Clinical trial NCT03976063: Tocolysis in the Management of Preterm Premature Rupture of Membranes Before 34 Weeks of Gestation
Official title: Tocolysis in the Management of Preterm Premature Rupture of Membranes Before 34 Weeks of Gestation: a Double-blinded Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Preterm Premature Rupture of Membrane
Keywords: Preterm premature rupture of membranes
Tocolysis
Nifedipine
Latency
Neonatal outcome
Preterm birth
Randomized controlled trial
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
name: Ministry of Health, France
name: Groupe de Recherche en Obstétrique et Gynécologie
First posted: 2019-06-05
Enrollment: 850
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Perinatal morti-morbidity
timeFrame: Up to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary outcomes:
measure: Prolongation of gestation
timeFrame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
measure: Prolongation of gestation
timeFrame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
measure: Prolongation of gestation
timeFrame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
measure: Prolongation of gestation
timeFrame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
measure: Prolongation of gestation
timeFrame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
measure: Maternal morbidity
timeFrame: During the first 10 days postpartum
measure: Maternal morbidity
timeFrame: At delivery
measure: Fetal mortality
timeFrame: Up to delivery so up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
measure: Neonatal mortality
timeFrame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
measure: Neonatal severe morbidity
timeFrame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
measure: Neonatal severe morbidity
timeFrame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
measure: Neonatal severe morbidity
timeFrame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
measure: Neonatal severe morbidity
timeFrame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
measure: Neonatal severe morbidity
timeFrame: From birth to Day 3 after birth.
measure: Neonatal severe morbidity
timeFrame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
measure: Neonatal severe morbidity
timeFrame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
measure: Neonatal morbidity
timeFrame: At birth.
measure: Neonatal morbidity
timeFrame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
measure: Neonatal morbidity
timeFrame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
measure: Neonatal morbidity
timeFrame: From birth to discharge from hospital, with a maximum of 24 weeks after birth.
measure: Neonatal morbidity
timeFrame: From Day 3 after birth to discharge from hospital, with a maximum of 24 weeks after birth.
measure: Vital status
timeFrame: At 22-26 months of corrected age
measure: Frequency of Gross motor impairment among children alive at 2 years of corrected age
timeFrame: At 22-26 months of corrected age
measure: Frequency of Neurosensory impairment among children alive at 2 years of corrected age
timeFrame: At 22-26 months of corrected age
measure: Frequency of Neurosensory impairment among children alive at 2 years of corrected age
timeFrame: At 22-26 months of corrected age
Other outcomes:
Locations:
city: Paris
country: France
facility: Trousseau University Hospital
Study officials:
affiliation: 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
name: Gilles Kayem, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: 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
name: Elsa Lorthe, RM, PhD
role: STUDY_DIRECTOR
References:
citation: 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;2014(2):CD007062. doi: 10.1002/14651858.CD007062.pub3.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Wilson A, Hodgetts-Morton VA, Marson EJ, Markland AD, Larkai E, Papadopoulou A, Coomarasamy A, Tobias A, Chou D, Oladapo OT, Price MJ, Morris K, Gallos ID. Tocolytics for delaying preterm birth: a network meta-analysis (0924). Cochrane Database Syst Rev. 2022 Aug 10;8(8):CD014978. doi: 10.1002/14651858.CD014978.pub2.
citation: Lorthe E, Kayem G; TOCOPROM Study Group and the GROG (Groupe de Recherche en Obstetrique et Gynecologie). Tocolysis in the management of preterm prelabor rupture of membranes at 22-33 weeks of gestation: study protocol for a multicenter, double-blind, randomized controlled trial comparing nifedipine with placebo (TOCOPROM). BMC Pregnancy Childbirth. 2021 Sep 8;21(1):614. doi: 10.1186/s12884-021-04047-2.