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 β 2 -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 β 2 -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 β 2 -adrenergic-receptor agonists and magnesium sulfate for tocolysis in women with preterm labor.
The World Health Organization has estimated that 12.9 million births, or 9.6% of all births worldwide, were preterm in 2005. 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. Trends in most other developed countries are similar to those in the United States. Preterm birth is the leading cause of perinatal morbidity and mortality and one of the leading causes of infant mortality. Despite the improvement in survival rates of preterm neonates, they are at increased risk of long-term neurodevelopmental disabilities and respiratory and gastrointestinal complications.
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 : (1) β 2 -adrenergic-receptor agonists reduce the rate of preterm delivery within 48 hours of initiation of treatment. 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 ; (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 ; (3) there is insufficient evidence of whether prostaglandin synthesis inhibitors reduce the risk of preterm birth ; (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 ; barusiban, a selective oxytocin antagonist, has not been found to be more effective than placebo in delaying delivery for 48 hours ; (5) there is currently insufficient evidence to support the use of nitric oxide donors as a tocolytic drug, although recent studies suggest that this option requires further consideration ; and (6) maintenance tocolysis with β 2 -adrenergic-receptor agonists and oral magnesium sulfate 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.
Some authors have proposed that nifedipine, a calcium channel blocker, could be used as a first-line tocolytic agent. 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. 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. 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.
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.easyaccess1.lib.cuhk.edu.hk/cochrane/cochrane_clcentral_articles_fs.html ) (1960 to December 31, 2010), ISI Web of Science ( http://www.isiknowledge.com.easyaccess1.lib.cuhk.edu.hk ) (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, 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 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. 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 (β 2 -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 I 2 , which describes the percentage of total variation across studies that is due to heterogeneity rather than chance. A value of 0% indicates no observed heterogeneity whereas I 2 values of 50% or more indicate a substantial level of heterogeneity. 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 I 2 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 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. 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). NNT was computed from the results of metaanalysis of relative risks as follows:
N N T = 1 c o n t r o l g r o u p e v e n t r a t e × ( 1 − r e l a t i v e r i s k )
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