Clinical trial NCT04799912: Labor Induction in Low-risk Nulliparous Women at 39 Weeks of Gestation to Reduce Cesarean: A Randomized Trial of Induction Versus Expectant Management in France (FRENCH-ARRIVE)
Official title: Labor Induction in Low-risk Nulliparous Women at 39 Weeks of Gestation to Reduce Cesarean: A Randomized Trial of Induction Versus Expectant Management in France (FRENCH-ARRIVE)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cesarean Section
Keywords: Cesarean section
Labor induction
Expectant management
Low risk nulliparous women
Maternal morbidity
Neonatal morbidity
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2021-03-16
Enrollment: 4200
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter open randomized controlled trial with 2 parallel arms
Primary purpose: PREVENTION

Brief summary: The recent ARRIVE trial conducted in United States of America in 2014-2017 demonstrates that elective induction of labor at 39 weeks for nulliparous women did result in a significantly lower frequency of cesarean delivery with no significant differences of adverse perinatal outcomes. But the expected benefits of elective labor induction at 39 weeks have to be confirmed in other settings outside US before considering routine induction of labor for all low-risk nulliparous women at 39 weeks of gestation worldwide.

Detailed description: The nadir of the neonatal risks seems to be at 39 weeks of gestation and there is an augmentation of maternal complications after 39 weeks. Nonetheless, planned induction of labor at 39 weeks was not encouraged in common practice due to a suspected higher risk of frequency cesarean delivery and other adverse maternal outcomes, especially among nulliparous women with unfavorable cervix, compared with expectant management. This suspected increased maternal morbidity especially the cesarean rate associated with the induction of labor was based on observational studies which suffer from methodological limitations or based on underpowered small randomized clinical trials.

A recent multicenter, randomized, controlled, unmasked trial conducted in United States of America in 2014-2017 (ARRIVE trial), provides new results with a high level of evidence. This trial conducted among 6,106 low-risk nulliparous women who were randomized, 3062 assigned to labor induction at 39 weeks 0 day to 39 weeks 4 days and 3,044 assigned to expectant management, demonstrates that induction of labor at 39 weeks did result in a trend but not significant lower frequency of the primary outcome - a composite adverse perinatal outcome - (relative risk \[RR\] 0.80, 95% confidence interval \[CI\] 0.64-1.00), but did result in a significantly lower frequency of cesarean delivery (RR 0.84, 95% CI 0.76-0.93).

Although the cesarean delivery rate was a secondary outcome of the study and the absence of any comparison for women's characteristics of those who were eligible and declined to participate and those who were randomized, the recommendations of the Society of Maternal-Fetal Medicine (SMFM), American College of Obstetricians and Gynecologists (ACOG) and numerous authors have already considered that induction of labor ≥ 39 weeks should be proposed in low-risk nulliparous women. In other words, on the basis mainly on the results of a secondary outcome from only one single randomized controlled trial, they have proposed to modify the management of the pregnant women who reach 39 weeks gestation (i.e. the large majority of the pregnant women) while until now induction of labor for those women was proposed only if abnormal medical condition occurred or beyond 41 weeks of gestation. Nevertheless, the findings of the ARRIVE trial are so important because the reduction of the cesarean rate is a worldwide goal and the elective induction of labor ≥ 39 weeks seems to be today the most effective way to achieve it. However, French context and obstetrical practices are different than USA, with a lower rate of cesarean. Women's characteristics are also different (i.e. lower body mass index in France). Consequently, the external validity of the ARRIVE trial needs to be confirmed. Moreover, in the ARRIVE trial, the labor management has to respect American recent guidelines with a longer duration of the latent phase and administration of oxytocin if needed for at least 12 hours after membrane rupture before deeming the induction a failure. A generalization of labor induction at 39 weeks without a strictly respect of the eligibility criteria or labor management could result to an increase of unexpected adverse maternal or neonatal outcomes.

Thus, the expected benefits of labor induction at 39 weeks have to be confirmed in other context, in particular in French settings with a lower cesarean rate than in USA by replicating the ARRIVE study conducting another randomized controlled trial for which the primary outcome will be the cesarean section rate.

This replication is crucial before leading to a such important change in daily practice that would be considering routine induction of labor for low-risk nulliparous women at 39 weeks of gestation and consequently modifying the organization of all maternity wards in order to achieve this policy.

