Vaginal Microbiome and Long and Short Outcomes of Cervical Balloon Catheter Induction of Labor: A Multicenter Prospective Cohort Study

doi:10.21203/rs.3.rs-4336060/v1

Background

Considering that balloon catheter placement for IOL involves a reproductive tract operation, its effectiveness may be affected by the reproductive tract environment. However, there is currently a lack of relevant evidence to support whether vaginal microbiota affects the maternal and neonatal pregnancy outcomes of balloon catheter placement for IOL. Therefore, In this multicenter prospective cohort study, we investigated the characteristics of vaginal microbiota in late pregnancy women and their relationship with short-term and long-term outcomes of cervical balloon catheter induced abortion.

Methods

We enrolled pregnant women from five hospitals in different cities in Jiangsu Province, China—including Nanjing Maternal and Child Health Care Hospital, Changzhou Maternal and Child Health Care Hospital, Wuxi Maternal and Child Health Care Hospital, Changzhou Second People's Hospital, and Suzhou Municipal Hospital and had them and their descendants follow up at the same hospital. Assessments during pregnancy include demographic data, pregnancy characteristics, complications of pregnancy, examinations in the third trimester. Before the balloon catheter placement, samples of vaginal secretions and prenatal maternal serum/plasma were collected from the study participants. Then the balloon catheter insertion was performed by a professional obstetrician. At birth, the immediate situation of the mother and newborn was recorded and biological samples such as amniotic fluid, maternal serum/plasma samples, mbilical cord samples, infant plantar blood spots collected. All biological samples were stored at -80°C, and metagenomic sequencing and human genome sequencing were performed uniformly after all samples had been collected. The offspring of the participants will continue to be followed up for a longer period of time (until the age of 3 years) to monitor their growth and development as well as disease outcomes. A research assistant will conduct the follow-up through phone calls and regularly organize physical examinations.

Discussion

This study is novel from the focuse on the interaction between metagenomics, metabolomics, proteomics, and other multi-omics. Moreover, the study involves significant effort on performing follow-up examinations of offspring, which many previous studies lacked. The

vaginal microbiome

cervical balloon catheter

induction of labor

adverse pregnancy outcomes

Induction of labor (IOL) in late pregnancy refers to the use of medication or mechanical interventions to initiate vaginal delivery before natural labor begins ^[1]. One in four pregnant women worldwide needs IOL ^[2]. IOL is usually used to prevent post-term pregnancy. In addition, for some women with pregnancy complications such as gestational diabetes mellitus ^[4], hypertensive disorders in pregnancy ^[5], and intrahepatic cholestasis ^[6], termination of pregnancy is required at a specific time to achieve the best pregnancy outcome ^[3].

The most common methods of IOL include mechanical methods, membrane sweeping, intracervical administration of prostaglandin E2, and oxytocin administration ^[7]. Among them, intracervical PGE2 administration or mechanical methods in combination with oxytocin administration were more suitable for pregnant women with an immature cervix. All mechanical labor induction methods have a similar mechanism of action, that is, the application of local pressure on the cervix and lower uterine segment stimulation promote its expansion and release of maternal endogenous prostaglandin, thereby initiating uterine contraction, and promote cervical ripening and IOL. The most common mechanical method of IOL is the use of a balloon catheter ^[7]. The balloon catheter is considered to be as effective as PGE2 in labor induction. However, compared with intracervical PGE2 administration, balloon catheter placement is gentler and may reduce uterine hyperstimulation ^[8]. Some studies indicate that the mechanical methods may have advantages over the pharmacological methods, as they are widely available and cost effective and may have fewer side effects ^{[9, 10]}. Nevertheless, balloon catheter placement for IOL has its limitations, including a low delivery rate in the first 24 h, failed IOL, and emergency cesarean section during induction ^{[9, 10]}.

