Advertisement

Nifedipine in the management of preterm labor: a systematic review and metaanalysis

  • Agustín Conde-Agudelo
    Affiliations
    Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, and Detroit, MI
    Search for articles by this author
  • Roberto Romero
    Affiliations
    Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, and Detroit, MI

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
    Search for articles by this author
  • Juan Pedro Kusanovic
    Affiliations
    Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
    Search for articles by this author

      Objective

      To determine the efficacy and safety of nifedipine as a tocolytic agent in women with preterm labor.

      Study Design

      A systematic review and metaanalysis of randomized controlled trials.

      Results

      Twenty-six trials (2179 women) were included. Nifedipine was associated with a significant reduction in the risk of delivery within 7 days of initiation of treatment and before 34 weeks' gestation, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, neonatal jaundice, and admission to the neonatal intensive care unit when compared with β2-adrenergic-receptor agonists. There was no difference between nifedipine and magnesium sulfate in tocolytic efficacy. Nifedipine was associated with significantly fewer maternal adverse events than β2-adrenergic-receptor agonists and magnesium sulfate. Maintenance nifedipine tocolysis was ineffective in prolonging gestation or improving neonatal outcomes when compared with placebo or no treatment.

      Conclusion

      Nifedipine is superior to β2-adrenergic-receptor agonists and magnesium sulfate for tocolysis in women with preterm labor.

      Key words

      The World Health Organization has estimated that 12.9 million births, or 9.6% of all births worldwide, were preterm in 2005.
      • Beck S.
      • Wojdyla D.
      • Say L.
      • et al.
      The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity.
      In the United States, the preterm birth rate has risen over the last 2 decades. In 2007, preterm births constituted 12.7% of live births, an increase of 20% since 1990, and 36% since the early 1980s.
      • Heron M.
      • Sutton P.D.
      • Xu J.
      • Ventura S.J.
      • Strobino D.M.
      • Guyer B.
      Annual summary of vital statistics: 2007.
      Trends in most other developed countries are similar to those in the United States.
      • Raju T.N.
      Epidemiology of late preterm (near-term) births.
      • Goldenberg R.L.
      • Culhane J.F.
      • Iams J.D.
      • Romero R.
      Epidemiology and causes of preterm birth.
      Preterm birth is the leading cause of perinatal morbidity and mortality
      • Goldenberg R.L.
      • Culhane J.F.
      • Iams J.D.
      • Romero R.
      Epidemiology and causes of preterm birth.
      and one of the leading causes of infant mortality.
      • Heron M.
      • Sutton P.D.
      • Xu J.
      • Ventura S.J.
      • Strobino D.M.
      • Guyer B.
      Annual summary of vital statistics: 2007.
      Despite the improvement in survival rates of preterm neonates, they are at increased risk of long-term neurodevelopmental disabilities and respiratory and gastrointestinal complications.
      • Saigal S.
      • Doyle L.W.
      An overview of mortality and sequelae of preterm birth from infancy to adulthood.
      For Editors' Commentary, see Table of Contents
      See related editorial, page 95
      Because uterine contractions are the most frequently recognized symptom and sign of preterm labor, inhibition of uterine contractility with tocolytic agents to prolong pregnancy and reduce neonatal complications continues to be the focus of treatment of preterm labor. Tocolytic agents are intended to arrest uterine contractions during an episode of preterm labor (acute tocolysis) or maintain uterine quiescence after an acute episode has abated (maintenance tocolysis).
      Several agents have been used for the inhibition of uterine contractility, but it remains unclear what the first-line tocolytic agent should be
      American College of Obstetricians and Gynecologists Committee on Practice Bulletins
      ACOG practice bulletin no. 43: clinical management guidelines for obstetrician-gynecologists. May 2003. Management of preterm labor.
      : (1) β2-adrenergic-receptor agonists reduce the rate of preterm delivery within 48 hours of initiation of treatment.
      • Anotayanonth S.
      • Subhedar N.V.
      • Garner P.
      • Neilson J.P.
      • Harigopal S.
      Betamimetics for inhibiting preterm labour.
      Nevertheless, there is no evidence that this delay in the timing of birth by itself translates into improvements in neonatal outcomes, and maternal side effects are considerable
      • Anotayanonth S.
      • Subhedar N.V.
      • Garner P.
      • Neilson J.P.
      • Harigopal S.
      Betamimetics for inhibiting preterm labour.
      ; (2) magnesium sulfate has not been proven to be an effective tocolytic agent, and its use could be associated with an increased risk of fetal, neonatal, and infant mortality
      • Crowther C.A.
      • Hiller J.E.
      • Doyle L.W.
      Magnesium sulphate for preventing preterm birth in threatened preterm labour.
      ; (3) there is insufficient evidence of whether prostaglandin synthesis inhibitors reduce the risk of preterm birth
      • King J.
      • Flenady V.
      • Cole S.
      • Thornton S.
      Cyclo-oxygenase (COX) inhibitors for treating preterm labour.
      ; (4) the oxytocin receptor antagonist atosiban was found to increase the proportion of patients remaining undelivered and not requiring an alternate tocolytic at 7 days when compared with placebo, yet this was not associated with an improvement in neonatal outcome, which has been attributed to the complexities of study design and interpretation of trials of tocolysis that involve a rescue intervention
      • Romero R.
      • Sibai B.M.
      • Sanchez-Ramos L.
      • et al.
      An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue.
      ; barusiban, a selective oxytocin antagonist, has not been found to be more effective than placebo in delaying delivery for 48 hours
      • Thornton S.
      • Goodwin T.M.
      • Greisen G.
      • Hedegaard M.
      • Arce J.C.
      The effect of barusiban, a selective oxytocin antagonist, in threatened preterm labor at late gestational age: a randomized, double-blind, placebo-controlled trial.
      ; (5) there is currently insufficient evidence to support the use of nitric oxide donors as a tocolytic drug,
      • Duckitt K.
      • Thornton S.
      Nitric oxide donors for the treatment of preterm labour.
      although recent studies suggest that this option requires further consideration
      • Smith G.N.
      • Guo Y.
      • Wen S.W.
      • Walker M.C.
      Canadian Preterm Labor Nitroglycerin Trial Group
      Secondary analysis of the use of transdermal nitroglycerin for preterm labor.
      • Smith G.N.
      • Walker M.C.
      • Ohlsson A.
      • O'Brien K.
      • Windrim R.
      Canadian Preterm Labour Nitroglycerin Trial Group
      Randomized double-blind placebo-controlled trial of transdermal nitroglycerin for preterm labor.
      ; and (6) maintenance tocolysis with β2-adrenergic-receptor agonists
      • Dodd J.M.
      • Crowther C.A.
      • Dare M.R.
      • Middleton P.
      Oral betamimetics for maintenance therapy after threatened preterm labour.
      and oral magnesium sulfate
      • Crowther C.A.
      • Moore V.
      Magnesium for preventing preterm birth after threatened preterm labour.
      is ineffective in prolonging gestation or reducing adverse neonatal outcomes. Atosiban maintenance treatment can increase the time interval to the next episode of preterm labor but does not reduce the rate of preterm delivery or improve infant outcomes.
      • Valenzuela G.J.
      • Sanchez-Ramos L.
      • Romero R.
      • et al.
      Maintenance treatment of preterm labor with the oxytocin antagonist atosiban The Atosiban PTL-098 Study Group.
      Some authors have proposed that nifedipine, a calcium channel blocker, could be used as a first-line tocolytic agent.
      • Tsatsaris V.
      • Papatsonis D.
      • Goffinet F.
      • Dekker G.
      • Carbonne B.
      Tocolysis with nifedipine or beta-adrenergic agonists: a meta-analysis.
      • King J.F.
      • Flenady V.
      • Papatsonis D.
      • Dekker G.
      • Carbonne B.
      Calcium channel blockers for inhibiting preterm labour; a systematic review of the evidence and a protocol for administration of nifedipine.
      • Simhan H.N.
      • Caritis S.N.
      Prevention of preterm delivery.
      The most recent substantial update of the Cochrane review regarding calcium channel blockers for acute tocolysis in preterm labor included 12 randomized controlled trials (10 using nifedipine) involving 1029 patients.
      • King J.F.
      • Flenady V.J.
      • Papatsonis D.N.
      • Dekker G.A.
      • Carbonne B.
      Calcium channel blockers for inhibiting preterm labour.
      This review concluded that calcium channel blockers (mainly nifedipine) reduce the risk of delivery within 7 days of initiation of treatment and delivery before 34 weeks' gestation with improvements in some clinically important neonatal outcomes such as respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and neonatal jaundice when compared to other tocolytic agents (mainly beta-mimetics).
      A second review from the Cochrane database on maintenance tocolysis reported that nifedipine neither reduces the risk of preterm birth before 37 weeks' gestation nor improves neonatal outcomes, compared with no treatment.
      • Gaunekar N.N.
      • Crowther C.A.
      Maintenance therapy with calcium channel blockers for preventing preterm birth after threatened preterm labour.
      However, this review included only 1 trial of 74 women. The literature searches on which these reviews were based were performed in 2002 and 2004, respectively. Since that time, additional randomized controlled trials with nifedipine have been published; therefore, reassessment of the efficacy and safety of this agent is justified.
      We conducted a systematic review and metaanalysis of all available randomized controlled trials to determine the efficacy and safety of nifedipine as a tocolytic agent in patients with preterm labor.

