Comparative effectiveness trial of metformin versus insulin for the treatment of gestational diabetes in the USA: clinical trial protocol for the multicentre DECIDE study.

INTRODUCTION: Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy. Glycaemic control decreases the risk of adverse pregnancy outcomes for the affected pregnant individual and the infant exposed in utero. One in four individuals with GDM will require pharmacotherapy to achieve glycaemic control. Injectable insulin has been the mainstay of pharmacotherapy. Oral metformin is an alternative option increasingly used in clinical practice. Both insulin and metformin reduce the risk of adverse pregnancy outcomes, but comparative effectiveness data from a well-characterised, adequately powered study of a diverse US population remain lacking. Because metformin crosses the placenta, long-term safety data, in particular, the risk of childhood obesity, from exposed children are also needed. In addition, the patient-reported experiences of individuals with GDM requiring pharmacotherapy remain to be characterised, including barriers to and facilitators of metformin versus insulin use. METHODS AND ANALYSIS: In a two-arm open-label, pragmatic comparative effectiveness randomised controlled trial, we will determine if metformin is not inferior to insulin in reducing adverse pregnancy outcomes, is comparably safe for exposed individuals and children, and if patient-reported factors, including facilitators of and barriers to use, differ between metformin and insulin. We plan to recruit 1572 pregnant individuals with GDM who need pharmacotherapy at 20 US sites using consistent diagnostic and treatment criteria for oral metformin versus injectable insulin and follow them and their children through delivery to 2 years post partum. More information is available at www.decidestudy.org. ETHICS AND DISSEMINATION: The Institutional Review Board at The Ohio State University approved this study (IRB: 2024H0193; date: 7 December 2024). We plan to submit manuscripts describing the results of each study aim, including the pregnancy outcomes, the 2-year follow-up outcomes, and mixed-methods assessment of patient experiences for publication in peer-reviewed journals and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: NCT06445946.

Pregnancy Outcomes in Patients With Hepatitis C Virus Infection.

OBJECTIVE: To evaluate the risks of adverse maternal and neonatal outcomes associated with pregnancies complicated by hepatitis C virus (HCV) infection. METHODS: This is a secondary analysis of a multicenter prospective cohort study of HCV infection in pregnancy. Participants were screened for HCV infection with serum antibody tests, and each participant with a positive HCV result (case group) was matched with up to two individuals with negative HCV results (control group) prospectively by gestational age (±2 weeks) at enrollment. Maternal outcomes included gestational diabetes, abruption, preeclampsia or gestational hypertension, cholestasis, and preterm delivery. Neonatal outcomes included hyperbilirubinemia, admission to neonatal intensive care (NICU); small-for-gestational-age (SGA) birth weight; and neonatal infection , defined as sepsis or pneumonia. Models were adjusted for maternal age, body mass index, injection drug use, and maternal medical comorbidities. RESULTS: The 249 individuals in the case group were prospectively matched to 486 individuals in the control group who met eligibility criteria. There were significant differences in demographic characteristics between the groups, including race, socioeconomic markers, education, insurance status, and drug and tobacco use. The frequencies of maternal outcomes of gestational diabetes, preeclampsia, and abruption were similar between the case and control groups. Preterm birth was similar between groups, but neonates born to individuals in the case group were more likely to be admitted to the NICU (45.1% vs 19.0%, adjusted odds ratio [aOR] 2.6, 95% CI, 1.8-3.8) and to have SGA birth weights below the 5th percentile (10.6% vs 3.1%, aOR 2.9, 95% CI, 1.4-6.0). There were no increased odds of hyperbilirubinemia or neonatal infection. CONCLUSION: Despite no increased odds of preterm birth or other adverse maternal outcomes in adjusted analyses, maternal HCV infection was associated with twofold increased odds of NICU admission and nearly threefold increased odds of SGA birth weight below the 5th percentile.

Optimizing Opioid Prescription Quantity After Cesarean Delivery: A Randomized Controlled Trial.

