Labor Induction in Low-risk Women at 39 Weeks of Gestation: A Randomized Trial in China
Phase: NA
Conditions: Cesarean Delivery
Sponsor: Women's Hospital School Of Medicine Zhejiang University

 
Labor Induction in Low-risk Women at 39 
Weeks of Gestation: A Randomized Trial in 
China (LIRIC) 
 
 
Protocol 
 
 
 
NCT number: NCT07082530 
Version Date: Jan 4, 2026 
 
 
 

CONTENTS 
1 Background ............................................................................................................................................................. 4 
1.1 Expectant Management Until 41 Weeks is Currently Recommended for Low-risk Pregnancies ......... 4 
1.2 Preliminary Evidence Supports Induction at 39 Weeks for Low-risk Pregnancies ............................... 4 
1.2.1 The ARRIVE Trial: Induction at 39 Weeks Reduces Cesarean Rates ........................................ 4 
1.2.2 Meta-analysis: Induction at 39 Weeks May Improve Maternal and Neonatal Outcomes .......... 4 
1.2.3 Long-term Effects of Induction at 39 Weeks on Offspring ......................................................... 4 
1.2.4 Further Research Needed on Induction at 39 Weeks for Low-risk Pregnancies ........................ 5 
1.3 Balloon Catheters as a Primary Method for Cervical Ripening ............................................................ 5 
1.3.1 RCT Meta-analysis Evidence: Balloon Catheters Are Safer ...................................................... 5 
1.3.2 Early Artificial Rupture of Membranes Combined with Balloon Catheters ............................... 5 
1.4 Rationale for This Study ........................................................................................................................ 5 
1.4.1 Establishing a Cohort Based on the Chinese Population ............................................................ 5 
1.4.2 Exploring Early Biological Changes in Offspring Using Multi-omics ...................................... 5 
1.4.3 Providing Decision-making Evidence for Large-scale RCTs ..................................................... 6 
2 Study Design ............................................................................................................................................................ 7 
2.1 Primary Research Question ................................................................................................................... 7 
2.2 Secondary Research Question ............................................................................................................... 7 
2.3 Design Overview ................................................................................................................................... 7 
2.4 Eligibility Criteria .................................................................................................................................. 7 
2.4.1 Inclusion Criteria ........................................................................................................................ 7 
2.4.2 Gestational Age Determination ................................................................................................... 7 
2.4.3 Exclusion Criteria ....................................................................................................................... 7 
2.5 Informed Consent .................................................................................................................................. 8 
2.6 Randomization and Blinding ................................................................................................................. 8 
3 Study Procedures .................................................................................................................................................... 9 
3.1 Screening and Consent ........................................................................................................................... 9 
3.2 Randomization ....................................................................................................................................... 9 
3.3 Data Collection ...................................................................................................................................... 9 
3.3.1 Maternal Baseline Data ............................................................................................................... 9 
3.3.2 Paternal Baseline Data ................................................................................................................ 9 
3.3.3 Maternal Follow-up Data ............................................................................................................ 9 
3.3.4 Offspring Follow-up Data ........................................................................................................... 9 
3.4 Interventions ........................................................................................................................................ 10 
3.4.1 Intervention Group: Induction at 39 Weeks .............................................................................. 10 
3.4.2 Control Group: Expectant Management or Induction at 41 weeks .......................................... 12 
3.5 Study Management .............................................................................................................................. 12 
3.5.1 Standardized Guidelines for Cesarean Delivery Not Requested by the Participant (22, 23) ... 12 
3.5.2 Guidelines for Intrapartum Antibiotic Use ............................................................................... 14 
3.5.3 Criteria for discontinuing or modifying allocated intervention/comparator ............................. 15 
3.6 Biological Sample Collection .............................................................................................................. 15 
3.6.1 Maternal Samples ..................................................................................................................... 15 
3.6.2 Offspring Samples .................................................................................................................... 15 
3.7 Outcome Measures .............................................................................................................................. 15 

3.7.1 Primary outcome ....................................................................................................................... 15 
3.7.2 Primary Secondary Outcome .................................................................................................... 15 
3.7.3 Maternal Secondary Outcomes ................................................................................................. 16 
3.7.4 Fetal and neonatal secondary outcomes .................................................................................... 17 
3.7.5 Infant early-development outcomes .......................................................................................... 18 
3.7.6 Multi-omics outcomes .............................................................................................................. 18 
3.7.7 Utilization of Medical Resources ............................................................................................. 19 
3.8 Adverse Event Reporting ..................................................................................................................... 19 
4 Statistical Considerations ..................................................................................................................................... 20 
4.1 Calculation of sample size based on the primary outcome .................................................................. 20 
4.2 Interim Analysis ................................................................................................................................... 20 
4.2.1 Interim Analysis Plan ................................................................................................................ 20 
4.2.2 Statistical Methods and Early Termination Criteria .................................................................. 21 
4.2.3 Data and Safety Monitoring Board (DSMB) ............................................................................ 21 
4.3 Data Analysis ....................................................................................................................................... 21 
4.3.1 Baseline Analysis ...................................................................................................................... 22 
4.3.2 Primary Outcome Analysis ....................................................................................................... 22 
4.3.3 Secondary Outcome Analysis ................................................................................................... 22 
4.3.4 Handling of Missing Data ......................................................................................................... 22 
4.3.5 Subgroup Analyses ................................................................................................................... 22 
4.3.6 Multi-omics Outcome Analysis ................................................................................................ 22 
5 Ethical Considerations ......................................................................................................................................... 23 
Reference .................................................................................................................................................................. 24 
 
 