In addition to the replication of the ARRIVE trial in a French context, a prospective observational cohort with 4,200 women is associated with this trial to identify a potential participant selection bias.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Nulliparous women (i.e. no previous pregnancy beyond 20 weeks)
* With singleton gestation. Twin gestation reduced to singleton, either spontaneously or therapeutically, is not eligible unless the reduction occurred before 14 weeks project gestational age
* Gestational age at randomization between 37 weeks of gestation 0 day and 38 weeks of gestation 6 days inclusive based on the crown rump length measured at the first trimester ultrasound before 14 weeks of gestation and 0 day, as recommended in France
* Affiliated or beneficiary to a health security system
* Signed informed consent

Exclusion Criteria:

* Project gestational age at date of first ultrasound \> 14 weeks
* Plan for induction of labor prior to 40 weeks 5 days
* Plan for cesarean delivery or contraindication to labor
* Breech presentation
* Multiple pregnancy
* Signs of labor (regular painful contractions with cervical change)
* Fetal demise or known major fetal anomaly
* Heparin or low-molecular weight heparin during the current pregnancy
* Placenta previa, accreta, vasa previa
* Active vaginal bleeding greater than bloody show
* Ruptured membranes
* Cerclage in current pregnancy
* Known oligohydramnios, defined as Amniotic Fluid Index \< 5 or Maximal Vertical Pocket \< 2 cm
* Fetal growth restriction, defined as Estimated Fetal Weight \< 10th percentile according to local curve
* Known HIV positivity because of modified delivery plan
* Major maternal medical illness associated with increased risk for adverse pregnancy outcome (for example, any diabetes mellitus, lupus, any hypertensive disorder, cardiac disease, renal insufficiency)
* Refusal of blood products
* Contraindication to oxytocin
* Participation in another interventional study that influences management of labor or delivery (labor induction, operative vaginal delivery, cesarean section, shoulder dystocia)
* Delivery planned elsewhere at a non-Network site
* History of myomectomy by laparotomy or laparoscopy
* Previous metroplasty for uterine malformation or Asherman syndrome
* Patient under legal protection
* Poor understanding of the French language

Primary outcomes:
measure: Incidence of cesarean section
timeFrame: Day 1
Secondary outcomes:
measure: Incidence of incisional extensions
timeFrame: Day 1
measure: Incidence of operative vaginal delivery
timeFrame: Day 1
measure: Incidence of operative vaginal delivery for cesarean
timeFrame: Day 1
measure: Incidence of third or fourth degree perineal laceration
timeFrame: Day 1
measure: Incidence of chorioamnionitis
timeFrame: Hospital discharge (Day 3-5)
measure: Incidence of postpartum hemorrhage
timeFrame: Hospital discharge (Day 3-5)
measure: Incidence of admission to intensive care unit
timeFrame: Hospital discharge (Day 3-5)
measure: Incidence of maternal death
timeFrame: Hospital discharge (Day 3-5)
measure: Incidence of preeclampsia/gestational hypertension
timeFrame: Hospital discharge (Day 3-5)
measure: Maternal pain
timeFrame: Hospital discharge (Day 3-5)
measure: Maternal satisfaction
timeFrame: Hospital discharge (Day 3-5)
measure: interval from randomization to delivery
timeFrame: Day 1
measure: gestational age at delivery
timeFrame: Day 1
measure: Incidence of maternal postpartum infection
timeFrame: Hospital discharge (Day 3-5)
measure: Incidence of maternal venous thromboembolism
timeFrame: Hospital discharge (Day 3-5)
measure: Cervical ripening and induction
timeFrame: Day 1-2
measure: Incidence of composite of severe neonatal morbidity and perinatal mortality
timeFrame: Hospital discharge (Day 3-5)
measure: Mean birth weight
timeFrame: Day 1
measure: Incidence of neonatal acidosis
timeFrame: Day 1
measure: Median duration of respiratory support
timeFrame: Hospital discharge (Day 3-5)
measure: Incidence of small for gestational age
timeFrame: Day 1
measure: Incidence of cephalohematoma
timeFrame: Hospital discharge (Day 3-5)
measure: Incidence of shoulder dystocia
timeFrame: Day 1
measure: Incidence of neonatal transfusion
timeFrame: Hospital discharge (Day 3-5)
measure: Incidence of hyperbilirubinemia
timeFrame: Hospital discharge (Day 3-5)
measure: Incidence of hypoglycemia
timeFrame: Hospital discharge (Day 3-5)
measure: Incidence of admission to neonatal intensive care unit
timeFrame: Hospital discharge (Day 3-5)
measure: Incidence of epidural use
timeFrame: Day 1
measure: Median hours on the labor and delivery unit
timeFrame: Day 1-2
measure: Median maternal postpartum length of hospital stay
timeFrame: Hospital discharge (Day 3-5)
measure: Median neonatal length of hospital stay
timeFrame: Hospital discharge (Day 3-5)
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU de Bordeaux
Study officials:
References: