Balloon + Oxytocin Versus Oral Misoprostol to Induce Labor in Case of PROM (RUBAPRO2)

University Hospital, Clermont-Ferrand

Status and phase: Enrolling; Phase 4

Conditions: Cervical Ripening; Premature Rupture of Fetal Membranes; Nulliparous; Induction of Labor

Treatments: Drug: Misoprostol Oral Tablet; Device: Balloon for cervical ripening (Teleflex French Dufour catheter CH20 reference 174000); Drug: Oxytocin

Study type: Interventional

Funder types: Other

Identifiers

NCT05568745

2022-501142-30-00 (Other Identifier)

PHRC N 2020 GALLOT

2022-A01479-34 (Other Identifier)

Details and patient eligibility

About

Premature rupture of membranes (PROM) at term complicates 6 to 22% of singleton pregnancies. Spontaneous labour occurs in 60-67% of these patients within 24h. If no effective uterine contraction occurs, induction of labour (IOL) is the strategy recommended by the French as well as the American College of Obstetricians and Gynecologists. The optimal strategy for IOL in case of PROM with an unfavourable cervix remains unknown and none of the studies conducted in nulliparous women showed the superiority of one induction method over another.

In the current project, we aimed to determine (1) if IOL with association of balloon catheter and oxytocin after 6 hours could increase the rate of delivery < 24h versus low dose of oral misoprostol (25 µg oral PGE1 every 2h) in case of PROM at term in nulliparous women and (2) patient satisfaction using EXIT survey assessed before hospital discharge.

Full description

Context : Premature rupture of membranes (PROM) at term complicates 6 to 22% of singleton pregnancies. Spontaneous labour occurs in 60-67% of these patients within 24hours. If no effective uterine contraction occurs, induction of labour (IOL) is the strategy recommended by the French as well as the American College of Obstetricians and Gynecologists. The optimal strategy for IOL in case of PROM with an unfavourable cervix remains unknown and none of the studies conducted in nulliparous women showed the superiority of one induction method over another1. Oral misoprostol (ProstaglandinE1, PGE1) usually demonstrated the lowest rate of c-section after IOL in general population and balloon catheter was associated with the lowest rate of uterine hyperstimulation. Recently, a comparison 1 to 1 between these two methods was conducted in singletons with comparable results. Despite recent studies demonstrating no higher risk of infectious complications using mechanical device in the context of PROM, only prostaglandins and oxytocin are usually recommended. Recently, Devillard et al. demonstrated that the combination of balloon catheter plus oxytocin systematically infused after 6 hours increased the rate of delivery <24h compared to dinoprostone vaginal insert group (90% versus 57.5% respectively) and decreased the time between induction and delivery in nulliparous group (17.0hours versus 26.5hours).

In the current project, we aimed to determine (1) if IOL with association of balloon catheter and oxytocin after 6 hours could increase the rate of delivery < 24hours versus low dose of oral misoprostol (25 µg oral PGE1 every 2h) in case of PROM at term in nulliparous women and (2) patient satisfaction using EXIT (EXperience of Induction Tool) survey assessed before hospital discharge.

We hypothesized that the rate of delivery < 24hours will be 15% higher in the group induced with balloon + oxytocin (estimated around 85 %) compared to the misoprostol group (estimated around 70 %). Patient satisfaction concerning experience of IOL will be assessed using a validated survey- the EXperience of Induction Tool (EXIT) - translated in French language (Beckman et al., 2017). We aimed to demonstrate a difference greater than an effect-size of 0.25.

Objectives: The main objective is to demonstrate higher rate of vaginal birth <24hours by insertion of a balloon catheter + oxytocin after 6hours, versus low dose of oral misoprostol (25 µg oral PGE1 every 2hours) in case of unfavorable cervix beyond 12 hours of PROM in nulliparous and to compare patient satisfaction using EXIT survey translated in French language before hospital discharge.

The secondary objectives are:

• To compare the rate of caesarean sections in the two groups.
• To compare the safety related to women of both induction methods in terms of maternal morbidities, uterine hyperstimulation, maternal infections and other reported adverse events (AEs).
• To compare the safety related to neonates of both induction methods in terms of neonatal morbidities, neonatal infections and other reported AEs.

Study type: Multi-center, randomized, controlled, open-label therapeutic trial with two parallel arms.

Number of centers: 5

Study Description:

The study group is the balloon catheter group with addition of oxytocin as early as 6h after the catheter insertion. After 12 hours of balloon insertion, induction of labour is continued by oxytocin alone. The control group corresponds to induction with misoprostol 25µg given orally (oral prostaglandin E1). The same dose is delivered every 2 hours until labour onset with a maximum of 8 administrations. Oxytocin can be started at least 4 hours after the last misoprostol administration.

Patients will be assigned by random allocation on a 1:1 basis in permuted blocks to either treatment group or control group using a dedicated, password-protected, SSL-encrypted website. To minimize the risk of imbalance between the study groups, the randomization will be stratified by trial site.

Primary endpoint: Hierarchical primary endpoint: (1) Proportion of patients vaginally delivered <24h and (2) patient satisfaction using EXIT survey assessed before hospital discharge.

Number of patients: 520

Enrollment: 520 estimated patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age > 18 years old,
• Pregnant, Gestational age ≥ 37 weeks
• Singleton pregnancy with cephalic presentation
• Nulliparous
• PROM without labour beyond 12 hours
• Unfavourable cervix (Bischop score < 6)
• Able to give her informed consent
• Ability to comply with the requirement of the study
• Covered by the French Social Security welfare system

Exclusion criteria

• Unable to understand French language

• Contraindication for vaginal delivery

• Loss of meconium amniotic fluid (LA)

• Temperature > 38.2°C

• Intrauterine infection

• IUGR with Doppler anomaly

• Fetus with expected polymalformative syndrome

• Scarred womb

• Suspicion of genital herpes

• Known HIV seropositivity

• Placenta praevia

• Fetal death

• Abnormal FHR (Fetal Heart Rate)

• Contraindication to misoprostol:

  • Allergy or hypersensibility
  • Suspicion or confirmation of a scarred uterus following past surgical intervention
  • Renal insufficiency
  • Malformation of the uterus

• Contraindication to balloon:

  • Vasa praevia, placenta praevia
  • Invasive cervical cancer

• Contraindication to oxytocin

  • Allergy or hypersensibility
  • Dystocia
  • Fragility or excessive distension of the uterus
  • Uterine hypertonia or fetal distress when delivery is not imminent
  • Cardiovascular disorders and severe preeclampsia
  • Predisposition to amniotic embolism (in utero fetal demise, abruption).

• Patient subject to a legal protection order (curatorship or tutorship)

• Refusal to participate

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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520 participants in 2 patient groups

Balloon+oxytocin

Experimental group

Description:

Mecanical cervical ripening will be done by transcervical balloon (Teleflex French Dufour catheter CH20 reference 174000). Oxytocin will be started 6 hours after balloon insertion. At H12 balloon will be removed and induction continued by oxytocin alone.

Treatment:

Device: Balloon for cervical ripening (Teleflex French Dufour catheter CH20 reference 174000)

Drug: Oxytocin

Oral misoprostol

Active Comparator group

Description:

Patients will receive misoprostol 25 micrograms given orally (oral prostaglandin E1). The same dose will be given every 2 hours until beginning of labor with a maximum of 8 administrations. (Oxytocin can be started at least 4 hours after the last misoprostol administration if patient remains not in labour.)

Treatment:

Drug: Misoprostol Oral Tablet