Recent research indicates that the success rate of balloon catheter insertion for IOL is influenced by various factors such as parity, cervical Bishop score, and gestational age ^[11]. Furthermore, there is an ecosystem composed of multiple microorganisms in the female reproductive tract, which coexist in a dynamic balance and maintain important physiological functions ^[12], producing metabolites that directly or indirectly affect maternal health and fetal development during pregnancy ^[13]. A characteristic of the cervical–vaginal microbiota during pregnancy is the dominance of a small number of lactobacilli ^{[14, 15]}. The cervical–vaginal microbiota dominated by Lactobacillus crispatus is considered to represent a relatively healthy state of the cervix and vagina ^[16]. Moreover, the current consensus is that the structural disruption of the vaginal microbiota in pregnant women is strongly correlated with premature birth ^[17–19]. Furthermore, a recent study reported an association between the dysregulation of vaginal microbiota during pregnancy and the risk of emergency cesarean section. Vaginal microbial abundance can also be used to construct predictive models to predict emergency cesarean delivery ^[20]. Considering that balloon catheter placement for IOL involves a reproductive tract operation, its effectiveness may also be affected by the reproductive tract environment. However, there is currently a lack of relevant evidence to support whether vaginal microbiota affects the maternal and neonatal pregnancy outcomes of balloon catheter placement for IOL. Although some relevant cohort studies have been conducted, they lack metagenomic data and multi-omics analysis. Furthermore, the long-term follow-up of newborns is crucial to gain a longer-term perspective.Therefore, the present study aims to explore the effect of vaginal microbiota on short-term and long-term outcomes of cervical balloon catheter induced abortion. In addition to simply collecting vaginal microbiota and conducting 16S rRNA sequencing-as done in previous studies-this study focuses on metagenomics and the interaction between microbiomics, proteomics, and metabolomics. Moreover, we aim to conduct a long-term follow-up of newborns for up to 3 years to monitor their subsequent growth and development and disease outcomes.

Aims of the study

The aims of the study are:

to investigate the characteristics of vaginal microbiota in late pregnancy women.

to explore the effect of vaginal microbiota on the success rate of labor induction, labor duration, standard perinatal outcomes, and neonatal outcomes of balloon catheter placement for IOL.

to conduct a long-term follow-up of newborns to monitor their subsequent growth and development and disease outcomes.

to construct a predictive model for the outcomes of balloon catheter placement for IOL by combining vaginal microbiome sequencing results with clinical information and preliminarily explore the underlying mechanisms.

Study design

This prospective cohort study follows 835 pregnant women and their infants up to 3 years old. Data and biological specimens are collected early pregnancy, mid-pregnancy, late pregnancy and at birth. The offspring of the participants will continue to be followed up for a longer period of time (until the age of 3 years) to monitor their growth and development as well as disease outcomes.

Recruitment of participants started on 1 October 2022 and completion of data collection is expected in October 2025.

Participants

The cohort study enrolled pregnant women from five hospitals in different cities in Jiangsu Province, China—including Nanjing Maternal and Child Health Care Hospital, Changzhou Maternal and Child Health Care Hospital, Wuxi Maternal and Child Health Care Hospital, Changzhou Second People's Hospital, and Suzhou Municipal Hospital. The inclusion criteria were pregnant women with full-term gestation who required termination of pregnancy by IOL. The cervical maturity of the women, assessed using the Bishop score, was determined by two physicians at the level of deputy chief or above, together with professional obstetricians. Typically, pregnant women with a Bishop score of less than 6 require balloon catheter placement to promote cervical maturation ^[21]. Owing to risks such as excessive contractions and other adverse pregnancy outcomes, IOL with balloon catheter is contraindicated in pregnant women under the following conditions:

1. Multiple pregnancy, improper fetal position, abnormal fetal heart rate, and fetal membrane rupture

2. Pregnant women who have received or plan to receive external prostaglandin therapy

3. Placenta previa, vascular previa or placental implantation, umbilical cord prolapse

4. History of scarred uterus, myomectomy, or any other full-thickness incision of the uterus

5. Hydramnios, macrosomia, fetal presentation is not in the pelvic cavity

6. Genital inflammation (vaginitis, severe cervical erosion, pelvic inflammation, or abnormal vaginal discharge)

7. Abnormal cervical structure, invasive cervical cancer

8. Fever (i.e., when the body temperature is measured twice on the same day [4 h interval] and both measurements are above 37.5 ℃)