      Materials and Methods

      The systematic review was performed following a prospectively prepared protocol and reported using the Preferred Reporting Items for Systematic reviews and Metaanalyses guidelines for metaanalysis of randomized controlled trials.
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.

      Search

      We searched (without language restrictions) the following computerized databases using the terms “nifedipine,” “calcium channel blocker,” “calcium antagonist,” “tocolysis,” “preterm labor,” “premature,” and their associated medical subject headings (MeSH): MEDLINE, EMBASE, CINAHL, and LILACS (all from inception to December 31, 2010), the Cochrane Central Register of Controlled Trials (http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html) (1960 to December 31, 2010), ISI Web of Science (http://www.isiknowledge.com) (1960 to December 31, 2010), Research Registers of Ongoing Trials (www.clinicaltrials.gov, www.controlled-trials.com, www.centerwatch.com, www.anzctr.org.au, and www.umin.ac.jp/ctr), and Google scholar. To ensure maximum sensitivity, we placed no limits or filters on the searches. Proceedings of the Society for Maternal-Fetal Medicine and international meetings on preterm birth and tocolysis, reference lists of identified studies, textbooks, previously published systematic reviews, and review articles were also searched. For studies with multiple publications, the data from the most complete report were used and supplemented if additional information appeared in other publications.

      Study selection

      We included randomized controlled trials in which nifedipine was used for tocolysis in patients with preterm labor compared with alternative tocolytic agents, placebo, or no treatment. Trials were excluded if they were quasi-randomized, if they compared only different doses of nifedipine or other calcium channel blockers, or if nifedipine was given in addition to or following failure of another tocolytic drug. Published abstracts alone were excluded if additional information on methodological issues and results could not be obtained. We classified trials according to the aim of the treatment with nifedipine into 2 groups: acute tocolysis and maintenance tocolysis. Two reviewers independently evaluated studies for inclusion, and disagreements were resolved through consensus among the authors. Investigators of selected studies were contacted to complement data on trial methods and/or outcomes.

      Outcome measures

      The primary outcomes of interest were delivery within 48 hours and 7 days of treatment for acute tocolysis; delivery before 34 and 37 weeks' gestation for maintenance tocolysis; and perinatal death, admission to neonatal intensive care unit (NICU), neurodevelopmental disability at 2 years of age, and severe maternal adverse drug reactions for both acute and maintenance tocolysis. Secondary outcomes included the interval between trial entry and delivery, gestational age at delivery, maternal adverse events, discontinuation of treatment because of adverse events, birthweight, Apgar score at 5 minutes, respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, neonatal jaundice, neonatal sepsis, fetal death, neonatal death, length of stay in the NICU, long-term psychosocial and motor function, and pregnancy/neonatal outcomes among women enrolled at less than 32 weeks' gestation.

      Study quality assessment

      We conducted quality assessment according to a modified scoring system proposed by Jadad et al,
      • Jadad A.R.
      • Moore R.A.
      • Carroll D.
      • Jenkinson C.
      • Reynolds D.J.
      • Gavaghan D.J.
      • et al.
      Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
      which considers 4 items: randomization, blinding, follow-up, and concealment of allocation. We assigned points to each trial as follows: (1) quality of randomization (2 points: computer-generated random numbers or similar; 1 point: not described; 0 points: quasi-randomized or not randomized [we excluded such studies]); (2) double blinding (2 points: neither the person doing the assessments nor the study participant could identify the intervention being assessed; 1 point: not described; 0 points: no blinding or inadequate method); (3) follow-up (2 points: number or reasons for dropouts and withdrawals described and assessment of primary outcomes in 95% or more of randomized women; 1 point: number or reasons for dropouts and withdrawals described but assessment of primary outcomes in less than 95% of randomized women; 0 points: number or reasons for dropouts and withdrawals not described); and (4) concealment of allocation (2 points: adequate method [central randomization; or drug containers or opaque, sealed envelopes that were sequentially numbered and opened sequentially only after they have been irreversibly assigned to the participant]; 0 points: no concealment of allocation or inadequate method or not described). Thus, the total score ranged from 0 (lowest quality) to 8 (highest quality). Studies that scored 6 points or more were considered to be of high quality. Two investigators (A.C.-A. and J.P.K.) independently assessed study quality, and discrepancies were resolved through discussion.

      Data extraction

      Two reviewers (A.C.-A. and J.P.K.) independently extracted data from each eligible study using a standardized data abstraction form. There was no blinding of authorship. From each article, we extracted data on study characteristics (randomization procedure, blinding of providers, patient and outcome assessors, follow-up period, intention-to-treat analysis, losses to follow-up, exclusions, and concealment allocation method), participants (inclusion and exclusion criteria, definition of preterm labor, cervical dilatation and effacement at trial entry, gestational age at randomization, number of women randomized, baseline characteristics, and country and date of recruitment), details of intervention (aim, loading and maintenance dose, route, duration, re-treatment, use of alternative tocolytic therapy, and routine administration of antenatal corticosteroids), and outcomes (number of outcome events and/or mean ± SD for each outcome).
      Unpublished additional data used in another metaanalysis
      • King J.F.
      • Flenady V.J.
      • Papatsonis D.N.
      • Dekker G.A.
      • Carbonne B.
      Calcium channel blockers for inhibiting preterm labour.
      were included. Studies reporting preterm birth before 36 weeks' gestation as an outcome measure were included into the group of studies reporting preterm birth before 37 weeks' gestation in our data synthesis because of the relatively similar neonatal outcomes. Disagreements regarding extracted data were resolved by discussion among the authors.

      Statistical analysis

      Statistical analyses were performed according to the guidelines of the Cochrane Collaboration.

