Preterm Premature Rupture of Membrane
Conditions
Keywords
Preterm premature rupture of membranes, Tocolysis, Nifedipine, Latency, Neonatal outcome, Preterm birth, Randomized controlled trial
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.
Interventions
DRUGNifedipine
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)
Oral Placebo of Nifedipine 20 mg, at T0, T0.5, T3, T11, T19, T27, T35 and T43
Sponsors
Assistance Publique - Hôpitaux de Paris
Institut National de la Santé Et de la Recherche Médicale, France
Ministry of Health, France
Groupe de Recherche en Obstétrique et Gynécologie
URC-CIC Paris Descartes Necker Cochin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Perinatal morti-morbidity | 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
| Measure | Time frame | Description |
|---|---|---|
| Prolongation of gestation | 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) |
| Maternal morbidity | 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. |
| Fetal mortality | 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 | From birth to discharge from hospital, with a maximum of 24 weeks after birth. | Neonatal death |
| Neonatal severe morbidity | From birth to discharge from hospital, with a maximum of 24 weeks after birth. | Mechanical ventilation ≥ 48 hrs |
| Neonatal morbidity | At birth. | Severe fetal acidemia |
| Vital status | 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 | At 22-26 months of corrected age | Cerebral palsy |
| Frequency of Neurosensory impairment among children alive at 2 years of corrected age | At 22-26 months of corrected age | Visual impairment |
Countries
France
Contacts
PRINCIPAL_INVESTIGATORGilles 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
STUDY_DIRECTORElsa 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
Outcome results
None listed