Tocolysis in the Management of Preterm Premature Rupture of Membranes Before 34 Weeks of Gestation

Overview

The purpose of this study is to assess whether short-term (48 hr) tocolysis reduces perinatal morti-morbidity in cases of PPROM at 22 to 33 completed weeks' gestation.

Full Title of Study: “Tocolysis in the Management of Preterm Premature Rupture of Membranes Before 34 Weeks of Gestation: a Double-blinded Randomized Controlled Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: November 2025

Detailed Description

Preterm premature rupture of membranes (PPROM) complicates 3% of pregnancies and accounts for one-third of preterm births. It is a leading cause of neonatal mortality and morbidity and increases the risk of maternal infectious morbidity. In cases of early PPROM (22 to 33 completed weeks' gestation), expectant management is recommended in the absence of labor, chorioamnionitis or fetal distress. Antenatal steroids and antibiotics administration are recommended by international guidelines. However, there is no recommendation regarding tocolysis administration in the setting of PPROM. In theory, reducing uterine contractility should delay delivery and reduce risks of prematurity and neonatal adverse consequences. Likewise, a prolongation of gestation may allow administering a corticosteroids complete course that is associated with a two-fold reduction of morbidity and mortality. However, tocolysis may prolong fetal exposure to inflammation and be associated with higher risk of materno-fetal infection, potentially associated with neonatal death or long-term sequelae, including cerebral palsy. The purpose of this study is to assess whether short-term (48 hr) tocolysis reduces perinatal morti-morbidity in cases of PPROM at 22 to 33 completed weeks' gestation.

Interventions

  • Drug: Nifedipine
    • Loading dose: Oral Nifedipine 20 mg prolonged-release at T0 and T0.5 (i.e. 30 min), total=2×20 mg Maintenance dose: Oral Nifedipine 20 mg prolonged-release at T3, then 1 pill every 8 hr for 48 hr (i.e. T11, T19, T27, T35 and T43, total=6×20 mg)
  • Drug: Placebo of Nifedipine
    • Oral Placebo of Nifedipine 20 mg, at T0, T0.5, T3, T11, T19, T27, T35 and T43

Arms, Groups and Cohorts

  • Active Comparator: Nifedipine
  • Placebo Comparator: Placebo

Clinical Trial Outcome Measures

Primary Measures

  • Perinatal morti-morbidity
    • Time Frame: Up to discharge from hospital, with a maximum of 24 weeks after birth.
    • Composite outcome including fetal death, neonatal death and/or neonatal severe morbidity (mechanical ventilation ≥ 48 hrs, severe bronchopulmonary dysplasia, severe intraventricular hemorrhage, cystic periventricular leucomalacia, neonatal early-onset sepsis, necrotizing enterocolitis, retinopathy of prematurity).

Secondary Measures

  • Prolongation of gestation
    • Time Frame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
    • Latency duration (defined as the duration from PPROM to delivery)
  • Prolongation of gestation
    • Time Frame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
    • Pregnancy prolongation beyond 48 hours after randomization
  • Prolongation of gestation
    • Time Frame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
    • Pregnancy prolongation beyond 1 week after randomization
  • Prolongation of gestation
    • Time Frame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
    • Gestational age at delivery
  • Prolongation of gestation
    • Time Frame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
    • Delivery after 37 weeks of gestation
  • Maternal morbidity
    • Time Frame: During the first 10 days postpartum
    • Endometritis, based on clinical diagnosis associating fever (temperature ≥ 38.0°C) with uterine tenderness, purulent or foul-smelling lochia, and in the absence of any other cause.
  • Maternal morbidity
    • Time Frame: At delivery
    • Intra-uterine infection, defined as fever (maternal temperature ≥38 °C), with no alternative cause identified, associated with at least two of the following criteria: persistent fetal tachycardia > 160 bpm, uterine pain or painful uterine contractions or spontaneous labor, purulent amniotic fluid.
  • Fetal mortality
    • Time Frame: Up to delivery so up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
    • Fetal death
  • Neonatal mortality
    • Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
    • Neonatal death
  • Neonatal severe morbidity
    • Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
    • Mechanical ventilation ≥ 48 hrs
  • Neonatal severe morbidity
    • Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
    • Severe bronchopulmonary dysplasia
  • Neonatal severe morbidity
    • Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
    • Severe intraventricular hemorrhage
  • Neonatal severe morbidity
    • Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
    • Cystic periventricular leucomalacia
  • Neonatal severe morbidity
    • Time Frame: From birth to Day 3 after birth.
    • Early-onset sepsis
  • Neonatal severe morbidity
    • Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
    • Necrotizing enterocolitis
  • Neonatal severe morbidity
    • Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
    • Retinopathy of prematurity
  • Neonatal morbidity
    • Time Frame: At birth.
    • Severe fetal acidemia
  • Neonatal morbidity
    • Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
    • Respiratory distress syndrome
  • Neonatal morbidity
    • Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
    • Mild or moderate bronchopulmonary dysplasia
  • Neonatal morbidity
    • Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
    • Grades I-II intraventricular hemorrhage
  • Neonatal morbidity
    • Time Frame: From Day 3 after birth to discharge from hospital, with a maximum of 24 weeks after birth.
    • Late-onset sepsis.
  • Vital status
    • Time Frame: At 22-26 months of corrected age
    • Death between discharge and follow up at 2 years
  • Frequency of Gross motor impairment among children alive at 2 years of corrected age
    • Time Frame: At 22-26 months of corrected age
    • Cerebral palsy
  • Frequency of Neurosensory impairment among children alive at 2 years of corrected age
    • Time Frame: At 22-26 months of corrected age
    • Visual impairment
  • Frequency of Neurosensory impairment among children alive at 2 years of corrected age
    • Time Frame: At 22-26 months of corrected age
    • Hearing impairment