      Deeks JJ, Higgins JPT, Altman DG, eds. Chapter 9: analysing data and undertaking meta-analyses. In: Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version 5.0.2 [updated September 2009]. The Cochrane Collaboration; 2009.

      We analyzed outcomes on an intention-to-treat basis. If this was not clear from the original article, then we carried out reanalysis when possible. If we found no evidence of a substantial difference in study populations, interventions, or outcome measurements, we performed a metaanalysis. We calculated the summary relative risk (RR) for dichotomous data and weighted mean difference (WMD) for continuous data with associated 95% confidence interval (CI).
      Four prespecified subgroup analyses were performed to compare nifedipine with other tocolytic agents (β2-adrenergic-receptor agonists, magnesium sulfate, atosiban, and nitric oxide donors) for acute tocolysis and 1 to compare nifedipine with placebo or no treatment for maintenance tocolysis. The subgroup analyses comparing nifedipine vs placebo or no treatment for acute tocolysis were not performed because trials addressing these comparisons were not identified.
      Heterogeneity of the results among studies was tested with the quantity I2, which describes the percentage of total variation across studies that is due to heterogeneity rather than chance.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      A value of 0% indicates no observed heterogeneity whereas I2 values of 50% or more indicate a substantial level of heterogeneity.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      We planned to pool data across studies using the fixed-effects models if substantial statistical heterogeneity was no present. We used random-effects models to pool data across studies if I2 values were 50% or greater. A predefined sensitivity analysis was performed to explore the impact of study quality on the effect size for the main outcomes. This analysis was performed by excluding trials with a modified Jadad score less than 6.
      We conducted additional analyses stratified according to the following characteristics: definition of preterm labor (based on uterine contractions plus cervical changes vs based on uterine contractions alone); mean or median cervical dilatation at trial entry (<2 vs ≥2 cm); participating patients in true preterm labor as judged by the authors (yes vs no/not reported); loading dose of nifedipine (10 vs 30 mg); membranes status (intact vs ruptured); plurality (singleton vs twin pregnancy); mean gestational age at trial entry (≤30 weeks vs >30 weeks); study setting (developed vs developing countries); maintenance therapy in studies evaluating acute tocolysis (yes vs no/not reported); use of alternative tocolytic therapy (yes vs no/not reported); and antenatal corticosteroid therapy (yes vs no/not reported). Metaanalyses according to plurality of pregnancy and membranes status, however, were not undertaken because of insufficient data.
      For the comparison nifedipine vs magnesium sulfate, we performed a subgroup analysis according to dosage of magnesium sulfate used (4 g loading dose and 2-4 g/h vs 6 g loading dose and 2-4 g/h). Univariable random effects metaregression models

      Deeks JJ, Higgins JPT, Altman DG, eds. Chapter 9: analysing data and undertaking meta-analyses. In: Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version 5.0.2 [updated September 2009]. The Cochrane Collaboration; 2009.

      were used to examine whether effect sizes were affected by these study characteristics.
      We assessed publication and related biases visually by examining the symmetry of funnel plots and statistically by using the Egger test.
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analyses detected by a simple graphical test.
      The larger the deviation of the intercept of the regression line from zero, the greater was the asymmetry and the more likely it was that the metaanalysis would yield a biased estimates of effect. We considered P < .1 to indicate significant asymmetry, as suggested by Egger.
      We also calculated the number needed to treat (NNT) for an additional beneficial outcome with its 95% CI for outcomes in which the treatment effect was significant at the 5% level (the 95% CI for the absolute risk difference did not include zero).
      • Altman D.G.
      Confidence intervals for the number needed to treat.
      NNT was computed from the results of metaanalysis of relative risks as follows:
      NNT=1controlgroupeventrate×(1relativerisk)


      In this review, NNT for an additional beneficial outcome is the number of women in preterm labor who need to be treated with nifedipine rather than with another tocolytic agent, placebo, or no treatment to prevent 1 case of delivery within 48 hours or 7 days or before 34 or 37 weeks or adverse neonatal outcome.
      Analyses were performed with the Review Manager (RevMan) software version 5.0.23 (The Nordic Cochrane Centre, København, Denmark), StatsDirect version 2.7.8 (StatsDirect Ltd, Cheshire, UK), and Stata, version 10.0 (StataCorp, College Station, TX).