OBJECTIVE: To test whether an individualized opioid-prescription protocol (IOPP) with a shared decision-making component can be used without compromising postcesarean pain management. METHODS: In this multicenter randomized controlled noninferiority trial, we compared IOPP with shared decision making with a fixed quantity of opioid tablets at hospital discharge. We recruited at 31 centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Study participants had uncomplicated cesarean births. Follow-up occurred through 12 weeks postdischarge. Individuals with complicated cesarean births or history of opioid use in the pregnancy were excluded. Participants were randomized 1:1 to IOPP with shared decision making or fixed quantity (20 tablets of 5 mg oxycodone). In the IOPP group, we calculated recommended tablet quantity based on opioid use in the 24 hours before discharge. After an educational module and shared decision making, participants selected a quantity of discharge tablets (up to 20). The primary outcome was moderate to severe pain (score 4 or higher [possible range 0-10]) on the BPI (Brief Pain Inventory) at 1 week after discharge. A total sample size of 5,500 participants was planned to assess whether IOPP with shared decision making was not inferior to the fixed quantity of 20 tablets. RESULTS: From September 2020 to March 2022, 18,990 individuals were screened and 5,521 were enrolled (n=2,748 IOPP group, n=2,773 fixed-quantity group). For the primary outcome, IOPP with shared decision making was not inferior to fixed quantity (59.5% vs 60.1%, risk difference 0.67%; 95% CI, -2.03% to 3.37%, noninferiority margin -5.0) and resulted in significantly fewer tablets received (median 14 [interquartile range 4-20] vs 20, P <.001) through 90 days postpartum. CONCLUSION: Compared with fixed quantity, IOPP with shared decision making was noninferior for outpatient postcesarean analgesia at 1 week postdischarge and resulted in fewer prescribed opioid tablets at discharge. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04296396.

Randomized Trial of Assisted Hybrid Closed-Loop Therapy Versus Sensor-Augmented Pump Therapy in Pregnancy.

Objective: Examine gestational safety, glycemic and health outcomes, of a hybrid closed-loop (HCL) system without pregnancy-specific glucose targets. Research Design: This was a pilot feasibility investigator-initiated, two-site, single-blind, randomized controlled trial of sensor-augmented pump therapy (SAPT) versus HCL therapy in type 1 diabetes pregnancies. Participants were enrolled in the first trimester and randomized at 14-18 weeks of gestation and used SAPT or HCL until 4-6 weeks postpartum. We compared continuous glucose monitoring (CGM) metrics, severe hypoglycemia (SH), diabetic ketoacidosis (DKA), adverse skin reactions, and pregnancy outcomes between groups. Results: Baseline characteristics were similar between groups (n = 11 HCL and n = 12 SAPT). There was no SH or DKA episode after randomization. Time spent <54 mg/dL did not differ between groups. Time spent <63 mg/dL decreased in both groups, significantly in the HCL group (3.5% [1.3% standard error] second trimester and 2.8% [1.3%] third trimester vs. 7.9% [1.3%] run-in phase, P < 0.05 for both). Mean sensor glucose was lower with SAPT compared to HCL therapy in the third trimester (119 [4] mg/dL SAPT vs. 132 [4] mg/dL HCL, P < 0.05). Third trimester time-in-range (TIR; 63-140 mg/dL) increased with SAPT (68.2% [3.1%] vs. 64.3% [3.1%] run-in phase, P < 0.05). Gestational health outcomes did not differ between groups. The HCL group used assistive techniques, such as fake carbohydrate boluses and exiting HCL overnight. Conclusions: CGM within group differences were seen for time <63 mg/dL favoring HCL therapy and TIR favoring SAPT (third trimester vs. baseline). Safety and adverse pregnancy outcomes were similar between groups.

Patient Priorities, Decisional Comfort, and Satisfaction with Metformin versus Insulin for the Treatment of Gestational Diabetes Mellitus.

