Obstetrics & Gynecology:
Tocolytic Therapy: A Meta-Analysis and Decision Analysis
Haas, David M. MD, MS; Imperiale, Thomas F. MD; Kirkpatrick, Page R.2,3; Klein, Robert W.4; Zollinger, Terrell W. DrPH1; Golichowski, Alan M. MD, PhD1
From the Departments of 1Obstetrics & Gynecology and 2Internal Medicine, Division of Gastroenterology, Indiana University School of Medicine; 3Regenstrief Institute, Inc.; and 4Medical Decision Modeling, Inc., Indianapolis, Indiana.
Supported in part by grant K24DK02756 from the National Institutes of Health to Dr. Imperiale.
The authors thank Patrick O. Monahan, PhD, and George Eckert for their statistical expertise and Ronald Wielage, MPH, for DA programming.
Corresponding author: David M. Haas, MD, MS, Department of OB/GYN, Wishard Memorial Hospital, 1001 West 10th Street, F-5, Indianapolis, IN 46202; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To determine the optimal first-line tocolytic agent for treatment of premature labor.
METHODS: We performed a quantitative analysis of randomized controlled trials of tocolysis, extracting data on maternal and neonatal outcomes, and pooling rates for each outcome across trials by treatment. Outcomes were delay of delivery for 48 hours, 7 days, and until 37 weeks; adverse effects causing discontinuation of therapy; absence of respiratory distress syndrome; and neonatal survival. We used weighted proportions from a random-effects meta-analysis in a decision model to determine the optimal first-line tocolytic therapy. Sensitivity analysis was performed using the standard errors of the weighted proportions.
RESULTS: Fifty-eight studies satisfied the inclusion criteria. A random-effects meta-analysis showed that all tocolytic agents were superior to placebo or control groups at delaying delivery both for at least 48 hours (53% for placebo compared with 75–93% for tocolytics) and 7 days (39% for placebo compared with 61–78% for tocolytics). No statistically significant differences were found for the other outcomes, including the neonatal outcomes of respiratory distress and neonatal survival. The decision model demonstrated that prostaglandin inhibitors provided the best combination of tolerance and delayed delivery. In a hypothetical cohort of 1,000 women receiving prostaglandin inhibitors, only 80 would deliver within 48 hours, compared with 182 for the next-best treatment.
CONCLUSION: Although all current tocolytic agents were superior to no treatment at delaying delivery for both 48 hours and 7 days, prostaglandin inhibitors were superior to the other agents and may be considered the optimal first-line agent before 32 weeks of gestation to delay delivery.
Preterm birth, defined as any birth before the gestational age of 37 weeks, is responsible for most of the neonatal morbidity and mortality in the United States1–3 and consumes 35% of all U.S. healthcare spending on infants.4 In the United States, 12.7% of infants are born preterm, totaling more than a half million births in 2005.2
To mitigate both maternal and neonatal risks resulting from preterm birth, current practice is to delay delivery for as long as possible.5 In extremely low birth weight infants, a delay of 1 week decreases neonatal mortality by 30%6 and allows opportunity to transfer the mother to a tertiary care facility with a neonatal intensive care unit and to administer antenatal corticosteroids.1
Tocolytic agents delay births caused by preterm labor. However, no one tocolytic has been identified as the best first-line option.1 Risks and benefits of all tocolytic options for both the fetus and the mother must be considered.7 Multiple Cochrane systematic reviews exist for individual tocolytic medications,7–11 but there has been no rigorous, quantitative synthesis of the data comparing tocolytic drug classes.
The objective of this study was to determine the optimal first-line tocolytic agent for the specific maternal and neonatal outcomes based on the existing literature. The optimal agent would combine the highest tolerability and the highest proportion of delayed delivery.
MATERIALS AND METHODS
This project was approved by the Indiana University-Purdue University Indianapolis-Clarian Institutional Review Board. We used the Quality of Reporting of Meta-analyses (QUOROM) statement as a guideline for conducting this analysis.12 QUOROM provides a standardized approach to performing and reporting a meta-analysis.