      Results

      We identified 1527 studies in our literature search and considered 61 to be potentially eligible (Figure). Twenty-six studies, including 2179 women, fulfilled inclusion criteria of which 23 evaluated acute tocolysis
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      • Kashanian M.
      • Akbarian A.R.
      • Soltanzadeh M.
      Atosiban and nifedipine for the treatment of preterm labor.
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      and 3 evaluated maintenance tocolysis.
      • Carr D.B.
      • Clark A.L.
      • Kernek K.
      • Spinnato J.A.
      Maintenance oral nifedipine for preterm labor: a randomized clinical trial.
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      There was strong agreement among authors on the inclusion of studies (κ = 0.89). Additional neonatal data and long-term follow-up data for one trial
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      were reported in 2 additional publications.
      • Papatsonis D.N.
      • Kok J.H.
      • van Geijn H.P.
      • Bleker O.P.
      • Adèr H.J.
      • Dekker G.A.
      Neonatal effects of nifedipine and ritodrine for preterm labor.
      • Houtzager B.A.
      • Hogendoorn S.M.
      • Papatsonis D.N.
      • et al.
      Long-term follow up of children exposed in utero to nifedipine or ritodrine for the management of preterm labour.
      Of the 23 trials on acute tocolysis, 16 evaluated nifedipine vs β2-adrenergic-receptor agonists (11 studies using ritodrine,
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      3 studies using terbutaline,
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      and 2 studies using isoxsuprine
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      ), 5 evaluated nifedipine vs magnesium sulfate,
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      and one each evaluated nifedipine vs atosiban
      • Kashanian M.
      • Akbarian A.R.
      • Soltanzadeh M.
      Atosiban and nifedipine for the treatment of preterm labor.
      and nifedipine vs nitric oxide donors.
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      There were no trials in which nifedipine was compared with placebo or no treatment in acute tocolysis.
      Figure thumbnail gr1
      FIGUREStudy selection process
      Conde-Agudelo. Nifedipine in the management of preterm labor. Am J Obstet Gynecol 2011.
      Of the 3 trials on maintenance tocolysis, 2 evaluated nifedipine vs no treatment
      • Carr D.B.
      • Clark A.L.
      • Kernek K.
      • Spinnato J.A.
      Maintenance oral nifedipine for preterm labor: a randomized clinical trial.
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      and 1 evaluated nifedipine vs placebo.
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      In the study by Koks et al,
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      only the subset of patients who were not treated with β2-adrenergic-receptor agonists before trial entry was included (57/102 women). Thirty-five studies were excluded for the following reasons: initially available in abstract form and subsequently published as a full-length report (n = 12); available only in abstract form with insufficient information on methods and results (n = 6); the method of generation of allocation to treatment was quasi-randomized (n = 4); an unclear method of randomization (n = 3); the study did not report relevant outcomes (n = 4); nifedipine was used in combination with other tocolytic agents (n = 2); comparison of 2 calcium channel blockers (n = 1); comparison of 2 dose regimens of nifedipine (n = 1); a nonrandomized trial (n = 1); and women were enrolled only after subcutaneous terbutaline failed to inhibit contractions (n = 1). The list of excluded studies is available from the authors upon request.
      Characteristics of the studies included in the review are summarized in Table 1. Seven studies were conducted in the United States,
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      • Carr D.B.
      • Clark A.L.
      • Kernek K.
      • Spinnato J.A.
      Maintenance oral nifedipine for preterm labor: a randomized clinical trial.
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      11 in Asian countries,
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      • Kashanian M.
      • Akbarian A.R.
      • Soltanzadeh M.
      Atosiban and nifedipine for the treatment of preterm labor.
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      7 in European countries,
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      and 1 in Brazil.
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      The sample size ranged from 40
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      to 192
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      (median, 74). Preterm labor was defined as the presence of uterine contractions with evidence of cervical changes in 18 trials.
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      • Kashanian M.
      • Akbarian A.R.
      • Soltanzadeh M.
      Atosiban and nifedipine for the treatment of preterm labor.
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      • Carr D.B.
      • Clark A.L.
      • Kernek K.
      • Spinnato J.A.
      Maintenance oral nifedipine for preterm labor: a randomized clinical trial.
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      Eight studies did not include cervical changes in the diagnosis of preterm labor.
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.
      TABLE 1Characteristics of studies included in the systematic review
      First author, yearLocationInclusion/exclusion criteriaGestational age (wks), cervical dilatation/effacement, and frequency of uterine contractions at trial entryInterventions (sample size)Alternative tocolytic therapy
      Acute tocolysis
      Nifedipine compared with β2-adrenergic-receptor agonists
      Read,
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      1986
      United Kingdom
      • Inclusion: women with singleton pregnancy in preterm labor (at least 1 uterine contraction every 10 min) and intact membranes.
      • Exclusion: multiple pregnancy, polyhydramnios, premature rupture of membranes, history of cervical surgery, history of midtrimester abortion or previous preterm delivery, history of any medical condition that would contraindicate the use of either of the drugs, chorioamnionitis, any irregularity of the fetal heart rate, and cervical dilatation greater than 4 cm.
      20-35; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry.
      • Nifedipine (n = 20): 30 mg orally, then 20 mg orally every 8 hours for 3 days.
      • Ritodrine (n = 20): 50 μg/min intravenously, increasing by 50 μg every 10 minutes to a maximum of 300 μg for 24 hours, then 10 mg orally oral every 4 hours for 48 hours.
      Ritodrine in nifedipine group
      Ferguson,
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      1990
      United States
      • Inclusion: women with singleton pregnancy in preterm labor (uterine contractions at a frequency of 8 or more per hour with a documented change in cervical dilatation or effacement) irrespective of the membranes status.
      • Exclusion: previous treatment with tocolytics in current pregnancy, diabetes, hyperthyroidism, cardiac disease, severe preeclampsia, eclampsia, placental abruption, chorioamnionitis, multiple pregnancy, polyhydramnios, cervical dilatation greater than 4 cm, fetal distress, severe intrauterine growth retardation, fetal death, and fetal anomaly incompatible with life.
      20-36; mean cervical effacement at trial entry was 60 ± 22% and 67 ± 25% for nifedipine and ritodrine groups, respectively; 82% of women had a cervical dilatation less than 2 cm and 18% had 2-3.9 cm at trial entry.
      • Nifedipine (n = 33): 10 mg sublingually. If uterine contractions persisted after 20 minutes, a similar dose was repeated at intervals of 20 minutes, up to a maximal total dose of 40 mg during the first hour of treatment, then 20 mg orally every 4-6 hours.
      • Ritodrine (n = 33): 50 μg/min intravenously increasing by 50 μg every 15-30 minutes up to a maximum of 350 μg/min, then 10-20 mg orally every 4-6 hours.
      Alternate regimen and terbutaline
      Janky,
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      1990
      France
      • Inclusion: women with singleton pregnancy in preterm labor (at least 2 uterine contractions every 10 minutes with cervical modifications).
      • Exclusion: chorioamnionitis, fetal death, fetal anomaly incompatible with life, medical condition contraindicating the use of betamimetics, cervix greater than 4 cm, and premature rupture of membranes after 34 weeks.
      28-36; 76% of women had a Baumgarten tocolytic score of 3-6 and 24% had a score less than 3 (true labor defined as a Baumgarten tocolytic score of ≥2.5). Mean number of uterine contractions in 20 minutes was 7 (range, 4–12).