OBJECTIVE: We compared patient priorities, decisional comfort, and satisfaction with treating gestational diabetes mellitus (GDM) with metformin versus insulin among pregnant individuals with GDM requiring pharmacotherapy. STUDY DESIGN: We conducted a cross-sectional study of patients' perspectives about GDM pharmacotherapy in an integrated prenatal and diabetes care program from October 19, 2022, to August 24, 2023. The exposure was metformin versus insulin as the initial medication decision. Outcomes included standardized measures of patient priorities, decisional comfort, and satisfaction about their medication decision. RESULTS: Among 144 assessed individuals, 60.4% were prescribed metformin and 39.6% were prescribed insulin. Minoritized individuals were more likely to receive metformin compared with non-Hispanic White individuals (34.9 vs. 17.5%; p = 0.03). Individuals who were willing to participate in a GDM pharmacotherapy clinical trial were more likely to receive insulin than those who were unwilling (30.4 vs. 19.5%; p = 0.02). Individuals receiving metformin were more likely to report prioritizing avoiding injections (62.4 vs. 19.3%; adjusted odds ratio [aOR]: 2.83; 95% confidence interval [CI]: 1.10-7.31), wanting to take a medication no more than twice daily (56.0 vs. 30.4%; aOR: 3.67; 95% CI: 1.56-8.67), and believing that both medications can equally prevent adverse pregnancy outcomes (70.9 vs. 52.6%; aOR: 2.67; 95% CI: 1.19-6.03). Conversely, they were less likely to report prioritizing a medication that crosses the placenta (39.1 vs. 82.5%; aOR: 0.09; 95% CI: 0.03-0.25) and needing supplemental insulin to achieve glycemic control (21.2 vs. 47.4%; aOR: 0.36; 95% CI: 0.15-0.90). Individuals reported similarly high (mean score > 80%) levels of decisional comfort, personal satisfaction with medication decision-making, and satisfaction about their conversation with their provider about their medication decision with metformin and insulin (p ≥ 0.05 for all). CONCLUSION: Individuals with GDM requiring pharmacotherapy reported high levels of decision comfort and satisfaction with both metformin and insulin, although they expressed different priorities in medication decision-making. These results can inform future patient-centered GDM treatment strategies. KEY POINTS: · Pregnant individuals with GDM requiring pharmacotherapy expressed a high level of decisional comfort and satisfaction with medication decision making.. · Individuals placed different priorities on deciding to take metformin versus insulin.. · These results can inform interventions aimed at delivering person-centered diabetes care in pregnancy that integrates patient autonomy and knowledge about treatment options..

Risk Factors for Perinatal Transmission of Hepatitis C Virus.

OBJECTIVE: To estimate the rate of perinatal transmission of hepatitis C virus (HCV) infection, to identify risk factors for perinatal transmission of HCV infection, and to determine the viremic threshold for perinatal transmission. METHODS: This was a prospective, multicenter, observational study of pregnant individuals at less than 24 weeks of gestation screened for HCV infection from 2012 to 2018 in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Individuals found to be HCV antibody-positive were followed throughout pregnancy. Children were followed for evidence of perinatal transmission at 2-6 months (HCV RNA testing) and at 18-24 months (HCV RNA and antibody testing) of life. The primary outcome was perinatal transmission, defined as positive test results at either follow-up time point. RESULTS: A total of 109,379 individuals were screened for HCV infection. Of the 1,224 participants who screened positive, 772 (63.1%) enrolled and 432 of those 772 (56.0%) had data available to assess primary outcome. The overall rate of perinatal transmission was 6.0% (26/432, 95% CI 4.0-8.7%). All children with HCV infection were born to individuals with demonstrable viremia. In viremic participants (n=314), the perinatal transmission rate was 8.0% (95% CI 5.2-11.5%). Risk factors for perinatal transmission included HCV RNA greater than 106 international units/mL (adjusted odds ratio [aOR] 8.22, 95% CI 3.16-21.4) and vaginal bleeding reported at any time before delivery (aOR 3.26, 95% CI 1.32-8.03). A viremic threshold for perinatal transmission could not be established. CONCLUSION: Perinatal transmission of HCV infection was limited to viremic individuals. High viral loads and antepartum bleeding were associated with perinatal transmission.

Multicomponent provider-patient intervention to improve glycaemic control in Medicaid-insured pregnant individuals with type 2 diabetes: clinical trial protocol for the ACHIEVE study.

INTRODUCTION: Type 2 diabetes (T2D) is one of the most frequent comorbid medical conditions in pregnancy. Glycaemic control decreases the risk of adverse pregnancy outcomes for the pregnant individual and infant. Achieving glycaemic control can be challenging for Medicaid-insured pregnant individuals who experience a high burden of unmet social needs. Multifaceted provider-patient-based approaches are needed to improve glycaemic control in this high-risk pregnant population. Mobile health (mHealth) applications (app), provider dashboards, continuous glucose monitoring (CGM) and addressing social needs have been independently associated with improved glycaemic control in non-pregnant individuals living with diabetes. The combined effect of these interventions on glycaemic control among pregnant individuals with T2D remains to be evaluated. METHODS AND ANALYSIS: In a two-arm randomised controlled trial, we will examine the combined effects of a multicomponent provider-patient intervention, including a patient mHealth app, provider dashboard, CGM, a community health worker to address non-medical health-related social needs and team-based care versus the current standard of diabetes and prenatal care. We will recruit 124 Medicaid-insured pregnant individuals living with T2D, who are ≤20 weeks of gestation with poor glycaemic control measured as a haemoglobin A1c ≥ 6.5% assessed within 12 weeks of trial randomisation or within 12 weeks of enrolling in prenatal care from an integrated diabetes and prenatal care programme at a tertiary care academic health system located in the Midwestern USA. We will measure how many individuals achieve the primary outcome of glycaemic control measured as an A1c<6.5% by the time of delivery, and secondarily, adverse pregnancy outcomes; patient-reported outcomes (eg, health and technology engagement, literacy and comprehension; provider-patient communication; diabetes self-efficacy; distress, knowledge and beliefs; social needs referrals and utilisation; medication adherence) and CGM measures of glycaemic control (in the intervention group). ETHICS AND DISSEMINATION: The Institutional Review Board at The Ohio State University approved this study (IRB: 2022H0399; date: 3 June 2023). We plan to submit manuscripts describing the user-designed methods and will submit the results of the trial for publication in peer-reviewed journals and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: NCT05662462.