1 Background 
1.1 Expectant Management Until 41 Weeks is Currently Recommended for Low-risk Pregnancies 
Labor induction is a critical component of obstetric clinical management. Globally, the number of labor induction is 
substantial. In 2022–2023, the induction rate in the United States reached 31.9% (1), while in the UK, it was 33.3% 
(2). Although official statistics are unavailable in China, a study covering 96 hospitals revealed that the induction 
rate among nulliparous women was 18.4% in 2015–2016 (3), and this figure is likely increasing as understanding of 
optimal delivery timing improves. 
Gestational duration directly impacts fetal maturity, but prolonged pregnancy may increase perinatal risks for 
both mother and child, including higher perinatal mortality (4). Large-scale, multicenter randomized controlled trials 
(RCTs) have provided evidence-based guidance on the optimal timing of delivery for low-risk pregnancies. The 
INDEX and SWEPIS studies, published in 2019, demonstrated that induction at 41 weeks, compared with expectant 
management until 42 weeks, significantly reduces neonatal mortality and other adverse perinatal outcomes without 
increasing maternal complications (5, 6). 
In 2020, the WHO updated its guidelines on labor induction, recommending induction at 41 weeks of gestation 
(7). China’s latest Guidelines for Cervical Ripening and Labor Induction in Late Pregnancy (2024) align with WHO 
recommendations, advising induction at 41 weeks for low-risk pregnancies. While expectant management until 41 
weeks is widely accepted in clinical practice, the potential benefits of lowering this threshold are under debate, 
prompting ongoing research worldwide to evaluate the risks and benefits of earlier induction. 
1.2 Preliminary Evidence Supports Induction at 39 Weeks for Low-risk Pregnancies 
1.2.1 The ARRIVE Trial: Induction at 39 Weeks Reduces Cesarean Rates 
The ARRIVE trial is the only large-scale RCT to date evaluating induction at 39 weeks, with significant influence 
in obstetrics (8). It included 6,106 low-risk nulliparous women randomized to either induction at 39 weeks or 
expectant management until 41 weeks. After adjusting for covariates, no significant differences were observed in 
the primary outcomes (including perinatal death, respiratory support, low Apgar scores, hypoxic-ischemic 
encephalopathy, seizures, infections, meconium aspiration syndrome, birth trauma, intracranial or subgaleal 
hemorrhage, and hypotension requiring vasopressor support). Secondary outcomes showed that induction at 39 
weeks significantly reduced cesarean rates, self-reported maternal pain during labor, and did not increase other 
adverse outcomes (8). 
Inspired by the ARRIVE trial, the FRENCH-ARRIVE study is currently underway at Bordeaux University 
Hospital, aiming to enroll 4,200 pregnant women, with completion expected by 2027. To date, no large-scale RCT 
has been conducted in Asia on induction at 39 weeks. 
1.2.2 Meta-analysis: Induction at 39 Weeks May Improve Maternal and Neonatal Outcomes 
In 2020, the Cochrane Library updated its review on labor induction at term, with a meta-analysis indicating that 
induction between 37 and 41 weeks reduces perinatal deaths, absolute mortality rates, and cesarean rates. The review 
highlighted the need for future research to focus on long-term child health outcomes (9). In 2023, Hong et al. 
conducted a meta-analysis of 12 retrospective cohort studies, 1 cross-sectional study, and 1 RCT involving 86,555 
pregnant women. The results showed that elective induction at 39 weeks reduced the risks of third- or fourth-degree 
perineal lacerations, macrosomia, and emergency cesarean delivery (10). 
1.2.3 Long-term Effects of Induction at 39 Weeks on Offspring 
Since the publication of the ARRIVE trial, three retrospective cohort studies have examined the long-term effects of 
induction at 39 weeks on offspring. These studies focused on academic performance or teacher-assessed composite 
scores during school-age years, with inconsistent results: two studies reported no significant effects, while one found 

an association between induction and lower academic performance in middle school (11-13). To date, no studies 
have explored the impact of induction at 39 weeks on early childhood growth or other health outcomes. 
1.2.4 Further Research Needed on Induction at 39 Weeks for Low-risk Pregnancies 
Given the limited evidence supporting the safety and potential benefits of induction at 39 weeks for low-risk 
pregnancies, the WHO’s 2020 guidelines adjusted their stance from "not recommending induction" to "not 
recommending routine induction" between 39 and 41 weeks. The WHO noted that in middle- and high-income 
countries, induction at 39 weeks may offer perinatal benefits but requires more evidence to support widespread 
adoption. China’s 2022 Expert Consensus on Timing of Delivery for Pregnancy Complications and Comorbidities 
states that the earliest timing for elective induction or cesarean delivery without medical indication should be 39 
weeks. However, the 2024 Guidelines for Cervical Ripening and Labor Induction in Late Pregnancy emphasize 
balancing the risks of adverse outcomes with potential neonatal complications due to prematurity, recommending 
induction at 39 weeks for suspected macrosomia (Grade 1B). 
1.3 Balloon Catheters as a Primary Method for Cervical Ripening 
In recent years, clinical methods for labor induction have evolved, introducing challenges in directly applying past 
evidence. 
1.3.1 RCT Meta-analysis Evidence: Balloon Catheters Are Safer 
For women requiring induction, if cervical conditions are unfavorable (Bishop score < 6), cervical ripening is 
typically performed before oxytocin induction. Common methods include vaginal prostaglandins and cervical 
balloon catheters. A 2023 meta-analysis by Jones et al. (CPI Collaborative) involving 12 RCTs found that balloon 
catheters significantly reduced composite adverse neonatal outcomes, uterine hyperstimulation, and improved 
neonatal acid-base balance compared to vaginal prostaglandins, demonstrating greater safety (14). 
1.3.2 Early Artificial Rupture of Membranes Combined with Balloon Catheters 
In current clinical practice, balloon catheter induction is often combined with active artificial rupture of membranes 
(ARM). Most prior RCTs did not standardize the use of ARM. A 2024 meta-analysis by Yara et al. compared early 
versus delayed ARM in women undergoing balloon catheter induction, including five trials with 849 participants. 
The results showed that early ARM did not increase cesarean rates, chorioamnionitis, or other adverse perinatal 
outcomes but significantly improved the probability of vaginal delivery within 24 hours (15). 
1.4 Rationale for This Study 
1.4.1 Establishing a Cohort Based on the Chinese Population 
Given existing evidence supporting the perinatal benefits of induction at 39 weeks for low-risk pregnancies, more 
clinicians may consider this approach. However, as the WHO guidelines indicate, broader adoption requires further 
evidence. Currently, the only cohorts studying induction at 39 weeks are the ARRIVE and FRENCH-ARRIVE trials, 
both conducted in Western populations. Research on East Asian populations, including Chinese women, is lacking. 
Notably, elective induction at 39 weeks is already common in Chinese clinical practice, underscoring the urgent need 
for localized studies to establish evidence-based guidelines for this population. 
Additionally, the ARRIVE trial was published seven years ago, with expectant management continuing until 
42 weeks and no strict control over induction methods. Current guidelines recommend terminating expectant 
management at 41 weeks, and induction methods have evolved. Thus, replicating the ARRIVE findings requires an 
optimized study design incorporating the latest guidelines and advancements. 
1.4.2 Exploring Early Biological Changes in Offspring Using Multi-omics 
 

Early-life influences may not immediately manifest as disease. For example, the effects of cesarean delivery on 
offspring health often emerge during childhood or adulthood (16). However, the biological foundations of disease 
may already be present in early life, making precise early detection and intervention critical. 
Advances in omics technologies provide powerful tools for early disease prediction. For instance, infants who 
later develop asthma, autism, or attention deficit disorders exhibit specific metabolic and gut microbiota profiles (17, 
18). Similarly, early differences in umbilical cord blood metabolomics and proteomics may serve as potential 
biomarkers for future diseases. 
Previous induction studies have not collected neonatal or infant biological samples, leaving the long-term 
effects of induction at 39 weeks uncertain. This study will collect early-life biological samples and perform multi-
omics analyses to explore the potential impact of induction at 39 weeks on offspring biology, enabling early 
predictions of long-term health outcomes. 
1.4.3 Providing Decision-making Evidence for Large-scale RCTs 
Comprehensive evaluation of perinatal outcomes requires large sample sizes. However, China lacks prior cohort 
studies on term induction and systematic follow-up data, making large-scale RCTs currently unfeasible. This pilot 
study aims to assess the impact of induction at 39 weeks versus expectant management or induction at 41 weeks on 
cesarean rates in low-risk pregnancies, while evaluating the feasibility of a large-scale RCT and providing decision-
making evidence for future research. 
 
 

2 Study Design 
2.1 Primary Research Question 
For low-risk parturient, can elective induction of labor at 39 weeks reduce the cesarean section rate compared with 
expectant management until 41 weeks? 
2.2 Secondary Research Question 
l 
For low-risk parturient, can elective induction of labor at 39 weeks reduce perinatal maternal risks compared 
with expectant management until 41 weeks? 
l 
Reduce perinatal offspring risks？ 
l 
Affect the early physical and neurodevelopment of offspring? 
l 
Affect the early intestinal flora development and metabolomic changes of offspring? 
l 
Affect the changes in cord blood metabolome and proteome? 
2.3 Design Overview 
This is an open-label, single-center, randomized controlled superiority trial. A total of 1,074 low-risk women will be 
randomized into two groups: 
l 
Intervention group: Induction at 39 weeks 0 days to 39 weeks 4 days. 
l 
Control group: Expectant management until spontaneous labor or induction at 41 weeks. 
2.4 Eligibility Criteria 
2.4.1 Inclusion Criteria 
1. 
Age ≥18 years. 
2. 
Singleton pregnancy or twin pregnancy reduced to singleton before 14 weeks. 
3. 
Gestational age between 38 weeks 4 days or 39 weeks 3 days at randomization. 
4. 
Eligible for vaginal delivery with a desire for vaginal birth. 
5. 
Reliable gestational age determination (confirmed by methods in Section 2.4.2). 
6. 
Maternal and fetal conditions assessed as favorable by at least two senior obstetricians, with no indications 
requiring delivery before 41 weeks. 
7. 
Ability to understand study information and provide informed consent. 
2.4.2 Gestational Age Determination 
Gestational age ("project gestational age") is determined as follows: 
l 
For pregnancies via in vitro fertilization (IVF-ET), gestational age is calculated based on the embryo transfer 
date and embryo age at transfer. 
l 
For natural conceptions (including ovulation induction and intrauterine insemination), gestational age is 
determined by the first-trimester ultrasound estimate and last menstrual period (LMP): 
1. 
If LMP is reliable and regular, and the ultrasound estimate matches (±7 days), LMP is used; otherwise, 
the project gestational age shall be determined based on the crown-rump length (CRL) measured by the 
first-trimester ultrasound scan; 
2. 
If LMP is unreliable, gestational age is determined by the first ultrasound crown-rump length (CRL) 
measurement before 14 weeks 0 days. 
2.4.3 Exclusion Criteria 
1. 
First-trimester ultrasound estimate >13 weeks 6 days. 
2. 
Planned induction before 41 weeks. 
3. 
Planned cesarean delivery or contraindications to vaginal delivery. 

4. 
Already delivered, in labor, or ruptured membranes at enrollment. 
5. 
Placenta previa, vasa previa, placenta accreta, or placental abruption. 
6. 
Contraindications to induction (e.g., cervical cancer, history of uterine rupture, genital tract malformations, 
abnormal fetal position, cord prolapse). 
7. 
Active vaginal bleeding exceeding spotting. 
8. 
History of cesarean delivery or uterine/cervical surgery. 
9. 
Cervical cerclage during this pregnancy. 
10. Maternal conditions not suitable for expectant management beyond 39 weeks (e.g., pregestational diabetes, 
gestational diabetes requiring insulin, hypertensive disorders, intrahepatic cholestasis of pregnancy). 
11. Fetal conditions not suitable for expectant management beyond 39 weeks (e.g., fetal death, major anomalies, 
growth restriction, macrosomia, anemia, oligohydramnios, polyhydramnios). 
12. Maternal infections or positive screenings for sexually transmitted pathogens or group B Streptococcus. 
13. Planned delivery at a non-study facility. 
14. Participation in another intervention study affecting delivery management. 
2.5 Informed Consent 
The informed consent form will be developed based on the template provided by the Ethics Committee of Women’s 
Hospital, Zhejiang University School of Medicine. A signed copy of the consent form will be provided to the patient. 
For non-Chinese-speaking participants, interpreters will assist, and verbal/written consent will be documented. 
This study involves a biological sample collection procedure, and a separate informed consent model will be 
adopted for primary trial participation and biological sample donation. Participants have the right to independently 
decide whether to donate biological samples: 
l 
If a participant only consents to the primary trial but declines to donate biological samples, his/her eligibility 
for trial participation will not be affected, and he/she can be normally enrolled, receive interventions, and 
complete follow-up for outcome assessment as scheduled. 
l 
Only when a participant additionally signs the informed consent form for biological sample donation will his/her 
biological samples be collected and used for subsequent analyses. 
2.6 Randomization and Blinding 
Stratified block randomization (1:1) will be used, with dynamic block sizes (2 or 4), stratified by maternal age (<35/
≥35 years) and parity (nulliparous/parous). An independent statistician will generate the randomization sequence 
using R Studio. Due to clinical practicality, blinding is not feasible; this is an open-label study. 
 
 

3 Study Procedures 
3.1 Screening and Consent 
All singleton pregnant women who have reached 37 weeks and came to our obstetric outpatient clinic are eligible 
for screening. After preliminary medical record review, researchers will introduce this study to potentially eligible 
participants. Upon obtaining consent, researchers will assign a screening number, conduct eligible assessments, and 
confirm the project gestational age. For women who meet the screening criteria, contact information will be retained 
to remind them to attend follow-up visits as scheduled. 
3.2 Randomization 
Prior to randomization, patient eligibility will be reconfirmed. Eligible participants who have provided informed 
consent will undergo randomization via the Electronic Data Capture (EDC) platform by certified researchers between 
38 weeks 4 days and 39 weeks 3 days of gestation. Patients will be randomly assigned to either the intervention 
group or the control group. Once randomization is completed, the allocation will be locked in the EDC system, and 
the result may be communicated to the patient on-site or by phone. 
The randomization sequence will be generated in advance by a third-party company and stored in the EDC 
system. This sequence will not be visible to researchers, healthcare providers, or patients. 
3.3 Data Collection 
3.3.1 Maternal Baseline Data 
The following maternal information will be collected from the hospital electronic medical records (EMR) system: 
l 
Demographics: Age, ethnicity 
l 
Obstetric history: Gravidity, parity, past medical history 
l 
Personal history: Marital status, smoking/alcohol use 
l 
Pregnancy details: Prenatal care records, current pregnancy complications 
l 
Anthropometrics: Current height, weight, gestational weight gain 
l 
Medication use: Medications taken during pregnancy 
l 
Cervical status: Bishop score at randomization 
3.3.2 Paternal Baseline Data 
The following paternal information will be collected via electronic questionnaires: 
l 
Demographics: Age, ethnicity, education level 
l 
Medical history: Past illnesses, personal habits 
3.3.3 Maternal Follow-up Data 
The following intrapartum and postpartum data will be recorded: 
l 
Timing: Randomization time, admission time, delivery time 
l 
Labor progression: Duration of first, second, and third stages of labor 
l 
Delivery details: Mode of delivery (vaginal/cesarean), artificial rupture of membranes (method and time from 
rupture to delivery) 
l 
Medications: Intrapartum drugs (name, dosage, administration), antibiotic use (intrapartum/postpartum), 
analgesia method 
l 
Pain assessment: Self-reported labor pain (Likert scale) 
l 
Surgical records: Operative notes (if applicable), estimated blood loss 
l 
Postpartum medications 
3.3.4 Offspring Follow-up Data 

Infant data will be collected at multiple follow-up time points (in-hospital, 7 days, 6 weeks, and 6 months) via 
electronic questionnaires: 
l 
Feeding history: 
1. 
Initial feeding: Breastfeeding within 1 hour after birth (yes/no) 
2. 
Current feeding mode: Breast milk, formula, cow’s milk, complementary foods, mixed feeding 
3. 
Breastfeeding frequency: Daily breastfeeding sessions 
4. 
Supplement use: Probiotics, complementary foods (type) 
5. 
Medication use 
l 
Growth and development assessments (at 6 weeks and 6 months): 
1. 
Anthropometrics: Weight, length, head circumference, chest circumference, sitting height, mid-upper 
arm circumference, subcutaneous fat, height-to-chest circumference ratio, crown-rump length/body 
length ratio 
2. 
Growth indices: Length-for-age, weight-for-age, weight-for-length Z-scores (calculated using WHO 
Anthro Survey Analyser) 
3. 
Stunting (defined as length-for-age Z-score < -2SD or below the 3rd percentile) 
4. 
Neurological examination: Hearing development, reflexes,  
5. 
Bayley Scales of Infant and Toddler Development (Bayley-4): Total score and domain scores (cognitive, 
language, motor, social-emotional, adaptive behavior);  
6. 
Ages & Stages Questionnaires (ASQ-3): Total score and subdomain scores (communication, gross motor, 
fine motor, problem-solving, personal-social); 
7. 
Allergic diseases: Whether the infant has allergic diseases will be diagnosed by neonatologists. 
3.4 Interventions 
Based on national clinical guidelines and expert consensus, and taking into account the practical context of clinical 
work in the hospital, the following management approaches for the intervention and control groups have been 
developed. All care will be provided by attending obstetricians, and other medical decisions during labor will be 
made by the attending physician according to the clinical situation. 
3.4.1 Intervention Group: Induction at 39 Weeks 
Women assigned to the intervention group will be admitted between 39 weeks +0 days to 39 weeks +4 days of 
gestation as Figure 1. 
l 
If Bishop score < 6: Cervical ripening will be performed first, followed by oxytocin induction if needed (19). 
l 
If Bishop score ≥6: Direct oxytocin induction will be initiated. 

 
Figure 1. Flow chart of induction of labor methods (post - randomization). 
Abbreviations: IOL, induction of labor; CTG, cardiotocography; BC, balloon catheter; ARM, artificial rupture of 
membrane. 
Table 1. Scoring System for the Bishop Score 
Score 
0 
1 
2 
3 
Cervical Dilation (cm) 
Unopened 
1-2 
3-4 
>4 
Cervical Effacement (%) 
0-30 
40-50 
60-70 
≥80 
Station of Presenting Part (in 
relation to ischial spines) 
 
-3 
-2 
-1/0 
+1/+2 
Cervical Consistency 
Hard 
Medium 
Soft 
 
Cervical Position 
Posterior 
Mid - position 
Anterior 
 
After enrollment, pre-IOL assessment
•
Review medical history
•
Confirm gestational age
•
Baseline observation
•
Abdominal palpation (presentation, attitude, position, lie, 
engagement)
•
CTG: consult obstetrician if abnormal
•
Vaginal examination:
•
Bishop assessment
•
Membrane status (intact or ruptured)
Membranes ruptured?
Bishop score ≥6
Balloon catheter (BC)
•
Vaginal and cervical disinfection
•
Sterile normal saline injection 
into the balloon
ARM 
consent
Oxytocin
Bishop score ≥6
No
Yes
No
No
Consider the doctor's 
suggestion and the 
parturient's preference.
Re - initiate cervical 
ripening.
Cesarean section
10mg dinoprostone 
PESSARY
Rest for 24h and 
place BC again
Conduct 
ARM
No
Bishop score ≥6
ARM 
consent
Or
Or
No
If dinoprostone 
PESSARY was 
previously inserted, 
wait at least 30min
after removal.
Reach the 
assessment node
Yes
Yes
Yes
Yes
Yes
No, and if contractions 
are inadequate
If contractions 
are inadequate
Remove the BC after 12 hours of
placement or when it spontaneously
drops.
If contractions 
are inadequate

Given the superior perinatal safety profile of balloon catheters compared to vaginal prostaglandins (14), and 
consistent with our institutional protocol of performing immediate cervical assessment post-balloon removal, this 
study adopts balloon catheter + early ARM as the primary cervical ripening strategy (see Figure 2 for procedure): 
After thorough vaginal and cervical disinfection, a single/double balloon catheter is inserted. The catheter is removed 
upon spontaneous expulsion or after 12 hours, with Bishop reassessment within 1 hour: 
l 
If Bishop score ≥6, ARM is performed after consent. Oxytocin infusion follows if inadequate contractions 
occur (19, 20). If ARM consent is not obtained but contractions are inadequate, perform oxytocin infusion.  
l 
If ripening proves ineffective (Bishop score < 6), the medical team will conduct a thorough reassessment of 
maternal and fetal conditions. Taking into account the patient’s preferences, cervical ripening may be 
reattempted, or the criteria for cesarean delivery may be reconsidered. The method for reinitiating cervical 
ripening will be determined by the attending physician, either through reinsertion of the balloon after a 24-hour 
interval or by a 10 mg dinoprostone vaginal insertion (see Figure 3 for guidelines). 
 