Participating in This Clinical Trial

Inclusion Criteria

  • Preterm premature rupture of membranes (PPROM) between 220/7 – 336/7 weeks of gestation, as diagnosed by obstetric team – Singleton gestation – Fetus alive at the time of randomization (reassuring fetal heart monitoring) – 18 years of age or older – French speaking – Affiliated to social security regime or an equivalent system – Informed consent and signed Exclusion Criteria:

  • PPROM ≥ 24 hours before diagnosis – Ongoing tocolytic treatment at the time of PPROM – Tocolytic treatment with Nifedipine between PPROM diagnosis and randomization – Fetal condition contraindicating expectant management including chorioamnionitis, placental abruption, intrauterine fetal demise, non-reassuring fetal heart rate at the time of randomization – Cervical dilation > 5 cm – Iatrogenic rupture caused by amniocentesis or trophoblast biopsy – Major fetal anomaly – Maternal allergy or contra-indication to Nifedipine or placebo drug components*: – Myocardial infarction – Unstable angina pectoris – Hepatic insufficiency – Cardiovascular shock – Beta blockers placebo drug components: lactose monohydrate, colloidal silica, microcrystalline cellulose – Coadministration of diltiazem or rifampicin – Hypotension (systolic pressure < 90 mmHg) – Participation to another interventional research (category 1) in which intervention could interfere with TOCOPROM's results (efficacy and safety)

Gender Eligibility: Female

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Assistance Publique – Hôpitaux de Paris
  • Collaborator
    • INSERM U1153
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Gilles Kayem, MD, PhD, Principal Investigator, INSERM UMR 1153, Obstetrical, Perinatal and PEdiatric Epidemiology (EPOPé) Research Team, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), DHU Risks in Pregnancy, Paris Descartes University, Trousseau University Hospital
    • Elsa Lorthe, RM, PhD, Study Director, INSERM UMR 1153, Obstetrical, Perinatal and PEdiatric Epidemiology (EPOPé) Research Team, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), DHU Risks in Pregnancy, Paris Descartes University
  • Overall Contact(s)
    • Gilles Kayem, MD, PhD, 00 33 1 44 73 51 18, gilles.kayem@aphp.fr

References

Mackeen AD, Seibel-Seamon J, Muhammad J, Baxter JK, Berghella V. Tocolytics for preterm premature rupture of membranes. Cochrane Database Syst Rev. 2014 Feb 27;(2):CD007062. doi: 10.1002/14651858.CD007062.pub3.

Lorthe E, Goffinet F, Marret S, Vayssiere C, Flamant C, Quere M, Benhammou V, Ancel PY, Kayem G. Tocolysis after preterm premature rupture of membranes and neonatal outcome: a propensity-score analysis. Am J Obstet Gynecol. 2017 Aug;217(2):212.e1-212.e12. doi: 10.1016/j.ajog.2017.04.015. Epub 2017 Apr 13.

Couteau C, Haumonte JB, Bretelle F, Capelle M, D'Ercole C. [Management of preterm and prelabour rupture of membranes in France]. J Gynecol Obstet Biol Reprod (Paris). 2013 Feb;42(1):21-8. doi: 10.1016/j.jgyn.2012.10.008. Epub 2012 Nov 24. French.

Schmitz T, Sentilhes L, Lorthe E, Gallot D, Madar H, Doret-Dion M, Beucher G, Charlier C, Cazanave C, Delorme P, Garabedian C, Azria E, Tessier V, Senat MV, Kayem G. Preterm premature rupture of the membranes: Guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF). Eur J Obstet Gynecol Reprod Biol. 2019 May;236:1-6. doi: 10.1016/j.ejogrb.2019.02.021. Epub 2019 Mar 2.

Flenady V, Wojcieszek AM, Papatsonis DN, Stock OM, Murray L, Jardine LA, Carbonne B. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev. 2014 Jun 5;2014(6):CD002255. doi: 10.1002/14651858.CD002255.pub2.

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