We searched the following computerized databases using the terms “preterm labor,” “tocolytic,” and “obstetric labor, premature”: MEDLINE (1950–present), MEDLINE In-Process (January 2008), EMBASE (1988– 2008), The Cochrane Database of Clinical Trials (4th quarter 2007), and CINAHL (1982–2008). We limited the search to articles reporting randomized controlled trials in humans. Duplicate trial entries were excluded. We performed the search in January 2008. To ensure completeness, we cross-referenced our search results with the Cochrane Reviews concerning tocolytic medications. We read abstracts of titles that appeared relevant and then obtained the full text articles of abstracts that appeared to fit the topic. Articles were reviewed by two authors (D.H. and P.K.), who read the articles and extracted data from those that satisfied the study entry criteria. Discordance between the two authors was resolved by consensus. Abstracts for articles in non-English languages were reviewed. If the article seemed relevant to the review, the full text was obtained and translated for possible data extraction. Six articles were translated (three in Chinese and one each in French, German, and Spanish). Published abstracts alone were not included because insufficient information was provided to conduct the quantitative analysis.
We included randomized controlled trials that reported a comparison between different medications or between a medication and a placebo or usual care. We included trials comparing tocolytic drugs in the same class (ie, two betamimetics like ritodrine compared with terbutaline) but excluded trials that only compared different doses of the same agent. Interventions were grouped into categories of control, betamimetics, calcium-channel blockers, magnesium sulfate, nitrates, oxytocin receptor antagonists, and prostaglandin inhibitors. Control treatments included placebo treatments, bed rest, intravenous fluids, and usual care. Betamimetic drugs included ritodrine, terbutaline, hexoprenaline, isoxsuprine, nydrilin, salbutamol, and fenoterol. Calcium-channel blockers included nifedipine and nicardipine. Oxytocin receptor antagonists included only atosiban. Prostaglandin inhibitors included indomethacin, sulindac, nimesulide, ketorolac, rofecoxib, celecoxib, and mefenamic acid. Nitrates included nitroglycerin and glyceryl trinitrate. We did not control for clinical heterogeneity in the medication dose and schedule.
We assessed articles for randomization allocation using the Cochrane Collaboration A, B, C criteria. In an effort to limit selection bias, we included articles with an allocation score of “A” (the assigned treatment was adequately concealed) or “B” (unclear whether the treatment assignment was adequately concealed), and excluded articles with an allocation score of “C” (assigned treatment was not adequately concealed).13 We did not exclude trials for a lack of investigator-blinding postallocation when comparing oral with intravenous tocolytic agents because the outcomes were objective in nature and reduced the effect of bias due to a lack of blinding. To increase the clinical homogeneity among the study groups, we excluded studies with a mean gestational age of participants at randomization of less than 28 weeks or 33 weeks or more. If the mean gestational ages of both comparison groups in a study were 28 weeks or more and less than 33 weeks but were statistically significantly different between the groups, we extracted data on tocolytic efficacy and adverse effects but not on neonatal outcomes.
Two authors independently extracted data, which included allocation quality, presence of blinding, mean gestational ages, interventions compared, use of antenatal corticosteroids, and study entry criteria. Outcomes data extracted included the numbers of participants who had delivery delayed by 48 hours, by 7 days, and until 37 weeks of gestation, as well as the number of women who had medication adverse effects severe enough to discontinue the drug or to switch to another drug. If the authors of the trial stated that antenatal corticosteroids were used, we included neonatal outcomes of the presence of respiratory distress syndrome (RDS) and neonatal death. Because current recommended practice includes use of antenatal corticosteroids to accelerate fetal lung maturity,14 we believe that neonatal outcomes reported in studies that did not use this therapy would not be applicable to the current standard of care. To clarify this issue, we attempted e-mail contact with the authors of studies that did not contain explicit statements regarding the use of antenatal corticosteroids. If we were unable to clarify, neonatal outcomes were not extracted.