Association between social vulnerability and influenza and tetanus-diphtheria-acellular pertussis vaccination in pregnant and postpartum individuals.

BACKGROUND: Despite current guidelines recommending universal vaccination, the frequency of vaccination in pregnancy for influenza and tetanus-diphtheria-acellular pertussis remains low. OBJECTIVE: This study aimed to evaluate the association between community-level social vulnerability and influenza and anticipated tetanus-diphtheria-acellular pertussis vaccinations among pregnant and postpartum individuals. STUDY DESIGN: We conducted a cross-sectional survey of vaccine hesitancy in the peripartum period among pregnant and postpartum participants enrolled in prenatal care at a single tertiary care center from March 22, 2021, to April 02, 2021. Participant addresses were geocoded using ArcGIS and linked at the census tract level. The primary exposure was community-level social vulnerability as measured by the US Centers for Disease Control and Prevention's Social Vulnerability Index. This index incorporates 15 census variables to produce a composite score and subscores across 4 major thematic domains (socioeconomic status, household composition and disability, minority status and language, and housing type and transportation). The scores range from 0 to 1, with higher values indicating greater social vulnerability. The primary outcomes were self-reported influenza vaccination during the current influenza season and having received or planning to receive the tetanus-diphtheria-acellular pertussis vaccination in pregnancy. We used multivariable logistic regression and adjusted for age, self-reported race and ethnicity, parity, trimester of pregnancy, and chronic comorbid conditions. RESULTS: Of 456 assessed individuals (95% pregnant individuals and 5% postpartum individuals), the frequency of influenza vaccination was 58% (95% confidence interval, 53-62), and the anticipated tetanus-diphtheria-acellular pertussis vaccination was 72% (95% confidence interval, 68-76). Individuals from communities with a higher Social Vulnerability Index were less likely to report vaccination in pregnancy than those from communities with a lower Social Vulnerability Index. Specifically, for each 0.1-unit increase in the Social Vulnerability Index, the odds of influenza vaccination (adjusted odds ratio, 0.23; 95% confidence interval, 0.11-0.46) and anticipated tetanus-diphtheria-acellular pertussis vaccination (adjusted odds ratio, 0.24; 95% confidence interval, 0.11-0.53) decreased by >70%. By domain, the Social Vulnerability Index subscores of socioeconomic status (influenza adjusted odds ratio, 0.20 [95% confidence interval, 0.10-0.40]; tetanus-diphtheria-acellular pertussis adjusted odds ratio, 0.25 [95% confidence interval, 0.12-0.53]) and housing type and transportation (influenza adjusted odds ratio, 0.41 [95% confidence interval, 0.19-0.84; tetanus-diphtheria-acellular pertussis adjusted odds ratio, 0.39 [95% confidence interval, 0.18-0.87) were inversely associated with a lower odds of influenza and tetanus-diphtheria-acellular pertussis vaccinations. CONCLUSION: Pregnant and postpartum individuals living in areas with higher social vulnerability were less likely to report influenza and anticipated tetanus-diphtheria-acellular pertussis vaccinations in pregnancy. The Social Vulnerability Index could be used as a tool to improve vaccine equity and address disparities in vaccination in pregnancy.

Characteristics Associated With Consent and Reasons for Declining in a Randomized Trial in Pregnancy.

