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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Preterm Premature Rupture of Membrane

Intervention / Treatment
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* Drug: Nifedipine
* Drug: Placebo of Nifedipine


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nifedipine<br> | Drug: Nifedipine<br>* 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)<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo of Nifedipine<br>* Oral Placebo of Nifedipine 20 mg, at T0, T0.5, T3, T11, T19, T27, T35 and T43<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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. | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preterm premature rupture of membranes, Tocolysis, Nifedipine, Latency, Neonatal outcome, Preterm birth, Randomized controlled trial