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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.
Eur J Obstet Gynecol Reprod Biol. 2016 Oct; 205:79-84.EJ

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.

STUDY DESIGN

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.

TRIAL REGISTRY

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).

CONCLUSION

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+Show Affiliations

Department of Obstetrics, Wilhelmina Hospital Birth Centre, Division Woman & Baby, University Medical Centre Utrecht, Utrecht, The Netherlands.Department of Obstetrics, Wilhelmina Hospital Birth Centre, Division Woman & Baby, University Medical Centre Utrecht, Utrecht, The Netherlands.Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.Department of Obstetrics and Gynecology, Academic Medical Centre, Amsterdam, The Netherlands.Department of Obstetrics and Gynecology, VU Medical Centre, Amsterdam, The Netherlands.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.Department of Obstetrics and Gynecology, Isala Clinics, Zwolle, The Netherlands.Department of Obstetrics and Gynecology, Academic Medical Centre, Amsterdam, The Netherlands.Department of Obstetrics and Gynecology, Maastricht University Medical Centre, Maastricht, The Netherlands.Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.Department of Obstetrics, Wilhelmina Hospital Birth Centre, Division Woman & Baby, University Medical Centre Utrecht, Utrecht, The Netherlands.The Robinson Research Institute, School of Pediatrics and Reproductive Health and The South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.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.

Pub Type(s)

Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

27567363

Citation

Nijman, Tobias A J., et al. "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." European Journal of Obstetrics, Gynecology, and Reproductive Biology, vol. 205, 2016, pp. 79-84.
Nijman TA, van Vliet EO, Naaktgeboren CA, et al. 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. Eur J Obstet Gynecol Reprod Biol. 2016;205:79-84.
Nijman, T. A., van Vliet, E. O., Naaktgeboren, C. A., Oude Rengerink, K., de Lange, T. S., Bax, C. J., Bloemenkamp, K. W., van Eyck, J., Kok, M., Scheepers, H. C., Woiski, M., Franx, A., Mol, B. W., & Oudijk, M. A. (2016). 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. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 205, 79-84. https://doi.org/10.1016/j.ejogrb.2016.08.024
Nijman TA, et al. 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. Eur J Obstet Gynecol Reprod Biol. 2016;205:79-84. PubMed PMID: 27567363.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Nijman,Tobias A J, AU - van Vliet,Elvira O G, AU - Naaktgeboren,Christiana A, AU - Oude Rengerink,Katrien, AU - de Lange,Thomas S, AU - Bax,Caroline J, AU - Bloemenkamp,Kitty W M, AU - van Eyck,Jim, AU - Kok,Marjolein, AU - Scheepers,Hubertina C J, AU - Woiski,Mallory, AU - Franx,Arie, AU - Mol,Ben Willem J, AU - Oudijk,Martijn A, Y1 - 2016/08/09/ PY - 2016/02/23/received PY - 2016/07/18/revised PY - 2016/08/01/accepted PY - 2016/8/28/entrez PY - 2016/8/28/pubmed PY - 2017/4/30/medline KW - Drug safety KW - Neonatal outcomes KW - Nifedipine KW - Preterm birth KW - Preterm prelabor rupture of membranes KW - Tocolytics SP - 79 EP - 84 JF - European journal of obstetrics, gynecology, and reproductive biology JO - Eur. J. Obstet. Gynecol. Reprod. Biol. VL - 205 N2 - 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. STUDY DESIGN: 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. TRIAL REGISTRY: 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). CONCLUSION: 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. SN - 1872-7654 UR - https://www.unboundmedicine.com/medline/citation/27567363/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0301-2115(16)30872-7 DB - PRIME DP - Unbound Medicine ER -