title: Nifedipine versus placebo in the treatment of preterm prelabor rupture of membranes: a randomized controlled trial: Assessment of perinatal outcome by use of tocolysis in early labor-APOSTEL IV trial.
abstract: OBJECTIVE
  Preterm birth is the most common cause of neonatal morbidity and mortality. Around one third of preterm deliveries starts with preterm prelabor rupture of membranes (PPROM). The aim of this trial was to study the effect of prolonged tocolysis with nifedipine versus placebo in women with PPROM on perinatal outcome and prolongation of pregnancy.
  
  
  METHODS
  The Apostel IV was a nationwide multicenter randomized placebo controlled trial. We included women with PPROM without contractions between 24(+0) and 33(+6) weeks of gestation. Participants were randomly allocated to daily 80mg nifedipine or placebo, until the start of labor, with a maximum of 18 days. The primary outcome measure was a composite of poor neonatal outcome, including perinatal death, bronchopulmonary dysplasia, periventricular leukomalacia>grade 1, intraventricular hemorrhage>grade 2, necrotizing enterocolitis>stage 1 and culture proven sepsis. Secondary outcomes were gestational age at delivery and prolongation of pregnancy. Analysis was by intention to treat. To detect a reduction of poor neonatal outcome from 30% to 10%, 120 women needed to be randomized.
  
  
  BACKGROUND
  NTR 3363.
  
  
  RESULTS
  Between October 2012 and December 2014 we randomized 25 women to nifedipine and 25 women to placebo. Due to slow recruitment the study was stopped prematurely. The median gestational age at randomization was 29.9 weeks (IQR 27.7-31.3) in the nifedipine group and 27.0 weeks (IQR 24.7-29.9) in the placebo group. Other baseline characteristics were comparable. The adverse perinatal outcome occurred in 9 neonates (33.3%) in the nifedipine group and 9 neonates (32.1%) in the placebo group (RR 1.04, 95% CI 0.49-2.2). Two perinatal deaths occurred, both in the nifedipine group. Bronchopulmonary dysplasia was seen less frequently in the nifedipine group (0% versus 17.9%; p=0.03). Prolongation of pregnancy did not differ between the nifedipine and placebo group (median 11 versus 8 days, HR 1.02; 95% CI 0.58-1.79).
  
  
  CONCLUSIONS
  This randomized trial did not show a beneficial effect of prolonged tocolysis on neonatal outcomes or prolongation of pregnancy in women with PPROM without contractions. However, since results are based on a small sample size, a difference in effectiveness cannot be excluded.
authors: Department of Obstetrics, Wilhelmina Hospital Birth Centre, Division Woman & Baby, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors: Tobias A J
authors: TA
authors: Nijman
authors: Department of Obstetrics, Wilhelmina Hospital Birth Centre, Division Woman & Baby, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors: Elvira O G
authors: EO
authors: van Vliet
authors: Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors: Christiana A
authors: CA
authors: Naaktgeboren
authors: Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors: Katrien
authors: K
authors: Oude Rengerink
authors: Department of Obstetrics and Gynecology, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Thomas S
authors: TS
authors: de Lange
authors: Department of Obstetrics and Gynecology, VU Medical Centre, Amsterdam, The Netherlands.
authors: Caroline J
authors: CJ
authors: Bax
authors: Department of Obstetrics, Wilhelmina Hospital Birth Centre, Division Woman & Baby, University Medical Centre Utrecht, Utrecht, The Netherlands; Department of Obstetrics and Gynaecology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Kitty W M
authors: KW
authors: Bloemenkamp
authors: Department of Obstetrics and Gynecology, Isala Clinics, Zwolle, The Netherlands.
authors: Jim
authors: J
authors: van Eyck
authors: Department of Obstetrics and Gynecology, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Marjolein
authors: M
authors: Kok
authors: Department of Obstetrics and Gynecology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors: Hubertina C J
authors: HC
authors: Scheepers
authors: Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Mallory
authors: M
authors: Woiski
authors: Department of Obstetrics, Wilhelmina Hospital Birth Centre, Division Woman & Baby, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors: Arie
authors: A
authors: Franx
authors: The Robinson Research Institute, School of Pediatrics and Reproductive Health and The South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.
authors: Ben Willem J
authors: BW
authors: Mol
authors: Department of Obstetrics, Wilhelmina Hospital Birth Centre, Division Woman & Baby, University Medical Centre Utrecht, Utrecht, The Netherlands; Department of Obstetrics and Gynecology, Academic Medical Centre, Amsterdam, The Netherlands. Electronic address: m.a.oudijk@amc.uva.nl.
authors: Martijn A
authors: MA
authors: Oudijk
mesh_terms: D000328:Adult; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000188:drug therapy*; D006801:Humans; D009543:Nifedipine / Q000627:therapeutic use*; D007752:Obstetric Labor, Premature / Q000188:drug therapy* / Q000517:prevention & control; D011247:Pregnancy; D011256:Pregnancy Outcome; D047928:Premature Birth / Q000188:drug therapy* / Q000517:prevention & control; D015145:Tocolysis / Q000379:methods*; D015149:Tocolytic Agents / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015149:Tocolytic Agents; D009543:Nifedipine
keywords: Drug safety; Neonatal outcomes; Nifedipine; Preterm birth; Preterm prelabor rupture of membranes; Tocolytics