Study participants enrolled in the trials were pregnant women diagnosed with preterm labor or threatened preterm delivery. When results were stratified based on membrane status or the presence of multiple gestation, data were extracted only for women with intact membranes and singleton pregnancies. For studies that did not stratify data, composite data were extracted.
Data were extracted for the outcomes identified and combined by drug category to calculate a weighted mean and standard error for proportions of successful outcomes using rmeta library software (2.14) for the statistical software R (2.5.1). Because we aggregated data from individual trials according to treatment group, effectively disassembling the trials, we generated weighted proportions based on the number of subjects in each study. Using the DerSimonian-Laird random-effects model, we compared each intervention to control, computing proportions and 95% confidence intervals for the rates of successful outcomes.15 Because disassembling the trials precluded the direct comparisons required for odds ratios and Forest plots, neither was generated.
After completing the meta-analysis, we constructed a decision tree using TreeAge Pro 2007 software (TreeAge Software, Inc. Williamstown, MA) to determine whether one tocolytic class of medication was superior to others. A superior tocolytic agent would have the highest efficacy-to-toxicity ratio. The weighted means and confidence intervals of the pooled studies from the meta-analysis were used to represent the probabilities of: delaying delivery by 48 hours, 7 days, until 37 weeks of gestation, proportion of women discontinuing therapy due to adverse effects, proportion of neonates with RDS, and neonatal death. The first chance node of the decision tree was “adverse effects requiring discontinuation of the medication.” If the patient had to stop or switch medication, we assumed that it would not be considered an effective first-line choice; the base case analysis considered stopping medication to be a failure. After medication tolerance, the next node indicated clinical outcome (eg, delaying delivery for 48 hours, RDS, etc). A probabilistic sensitivity analysis was performed to determine how frequently each comparator treatment was most preferred for each outcome. We used the standard error of each base case proportion in distributions of nodal branching probabilities. One thousand samples were generated for each outcome, and the proportions where each treatment had the lowest failure rate were determined.
Figure 1 depicts the decision tree combining the chance nodes for tolerability and subsequent delay of delivery to at least 48 hours after admission. All base-case models had the same structure, with varying outcomes but with outcome-specific probabilities. An alternative, intention-to-treat approach placed chance nodes after intolerance, assuming that intolerance resulted in the same failure rates as placebo. An additional analysis was performed in which delaying to 7 days was conditional on successfully delaying delivery for 48 hours.
We retrieved 136 full-text articles, of which 58 satisfied the study inclusion and exclusion criteria. The steps to the meta-analysis are summarized in Figure 2. Table 1 lists the studies in the final analysis. Among the included studies, 10 contained data on a placebo or control arm,16–25 39 reported results for betamimetics,16–18,22,24,26–59 20 reported results for calcium-channel blockers,28,32,35,39–42,44,46,47,51,52,55,58–64 19 reported results for magnesium sulfate,16,25,29,38,48,54,56,57,60,61,63–71 8 reported results for oxytocin receptor antagonists,20,26,27,36,39,50,53,62 12 reported results for prostaglandin inhibitors,19,23,30,43,45,49,65,68,70–73 and 3 reported results using nitrates.21,31,66 A total of 16 different head-to-head comparisons were made among the trials. Aggregated trial group characteristics are shown in Table 1. We were unable to confirm antenatal corticosteroid use for 20 trials. Data from subjects using nitrates were not included due to a paucity of studies with all data points.
Aggregated proportions and 95% confidence intervals for each outcome are shown in Table 2 and Figure 3. All tocolytic agents were superior to placebo or control groups at delaying delivery for at least 48 hours and for at least 7 days. However, none of them was superior statistically to placebo or controls for delay of delivery to 37 weeks of gestation. The 95% confidence intervals for rates of RDS overlapped with the placebo or control group for all tocolytic drugs, although the overlap for betamimetics and prostaglandin inhibitors was minimal. Rates of neonatal death were low and were not significantly different among treatment groups. The proportion of women experiencing adverse effects that required discontinuing the medication was similar for all groups except for betamimetics, which had a significantly higher rate of discontinuation.
