Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Institut National de la Santé Et de la Recherche Médicale, France | OTHER_GOV |
| Ministry of Health, France | OTHER_GOV |
| Groupe de Recherche en Obstétrique et Gynécologie | UNKNOWN |
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Nifedipine | Active Comparator |
| |
| Placebo | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nifedipine | Drug | Loading dose: Oral Nifedipine 20 mg prolonged-release at T0 and T0.5 (i.e. 30 min), total=2x20 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=6x20 mg) |
| Measure | Description | Time Frame |
|---|---|---|
| Perinatal morti-morbidity | 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). | Up to discharge from hospital, with a maximum of 24 weeks after birth. |
| Measure | Description | Time Frame |
|---|---|---|
| Prolongation of gestation | Latency duration (defined as the duration from PPROM to delivery) | Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) |
| Prolongation of gestation |
Not provided
Inclusion Criteria:
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*:
placebo drug components: lactose monohydrate, colloidal silica, microcrystalline cellulose
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Gilles Kayem, MD, PhD | 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 | Principal Investigator |
| Elsa Lorthe, RM, PhD | 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 | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Trousseau University Hospital | Paris | 75012 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24578236 | Background | 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. | |
| 28412086 | Background | 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. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| C563032 | Preterm Premature Rupture of the Membranes |
| D047928 | Premature Birth |
| ID | Term |
|---|---|
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
Not provided
Not provided
| ID | Term |
|---|---|
| D009543 | Nifedipine |
| ID | Term |
|---|---|
| D004095 | Dihydropyridines |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
Not provided
Not provided
| URC-CIC Paris Descartes Necker Cochin |
| OTHER |
Not provided
Not provided
Not provided
Not provided
| Placebo of Nifedipine | Drug | Oral Placebo of Nifedipine 20 mg, at T0, T0.5, T3, T11, T19, T27, T35 and T43 |
|
Pregnancy prolongation beyond 48 hours after randomization
| Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) |
| Prolongation of gestation | Pregnancy prolongation beyond 1 week after randomization | Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) |
| Prolongation of gestation | Gestational age at delivery | Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) |
| Prolongation of gestation | Delivery after 37 weeks of gestation | Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) |
| Maternal morbidity | 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. | During the first 10 days postpartum |
| Maternal morbidity | 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. | At delivery |
| Fetal mortality | Fetal death | Up to delivery so up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) |
| Neonatal mortality | Neonatal death | From birth to discharge from hospital, with a maximum of 24 weeks after birth. |
| Neonatal severe morbidity | Mechanical ventilation ≥ 48 hrs | From birth to discharge from hospital, with a maximum of 24 weeks after birth. |
| Neonatal severe morbidity | Severe bronchopulmonary dysplasia | From birth to discharge from hospital, with a maximum of 24 weeks after birth. |
| Neonatal severe morbidity | Severe intraventricular hemorrhage | From birth to discharge from hospital, with a maximum of 24 weeks after birth. |
| Neonatal severe morbidity | Cystic periventricular leucomalacia | From birth to discharge from hospital, with a maximum of 24 weeks after birth. |
| Neonatal severe morbidity | Early-onset sepsis | From birth to Day 3 after birth. |
| Neonatal severe morbidity | Necrotizing enterocolitis | From birth to discharge from hospital, with a maximum of 24 weeks after birth. |
| Neonatal severe morbidity | Retinopathy of prematurity | From birth to discharge from hospital, with a maximum of 24 weeks after birth. |
| Neonatal morbidity | Severe fetal acidemia | At birth. |
| Neonatal morbidity | Respiratory distress syndrome | From birth to discharge from hospital, with a maximum of 24 weeks after birth. |
| Neonatal morbidity | Mild or moderate bronchopulmonary dysplasia | From birth to discharge from hospital, with a maximum of 24 weeks after birth. |
| Neonatal morbidity | Grades I-II intraventricular hemorrhage | From birth to discharge from hospital, with a maximum of 24 weeks after birth. |
| Neonatal morbidity | Late-onset sepsis. | From Day 3 after birth to discharge from hospital, with a maximum of 24 weeks after birth. |
| Vital status | Death between discharge and follow up at 2 years | At 22-26 months of corrected age |
| Frequency of Gross motor impairment among children alive at 2 years of corrected age | Cerebral palsy | At 22-26 months of corrected age |
| Frequency of Neurosensory impairment among children alive at 2 years of corrected age | Visual impairment | At 22-26 months of corrected age |
| Frequency of Neurosensory impairment among children alive at 2 years of corrected age | Hearing impairment | At 22-26 months of corrected age |
| 23182704 | Background | 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. |
| 30870741 | Background | 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. |
| 24901312 | Background | 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. |
| 35947046 | Derived | 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. |
| 34496799 | Derived | 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. |
| D000091642 | Urogenital Diseases |