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)

Cesarean Section Clinical Trial

— 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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04799912
• Other study ID #: CHUBX 2019/58
• Status: Recruiting
• Phase: N/A
• Start date: April 12, 2021
• Est. completion date: June 30, 2027

Study information

• Verified date: December 2023
• Source: University Hospital, Bordeaux
• Contact: Loic Sentilhes, MD, PhD
• Phone: +33556795579
• Email: loic.sentilhes[@]chu-bordeaux.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 4200
• Est. completion date: June 30, 2027
• Est. primary completion date: June 15, 2027
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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 38 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 or perinatal morbidity or mortality

• 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

Related Conditions & MeSH terms

• Cesarean Section

Intervention

Procedure:
• Elective labor induction
Elective labor induction at 39 weeks of gestation

Locations

Country	Name	City	State
France	CHU de Bordeaux	Bordeaux

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Bordeaux	Ministry of Health, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of cesarean section	Incidence of cesarean section defined as a cesarean birth regardless of the indication from the time the woman is randomized	Day 1
Secondary	Incidence of incisional extensions	Incidence of incisional extensions at cesarean section or cervical traumas	Day 1
Secondary	Incidence of operative vaginal delivery	Incidence of operative vaginal delivery and indication	Day 1
Secondary	Incidence of third or fourth degree perineal laceration	Incidence of third or fourth degree perineal laceration	Day 1
Secondary	Incidence of chorioamnionitis	Incidence of chorioamnionitis, defined as a clinical diagnosis before delivery as: maternal fever (body temperature = 38°C) with no alternative cause identified and at least one sign among the following: fetal tachycardia>160 bpm for = 10min or purulent amniotic fluid from the cervical canal	Hospital discharge (Day 3-5)
Secondary	Incidence of postpartum hemorrhage	Incidence of postpartum hemorrhage defined similarly as Grobman et al. in ARRIVE trial as any of the following: Transfusion; Non-elective hysterectomy; Use of sulprostone; Other surgical interventions such as uterine compression sutures, uterine artery ligation, embolization and hypogastric ligation, balloon tamponade; Curettage	Hospital discharge (Day 3-5)
Secondary	Incidence of admission to intensive care unit	Incidence of admission to intensive care unit	Hospital discharge (Day 3-5)
Secondary	Incidence of maternal death	Incidence of maternal death	Hospital discharge (Day 3-5)
Secondary	Incidence of preeclampsia/gestational hypertension	Incidence of preeclampsia/gestational hypertension	Hospital discharge (Day 3-5)
Secondary	Maternal pain	Median patient-reported pain outcomes with a 10-point Likert scale	Hospital discharge (Day 3-5)
Secondary	Maternal satisfaction	Maternal satisfaction with a satisfaction questionnaire derived from the childbirth experience questionnaire and satisfaction questionnaire	Hospital discharge (Day 3-5)
Secondary	interval from randomization to delivery	Median interval from randomization to delivery	Day 1
Secondary	gestational age at delivery	Median gestational age at delivery	Day 1
Secondary	Incidence of maternal postpartum infection	Incidence of maternal postpartum infection defined similarly as Grobman et al. in ARRIVE trial as any of the following: Clinical diagnosis of endometritis; Wound reopened for hematoma, seroma, infection or other reasons; Cellulitis requiring antibiotics; Pneumonia; Pyelonephritis; Bacteremia unknown source; Septic pelvic thrombosis	Hospital discharge (Day 3-5)
Secondary	Incidence of maternal venous thromboembolism	Incidence of maternal venous thromboembolism (deep venous thrombosis diagnosed using bilateral leg Doppler ultrasound or pulmonary embolism diagnosed using bilateral ventilation-perfusion lung scanning or computed tomographic pulmonary angiography)	Hospital discharge (Day 3-5)
Secondary	Cervical ripening and induction	Method used for cervical ripening and induction	Day 1-2
Secondary	Incidence of composite of severe neonatal morbidity and perinatal mortality	Incidence of composite of severe neonatal morbidity and perinatal mortality (any one of the following): Antepartum, intrapartum, or neonatal death; Intubation, continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) for ventilation or cardiorespiratory support within first 72 hours; Apgar = 3 at 5 minutes; Neonatal encephalopathy; Seizures; Sepsis (presence of a clinically ill infant in whom systemic infection is suspected with a positive blood, cerebral spinal fluid (CSF), or catheterized/suprapubic urine culture; or, in the absence of positive cultures, clinical evidence of cardiovascular collapse or an unequivocal X-ray confirming infection).; Pneumonia confirmed by X-ray or positive blood culture.; Meconium aspiration syndrome; Birth trauma (bone fractures, brachial plexus palsy, other neurologic injury, retinal hemorrhage, facial nerve injury); Intracranial hemorrhage or subgaleal hemorrhage; Hypotension requiring pressor support	Hospital discharge (Day 3-5)
Secondary	Mean birth weight	Mean birth weight, incidence of macrosomia > 4,000 g, incidence of large for date fetuses defined as > 90th percentile weight for gestational age	Day 1
Secondary	Incidence of neonatal acidosis	Incidence of neonatal acidosis (defined by umbilical cord arterial pH < 7.00)	Day 1
Secondary	Median duration of respiratory support	Median duration of respiratory support including ventilator, CPAP, HFNC	Hospital discharge (Day 3-5)
Secondary	Incidence of small for gestational age	Incidence of small for gestational age defined as < 5th and < 10th percentile weight for gestational age	Day 1
Secondary	Incidence of cephalohematoma	Incidence of cephalohematoma	Hospital discharge (Day 3-5)
Secondary	Incidence of shoulder dystocia	Incidence of shoulder dystocia	Day 1
Secondary	Incidence of neonatal transfusion	Incidence of neonatal transfusion of blood products or blood	Hospital discharge (Day 3-5)
Secondary	Incidence of hyperbilirubinemia	Incidence of hyperbilirubinemia requiring phototherapy or exchange transfusion	Hospital discharge (Day 3-5)
Secondary	Incidence of hypoglycemia	Incidence of hypoglycemia (glucose < 35 mg/L) requiring IV therapy	Hospital discharge (Day 3-5)
Secondary	Incidence of admission to neonatal intensive care unit	Incidence of admission to neonatal intensive care unit or intermediate care unit	Hospital discharge (Day 3-5)
Secondary	Incidence of epidural use	outcomes: Incidence of epidural use	Day 1
Secondary	Median hours on the labor and delivery unit	Median hours on the labor and delivery unit	Day 1-2
Secondary	Median maternal postpartum length of hospital stay	Median maternal postpartum length of hospital stay	Hospital discharge (Day 3-5)
Secondary	Median neonatal length of hospital stay	Median neonatal length of hospital stay	Hospital discharge (Day 3-5)