The initial oxytocin solution should be prepared as a 0.5% concentration (2.5 IU oxytocin in 500 mL lactated 
Ringer's or normal saline). Infusion should begin at 8 drops/min, with subsequent adjustments made based on uterine 
contraction patterns. The drip rate is typically increased incrementally every 20 minutes until effective 
contractions are achieved. Effective contractions are defined as 3 contractions per 10 minutes, each lasting 30–60 
seconds, accompanied by cervical shortening and dilation. Maximum infusion rate is 40 drops/min (13.2 mIU/min) 
for the 0.5% solution. If effective contractions are not achieved at the maximum rate, the oxytocin concentration 
may be increased to 1% (5 IU in 500 mL lactated Ringer's solution). In this case, the drip rate should first be halved 
before gradual re-titration, with a new maximum of 40 drops/min (26.4 mIU/min). Neither the drip rate nor the 
concentration should be further increased beyond these limits (21). 
3.4.2 Control Group: Expectant Management or Induction at 41 weeks 
Women assigned to the control group will be followed up by their attending physicians at least once a week. Unless 
there is a newly developed medical indication after randomization—such as fetal distress, oligohydramnios, or 
preeclampsia—no artificial intervention will be initiated to induce labor. Participants will be admitted to the hospital 
upon the spontaneous onset of labor. 
If spontaneous labor has not occurred by 40 weeks 5 days, labor induction will be initiated using oxytocin (19). 
For women with a Bishop score < 6, cervical ripening will be performed prior to induction, with a preference for the 
use of a balloon catheter combined with early amniotomy. The induction procedures will be the same as those used 
in the intervention group. 
3.5 Study Management 
3.5.1 Standardized Guidelines for Cesarean Delivery Not Requested by the Participant (22, 23) 
l 
Failed induction: If the woman fails to enter active labor or remains in the latent phase after 18 hours of adequate 
uterine contractions (more than 3 contractions per 10 minutes accompanied by pain) following amniotomy and 
intravenous oxytocin administration, cesarean delivery may be considered for “failed induction.” 
l 
Failed cervical ripening: If the cervix remains unfavorable (Bishop score < 6) after balloon removal, a 
comprehensive maternal-fetal assessment should be performed. If maternal and fetal conditions allow, cervical 
ripening may be repeated under close monitoring. If continued waiting is not advisable, cesarean delivery should 
be performed. If the woman no longer wishes to attempt vaginal delivery, indications for cesarean section may 
be appropriately broadened. 
l 
Fetal distress: Cesarean delivery is recommended if Category III fetal heart rate tracings are present, or if 
Category II tracings are assessed as threatening fetal well-being and vaginal delivery is not feasible. 

l 
Labor arrest: If labor fails to progress due to uterine dysfunction or other causes despite adequate trial of labor, 
and vaginal delivery is not indicated, cesarean delivery is recommended. 
l 
Other emergencies: Cesarean delivery may also be indicated in confirmed cases of umbilical cord prolapse, 
uterine rupture, placental abruption, preeclampsia/eclampsia, or acute maternal complications (e.g., infectious 
shock, severe cardiopulmonary failure) that preclude the continuation of labor. 
 
 
 
 
Figure 2. Flow chart of balloon catheter. 
Abbreviations: IOL, induction of labor; CTG, cardiotocography; BC, balloon catheter; BP, blood pressure; FHR, 
fetal heart rate; SROM, spontaneous rupture of membranes; ARM, artificial rupture of membrane. 
Pre catheter insertion
•
Already enrolled in the group, complete pre IOL 
assessment
•
Vaginal and cervical infection
Bishop score ≥6
•
Remove BC
•
Provide indicated 
treatment
Remove the BC after 12 
hours of placement or when it 
spontaneously drops.
No
Yes
•
Recommend immediate ARM
•
Oxytocin if inadequate contractions
Yes
No
Insertion procedure
•
Inflate BC with 0.9% sodium chloride:
•
Single balloon: 150mL
•
Double balloon: 80mL+80mL
•
Document inflation volume and time of insertion
•
Contact a more experienced clinician if two 
unsuccessful attempts
Post catheter insertion
•
Immediately assess pulse, BP, FHR, uterine 
activity, engagement of fetal head and vaginal 
discharge
•
Perform CTG if regular contractions occur
Is any present?
•
SROM?
•
Observations abnormal?
•
Labor commenced?
•
Moderate or severe discharge, 
and ongoing after reduction 
of balloon volume?
Re - initiate cervical 
ripening
Consider the doctor's suggestion and 
the parturient's preference.
Cesarean 
section
Or

 
Figure 3. Flow chart of dinoprostone insertion. 
Abbreviations: IOL, induction of labor; NST, Non-stress test; BC, balloon catheter; ARM, artificial rupture of 
membrane. 
3.5.2 Guidelines for Intrapartum Antibiotic Use 
l 
Antibiotics should be administered promptly in cases of clinical or suspected chorioamnionitis. Diagnostic 
criteria include maternal fever (≥37.8°C or ≥38.0°C) and at least two of the following: 
1. 
Maternal tachycardia (>100 bpm); 
2. 
Fetal tachycardia (>160 bpm); 
3. 
Uterine tenderness; 
4. 
Purulent or foul-smelling amniotic fluid or vaginal discharge; 
5. 
Maternal leukocytosis (white blood cell count >15,000/mm³) (23, 24). 
Pre dinoprostone insertion
•
Complete pre IOL assessment
•
Previously used BC with suboptimal 
cervical ripening effect
•
Carefully assess contraindications to 
prostaglandins
•
Positive NST within30min
Bishop score ≥6
No
Remove
Further management based on the status
of uterine contractions. Oxytocin can be
administered
at
least
30min
after
removal.
Assess every 4 - 6 hours for regular uterine
contractions,
and
every
12
hours
for
irregular uterine contractions.
•
10mg dinoprostone PESSARY
•
Position transversely in posterior fornix
Continue placement
Recommend immediate 
ARM
Remove in case of any of the followings:
•
Rupture of membranes
•
Spontaneous expulsion
•
Placement for 24 hours
•
Fetal distress
•
Uterine hyperstimulation or hypertonic 
uterine contractions
Bishop score ≥6
Consider the doctor’s suggestion and the 
parturient’s preference 
Or
Yes
Yes
No
After removal, assess
Re-initiate 
cervical ripening
Cesarean
section
No