9. Severe hypertension, heart disease, or acute phase of other diseases

10. Recurrent vaginal bleeding during pregnancy and conditions in which abnormal placental position cannot be excluded

11. Any other contraindications related to labor induction

In addition to the above contraindications, some other exclusion criteria were developed to exclude confounding factors that may significantly affect the results, including maternal age of <20 years and >40 years; severe congenital malformations of the fetus; and complication of major diseases during pregnancy, such as malignant tumors.

Enrollment and informed consent

Pregnant women who attended antenatal visits and delivered at the five hospitals were identified as potential study participants. At each hospital, trained research assistants screened potential participants on the basis of detailed inclusion criteria and asked if they are willing to participate. If mothers were interested in participation, research assistants contacted them to provide additional information and asked them to provide informed consent.

The study design is shown in Figure 1 and Figure 2.

Data collection

Collection of medical history information

If a pregnant woman met all inclusion criteria and provided informed consent, the following relevant medical history data were collected through electronic medical record system:

1)Demographic data: maternal characteristics (e.g., age, race, occupation, height, pre-pregnancy body–mass index [BMI]) and past medical history (e.g., infectious diseases, allergy history, blood transfusion history, surgery history, past pregnancy and birth history)

2) Pregnancy characteristics such as fundal height, abdominal circumference, body weight, fetal position, and fetal heart rate, cervical condition, mode of pregnancy, parity, and fetal presentation (head or breech position) as well as complications of pregnancy (e.g., anemia, polyhydramnios, premature rupture of membranes, placental abruption, placenta previa, intrahepatic cholestasis during pregnancy, hypertension in pregnancy, hypothyroidism, gestational diabetes mellitus, pre-eclampsia, immune diseases and pre-eclampsia, fetal growth restriction, pregnancy with chronic nephritis and heart disease in pregnancy); for the above diseases, diagnostic criteria described in Obstetrics and Gynecology (9th edition) were used.

3)Examinations in the third trimester: For example, fetal monitoring, umbilical cord blood flow examination, B-ultrasound examination, electrocardiogram examination, blood routine examination, urine routine examination, coagulation function, liver function, and kidney function. Part of baseline characteristics of study participants as of June 2023 shows in table 1.

Table 1 Baseline characteristics of study participants as of June 2023

	Changzhou Second People's Hospital	Changzhou Maternal and Child Health Hospital	Nanjing Women and Children's Healthcare Hospital	Suzhou Municipal Hospital	Wuxi Maternal and Child Health Hospital
	n = 69	n = 54	n = 419	n = 27	n = 66
Age	28.8 (4.62)	29.1 (3.99)	29.9 (3.12)	30.0 (3.16)	29.1 (3.65)
Gravidity	2.09 (1.47)	1.83 (1.04)	1.55 (0.92)	1.33 (0.55)	1.48 (0.81)
Parity	0.77 (0.96)	0.31 (0.54)	0.16 (0.40)	0.00 (0.00)	0.18 (0.39)
Weight (kg)	75.8 (13.5)	74.0 (10.7)	72.7 (10.2)	70.6 (9.76)	73.2 (10.1)
Height (cm)	161 (4.89)	162 (5.02)	162 (4.80)	162 (4.84)	162 (4.74)
Pre-pregnancy BMI	23.8 (4.22)	22.6 (4.05)	22.4 (3.41)	22.1 (2.75)	23.2 (3.87)
Occupation	0.46 (0.50)	0.78 (0.42)	0.94 (0.23)	1.00 (0.00)	0.89 (0.31)
OGTT FPG (mmol/L)	4.70 (0.79)	4.50 (0.54)	4.52 (0.60)	4.46 (0.44)	4.60 (0.51)
OGTT 1 h (mmol/L)	7.79 (2.20)	8.31 (1.41)	7.79 (1.62)	7.56 (2.23)	8.56 (2.17)
OGTT 2 h (mmol/L)	7.09 (1.82)	6.95 (1.54)	6.79 (1.38)	6.90 (1.71)	7.42 (2.04)
HbA1c (%)	5.10 (0.73)	5.09 (1.01)	5.00 (0.29)	5.24 (1.20)	5.63 (0.33)
WBC (10⁹/L)	8.23 (2.22)	8.32 (2.34)	8.56 (2.06)	9.02 (2.33)	7.98 (1.91)

Note: Data are presented as mean (SD) or n (%).