      • Nifedipine (n = 30): 10 mg sublingually, then 20 mg orally every 8 hours for 7 days.
      • Ritodrine (n = 32): 200-300 μg/min intravenously until contractions ceased, then 100 μg/min for 24 hours, thereafter 20 mg orally every 4-6 hours for 6 days.
      Permitted but unspecified
      Bracero,
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      1991
      United States
      • Inclusion: women with singleton pregnancy in preterm labor (cervical dilatation ≥2 cm or effacement ≥80%, or ≥2 contractions lasting more than 30 seconds with cervical changes) and intact membranes.
      • Exclusion: multiple pregnancy, premature rupture of membranes
      20-36; mean Bishop score at trial entry was 6.6 ± 1.8 and 5.9 ± 2.4, for nifedipine and ritodrine groups, respectively.
      • Nifedipine (n = 26): 30 mg orally, then 20 mg orally every 6 hours for 24 hours, then decreased to 8 hour intervals for an additional 24 hours, thenceforth 20 mg every 8-12 hours. No data on duration of treatment.
      • Ritodrine (n = 23): 100 μg/min intravenously increasing by 50 μg/min every 10 minutes to a maximum of 350 μg/min. Thirty minutes prior to discontinuation of intravenous ritodrine, 10 mg orally every 2 hours for 24 hours, then 10 mg every 4 hours for 24 hours, then 20 mg every 8-12 hours, thereafter 10-20 mg orally every 4-6 hours. No data on duration of treatment.
      Ritodrine and magnesium sulfate in nifedipine group and magnesium sulfate in ritodrine group
      Kupferminc,
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      1993
      Israel
      • Inclusion: women with singleton or twin pregnancy in preterm labor (uterine contractions at least every 6 minutes with evidence of change in cervical dilatation or effacement between consecutive digital examinations) and intact membranes.
      • Exclusion: polyhydramnios, placental abruption, hypertension, infection, any medical condition that would contraindicate tocolytic therapy, cervical dilatation greater than 4 cm, and premature rupture of membranes.
      26-34; mean cervical dilatation and effacement at trial entry was 1.8 ± 0.6 and 1.9 ± 0.7 cm and 42 ± 17% and 43 ± 14% for nifedipine and ritodrine groups, respectively.
      • Nifedipine (n = 36): 30 mg orally, then 20 mg after 90 minutes if contractions persisted, thereafter 20 mg every 8 hours until 34-35 weeks.
      • Ritodrine (n = 35): 50 μg/min intravenously increasing by 15 μg/min every 15 minutes to a maximum of 300 μg/min for 12 hours, then 10 mg orally every 3 hours until 34-35 weeks.
      Ritodrine in nifedipine group
      Papatsonis,
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      1997
      The Netherlands
      • Inclusion: women with singleton pregnancy in preterm labor (at least 1 uterine contraction every 10 minutes during at least 1 hour; cervical changes were not obligatory for inclusion) irrespective of the membranes status.
      • Exclusion: multiple pregnancy, intrauterine infection, fetal congenital anomalies, abruption placenta, severe fetal growth restriction, and any contraindication for the use of beta-adrenergic drugs.
      20-33 4/7; mean cervical dilatation in women with intact membranes at trial entry was 1.5 ± 2.1 and 1.8 ± 2.2 cm for nifedipine and ritodrine groups, respectively.
      • Nifedipine (n = 95): 10 mg sublingually. If contractions persisted, this dose was repeated every 15 minutes to maximum of 40 mg during the first hour of treatment, then 60-160 mg/day of slow-release nifedipine until 34 weeks.
      • Ritodrine (n = 90): 383 μg/min intravenously after which the infusion rate was determined by the time lag after which tocolysis is established (minimum 100 μg/min) for at least 3 days. Then ritodrine 40 mg orally every 8 hours until 34 weeks in 2 of the 3 participating hospitals.
      Nifedipine in ritodrine group; Indomethacin in both groups
      Koks,
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      1998
      Women receiving β2-agonists immediately before randomization (n = 45) were excluded from analyses.
      The Netherlands
      • Inclusion: women with singleton or twin pregnancy in preterm labor (≥6 uterine contractions per hour with a duration of ≥30 seconds with and without cervical dilatation or effacement) irrespective of the membranes status.
      • Exclusion: any contraindication for the use of nifedipine or betamimetic, intrauterine infection, irregular fetal heart rate, antepartum hemorrhage, and polyhydramnios.
      24-34; 86% of women had a cervical dilatation 2 cm or less and 14% had greater than 2 cm at trial entry.
      • Nifedipine (n = 32): 30 mg sublingually, then 20 mg orally every 6-12 hours, which was reduced to 20 mg every 8 hours until 34 weeks.
      • Ritodrine (n = 25): 200 μg/min intravenously up to maximum of 400 μg/min, then 80 mg orally every 8 hours until 34 weeks.
      Indomethacin in both groups
      García-Velasco,
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      1998
      Spain
      • Inclusion: women with singleton pregnancy in preterm labor (≥4 uterine contractions in 30 minutes, irrespective of cervical changes) and intact membranes.
      • Exclusion: previous tocolytic treatment, cervical dilatation 3 cm or greater, maternal infection, vaginal bleeding, and any medical or obstetrical condition contraindicating tocolytic therapy.
      26-34; mean Bishop score at trial entry was 2.9 ± 0.9 and 2.6 ± 0.9 for nifedipine and ritodrine groups, respectively.
      • Nifedipine (n = 26): 30 mg (20 mg orally and 10 mg sublingually), then 10-20 mg every 4-6 hours. No data on duration of treatment or maintenance therapy.
      • Ritodrine (n = 26): 50 μg/min intravenously increasing by 50 μg/min every 20 minutes to a maximum of 350 μg/min for 12 hours, then 5 mg orally every 3 hours. No data on duration of treatment or maintenance therapy.
      Indomethacin in both groups
      Ganla,
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      1999
      India
      • Inclusion: women with singleton pregnancy in preterm labor (uterine contractions occurring at interval of <10 minutes recorded for at least 30 minutes). No data on membranes status.
      • Exclusion: diabetes, hyperthyroidism, cardiac disease, severe preeclampsia, eclampsia, placental abruption, chorioamnionitis, cervical dilatation greater than 3 cm, severe fetal growth restriction, and lethal fetal anomalies.
      26-36; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry.
      • Nifedipine (n = 50): 5 mg sublingually. If contractions persisted, this dose was repeated every 15 minutes to maximum of 40 mg during the first 2 hours of treatment, then 10 mg orally every 8 hours for 48 hours, thereafter 10-20 mg orally every 12 hours until 36 weeks.
      • Isoxsuprine (n = 50): 0.5 mg/min intravenously increasing to a maximum of 10 mg/min for 12 hours, then 10 mg intramuscularly every 8 hours for 48 hours, thereafter 10-20 mg orally every 8 hours until 36 weeks.
      Not reported
      Al-Qattan,
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      2000
      Kuwait
      • Inclusion: women with singleton pregnancy in preterm labor (uterine contractions at a frequency of 2-3 per 10 minute interval with a documented change in cervical dilatation or effacement) and intact membranes.
      • Exclusion: multiple pregnancy, cardiac disease, placental abruption, hyperthyroidism, severe preeclampsia, eclampsia, infection, cervical dilatation 4 cm or greater, polyhydramnios, fetal pathology, premature rupture of membranes, breech presentation, fetal death, fetal distress, and congenital malformation.
      24-34; 9% of women had a closed cervix, 72% had a cervical dilatation of 1-2 cm, and 19% had greater than 2 cm at trial entry.
      • Nifedipine (n = 30): 30 mg orally. If contractions persisted after 2 hours, a second dose of 20 mg was given, then 20 mg orally every 6 hours until 34 weeks.
      • Ritodrine (n = 30): 50 μg/min intravenously, then 10 mg orally every 4-6 hours until 34 weeks.
      Not reported
      Weerakul,
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      2002
      Thailand
      • Inclusion: women with singleton pregnancy in preterm labor (definition not provided) and intact membranes.
      • Exclusion: multiple pregnancy, premature rupture of membranes, previous tocolytics, cervical dilatation greater than 3 cm, chorioamnionitis, infection, fetal distress, fetal anomalies, and medical or obstetrical complications.
      28-34; mean Bishop score at trial entry was 6.2 ± 2.8 and 5.2 ± 2.6 for nifedipine and terbutaline groups, respectively.
      • Nifedipine (n = 45): 10 mg sublingually. If contractions persisted after 15 minutes, a second dose of 10 mg was given, then 20 mg after 30 minutes to a maximum in the first hour of 40 mg, then 60-120 mg orally per day for 3 days. No data on maintenance therapy.