Table 3 displays the results of the decision analysis. The individual treatment options are compared for each outcome to determine which agent might be considered the optimal first-line treatment. The decision model shows that prostaglandin inhibitors provide superior results for all outcomes except delaying delivery until 37 weeks, where calcium-channel blockers were the superior agent. To enhance the clinical relevance of the analysis, a hypothetical cohort of 1,000 women were simulated, and the number of failures for the individual therapies was calculated for each outcome. Only 80 of 1,000 women treated initially with prostaglandin inhibitors would deliver within 48 hours, as compared with 182 to 416 for other treatments. An intent-to-treat sensitivity analysis did not substantially change the results. The probabilistic sensitivity analysis showed that the treatment rankings of the alternatives were robust, with prostaglandin inhibitors most frequently yielding the lowest number of failures for each outcome except for delaying delivery to 37 weeks of gestation, where calcium-channel blockers were superior. For the 7-day contingent outcome, oxytocin antagonists and prostaglandin inhibitors were essentially equivalent.
Deciding which tocolytic agent to use as the first-line drug is a difficult decision for clinicians. This quantitative analysis demonstrated that all tocolytic drugs were superior to placebo at delaying delivery for 48 hours and 7 days, although not at delaying delivery until 37 weeks. No significant therapeutic differences were seen in the outcomes of RDS or neonatal death. Our analysis suggests that prostaglandin inhibitors may be the superior first-line tocolytic agent because of high tolerability and effectiveness at delaying delivery by at least 7 days. Delaying delivery long enough to administer antenatal corticosteroids is pivotal to improving neonatal outcomes.74
Prostaglandin inhibitors have been used safely in the mid trimester for many years. However, there is concern about their use after 32 weeks of gestation due to the risk of premature closure of the fetal ductus arteriosus.5 A retrospective study of 57 infants whose mothers were treated with indomethacin at or before 30 weeks showed a higher rate of necrotizing enterocolitis, intracranial hemorrhage, and patent ductus arteriosus.75 However, the Cochrane Review for this class of drugs failed to demonstrate a statistically significant increase in any adverse neonatal outcomes.8 Because our analysis was limited to studies with fetuses of mean gestational ages between 28 weeks and 32 weeks, the combination of tolerability and efficacy makes prostaglandin inhibitors seem to be the superior first-line tocolytic therapy. One reason why prostaglandin inhibitors may be superior is the large proportion of cases of preterm labor that are associated with inflammation and subclinical infection.76
We are unaware of another combined meta-analysis and decision analysis designed to determine the optimal first-line tocolytic drug. A decision analysis by Macones et al77 discussed preterm labor management strategies at different gestational ages, starting at 32 weeks. These investigators found that at 32 weeks, tocolysis was superior to no tocolysis or amniocentesis for fetal lung maturity; at 34 weeks, tocolysis and no tocolysis yielded equal outcomes; and at 36 weeks, no tocolysis was the preferred strategy. Their analysis focused on ritodrine for tocolysis. As demonstrated in our analysis, betamimetics were found to have the highest rate of adverse effects requiring discontinuation, which may limit their desirability as a first-line agent. Similar to Macones et al, we found tocolysis superior to no tocolysis in a gestational age range from 28–32 weeks, but we also assessed a variety of tocolytic medications. A cost-effectiveness analysis performed by Ferriols Lisart and colleagues78 found that using ritodrine as the first-line agent with atosiban as a rescue agent was the more cost-effective option. A cost-effectiveness analysis of tocolysis compared with fetal lung maturity testing by Myers et al79 found that treating with tocolytic medication (the model assumed betamimetics) was preferred over fetal lung maturity testing under 34 weeks of gestation. While these analyses attempted to answer a question about the preferred treatment strategy, our analysis went further by considering all commonly used tocolytic drug options. Additionally, our analysis included many recently reported trials and several foreign language trials not included in older reviews.