Abbreviation: BMI: body mass index; OGTT; oral glucose tolerance test; FPG: fasting plasma glucose; HbA1c: hemoglobin A1c; WBC: white blood cell

Tracking of induction of labor and pregnancy outcomes

Research assistants and professional nurses monitored the outcomes of maternal labor induction, including the delivery time, success rate of labor induction (if by cesarean section, the research assistant recorded the reasons for surgery), vaginal midwifery rate (forceps, fetal aspiration), length of induction in combination with oxytocin, altered cervical maturity, duration of labor, estimated total blood loss, postpartum hemorrhage (PPH; defined as bleeding 500 mL or more), and severe PPH (defined as bleeding 1,000 mL or more), vaginal laceration rate, perineal tear rate, chorioamnionitis, infection (defined as at least one of the following: endometritis, episiotomy infection, or wound infection requiring surgery), blood transfusion, thromboembolic events, intensive care unit admission, and maternal death. Moreover, newborn information was also recorded, including data of the newborn infant at birth (gestational age at birth, sex, birth weight, head circumference, abdominal circumference, length, Apgar scores at 1 and 5 min after birth, amniotic fluid volume and characteristics, placental size, and cord blood gas analysis), occurrence of stillbirth or death within 72 h after birth; and neonatal complications and treatment of neonatal period, including neonatal asphyxia, respiratory diseases (e.g., neonatal respiratory distress syndrome, wet lung, apnea, bronchopulmonary dysplasia, pneumonia), intracranial hemorrhage (including intraventricular hemorrhage grade), neonatal necrotizing enterocolitis, preterm retinopathy, neonatal sepsis, hypoglycemia, neonatal jaundice, neonatal resuscitation, use of pulmonary surfactant status, continuous positive pressure ventilation, mechanical ventilation, hospital stay (including NICU), and neonatal death during hospitalization. Diagnostic criteria outlined in Practical Neonatology were used. Table 1 shows the delivery outcomes and newborn information of some pregnant and postpartum women. More detailed clinical information is presented. Part of the maternal labor outcomes and newborn data as of June 2023 show in table 2.