      • Terbutaline (n = 44): 0.25 mg intravenously followed by continuous intravenous infusion started at 5 μg/min and increased by 5 μg/min every 15 minutes up to a maximum of 15 μg/min. Then the infusion was maintained at the same rate for 2 h, after which the treatment was continued with subcutaneous injection of 0.25 mg every 4 hours for 24 hours. No data on maintenance therapy.
      Not reported
      Rayamahji,
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      2003
      Nepal
      • Inclusion: women with singleton or twin pregnancy in preterm labor (uterine contractions at least 1 every 10 minutes, with even minimal cervical changes) and intact membranes.
      • Exclusion: premature rupture of membranes, advanced labor, preeclampsia, eclampsia, cardiac disease, thyroid disorder, antepartum hemorrhage, polyhydramnios, chorioamnionitis, severe fetal growth restriction, fetal death, oligoamnios, fetal anomalies incompatible with life.
      28-36; 39% had a cervical dilatation less than 1.5 cm and 61% had 1.5-3 cm at trial entry.
      • Nifedipine (n = 32): 10 mg sublingually. This dose was repeated every 20 minutes to maximum of 40 mg during the first hour of treatment, then 10-20 mg orally every 6-8 hours for up to 7 days.
      • Isoxsuprine (n = 30): 0.08 mg/min intravenously increasing to a maximum of 0.24 mg/min, then 10 mg orally every 8 hours for up to 7 days.
      Not reported
      Cararach,
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      2006
      Spain
      • Inclusion: women with singleton pregnancy in preterm labor (at least 2 uterine contractions within a 10 minutes period during 60 minutes) and intact membranes.
      • Exclusion: cervical dilatation greater than 5 cm, polyhydramnios, fetal anomalies, fetal distress, intrauterine infection, fetal growth restriction, contraindication for the use of betamimetic drugs, and previous treatment with tocolytics in current pregnancy.
      22-35; mean Bishop score at trial entry was 2.7 ± 1.8 and 2.9 ± 1.9 for nifedipine and ritodrine groups, respectively.
      • Nifedipine (n = 40): 30 mg (20 mg orally and 10 mg sublingually), then 20 mg orally every 6 hours for 48 hours. There was no maintenance therapy.
      • Ritodrine (n = 40): 100 μg/min intravenously increasing by 50 μg/min every 20 min to a maximum of 350 μg/min for 48 hours followed by 10 mg orally every 6 hours until discharge. There was no maintenance therapy.
      Alternate regimen and indomethacin
      Laohapojanart,
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      2007
      Thailand
      • Inclusion: women with singleton pregnancy in preterm labor (≥4 uterine contractions per 20 minutes with cervical dilatation of 1-4 cm and/or documented changing in cervical effacement) irrespective of the membranes status.
      • Exclusion: multiple pregnancy, heart or renal disease, hypertension, chorioamnionitis, placental abruption, placenta previa, preeclampsia, diabetes, and thyrotoxicosis.
      24-36; mean cervical dilatation and effacement at trial entry was 1.4 ± 0.7 and 1.4 ± 0.6 cm and 59 ± 17% and 64 ± 14% for nifedipine and terbutaline groups, respectively.
      • Nifedipine (n = 20): 10 mg orally. If contractions persisted, 10 mg orally every 4 hours to a maximum in the first hour of 40 mg. Then 20 mg every 4 hours for 3 days. No data on maintenance therapy.
      • Terbutaline (n = 20): 10 μg/min intravenously followed by continuous intravenous infusion with an increment 5 μg/min every 10 minutes until 25 μg/min was reached, then subcutaneous injection of 0.25 mg every 4 hours for 24 hours. No data on maintenance therapy.
      Alternate regimen and indomethacin
      Mawaldi,
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      2008
      Saudi Arabia
      • Inclusion: women with singleton or twin pregnancy in preterm labor (1-3 uterine contractions within a 10 minute period during 60 minutes with cervical dilatation of 0-3 cm in primigravidas and 1-3 cm in multigravidas and cervical effacement <50%) and intact membranes.
      • Exclusion: women carrying more than 2 fetuses, major antepartum hemorrhage, premature rupture of membranes, major medical disorder, temperature higher than 37.5°C, blood pressure less than 90/50 mm Hg, compromised fetus, and lethal fetal anomalies
      24-34; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry.
      • Nifedipine (n = 79): 30 mg orally followed by 20 mg after 90 min. If contractions persisted, 20 mg orally every 8 h for 48 h. No data on maintenance therapy.
      • Terbutaline (n = 95): 0.25 mg subcutaneous repeated every 45 minutes if the uterine contractions persisted. No data on maintenance therapy.
      Not reported
      Van De Water,
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      2008
      The Netherlands
      • Inclusion: women with singleton pregnancy in preterm labor (>1 uterine contraction every 10 minutes for at least 60 minutes) irrespective of the membranes status.
      • Exclusion: multiple pregnancy, intrauterine infection, fetal congenital defects, placental abruption, diabetes mellitus, cardiovascular diseases, hyperthyroidism, and preeclampsia.
      24-34; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry.
      • Nifedipine (n = 48): 20 mg orally. If contractions persisted after 30 minutes, a second dose of 20 mg was given, then 90-120 mg orally per day for 48 hours, thereafter 90 mg/day for 7 days.
      • Ritodrine (n = 43): 200 μg/min intravenously increasing by 50 μg/min every 30 minutes until quiescence was achieved for 48 hours, then 80 mg orally every 8 hours for a total duration of 7 days.
      Indomethacin
      Nifedipine compared with magnesium sulfate
      Glock,
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      1993
      United States
      • Inclusion: primigravid women with singleton pregnancy in preterm labor (regular uterine contractions less than 10 minutes apart with documented cervical change or cervical dilatation 2 cm or greater) and intact membranes.
      • Exclusion: multiple pregnancy, premature rupture of membranes, known tocolytic drug exposure during the study pregnancy, diabetes, hyperthyroidism, cardiac disease, preeclampsia, abruptio placentae, chorioamnionitis, hydramnios, renal failure, cervical dilatation 4 cm or greater, fetal distress, severe intrauterine growth restriction, and fetal anomaly incompatible with life
      20-34; mean cervical dilatation and effacement, and uterine contraction frequency at trial entry was 2.0 ± 0.8 and 2.0 ± 0.9 cm, 43 ± 7% and 44 ± 8%, and 4.4 ± 1.0 and 4.4 ± 1.1 for nifedipine and magnesium sulfate groups, respectively.
      • Nifedipine (n = 39): 10 mg sublingually. If contractions persisted, this dose was repeated every 20 minutes to maximum of 40 mg during the first hour of treatment. Once contractions ceased, 20 mg orally every 4 hours for 48 hours, then 10 mg orally every 8 hours until 34 weeks.
      • Magnesium sulfate (n = 41): 6 g bolus, then 2 g/h, increased to maximum of 4 g/h until quiescence for 24 hours, then weaned at 0.5 g every 4-6 hours, thereafter terbutaline 5 mg orally every 6 hours until 34 weeks.
      Intravenous ritodrine
      Floyd,
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      1995
      United States
      • Inclusion: women with singleton pregnancy in preterm labor (at least 1 uterine contractions every 10 minutes with documented cervical change or cervical dilatation ≥2 cm) and intact membranes.
      • Exclusion: Previous tocolytic therapy in current pregnancy, allergy to either study drug, medical or obstetric complications precluding treatment with either drug, and chorioamnionitis.
      20-34; mean cervical dilatation and effacement and number of uterine contractions per hour at trial entry was 1.8 ± 1.0 and 1.5 ± 1.2 cm, 46 ± 27% and 51 ± 21%, and 18 ± 6 and 17 ± 0.6 for nifedipine and magnesium sulfate groups, respectively.
      • Nifedipine (n = 50): 30 mg orally followed by 20 mg every 8 hours until quiescence, then 20 mg orally every 8 h until 37 weeks or delivery, whichever occurred first.
      • Magnesium sulfate (n = 40): 4-g bolus then 4-6 g/h continued for 6 hours after quiescence, then magnesium gluconate 2 g orally every 4 hours until 37 weeks or delivery, whichever occurred first.
      Not reported
      Haghighi,
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.
      1999
      Iran
      • Inclusion: women with singleton pregnancy in preterm labor (regular uterine contractions less than 10 minutes apart) and intact membranes.
      • Exclusion: known tocolytic drug exposure during the study pregnancy, diabetes, hyperthyroidism, cardiac disease, preeclampsia, placental abruption, chorioamnionitis, polyhydramnios, renal failure, cervical dilatation 4 cm or greater, fetal distress, severe intrauterine growth restriction, and fetal anomaly incompatible with life.
      23-36; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry.
