The WAIT Trial: Waiting Versus Active Induction at Term in Women With A1 Gestational Diabetes Mellitus

（A）Study Title The WAIT trial: Induction of Labor at 40 Weeks versus Expectant Management until 41 Weeks in Women with A1 Gestational Diabetes Mellitus: A Multicenter, Open-Label, Superiority Randomized Controlled Trial.

（B）Background and Rationale Gestational diabetes mellitus (GDM) is increasingly common, affecting approximately 12-18% of pregnancies. Hyperglycemia may increase risks for both mothers and infants, including vascular dysfunction, hypertensive disorders, infections, postpartum hemorrhage, polyhydramnios, fetal macrosomia, congenital anomalies, and stillbirth. GDM is also associated with long-term metabolic consequences, including persistent insulin resistance and impaired β-cell function, which increase the risk of type 2 diabetes after pregnancy.

Although induction of labor may affect maternal and neonatal outcomes, the optimal timing of delivery in women with A1 GDM remains uncertain, and recommendations in guidelines are inconsistent. Chinese guidelines recommend induction at 40-41 weeks; however, the evidence level for this recommendation is C. Studies on the timing of induction in GDM are mostly observational, and their findings are heterogeneous. Notably, randomized controlled trial evidence specifically in women with A1 GDM comparing planned induction at 40 weeks with induction after expectant management until 41 weeks is currently limited.

In China, cesarean delivery rates remain high. Reducing unnecessary cesarean delivery is important for public health, but any change in timing must be weighed against maternal and neonatal safety. Therefore, this trial primarily uses the cesarean delivery rate as the primary outcome, and also evaluates maternal and neonatal safety outcomes and health-economic impacts to assess net clinical benefit.

（C）Objectives Primary objective: To determine whether planned induction at 41 weeks (after expectant management from 40 weeks) reduces the cesarean delivery rate compared with planned induction at 40 weeks in women with A1 GDM.

Secondary objectives: To compare safety outcomes for mothers and neonates, and to evaluate health-economic outcomes and prespecified subgroup effects.

（D）Study Design and Setting Design: multicenter, open-label, superiority randomized controlled trial. Centers: 3 hospitals in China. Masking: open-label for participants and clinicians; adjudication of the primary outcome is performed with independent assessment. Statistical analysis is conducted without knowledge of group allocation.

（E）Study Population Women with A1 GDM, singleton pregnancy, and primarily planned vaginal delivery will be screened and recruited. For inclusion and exclusion criteria, please refer to the Eligibility module. All inclusion and exclusion criteria of this study are implemented in accordance with current obstetric clinical guidelines.

（F）Recruitment, Screening, Randomization, and Follow-up Pre-screening window: 37+0 to 39+5 weeks. Formal screening window: 38+0 to 39+5 weeks. Randomization window: 39+0 to 39+5 weeks. Randomization should be performed after eligibility is confirmed; if there is a time gap, eligibility will be re-verified via outpatient visit, telephone follow-up or medical record review to rule out new onset labor, prelabor rupture of membranes or other new delivery indications before randomization.

Randomization adopts a dynamic block randomization method, stratified by study center with a 1:1 allocation ratio between groups; random block sizes of 4, 6, and 8 are mixed randomly throughout the recruitment period. If only two allocations remain in the randomization sequence, a special block size of 2 will be used to preserve the 1:1 allocation ratio.

Randomization is performed within a centralized, password-protected REDCap system; randomization sequences are generated by independent experts using SAS/R software.

Allocation concealment is ensured until randomization is executed by the authorized research team via secure access.

Although the trial is open-label, statistical analysis will be conducted by personnel blinded to group allocation.

（G）Intervention Strategies Control Group: Planned Induction at 39+6 to 40+0 Weeks. From admission to induction, participants will undergo standardized maternal-fetal monitoring including physical examinations, electronic fetal heart rate monitoring, Bishop scoring, and obstetric ultrasound (if applicable). Induction is performed according to the Bishop score. Cervical ripening and induction procedures are standardized across centers. Safety management includes predefined criteria to pause or stop induction. If labor does not occur after failure criteria are met (e.g., after appropriate oxytocin induction post membrane rupture), delivery will proceed according to clinical judgment, including possible cesarean delivery.

Intervention Group: Expectant Management until 41 Weeks (Planned Induction at 41+0 to 41+1 Weeks).

The intervention group follows the same induction and monitoring procedures as the control group once planned induction time is reached, but the planned induction window is delayed until 41+0 to 41+1 weeks. If spontaneous labor occurs before or within the planned window, routine obstetric management will be used rather than delaying further.

（H）Premature/Emergency Termination Criteria Participants will undergo earlier or emergency delivery if clinicians determine that ongoing pregnancy is unsafe for mother or fetus. Predefined termination indications include: Spontaneous labor, Prelabor rupture of membranes, Oligohydramnios, Abnormal fetal monitoring/fetal movement reduction, Maternal comorbidities or pregnancy complications requiring termination, and Other medical indications.

All reasons for early/emergency termination are documented in the case report form or the electronic data capture system.

（I）Monitoring and Data Collection In general, both groups use standardized clinical routine monitoring medical record forms throughout the study to document all examination results and clinical manifestations. During spontaneous labor or labor induction, continuous electronic fetal heart rate monitoring will be performed only when clinically indicated. Uterine contractions are recorded hourly, maternal vital signs are monitored periodically, and changes in the Bishop score are dynamically assessed. Medication information is documented in detail. All abnormal findings shall be recorded promptly and reported to the study investigator. All monitoring and interventions will follow clinical standard operating procedures to ensure standardized study conduct and reliable data.