Our analysis is limited by the data presented in the studies obtained. We were unable to use the neonatal outcome data for several studies that either did not state the use of or did not use antenatal corticosteroids. Although we attempted to obtain this information, we were unable to do so for several trials. This limitation may affect the validity of our findings for RDS and neonatal death. The proportion of occurrence of these outcomes, however, is relatively consistent among studies, suggesting that the data we have for RDS and neonatal death are representative of this literature. These neonatal outcomes are the desired endpoints. However, no tocolytic improved these outcomes compared with controls. Perhaps if the meta-analysis were performed for studies reporting outcomes for pregnancies less than 28 weeks, when these neonatal outcomes are more prevalent, differences in individual tocolytic classes might be present. We did not stratify the trials by medication dosage used. Although there is variation in treatment regimen among the trials, drug dose and schedules were similar to commonly used doses and schedules. Using weighted proportions helped minimize the contribution of smaller trials that used less common dosing strategies. Our decision analysis was a simple model of tolerability and outcome. Tocolytic therapies vary in their costs. Our analysis did not consider cost of the medications or the cost of administration of the medications. A future analysis may include the costs of the therapeutic options and adverse events in the decision model. Standard utility estimates for various obstetric and neonatal outcomes are lacking in the literature. Ascertaining utilities for the outcomes of preterm delivery would also allow for a richer decision tree.
Our analysis deconstructed the individual trials and aggregated the data by treatment arm. This methodology has been reported for other conditions with multiple treatment options80–82 and is a practical approach to pooling data across trials comparing different interventions. Because generating individual odds ratios for each of the 16 different paired comparisons was impractical, this disassembling of trials was necessary. Thus, there were no “paired” groups with which to generate odds ratios or Forest plots for the outcomes. This disassembly of trials, however, did limit the available diagnostic capabilities in the software. An indirect comparison meta-analysis (also known as multiple treatment meta-analysis or network meta-analysis) would be a method to attempt meta-analysis while not deconstructing the trials.83 An indirect comparison analysis has the potential to generate more precise estimates of effect. This type of analysis carries with it other sets of assumptions, however, and is beyond the scope of the current analysis. Although a clinical trial comparing six treatments would be a more rigorous approach to answer the research question, there are logistical limitations to conducting such a trial, not the least of which is the sample size requirement. Accounting for multiple comparisons, a six-armed trial would need nearly 2,000 subjects in each arm to achieve adequate power to determine a statistically significant difference in delayed delivery until 37 weeks of the magnitude observed in our analysis. The random-effects model analyzes variance within the individual treatment arms, not by individual study and accounts for some of the individual trial variation. Table 1 demonstrates that the treatment arms were of similar mean gestational ages and had similar proportions of trials of the highest quality. Thus, a meta-regression controlling for these factors was not performed. A meta-regression would not analyze the direct effect of a covariate on an individual subject’s outcome and would add little to the random-effects model used to compare the aggregated data.
In conclusion, this analysis suggests that tocolytic drugs are superior to placebo or control at delaying delivery by 48 hours and 7 days. There is little difference among treatments in RDS or neonatal death. The decision analysis demonstrated that prostaglandin inhibitors may be the superior first-line tocolytic agents before 32 weeks of gestation to delay delivery for 48 hours and 7 days, whereas calcium-channel blockers may be superior first-line agents to delay delivery until 37 weeks of gestation. These agents have the best combination of tolerability and efficacy and should be considered the best choices for first-line tocolysis, taking into account maternal and fetal factors that might influence the choice of tocolytic agent.
1.ACOG Committee on Practice Bulletins–Obstetrics. ACOG practice bulletin. Management of preterm labor. Number 43, May 2003. Int J Gynaecol Obstet 2003;82:127–35.
2.Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S, et al. Births: final data for 2005. Natl Vital Stat Rep 2007;56:1–103.
3.McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985;312:82–90.
4.Lewit EM, Baker LS, Corman H, Shiono PH. The direct cost of low birth weight. Future Child 1995;5:35–56.
5.Goldenberg RL. The management of preterm labor. Obstet Gynecol 2002;100:1020–37.
6.Finnstrom O, Olausson PO, Sedin G, Serenius F, Svenningsen N, Thiringer K, et al. The Swedish national prospective study on extremely low birthweight (ELBW) infants. Incidence, mortality, morbidity and survival in relation to level of care. Acta Paediatr 1997;86:503–11.