OBJECTIVE: To evaluate the maternal characteristics associated with consent to a randomized trial of labor induction in pregnancy. METHODS: This is a secondary analysis of low-risk nulliparous women randomized to induction of labor at 39 weeks or expectant management. During the trial, the Data and Safety Monitoring Committee requested additional fields on the screening log, which already included race and ethnicity: maternal age, type of insurance, and the reason for declining consent if declined. RESULTS: From August 2016 (start of additional data collection) to August 2017, 1,965 (28%) of the 7,112 eligible women consented to the trial. Consent was more likely for Black women (41%, adjusted odds ratio [aOR] 1.47, 95% CI 1.24-1.74), and less likely for Asian women (15%, aOR 0.64, 95% CI 0.48-0.84), compared with White women (24%). Women without private insurance were more likely to consent (38%, aOR 1.55, 95% CI 1.34-1.79), compared with those with private insurance (22%). Younger women were also more likely to consent. Among eligible women who declined participation and provided a reason (68%), preference to be expectantly managed (85%) was most common, a response more common in Asian women (aOR 1.75, 95% CI 1.31-2.33) and less common in women without private insurance (aOR 0.60, 95% CI 0.51-0.70). Not wanting to participate in research was more common in Asian women (aOR 2.41, 95% CI 1.44-4.03). Declining consent because family or friends objected was more common in Asian women (aOR 2.51, 95% CI 1.27-4.95) and women without private insurance (aOR 1.68, 95% CI 1.10-2.59). CONCLUSION: Frequency of consent and reasons for declining consent were associated with age, type of insurance, and race and ethnicity. These findings should be considered when developing recruitment strategies that promote diverse participant representation. CLINICAL TRIAL REGISTRATION: ClinialTrials.gov, NCT01990612.

Acute Glucose Load, Inflammation, Oxidative Stress, Nonenzymatic Glycation, and Screening for Gestational Diabetes.

AIMS: To investigate if oral glucose tolerance test (OGTT) associates with changes in maternal symptoms (ie, flushing, sweating), blood nonenzymatic advanced glycation end products (AGE), acute-phase reactive inflammatory markers, and oxidative stress. METHODS: Prospective case-control study of patients screened for gestational diabetes mellitus (GDM). One hundred nonfasting, second-trimester consecutive pregnant women allocated to either 50 g OGTT or water. Five women who had a 3-hour fasting 100 g OGTT also enrolled. Maternal serum glucose, AGE, soluble receptor for AGE (sRAGE), interleukin (IL)-6, and C-reactive protein (CRP) were immunoassayed. Total radical-trapping antioxidant parameter (TRAP) estimated with antioxidant capacityperoxyl assay. Data corrected for gestational age and maternal body mass index. RESULTS: During 50 g OGTT there was a decrease in systolic blood pressure not accompanied by the onset of adverse clinical symptoms. There was a decrease in serum glucose levels 1 hour after water (P = .019) but not glucose ingestion. Serum CRP (P = .001) but not IL-6 was increased. The AGE, sRAGE, and TRAP levels remained unchanged. Similar results were seen during 100 g OGTT, except serum glucose was significantly elevated after 1 hour. CONCLUSION: Results suggest screening tools for gestational diabetes are safe and clinically well tolerated during pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03029546.

Acute Glucose Load, Inflammation, Oxidative Stress, Nonenzymatic Glycation, and Screening for Gestational Diabetes.

AIMS:: To investigate if oral glucose tolerance test (OGTT) associates with changes in maternal symptoms (ie, flushing, sweating), blood nonenzymatic advanced glycation end products (AGE), acute-phase reactive inflammatory markers, and oxidative stress. METHODS:: Prospective case-control study of patients screened for gestational diabetes mellitus (GDM). One hundred nonfasting, second-trimester consecutive pregnant women allocated to either 50 g OGTT or water. Five women who had a 3-hour fasting 100 g OGTT also enrolled. Maternal serum glucose, AGE, soluble receptor for AGE (sRAGE), interleukin (IL)-6, and C-reactive protein (CRP) were immunoassayed. Total radical-trapping antioxidant parameter (TRAP) estimated with antioxidant capacity-peroxyl assay. Data corrected for gestational age and maternal body mass index. RESULTS:: During 50 g OGTT there was a decrease in systolic blood pressure not accompanied by the onset of adverse clinical symptoms. There was a decrease in serum glucose levels 1 hour after water ( P = .019) but not glucose ingestion. Serum CRP ( P = .001) but not IL-6 was increased. The AGE, sRAGE, and TRAP levels remained unchanged. Similar results were seen during 100 g OGTT, except serum glucose was significantly elevated after 1 hour. CONCLUSION:: Results suggest screening tools for gestational diabetes are safe and clinically well tolerated during pregnancy. Clinical Trial Registration: ClinicalTrials.gov NCT03029546.