Table 2 Part of the maternal labor outcomes and newborn data as of June 2023

	Changzhou Second People's Hospital	Changzhou Maternal and Child Health Hospital	Nanjing Women and Children's Healthcare Hospital	Suzhou Municipal Hospital	Wuxi Maternal and Child Health Hospital
	*n = 69*	*n = 54*	*n = 419*	*n = 27*	*n = 66*
Gestational age (wk)	40.0 (0.83)	40.2 (1.05)	40.3 (0.81)	39.6 (1.12)	40.3 (0.71)
Cervical score before balloon placement	3.54 (0.87)	4.81 (1.04)	4.83 (0.42)	4.44 (0.70)	3.83 (0.54)
Time from balloon placement to onset of labor (h)	18.3 (7.83)	15.8 (5.68)	26.4 (14.5)	17.6 (6.10)	18.3 (5.02)
Balloon retention time (h)	12.0 (3.69)	11.6 (3.03)	14.2 (3.57)	16.2 (4.69)	15.3 (3.58)
Cervical score after balloon removal	4.70 (1.09)	6.28 (1.16)	6.44 (0.97)	6.04 (0.82)	6.18 (0.72)
Artificial membrane rupture
/	0 (0.00%)	0 (0.00%)	0 (0.00%)	1 (3.70%)	0 (0.00%)
0	8 (11.6%)	6 (11.1%)	163 (39.2%)	3 (11.1%)	7 (10.6%)
1	61 (88.4%)	48 (88.9%)	253 (60.8%)	23 (85.2%)	59 (89.4%)
First stage of labor (h)	5.73 (3.43)	8.50 (4.43)	7.60 (3.37)	8.71 (6.16)	8.63 (4.09)
Second stage of labor (h)	0.82 (0.98)	0.76 (0.56)	0.66 (0.37)	0.71 (0.39)	0.65 (0.58)
Third stage of labor (h)	10.0 (9.24)	7.33 (5.24)	9.05 (4.59)	7.39 (5.13)	9.22 (6.17)
Lateral perineal incision
/	0 (0.00%)	0 (0.00%)	0 (0.00%)	0 (0.00%)	1 (1.96%)
0	28 (52.8%)	33 (67.3%)	226 (73.4%)	18 (78.3%)	37 (72.5%)
1	25 (47.2%)	16 (32.7%)	82 (26.6%)	5 (21.7%)	13 (25.5%)
Intrapartum hemorrhage (mL)	341 (728)	254 (97.1)	348 (123)	259 (69.6)	380 (213)
Cesarean section
0	53 (76.8%)	49 (90.7%)	310 (74.0%)	23 (85.2%)	50 (75.8%)
1	16 (23.2%)	5 (9.26%)	109 (26.0%)	4 (14.8%)	16 (24.2%)
Obstetric forceps
0	43 (81.1%)	47 (95.9%)	285 (91.9%)	22 (95.7%)	47 (94.0%)
1	10 (18.9%)	2 (4.08%)	25 (8.06%)	1 (4.35%)	3 (6.00%)
Infant sex
/	0 (0.00%)	1 (1.85%)	1 (0.24%)	0 (0.00%)	0 (0.00%)
1	43 (62.3%)	28 (51.9%)	201 (48.0%)	11 (40.7%)	29 (43.9%)
2	26 (37.7%)	25 (46.3%)	217 (51.8%)	16 (59.3%)	37 (56.1%)
Birth weight (g)	3458 (426)	3384 (409)	3445 (395)	3102 (416)	3329 (426)
Apgar 1 min	8.90 (0.55)	9.94 (0.41)	9.95 (0.32)	9.85 (0.60)	9.92 (0.51)
Apgar 5 min	11.2 (10.9)	9.98 (0.14)	9.99 (0.13)	10.0 (0.00)	9.98 (0.12)
Postpartum hemorrhage (mL)	321 (153)	422 (153)	473 (254)	106 (155)	488 (328)

Note: Data are presented as mean (SD) or n (%).

Long-term follow-up of offspring

The offspring of the participants will continue to be followed up for a longer period of time (until the age of 3 years) to monitor their growth and development as well as disease outcomes. A research assistant will conduct the follow-up through phone calls and regularly organize physical examinations.

The first follow-up is 28 days after birth. At this time point, we will investigate whether the newborn has congenital malformations and refer them to improve the screening of congenital genetic diseases. Moreover, we will assess whether the newborn has infections. Between 28 days and 1 year after birth, we will conduct follow-up examinations every 6 months. During this period, we will examine whether the baby has digestive disorders and nutritional deficiencies. Furthermore, we will record their height, weight, and head circumference as well as monitor their movement, language development, muscle tone, hearing impairment, and eye diseases. Similarly, the follow-up of the offspring will be performed every 6 months for the age range of 1–3 years old, and the focus will shift to the children's language development, intellectual development, neuromotor development, and allergies. Additionally, we will perform laboratory and auxiliary examinations of the offspring at each stage, including blood, urine, and fecal routine examinations, liver and kidney function, serum enzymes, blood sugar and lipids, serum iron and tin, thyroid hormone, growth hormone, sex hormone, pancreatic function, cardiac ultrasound, brain magnetic resonance imaging, bone age, and electrocardiogram.