      • Nifedipine (n = 34): 10 mg sublingually. If contractions persisted, this dose was repeated every 20 minutes to maximum of 40 mg during the first hour of treatment. Once contractions ceased, 20 mg orally every 6 hours during the first 24 hours and 20 mg every 8 hours the second day. No data on maintenance therapy.
      • Magnesium sulfate (n = 40): 6 g bolus, then 2 g/h, increased to maximum of 4 g/h until quiescence for up to 48 hours. Then terbutaline 5 mg orally every 6 h. No data on maintenance therapy.
      Not reported
      Taherian,
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      2007
      Iran
      • Inclusion: women with singleton pregnancy in preterm labor (≥4 uterine contractions per 10 minutes with duration of at least 30 seconds and progressive cervical dilatation and effacement) and intact membranes.
      • Exclusion: taking other tocolytic agents, cervical dilatation 5 cm or greater or obstetrical contraindications for tocolysis such as severe preeclampsia, lethal fetal anomalies, chorioamnionitis, significant antepartum hemorrhage, and maternal cardiac or liver diseases.
      26-36; mean cervical dilatation and effacement at trial entry was 1.5 ± 1.1 and 1.6 ± 1.1 cm and 53 ± 25% and 54 ± 22% for nifedipine and magnesium sulfate groups, respectively.
      • Nifedipine (n = 57): 10 mg orally every 20 minutes (maximal dose of 40 mg in first hour). Once contractions ceased, 10-20 mg orally every 6 hours. No data on duration of treatment or maintenance therapy.
      • Magnesium sulfate (n = 63): 4 g bolus, then 2-3 g/h. No data on duration of treatment or maintenance therapy.
      Ritodrine or indomethacin (18% in nifedipine group and 13% in magnesium sulfate group)
      Lyell,
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      2007
      United States
      • Inclusion: women with singleton or twin pregnancy in preterm labor (≥2 uterine contractions every 10 minutes with cervical change or cervical dilatation ≥2 cm and 80% effacement) irrespective of the membranes status.
      • Exclusion: placental abruption, placenta previa, nonreassuring fetal status, intrauterine growth restriction, chorioamnionitis, and maternal medical disease.
      24-33; mean cervical dilatation and effacement and uterine contraction frequency at trial entry was 1.8 ± 0.9 and 1.9 ± 1.0 cm, 2.2 ± 1.2 and 2.2 ± 1.1 cm, and 3.5 ± 1.2 and 3.6 ± 1.5 for nifedipine and magnesium sulfate groups, respectively.
      • Nifedipine (n = 100): 10 mg sublingually every 20 minutes for three doses total, followed by 20 mg orally every 4-6 hours until at least 12 hours of uterine quiescence occurred within the first 48 hours. Maintenance therapy with nifedipine in 42% of women.
      • Magnesium sulfate (n = 92): 4 g bolus, then 2 g/h, increased to maximum of 4 g/h, until at least 12 hours of uterine quiescence occurred within the first 48 hours. Maintenance therapy with nifedipine in 38% of women.
      Permitted but unspecified
      Nifedipine compared with atosiban
      Kashanian,
      • Kashanian M.
      • Akbarian A.R.
      • Soltanzadeh M.
      Atosiban and nifedipine for the treatment of preterm labor.
      2005
      Iran
      • Inclusion: women with singleton or twin pregnancy in preterm labor (≥4 uterine contractions in 20 minutes or ≥8 in 60 minutes and cervical dilatation and effacement ≥1 cm and ≥50%, respectively) and intact membranes.
      • Exclusion: premature rupture of membranes, vaginal bleeding, fetal death, fetal distress, fetal growth restriction, history of trauma, cervical dilatation greater than 3 cm, maternal systemic disorders, uterine anomaly, and blood pressure less than 90/50 mm Hg.
      26-34; no data on cervical dilatation and effacement, and frequency of uterine contractions at trial entry.
      • Nifedipine (n = 40): 10 mg sublingually every 20 minutes to a maximum in the first hour of 40 mg. Then 20 mg orally every 6 hours for the first 24 hours, then every 8 h for the following 24 h, thereafter 10 mg orally every 8 hours for the last 24 hours. There was no maintenance therapy.
      • Atosiban (n = 40): 300 μg/min intravenously, continued for a maximum of 12 hours, or 6 hours after contractions were inhibited. There was no maintenance therapy.
      Not reported
      Nifedipine compared with nitric oxide donors
      Amorim,
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      2009
      Brazil
      • Inclusion: women with singleton pregnancy in preterm labor (≥4 uterine contractions in 30 minutes with duration of at least 30 seconds and cervical changes) and intact membranes.
      • Exclusion: premature rupture of membranes, preeclampsia, diabetes, placental abruption, fetal malformation, and previous treatment with tocolytics.
      24-34; median (range) cervical dilatation and number of uterine contractions per 10 minutes at trial entry was 2 (2–4) cm and 3 (2–4) cm, respectively.
      • Nifedipine (n = 24): 10 mg sublingually repeated after 30 minutes, then 20 mg orally every 6 hours for at least 24 hours. No data on maintenance therapy.
      • Nitroglycerin (n = 26): 10 mg transdermal patch. If contractions persisted after 6 hours, a second patch of 10 mg was placed (maximum dose of 20 mg per 24 hours). No data on maintenance therapy.
      Terbutaline
      Maintenance tocolysis
      Nifedipine compared with placebo/no treatment
      Carr,
      • Carr D.B.
      • Clark A.L.
      • Kernek K.
      • Spinnato J.A.
      Maintenance oral nifedipine for preterm labor: a randomized clinical trial.
      1999
      United States
      • Inclusion: women with singleton pregnancy who had been in active preterm labor (≥6 uterine contractions per hour for ≥2 hours, cervical dilatation of 2-4 cm, ≥75% effacement, or evidence of cervical change) successfully arrested with intravenous magnesium sulfate.
      • Exclusion: cervical dilatation 5 cm or greater, obstetric contraindications to tocolysis (severe preeclampsia, lethal fetal anomalies, chorioamnionitis, significant antepartum hemorrhage), or maternal cardiac or liver disease.
      24-33; median (range) cervical dilatation and effacement at trial entry was 2 (1–4) cm and 50% (0–100%), respectively
      • Nifedipine (n = 37): 20 mg orally every 4-6 hours until 37 weeks. It was initiated after discontinuation of acute intravenous tocolysis.
      • Control (n = 37): no treatment
      Magnesium sulfate or terbutaline
      Sayin,
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      2004
      Turkey
      • Inclusion: women with singleton or twin pregnancy and intact membranes who had been in active preterm labor (≥4 uterine contractions per hour with evidence of cervical change on serial digital examinations) successfully arrested with intravenous ritodrine and verapamil.
      • Exclusion: cervical dilatation ≥4 cm or greater, triple or higher-order pregnancy, intrauterine infection, fetal congenital anomalies, fetal growth restriction, and any contraindication to betamimetics such as diabetes mellitus, cardiac disease, or hyperthyroidism.
      Not stated; mean Bishop score at trial entry was 2.4 ± 0.8 and 2.6 ± 0.8 for nifedipine and no treatment groups, respectively.
      • Nifedipine (n = 37): 20 mg orally every 6 hours until 37 weeks. It was initiated after discontinuation of acute intravenous tocolysis.
      • Control (n = 36): no treatment
      Ritodrine and verapamil
      Lyell,
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      2008
      United States
      • Inclusion: women with singleton or twin pregnancy and intact membranes who had been in active preterm labor (uterine contractions with cervical change) successfully arrested with intravenous magnesium sulfate or oral nifedipine.
      • Exclusion: placental abruption, placenta previa, fetal anomaly incompatible with life, triple or higher-order multiple pregnancies, intrauterine infection, or a maternal medical contraindication to ongoing tocolysis.
      24-34; mean cervical dilatation and length by digital examination at trial entry was 2.0 ± 0.9 and 2.5 ± 0.9 cm and 2.2 ± 1.2 and 1.6 ± 1.1 cm for nifedipine and magnesium sulfate groups, respectively.
      • Nifedipine (n = 33): 20 mg orally every 6 hours until 37 weeks. It was initiated after discontinuation of acute intravenous tocolysis.
      • Control (n = 35): placebo
      Magnesium sulfate
      Conde-Agudelo. Nifedipine in the management of preterm labor. Am J Obstet Gynecol 2011.
      a Women receiving β2-agonists immediately before randomization (n = 45) were excluded from analyses.
      According to the widely used diagnostic criteria for preterm labor,
      • Gonik B.
      • Creasy R.K.
      Preterm labor: its diagnosis and management.
      we considered that participating women in 20 trials were in “true preterm labor.”
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      • Carr D.B.
      • Clark A.L.
      • Kernek K.
      • Spinnato J.A.
      Maintenance oral nifedipine for preterm labor: a randomized clinical trial.