Participants will be followed from randomization until discharge after delivery, with selected outcomes followed up to 42 days postpartum. The vast majority of data are collected and organized via standardized electronic medical record forms. Patient-reported information including maternal satisfaction, perceived control during childbirth, and postpartum depression will be collected using separate questionnaires or validated scales. All data will be securely stored in the case report form, the electronic data capture system, or the hospital's health information system.

（J）Outcomes

1. Primary Outcome The primary outcome is the cesarean delivery rate.
2. Secondary Outcomes 2.1 Key Secondary Outcomes Key secondary outcomes include postpartum hemorrhage volume, macrosomia rate, perinatal mortality, and neonatal respiratory support.

2.2 Other Secondary Outcomes Other secondary maternal outcomes include cervical ripening rate, cervical ripening methods, induction of labor rate, cesarean delivery rate among participants undergoing induction of labor, intrapartum cesarean delivery rate, instrumental vaginal delivery rate, episiotomy rate, maternal cardiac or respiratory arrest, new-onset hypertensive disorders of pregnancy, birth canal trauma, uterine scar dehiscence or rupture, visceral organ injury, rate of postpartum hemorrhage ≥500 mL, hysterectomy for delivery-related complications, maternal intensive care unit admission, total maternal hospital stay, antenatal hospital stay, postpartum hospital stay, time spent in the labor or delivery unit, time from randomization to delivery, total duration of labor, duration of the second stage of labor, time from induction to onset of labor, time from induction to delivery, gestational age at delivery, maternal death, chorioamnionitis, puerperal infection, shoulder dystocia, pulmonary embolism, stroke, uterine tachysystole, other intrapartum complications, childbirth satisfaction, sense of control during labor, childbirth pain score, postpartum depression, and postpartum feeding method.

Other secondary fetal/neonatal outcomes include birth weight, fetal distress, neonatal respiratory distress syndrome, neonatal ward admission, neonatal length of hospital stay, birth trauma, intracranial or subgaleal hemorrhage, hypoxic-ischemic encephalopathy, including cases requiring therapeutic hypothermia, meconium aspiration syndrome, umbilical artery blood pH, 1-minute, 5-minute and 10-minute Apgar scores and 5-minute Apgar score ≤3, neonatal asphyxia, duration of respiratory support, neonatal infection, neonatal hyperbilirubinemia requiring phototherapy or exchange transfusion, neonatal hypoglycemia, neonatal seizures, congenital anomalies, neonatal blood transfusion excluding exchange transfusion for hyperbilirubinemia, and neonatal hypotension requiring vasopressor support.

Health economic outcomes include investigation and collection of direct medical costs, including average daily hospitalization cost, total hospitalization cost, and incremental cost-effectiveness ratios (ICERs).

（K）Sample Size Based on data from three centers, with a control-group cesarean delivery rate of 33.0% and a conservative absolute risk reduction of 8% for the delayed induction strategy, the sample-size calculation for this superiority design uses a significance level α=0.025 (one-sided) and power 1-β=0.90.

Accounting for center heterogeneity and expected loss/withdrawal (increase of 10%), the total planned enrollment is 1,500 participants (750 per group).

（L）Statistical Analysis Primary analysis set: Intention-to-Treat (ITT) - includes all randomized participants analyzed according to assigned group.

Sensitivity analysis set: Per-Protocol (PP) - includes participants who meet key criteria and without major protocol deviations that substantially affect interpretation.

Baseline characteristics and clinical outcomes will be summarized by group. Missing data will be handled using multiple imputation, with sensitivity analyses reported.

Primary outcome analysis: This trial adopts a superiority design. Null hypothesis: PT-PC≥0; Alternative hypothesis: PT-PC<0, where PT and PC denote the cesarean delivery rates in the experimental group and control group, respectively. The between-group risk difference (experimental minus control) and its 95% confidence interval will be calculated at a one-sided α of 0.025. Superiority will be established if the upper bound of the 95% confidence interval for the risk difference is less than 0.

One interim analysis will be conducted upon reaching 50% of primary endpoints (750 randomized participants), applying the O'Brien-Fleming spending function for type-I error control. Nominal one-sided α1=0.0027 for interim analysis and nominal one-sided α2=0.0296 for final analysis. Decision rules for continuing, adjusting sample-size or early-stopping for futility are predefined in the Statistical Analysis Plan (SAP) and DSMB charter.

The specific statistical analysis procedures and multiplicity adjustment methods for key secondary outcomes are detailed in the SAP; other outcomes will be treated as exploratory.

All analyses will be performed using SAS/R. Statistical significance is assessed at the prespecified alpha level; unless otherwise stated, two-sided tests will be used with P<0.05.

（M）Safety Oversight and Quality Control A Trial Management Committee (TMC) oversees day-to-day conduct and data quality.

A Data and Safety Monitoring Board (DSMB) independently reviews safety, efficacy, data quality, and adverse event signals, and can recommend protocol modifications, pausing enrollment, sample size adjustment, or early termination based on predefined stopping rules specified in the DSMB charter, including pre-defined safety stopping thresholds for perinatal adverse events.

A Clinical Endpoint Committee (CEC) independently and blindedly adjudicates the primary outcome, especially cesarean delivery indications and other pre-specified clinical outcomes.

（N）Study Duration and Expected Completion Recruitment and intervention/follow-up are planned from 2026 to 2028, with final data analysis, reporting, and dissemination completed by the end of the study period. The overall timeline is designed to complete the study within approximately 18 months from the main operational start, and to provide evidence on the optimal induction timing strategy for A1 GDM.