l 
Prophylactic antibiotics should be considered if the duration of membrane rupture exceeds 12 hours and the 
fetus has not been delivered. 
3.5.3 Criteria for discontinuing or modifying allocated intervention/comparator 
Participants can withdraw at any time on their own initiative, or the research institution will terminate their 
participation or modify the intervention/comparator in the following circumstances: 
l 
The doctors think they need other treatments, or they do not comply with the research plan; 
l 
The study is terminated early; 
l 
Other special circumstances required by the ethics committee, such as the occurrence of serious adverse events. 
3.6 Biological Sample Collection 
3.6.1 Maternal Samples 
l 
Late-pregnancy vaginal secretions: Collected at 39 weeks during outpatient visit after informed consent is 
obtained. Samples will be frozen at −80°C as soon as possible. 
l 
Maternal stool: Collected at any time between 39 weeks and puerperium. Samples are snap-frozen on dry ice 
and stored at −80°C. 
3.6.2 Offspring Samples 
l 
Cord blood: Collected by midwives using anticoagulant tubes at the time of delivery. Samples are stored 
overnight at 4°C. The next day, 1/3 of the whole blood is stored directly at −80°C, and 2/3 is centrifuged to 
isolate plasma, which is then frozen at −80°C. 
l 
Meconium: Collected by midwives or obstetric nurses, snap-frozen on dry ice, and stored at −80°C. 
l 
Neonatal stool: Collected twice — once within 48 hours after birth (in hospital or at home), and once at 1 week 
of age. 
l 
Infant stool: Collected four times—3 weeks, 6 weeks, 3 months and 6 months postpartum. Samples are collected 
at home, placed in a cold box by caregivers, and delivered to the hospital within 2 hour for −80°C storage. 
3.7 Outcome Measures 
3.7.1 Primary outcome 
Outcome Measure 
Measure Description 
Time Frame 
Incidence of cesarean section 
The proportion of deliveries completed by cesarean section 
Delivery day 
3.7.2 Primary Secondary Outcome 
Outcome Measure 
Measure Description 
Time Frame 
Composite incidence of severe 
neonatal morbidity and perinatal 
mortality 
The composite incidence of any of the following: 
1. 
Antepartum, intrapartum, or neonatal death 
2. 
Intubation, continuous positive airway pressure 
(CPAP) or high-flow nasal cannula (HFNC) for 
ventilation or cardiorespiratory support within first 
72 hours 
3. 
Apgar ≤ 3 at 5 minutes 
4. 
Neonatal encephalopathy 
5. 
Seizures 
6. 
Sepsis (presence of a clinically ill infant in whom 
systemic infection is suspected with a positive blood, 
cerebral 
spinal 
fluid 
(CSF), 
or 
Hospital 
discharge 

catheterized/suprapubic urine culture; or, in the 
absence of positive cultures, clinical evidence of 
cardiovascular collapse or an unequivocal X-ray 
confirming infection). 
7. 
Pneumonia confirmed by X-ray or positive blood 
culture. 
8. 
Meconium aspiration syndrome 
9. 
Birth trauma (bone fractures, brachial plexus palsy, 
other neurologic injury, retinal hemorrhage, facial 
nerve injury) 
10. 
Intracranial hemorrhage or subgaleal hemorrhage 
11. 
Hypotension requiring pressor support 
3.7.3 Maternal Secondary Outcomes 
Outcome Measure 
Measure Description 
Time Frame 
Emergency Cesarean Rate 
Cesarean delivery performed immediately or shortly after clinical 
decision due to imminent threat to the life of the mother or fetus 
Delivery day 
Category 1 Emergency 
Cesarean Rate 
Cesarean performed within approximately 30 minutes due to 
immediate life-threatening conditions (e.g., uterine rupture, severe 
fetal distress) 
Delivery day 
Category 2 Emergency 
Cesarean Rate 
Cesarean performed within 60–75 minutes due to urgent but not 
immediately life-threatening indications (e.g., progressive fetal 
distress, labor arrest) 
Delivery day 
Elective Cesarean Rate 
Planned cesarean performed at or after 39 weeks in the absence of 
emergency conditions, meeting all of the following: 
1. 
Surgery scheduled ≥24 hours before onset of labor; 
2. 
No spontaneous contractions or rupture of membranes; 
3. 
Clear medical indications (e.g., placenta previa, breech 
presentation) or maternal request. 
Delivery day 
Operative 
Vaginal 
Delivery  
The rate of vaginal deliveries assisted with instruments such as 
forceps or vacuum. 
Delivery day 
Gestational 
Age 
at 
Delivery 
Expressed in weeks and decimal days (e.g., 39 weeks + 5 days = 
39.7 weeks). 
Delivery day 
Chorioamnionitis 
Incidence of chorioamnionitis, defined as a clinical diagnosis 
before delivery as: maternal body temperature rises (>38°C) with 
2 or more of the following symptoms:  
1. 
Maternal tachycardia (>100 beats/min);  
2. 
Fetal tachycardia (>160 beats/min) 
3. 
Uterine tenderness and irritability 
4. 
Purulent or malodorous amniotic fluid or vaginal discharge 
5. 
Maternal leukocytosis (white blood cell count > 
15000/mm3) 
Delivery day 
Third-or 
fourth-degree 
perineal laceration 
The incidence of third-or fourth-degree perineal laceration 
Delivery day 

Postpartum hemorrhage 
Refer to the ARRIVE cohort, defined as any of the following 
situations: 
1. 
Transfusion 
2. 
Non-elective hysterectomy 
3. 
Use of two or more uterotonics other than oxytocin 
4. 
Other surgical interventions such as uterine compression 
sutures, uterine artery ligation, embolization and hypogastric 
ligation, balloon tamponade 
5. 
Curettage 
Hospital 
discharge 
Postpartum infection 
Refer to the ARRIVE cohort, defined as any of the following 
situations:  
1. 
Clinical diagnosis of endometritis 
2. 
Wound reopened for hematoma, seroma, infection or other 
reasons 
3. 
Cellulitis requiring antibiotics 
4. 
Pneumonia 
5. 
Pyelonephritis 
6. 
Bacteremia unknown source 
7. 
Septic pelvic thrombosis 
Hospital 
discharge 
ICU admission 
The proportion of admission to the ICU 
Hospital 
discharge 
Maternal death 
The incidence of maternal death 
Hospital 
discharge 
Preeclampsia/gestational 
hypertension 
The incidence of preeclampsia or gestational hypertension 
diagnosed during labor 
Hospital 
discharge 
Maternal 
venous 
thromboembolism 
Deep vein thrombosis or pulmonary embolism 
Hospital 
discharge 
Maternal pain 
Median patient-reported pain outcomes with a 10-point Likert 
scale 
Hospital 
discharge 
3.7.4 Fetal and neonatal secondary outcomes 
Outcome Measure 
Measure Description 
Time Frame 
Birth weight 
The mean birth weight 
Delivery day 
Female gender 
The proportion of female offspring in terms of physiological 
gender 
Delivery day 
Macrosomia 
Birth weight > 4000g 
Delivery day 
Incidence of large for 
gestational age 
According to the infant's gender and gestational age, the birth 
weight exceeds the 90th percentile of infants of the same 
gestational age 
Delivery day 
Incidence of small for 
gestational age 
According to the infant's gender and gestational age, the birth 
weight is less than the 10th percentile of infants of the same 
gestational age 
Delivery day 
Apgar scores at 5 min 
Apgar score at 5 minutes after birth 
Delivery day 
Neonatal acidosis 
The incidence of neonatal acidosis defined as umbilical artery 
Delivery day 