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      Nineteen studies were limited to women with intact membranes,
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      • Kashanian M.
      • Akbarian A.R.
      • Soltanzadeh M.
      Atosiban and nifedipine for the treatment of preterm labor.
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      • Carr D.B.
      • Clark A.L.
      • Kernek K.
      • Spinnato J.A.
      Maintenance oral nifedipine for preterm labor: a randomized clinical trial.
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      7 also included women with ruptured membranes,
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      and 8 included women with a twin pregnancy.
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      • Kashanian M.
      • Akbarian A.R.
      • Soltanzadeh M.
      Atosiban and nifedipine for the treatment of preterm labor.
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      Standard maternal and fetal contraindications to tocolysis were reported as exclusion criteria in the great majority of included studies.
      The gestational age at inclusion varied from 20 to 36 weeks. The minimum gestational age at trial entry ranged from 20 to 28 weeks, and the maximum ranged from 33 to 36 weeks. Most trials included women between 24 and 34 weeks' gestation. Mean gestational age at each trial's entry varied from 29.1 to 32.4 weeks.
      For studies evaluating acute tocolysis, nifedipine dosing regimens were similar across the trials with loading doses of 10-30 mg administered orally or sublingually, followed by 10-20 mg orally every 4-8 hours for 24-72 hours. Twelve studies used a 30 mg loading dose of nifedipine,
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      • Kashanian M.
      • Akbarian A.R.
      • Soltanzadeh M.
      Atosiban and nifedipine for the treatment of preterm labor.
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      9 used 10 mg,
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      and 1 each used 5 mg
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      and 20 mg.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      Twelve studies
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      • Kashanian M.
      • Akbarian A.R.
      • Soltanzadeh M.
      Atosiban and nifedipine for the treatment of preterm labor.
      repeated a loading dose every 15-20 minutes to a maximum of 40 mg during the first hour of treatment if contractions persisted. Eleven trials
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      reported maintenance therapy, 9
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      did not, and 3
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Kashanian M.
      • Akbarian A.R.
      • Soltanzadeh M.
      Atosiban and nifedipine for the treatment of preterm labor.
      stated there was no maintenance therapy. Seven studies
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      used oral maintenance therapy in both treatment groups until 34-37 weeks' gestation. All but 3 trials
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      reported the total duration of treatment.
      All studies evaluating maintenance tocolysis
      • Carr D.B.
      • Clark A.L.
      • Kernek K.
      • Spinnato J.A.
      Maintenance oral nifedipine for preterm labor: a randomized clinical trial.
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      used nifedipine 20 mg orally every 4-6 hours until 37 weeks' gestation or delivery, whichever occurred first. Use of alternative tocolytic therapy was explicitly mentioned in 18 studies
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      • Carr D.B.
      • Clark A.L.
      • Kernek K.
      • Spinnato J.A.
      Maintenance oral nifedipine for preterm labor: a randomized clinical trial.
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      Twenty trials
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      • Al-Qattan F.
      • Omu A.E.
      • Labeeb N.
      A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour.
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      • Laohapojanart N.
      • Soorapan S.
      • Wacharaprechanont T.
      • Ratanajamit C.
      Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Taherian A.A.
      • Dehdar P.
      Comparison of efficacy and safety of nifedipine versus magnesium sulfate in treatment of preterm labor.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      • Kashanian M.
      • Akbarian A.R.
      • Soltanzadeh M.
      Atosiban and nifedipine for the treatment of preterm labor.
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      • Carr D.B.
      • Clark A.L.
      • Kernek K.
      • Spinnato J.A.
      Maintenance oral nifedipine for preterm labor: a randomized clinical trial.
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      reported administration of antenatal corticosteroids for all women enrolled. In the remaining 6 trials,
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.
      antenatal corticosteroids use was not reported.
      Table 2 shows quality assessment of included studies. All but 5 studies
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      • Rayamajhi R.
      • Pratap K.
      A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.
      • Sayin N.C.
      • Varol F.G.
      • Balkanli-Kaplan P.
      • Sayin M.
      Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor.
      had an adequate generation of allocation sequence. Sixteen studies
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      • Glock J.L.
      • Morales W.J.
      Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      • Lyell D.J.
      • Pullen K.
      • Campbell L.
      • et al.
      Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.
      • Amorim M.M.
      • Lippo L.A.
      • Costa A.A.
      • Coutinho I.C.
      • Souza A.S.
      Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial [in Portuguese].
      • Carr D.B.
      • Clark A.L.
      • Kernek K.
      • Spinnato J.A.
      Maintenance oral nifedipine for preterm labor: a randomized clinical trial.
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      reported adequate concealment of allocation. For all of the 23 studies evaluating acute tocolysis, blinding of the intervention was not performed and blinding assessment of outcomes was not reported. Only 1 study
      • Lyell D.J.
      • Pullen K.M.
      • Mannan J.
      • et al.
      Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.
      evaluating maintenance tocolysis was double blinded. Eighteen trials reported the assessment of primary outcomes in 95% or more of the randomized women.
      • Read M.D.
      • Wellby D.E.
      The use of a calcium antagonist (nifedipine) to suppress preterm labour.
      • Ferguson 2nd, J.E.
      • Dyson D.C.
      • Schutz T.
      • Stevenson D.K.
      A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
      • Janky E.
      • Leng J.J.
      • Cormier P.H.
      • Salamon R.
      • Meynard J.
      A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine [in French].
      • Bracero L.A.
      • Leikin E.
      • Kirshenbaum N.
      • Tejani N.
      Comparison of nifedipine and ritodrine for the treatment of preterm labor.
      • Kupferminc M.
      • Lessing J.B.
      • Yaron Y.
      • Peyser M.R.
      Nifedipine versus ritodrine for suppression of preterm labour.
      • Papatsonis D.N.
      • Van Geijn H.P.
      • Adèr H.J.
      • Lange F.M.
      • Bleker O.P.
      • Dekker G.A.
      Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.
      • Koks C.A.
      • Brölmann H.A.
      • de Kleine M.J.
      • Manger P.A.
      A randomized comparison of nifedipine and ritodrine for suppression of preterm labor.
      • García-Velasco J.A.
      • González González A.
      A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
      • Ganla K.M.
      • Shroff S.A.
      • Desail S.
      • Bhinde A.G.
      a prospective comparison of nifedipine and isoxsuprine for tocolysis.
      • Weerakul W.
      • Chittacharoen A.
      • Suthutvoravut S.
      Nifedipine versus terbutaline in management of preterm labor.
      • Cararach V.
      • Palacio M.
      • Martínez S.
      • et al.
      Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects.
      • Mawaldi L.
      • Duminy P.
      • Tamim H.
      Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor.
      • Van De Water M.
      • Kessel E.T.
      • De Kleine M.J.
      • Oei S.G.
      Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial.
      • Floyd R.C.
      • McLaughlin B.N.
      • Perry Jr, K.G.
      • Martin R.W.
      • Sullivan C.A.
      • Morrison J.C.
      Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects.
      • Haghighi L.
      Prevention of preterm delivery: nifedipine or magnesium sulfate.