7.Anotayanonth S, Subhedar NV, Garner P, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. The Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD004352. DOI: 10.1002/14651858.CD004352.pub2.
8.King J, Flenady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. The Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD001992. DOI: 10.1002/14651858.CD001992.pub2.
9.King JF, Flenady VJ, Papatsonis DN, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. The Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD002255. DOI: 10.1002/14651858.CD002255.
10.Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD001060. DOI: 10.1002/14651858.CD001060.
11.Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD004452. DOI: 10.1002/14651858.CD004452.pub2.
12.Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999;354:1896–900.
13.Higgins JP, Green S, editors. Assessment of study quality. Cochrane handbook for systematic reviews of interventions 4.2.5 [updated May 2005]. The Cochrane Library, Issue 3. Section 6 ed. Chichester (UK): John Wiley & Sons, Ltd; 2005.
14.American College of Obstetricians and Gynecologists Committee on Obstetric Practice. ACOG Committee Opinion No. 402: Antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2008;111:805–7.
15.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88.
16.Cotton DB, Strassner HT, Hill LM, Schifrin BS, Paul RH. Comparison of magnesium sulfate, terbutaline and a placebo for inhibition of preterm labor. A randomized study. J Reprod Med 1984;29:92–7.
17.Ingemarsson I. Effect of terbutaline on premature labor. A double-blind placebo-controlled study. Am J Obstet Gynecol 1976;125:520–4.
18.Leveno KJ, Klein VR, Guzick DS, Young DC, Hankins GD, Williams ML. Single-centre randomised trial of ritodrine hydrochloride for preterm labour. Lancet 1986;1:1293–6.
19.Niebyl JR, Blake DA, White RD, Kumor KM, Dubin NH, Robinson JC, et al. The inhibition of premature labor with indomethacin. Am J Obstet Gynecol 1980;136:1014–9.
20.Romero R, Sibai BM, Sanchez-Ramos L, Valenzuela GJ, Veille JC, Tabor B, et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000;182:1173–83.
21.Smith GN, Walker MC, Ohlsson A, O’Brien K, Windrim R. Randomized double-blind placebo-controlled trial of transdermal nitroglycerin for preterm labor. Am J Obstet Gynecol 2007;196:37 e1–8.
22.Spellacy WN, Cruz AC, Birk SA, Buhi WC. Treatment of premature labor with ritodrine: a randomized controlled study. Obstet Gynecol 1979;54:220–3.
23.Zuckerman H, Shalev E, Gilad G, Katzuni E. Further study of the inhibition of premature labor by indomethacin. Part II double-blind study. J Perinat Med 1984;12:25–9.
24.Treatment of preterm labor with the beta-adrenergic agonist ritodrine. The Canadian Preterm Labor Investigators Group. N Engl J Med 1992;327:308–12.
25.Cox SM, Sherman ML, Leveno KJ. Randomized investigation of magnesium sulfate for prevention of preterm birth. Am J Obstet Gynecol 1990;163:767–72.
26.European Atosiban Study Group. The oxytocin antagonist atosiban versus the beta-agonist terbutaline in the treatment of preterm labor. A randomized, double-blind, controlled study. Acta Obstet Gynecol Scand 2001;80:413–22.
27.French/Australian Atosiban Investigators Group. Treatment of preterm labor with the oxytocin antagonist atosiban: a double-blind, randomized, controlled comparison with salbutamol. Eur J Obstet Gynecol Reprod Biol 2001;98:177–85.
28.Al-Qattan F, Omu AE, Labeeb N. A prospective randomized study comparing nifedipine versus ritodrine for the suppression of preterm labour. Med Principles Pract 2000;9:164–73.
29.Beall MH, Edgar BW, Paul RH, Smith-Wallace T. A comparison of ritodrine, terbutaline, and magnesium sulfate for the suppression of preterm labor. Am J Obstet Gynecol 1985;153:854–9.