Collection of biological samples

Before the balloon catheter placement, samples of vaginal secretions and prenatal maternal serum/plasma were collected from the study participants. Figure 3 provides a brief overview of the process used for vaginal and cervical secretion sampling. Amniotic fluid was collected during labor and cultured. Maternal serum/plasma samples collected during pregnancy and the puerperium were also assessed. After birth, feces, placental tissue, and umbilical cord samples were collected, and infant plantar blood spots were assessed 72 h later.

The vaginal and cervical secretion samples were collected as follows:

① A sterile speculum was inserted into the vagina. Six sterile cotton swabs moistened with normal saline were used to swab the vagina five times each to collect secretions and then placed into two red sterile cryopreservation tubes containing a buffer placed on ice (to assess the vaginal microbiota and metabolites), with three swabs per tube. Finally, the heads of the cotton swabs were aseptically broken off into the tubes, and the tubes were tightly closed and appropriately labelled.

② For the collection of cervical secretion samples, six sterile cotton swabs moistened with normal saline were used. The swabs were inserted into the cervical canal (2 cm) and rotated twice. The cotton swabs were placed into two blue sterile cryopreservation tubes, with three swabs per tube. Finally, the heads of the cotton swabs were aseptically broken off into the tubes, and the tubes were tightly closed and appropriately labelled.

③ The cryopreservation tubes were placed on ice or in a refrigerator at 4 ℃ and transferred to -80 ℃ within 1 h.

Procedure of balloon catheter insertion

The Cook balloons used in the study were obtained from Jiangsu Aobojin Pharmaceutical Technology Co., Ltd. The balloon catheter insertion was performed by a professional obstetrician. The operation procedure was as follows:

Pregnant women were asked to empty their bladder and placed in the bladder lithotomy position; then, the perineum was routinely disinfected. Subsequently, a doctor exposed the cervix with a speculum to disinfect the cervix and vagina again. Then, they used a cervical clamp to secure the anterior or posterior cervical lip and gripped the distal end of the balloon with elliptical forceps to slowly feed the balloon along the lateral wall of the neck into the uterine cavity. Next, the doctor injected 20 mL of normal saline into the uterine balloon catheter and pulled out the device and removed the speculum. Subsequently, they would continue injecting saline into the balloon catheter, at increments of 20 mL each, until the total amount reached 60–80 mL. Finally, the doctor used a tape to fix the catheter to the inner thigh to observe the maternal response and cervical dilatation ^[22]. Figure 4 provides a brief overview of the procedure of balloon catheter insertion.

Management of established labor

The balloon catheter was typically placed in the evening. In some pregnant women, the balloon catheter automatically came off because of cervical dilatation. If the balloon catheter did not come off automatically, it was removed the next morning after being left overnight. If regular contractions or premature rupture of membranes occurred, the balloon catheter would be removed in advance. The retention time of the balloon in the cervix was also recorded. After the balloon catheter was removed, most pregnant women who were not in labor required oxytocin and membrane sweeping to continue IOL. The process of IOL after balloon catheter implantation was continuously tracked and recorded by the research assistants, including the gestational age at the time of induction, the duration of labor induced by oxytocin, whether artificial rupture of membranes was performed, and the duration of the three labor stages.

Biological sample processing

All biological samples were stored at -80 °C, and metagenomic sequencing and human genome sequencing were performed uniformly after all samples had been collected. DNA from vaginal and cervical secretions was extracted using the MolPure® Magnetic Universal Viral DNA/RNA Kit according to the manufacturer’s instructions. Then, 1% agarose gel electrophoresis was used to analyze the purity and integrity of the extracted DNA, and Qubit 2.0 was used to quantify the DNA. Next, the NEBNext® Ultra DNA Library Prep Kit for Illumina (NEB, USA) was used for DNA processing. Finally, a metagenomic sequencing library with an insert size of 350 bp was constructed. Library quantification was performed using Qubit and real-time PCR, and size distribution was assessed using BioAnalyzer. Quantified libraries were pooled according to effective library concentration and the expected data volume and sequenced on the Illumina platform. Readfq (https://github.com/cjfields/readfq) was used for preprocessing the raw data from Illumina sequencing to obtain clean data for subsequent analyses. The assembly of clean data was performed using MEGAHIT. DIAMOND software (https://github.com/bbuchfink/diamond/) was used to align the unigene sequences with those of bacteria, fungi, archaea, and viruses obtained from NCBI's NR database (https://www.ncbi.nlm.nih.gov/).