blood pH < 7.10 
Shoulder dystocia 
The incidence of shoulder dystocia 
Delivery day 
Hyperbilirubinemia 
The incidence of hyperbilirubinemia requiring phototherapy or 
exchange transfusion 
Hospital 
discharge 
Transfusion 
of 
blood 
products or blood 
The incidence of neonatal transfusion of blood products or 
blood 
Hospital 
discharge 
Hypoglycemia incidence 
The incidence of hypoglycemia (blood glucose < 35mg/L) 
requiring intravenous treatment 
Hospital 
discharge 
Neonatal intensive care 
unit (NICU) admission 
The incidence rate of NICU admission lasting more than 48 
hours 
Hospital 
discharge 
3.7.5 Infant early-development outcomes 
Outcome Measure 
Measure Description 
Time Frame 
Physical measurement indicators 
Infant weight, length, head circumference, chest 
circumference, sitting height, upper arm circumference, 
subcutaneous fat, height-chest circumference index, 
crown-rump length/length 
6 weeks and 6 
months 
Growth balance indicators 
Weight-for-length, length-for-age, weight-for-age z 
scores of infants, calculated using the WHO tool WHO 
Anthro Survey Analyser 
6 weeks and 6 
months 
Growth retardation 
Height standard deviation for age < mean-2S or 
percentile method < P3 
6 weeks and 6 
months 
Abnormal 
neurological 
examination 
The proportion of abnormal results in neurological 
examinations (hearing development, nerve reflexes) 
6 weeks and 6 
months 
Bayley-4 scores of the Infant 
Development Scale 
Total score, cognitive scale score, language scale score, 
motor scale score, social-emotional scale score, adaptive 
behavior scale score 
6 weeks and 6 
months 
ASQ-3 scores of the Ages and 
Stages Questionnaires 
Total score, communication domain score, gross motor 
domain score, fine motor domain score, problem-solving 
domain score, personal-social domain score 
6 weeks and 6 
months 
Incidence of allergic diseases 
Allergic diseases diagnosed by neonatologists, including 
cow’s milk allergy, allergic rhinitis, eczema/allergic 
dermatitis, asthma, wheezing and other allergic disorders 
6 weeks and 6 
months 
3.7.6 Multi-omics outcomes 
Outcome Measure 
Measure Description 
Time Frame 
Gut microbiota development 
Microbiota 
richness, 
dominant 
species, 
species 
transferred from mother to child, sub-group functional 
trajectory changes of the dominant species in offspring, 
and the transmissibility of species number and function 
Meconium, 
first 
48h, 
7 
days, 3 weeks, 
6 
weeks, 
3 
months and 6 
months 
Fecal metabolomic characteristics 
Non-targeted metabolomic macroscopic differences, 
core metabolomic differences (including tryptophan, 
fatty acids), and differences in gut microbiota metabolites 
Meconium, 
first 
48h, 
7 
days, 3 weeks, 

6 
weeks, 
3 
months and 6 
months 
Cord 
blood 
metabolomic 
characteristics 
Assessment of non-targeted metabolomic macroscopic 
differences and core metabolomic differences (including 
tryptophan, fatty acids) in cord blood plasma 
Delivery day 
Cord 
blood 
proteomic 
characteristics 
Analysis of the proteomic characteristics of cord blood 
whole blood to trace back the health status during the 
fetal period 
Delivery day 
3.7.7 Utilization of Medical Resources 
Outcome Measure 
Measure Description 
Time Frame 
Use of epidural analgesia 
Rate of epidural analgesia use 
Delivery day 
Maternal length of hospital stays 
Median maternal hospital stays, measured in hours 
Delivery day 
Neonatal length of hospital stays 
Median neonatal hospital stays, measured in hours 
Delivery day 
Pre-insurance hospitalization cost 
Total hospitalization cost during delivery, before 
insurance reimbursement 
Delivery day 
Out-of-pocket hospitalization cost 
Out-of-pocket 
cost 
incurred 
during 
delivery 
hospitalization 
Delivery day 
3.8 Adverse Event Reporting 
Throughout the implementation of the study protocol, detailed information on adverse events will be collected and 
evaluated. Serious adverse events (SAEs) include maternal death, perinatal death, and life-threatening maternal 
complications occurring in the study hospital (e.g., uterine rupture, cervical laceration, amniotic fluid embolism 
syndrome). For all SAEs, a case report must be submitted to the hospital’s Ethics Committee and Biostatistics 
Coordinating Center within 72 hours. The Coordinating Center will forward the information to the Data and Safety 
Monitoring Committee (DSMC) within 24 hours. In the event of a death, a copy of the patient’s medical record must 
also be submitted. 
Adverse events not meeting the above criteria for severity will be summarized along with other safety data and 
included in the DSMC’s annual safety review report. 
 
 

4 Statistical Considerations 
4.1 Calculation of sample size based on the primary outcome 
This is a superiority trial. Considering the potentially low incidence of the primary outcome, we calculated the 
sample size using the Fleiss correction based on normal approximation (25). For a 1:1 allocation, the formula for 
comparing two proportions is: 
𝑛!"#_%#&'! = (𝑍()*/,*2𝑝̅(1 −𝑝̅) + 𝑍()-*𝑝((1 −𝑝() + 𝑝,(1 −𝑝,)3
,
(𝑝( −𝑝,),
，𝑝̅ = 𝑝( + 𝑝,
2
 
This calculation was implemented using the stats package in R. The assumptions were a two-sided alpha of 5% 
(α = 0.05) and a power of 80% (1–β = 0.80). 
In our hospital, approximately 30% of women initially planning vaginal delivery ultimately undergo cesarean 
section. After excluding cesarean deliveries performed upon maternal request and assuming stricter control over 
cesarean indications in this interventional trial, we estimate the cesarean rate in the expectant management group 
(p₁) to be between 13% and 18%. Preliminary observational pilot results suggest a cesarean rate of 9.5% in the 39-
week induction group (p₂), so we consider p₂ to range from 8% to 11% (Table 2). 
Additionally, some participants in the induction group may go into spontaneous labor before the planned 
intervention, while some in the expectant management group may undergo elective induction without medical 
indication. These protocol deviations can reduce the observed effect size. In the ARRIVE trial, the protocol deviation 
rate was approximately 5%; here, we consider a deviation range of 0–7.5%. 
For example, assuming a cesarean rate of 16% in the expectant group and 9.5% in the induction group, with a 
5% protocol deviation rate, each group would require 510 participants. Accounting for a 5% loss to follow-up, the 
final estimated sample size is n = 537 per group. 
Table 2. Sample Sizes per Group for Different Primary Outcome Rates 
Nominal Primary Outcome 
Rate in Induction Group 
Nominal Primary Outcome Rate in Expectant Management Group 
13% 
14% 
15% 
16% 
17% 
18% 
0% not delivering per protocol 
8% 
589 
426 
325 
258 
211 
177 
9.50% 
1279 
803 
557 
413 
320 
257 
11% 
4144 
1907 
1109 
733 
524 
396 
2.5% not delivering per protocol 
8% 
653 
472 
361 
286 
234 
196 
9.50% 
1417 
890 
617 
457 
355 
285 
11% 
4591 
2113 
1229 
812 
581 
439 
5% not delivering per protocol 
8% 
728 
526 
402 
319 
261 
219 
9.50% 
1579 
992 
688 
510 
395 
317 
11% 
5116 
2355 
1369 
905 
647 
490 
7.5% not delivering per protocol 
8% 
816 
590 
451 
358 
293 
245 
9.50% 
1770 
1112 
771 
571 
443 
356 
11% 
5735 
2640 
1535 
1014 
726 
549 
4.2 Interim Analysis 
4.2.1 Interim Analysis Plan 

