A 10-year consecutive cohort of pregnancies complicated by PGDM, from Jan 2010 until Dec 2019, was examined for HbA1c data in the first trimester and within 6 weeks of delivery. Perinatal outcome data, including gestational age at delivery, mode of delivery and birthweight centile, were obtained from hospital records. The Spearman Rank correlation was used to correlate HcA1c levels in the first trimester with birthweight centiles. Non-parametric summaries and rank-based tests, Signed-rank test and Kruskal-Wallis test, were used to compare Hba1c levels. RESULTS: During the 10-year study period, a consecutive cohort of 396 pregnancies that attained a viable gestational age (>24 weeks' gestation) and complicated by pregestational diabetes was identified; representing 81 % of the population of pregestational diabetic pregnancies managed by this service during the study period. The median [IQR] HbA1c levels (mmol/mol) in the first trimester, pre-delivery and the differential across gestation were 51 [19] mmol/mol, 43 [11] mmol/mol and -8 [13] mmol/mol, respectively. A statistically significant reduction in HbA1c levels throughout gestation was observed (p < 0.001). The median [IQR] birthweight centile was 69 [50 - 96]. The distributions in HbA1c levels and birthweight centiles were heavily skewed. No correlation was identified between HbA1c levels and mode of delivery. CONCLUSION: Neither baseline HbA1c levels, pre-delivery values, nor trends across gestation appear to impact birthweight centile or mode of delivery in PGDM. While optimising glycaemic control can affect the long term health of the mother, these indices cannot be relied upon to reflect the impact of glycaemic control on fetal growth aberrations that influence mode of delivery.

Effect of maternal pregestational diabetes mellitus on congenital heart diseases.

BACKGROUND: The increasing population of diabetes mellitus in adolescent girls and women of childbearing age contributes to a large number of pregnancies with maternal pregestational diabetes mellitus. Congenital heart diseases are a common adverse outcome in mothers with pregestational diabetes mellitus. However, there is little systematic information between maternal pregestational diabetes mellitus and congenital heart diseases in the offspring. DATA SOURCES: Literature selection was performed in PubMed. One hundred and seven papers were cited in our review, including 36 clinical studies, 26 experimental studies, 31 reviews, eight meta-analysis articles, and six of other types. RESULTS: Maternal pregestational diabetes mellitus poses a high risk of congenital heart diseases in the offspring and causes variety of phenotypes of congenital heart diseases. Factors such as persistent maternal hyperglycemia, oxidative stress, polymorphism of uncoupling protein 2, polymorphism of adiponectin gene, Notch 1 pathway, Nkx2.5 disorders, dysregulation of the hypoxia-inducible factor 1, and viral etiologies are associated with the occurrence of congenital heart diseases in the offspring of mothers with pregestational diabetes mellitus. Treatment options including blood sugar-reducing, anti-oxidative stress drug supplements and exercise can help to prevent maternal pregestational diabetes mellitus from inducing congenital heart diseases. CONCLUSIONS: Our review contributes to a better understanding of the association between maternal pregestational diabetes mellitus and congenital heart diseases in the offspring and to a profound thought of the mechanism, preventive and therapeutic measurements of congenital heart diseases caused by maternal pregestational diabetes mellitus.