Statistical analyses

We will use Spearman correlation analysis to compare the correlation between clinical phenotypes and bacterial strains. To minimize the impact of covariates on the results, we will use multiple linear regression to adjust for covariates. Between-group comparisons will be made using T-test and analysis of variancet. Each estimate will be accompanied by a 95% confidence interval and a 5% level of significance will be used in all statistical tests.

This cohort explored the effect of vaginal microbiota on the success rate of labor induction, labor duration, standard perinatal outcomes, and neonatal outcomes of balloon catheter placement for IOL. This study is novel from the focuse on the interaction between metagenomics, metabolomics, proteomics, and other multi-omics. Moreover, the study involves significant effort on performing follow-up examinations of offspring, which many previous studies lacked. Meanwhile, five hospitals participated in this study, making it a multicenter study, which effectively reduces the error caused by a single external environment and operating practices, and the study results are therefore more universal.

Nevertheless, there remain some limitations in this study. For example, the sample size included in each research center varied significantly.

Even so, owing to the combination of microbiome sequencing technology with clinical data, this study is expected to provide a strong basis for the selection of clinical diagnostic and treatment protocols, break through the bottleneck of choosing the method of pregnancy termination in the third trimester, and reduce the probability of adverse pregnancy outcomes caused by cesarean section and induced labor, which are commonly feared by pregnant women in clinical practice.

IOL: induction of labor; PGE2: prostaglandin E2; BMI: body mass index; NICU: neonatal intensive care unit; OGTT; oral glucose tolerance test; FPG: fasting plasma glucose; HbA1c: hemoglobin A1c; WBC: white blood cell

ACKNOWLEDGMENTS

This work was supported by grants from National Key R&D Program of China (2022YFC2703503), National Natural Science Foundation of China (82371697) and Key Project of Changzhou Medical Center of Nanjing Medical University (CMCM202312)

FUNDING

National Key R&D Program of China (2022YFC2703500), National Natural Science Foundation of China (82371697, 81971410), Key Project of Changzhou Medical Center of Nanjing Medical University （CMCM202312）, Cohort of the State Key Laboratory of Reproductive Medicine (NMUC2021016A), The Open Project of Jiangsu Biobank of Clinical Resources, No. TC2021B02

AVAILABILITY OF DATA AND MATERIALS

The authors confirm that the data supporting the findings of this study are available within the article [and/or its supplementary materials].

AUTHOR CONTRIBUTIONS

STK and QYZ did the experiments, analyzed data, and wrote the manuscript. Author QYZ, XHC, JLX, YG, HBX, LPZ, SMH, HYW and LPZ performed clinical sample collection and processing. Author XCW and BNM analyzed data and revised the manuscript. Author ZHS and LMC supervised this project. All authors have read the final manuscript and approved it for publication.

ETHICS STATEMENT

The ethics application (No. 2022KY-131) was approved by the Research Ethics Committee of the Women’s Hospital of Nanjing Medical University. All Ethical Approval files need upload in the system as “Additional File for Review but NOT for publication”.

CONFLICT OF INTEREST STATEMENT

The authors have declared no competing interests

SUPPORTING INFORMATION

Table S1 Baseline characteristics of the participants as of June 2023.

Table S2 The outcomes of maternal labor and newborn information as of June 2023.

Document 1 Ethical review approval.

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No competing interests reported.

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Vaginal Microbiome and Long and Short Outcomes of Cervical Balloon Catheter Induction of Labor: A Multicenter Prospective Cohort Study

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Abstract

Background

Methods

Discussion

Figures

BACKGROUND

Aims of the study

METHODS/DESIGN

DISCUSSION

ABBREVIATIONS

Declarations

References

Additional Declarations

Supplementary Files

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Version 1