To account for potential challenges in participant recruitment and biospecimen collection, one pre-specified interim 
analyses will be conducted: 
l 
Timing: Upon enrollment and follow-up of 500 participants through the primary outcome. 
l 
Content: 
1. 
Effect sizes of primary and secondary outcomes; 
2. 
Reassessment of sample size (based on observed effect size and variability); 
3. 
Safety data (serious adverse event rate). 
4. 
Biospecimen collection rate and quality; 
5. 
Preliminary assessment of multi-omics data (and whether biospecimen targets need to be revised); 
4.2.2 Statistical Methods and Early Termination Criteria 
l 
Statistical Methods: 
n 
Two-sided significance testing will be used; the Haybittle-Peto alpha-spending function will be applied to 
control the overall type I error rate (total α = 5%). 
n 
The significance threshold for interim analyses is set at p < 0.002 (Z ≥ 3.0), to minimize false positives. 
l 
The trial may be recommended for early termination if: 
n 
In interim analysis: 
1. 
There is clear evidence of efficacy (p < 0.002 and favorable risk-benefit profile); 
2. 
There are safety concerns (e.g., a significantly higher SAE rate in the intervention group); 
3. 
Futility is determined (the primary endpoint is unlikely to be achieved). 
n 
Final decisions regarding early termination must be proposed by the DSMB and approved by the Ethics 
Committee. 
4.2.3 Data and Safety Monitoring Board (DSMB) 
l 
Composition and Responsibilities:  
The DSMB will consist of three members, including experts in clinical medicine, biostatistics, and ethics. 
Responsibilities include: 
n 
Periodic review of safety data and efficacy trends (at least annually or more frequently depending on 
recruitment pace); 
n 
Providing recommendations regarding continuation, modification, or termination of the trial based on 
interim results. 
l 
Reporting Requirements: 
Prior to each DSMB meeting, the Biostatistics Coordinating Center will submit a detailed report including: 
n 
Baseline characteristics: participant demographics and clinical features; 
n 
Protocol adherence: deviations and corrective actions; 
n 
Safety data: summary of adverse events categorized by SOC/PT codes; 
n 
Site performance: recruitment progress, data quality, loss to follow-up, biospecimen collection rate. 
4.3 Data Analysis 
Statistical analysis will follow the intention-to-treat (ITT) principle. All randomized participants who have not 
withdrawn informed consent will be included in the primary comparisons. Per-protocol (PP) analysis may also be 
performed to account for protocol deviations, but will be considered exploratory. 
All statistical tests will be two-sided, and p < 0.05 will be considered statistically significant. A detailed 
statistical analysis plan (SAP) will be developed prior to the enrollment of the final participant. This protocol outlines 
only the general principles of analysis. 

4.3.1 Baseline Analysis 
Baseline characteristics will be described using descriptive statistics to assess balance between groups. Categorical 
variables will be presented as counts (percentages) and compared using chi-square tests or Fisher’s exact tests (if 
expected cell counts <5). Continuous variables will be assessed for normality (Shapiro-Wilk test + histogram). 
Normally distributed variables: mean ± SD, compared using t-tests; 
Non-normally distributed variables: median and interquartile range (IQR), compared using the Mann-Whitney 
U test. 
Recruitment numbers, loss to follow-up, and protocol deviation rates will also be reported. 
4.3.2 Primary Outcome Analysis 
The cesarean delivery rate will be compared using modified Poisson regression or log-binomial regression to 
estimate the relative risk (RR), risk difference (RD), and 95% confidence intervals (CIs), adjusting for stratification 
factors (maternal age and parity). In cases of baseline imbalance in potential confounders, multivariable adjusted 
models with robust variance estimation will be applied. 
4.3.3 Secondary Outcome Analysis 
l 
Binary variables: analyzed as for the primary outcome; 
l 
Continuous variables: t-test for normally distributed variables; non-parametric tests for skewed data (as per 
baseline analysis); 
l 
Time-to-event data: analyzed using Kaplan-Meier curves and log-rank tests. 
4.3.4 Handling of Missing Data 
l 
Baseline data: complete case analysis followed by multiple imputation. 
l 
Loss to follow-up and protocol deviations: sensitivity analysis will be conducted using worst-/best-case 
imputation. Per-protocol analysis will be used for protocol deviations. In cases where pregnancy is terminated 
(e.g., stillbirth), competing risk analysis will be used in place of traditional methods. If the rate of loss to follow-
up is high, inverse probability of censoring weighting (IPCW) may be applied to correct for selection bias. 
4.3.5 Subgroup Analyses 
Subgroup analyses for the primary outcome will be performed by stratifying participants according to: parity 
(nulliparous vs. multiparous), maternal age (<35 vs. ≥35 years), bishop score at randomization (<6 vs. ≥6), BMI 
(<30 vs. ≥30 kg/m²). 
Subgroup-specific effects will be estimated using the same methods as for the main analysis. Interaction terms 
between subgroup variables and treatment assignment will be tested. All subgroup analyses will be considered 
exploratory. 
4.3.6 Multi-omics Outcome Analysis 
Multi-omics analysis will involve multi-dimensional detection of biological samples collected in the study. 
Subsequent multi-modal integration analysis will be performed based on the detection data to fully explore the 
scientific research value of the sample resources. The results of the multi-omics study will be compiled into an 
independent paper and submitted for publication. 
 

5 Ethical Considerations 
The expectant management arm will follow current WHO and Chinese national guidelines. Elective induction at 39 
weeks in low-risk pregnancies is not prohibited by current international or domestic guidelines. Existing evidence 
suggests that the enrolled population may derive certain perinatal benefits. Therefore, both treatment arms align with 
current clinical practice and pose no harm to participants. 
Before initiation of the study, the final version of the protocol—including the informed consent form and all 
participant-facing materials—must receive written approval from the appropriate ethics committee. The 
investigators are responsible for submitting all documents and obtaining formal approval. All ethics committee 
decisions must be documented in writing and archived. 
This study will collect basic maternal data while maintaining strict confidentiality. All patient information and 
data will be handled securely throughout the study and during manuscript preparation and publication. 
 
 

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