30.Besinger RE, Niebyl JR, Keyes WG, Johnson TR. Randomized comparative trial of indomethacin and ritodrine for the long-term treatment of preterm labor. Am J Obstet Gynecol 1991;164:981–6.
31.Bisits A, Madsen G, Knox M, Gill A, Smith R, Yeo G, et al. The Randomized Nitric Oxide Tocolysis Trial (RNOTT) for the treatment of preterm labor. Am J Obstet Gynecol 2004;191:683–90.
32.Cararach V, Palacio M, Martinez S, Deulofeu P, Sanchez M, Cobo T, et al. Nifedipine versus ritodrine for suppression of preterm labor. Comparison of their efficacy and secondary effects. Eur J Obstet Gynecol Reprod Biol 2006;127:204–8.
33.Caritis SN, Toig G, Heddinger LA, Ashmead G. A double-blind study comparing ritodrine and terbutaline in the treatment of preterm labor. Am J Obstet Gynecol 1984;150:7–14.
34.Essed GG, Eskes TK, Jongsma HW. A randomized trial of two beta-mimetic drugs for the treatment of threatening early labor: clinical results in a prospective comparative study with ritodrine and fenoterol. Eur J Obstet Gynecol Reprod Biol 1978;8:341–8.
35.Garcia-Velasco JA, Gonzalez Gonzalez A. A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor. Int J Gynaecol Obstet 1998;61:239–44.
36.Goodwin TM, Valenzuela GJ, Silver H, Creasy G. Dose ranging study of the oxytocin antagonist atosiban in the treatment of preterm labor. Atosiban Study Group. Obstet Gynecol 1996;88:331–6.
37.Gummerus M. Tocolysis with hexoprenalin and salbutamol in a clinical comparison [in German]. Geburtshilfe Frauenheilkd 1983;43:151–5.
38.Hollander DI, Nagey DA, Pupkin MJ. Magnesium sulfate and ritodrine hydrochloride: a randomized comparison. Am J Obstet Gynecol 1987;156:631–7.
39.Husslein P, Cabero Roura L, Dudenhausen JW, Helmer H, Frydman R, Rizzo N, et al. Atosiban versus usual care for the management of preterm labor. J Perinat Med 2007;35:305–13.
40.Janky E, Leng JJ, Cormier PH, Salamon R, Meynard J. A randomized study of the treatment of threatened premature labor. Nifedipine versus ritodrine [in French]. J Gynecol Obstet Biol Reprod (Paris) 1990;19:478–82.
41.Jannet D, Abankwa A, Guyard B, Carbonne B, Marpeau L, Milliez J. Nicardipine versus salbutamol in the treatment of premature labor. A prospective randomized study. Eur J Obstet Gynecol Reprod Biol 1997;73:11–6.
42.Koks CA, Brolmann HA, de Kleine MJ, Manger PA. A randomized comparison of nifedipine and ritodrine for suppression of preterm labor. Eur J Obstet Gynecol Reprod Biol 1998;77:171–6.
43.Kramer WB, Saade GR, Belfort M, Dorman K, Mayes M, Moise KJ Jr. A randomized double-blind study comparing the fetal effects of sulindac to terbutaline during the management of preterm labor. Am J Obstet Gynecol 1999;180:396–401.
44.Kupferminc M, Lessing JB, Yaron Y, Peyser MR. Nifedipine versus ritodrine for suppression of preterm labour. Br J Obstet Gynaecol 1993;100:1090–4.
45.Kurki T, Eronen M, Lumme R, Ylikorkala O. A randomized double-dummy comparison between indomethacin and nylidrin in threatened preterm labor. Obstet Gynecol 1991;78:1093–7.
46.Laohapojanart N, Soorapan S, Wacharaprechanont T, Ratanajamit C. Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor. J Med Assoc Thai 2007;90:2461–9.
47.Mawaldi L, Duminy P, Tamim H. Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor. Int J Gynaecol Obstet 2008;100:65–8.
48.Miller JM Jr, Keane MW, Horger EO 3rd. A comparison of magnesium sulfate and terbutaline for the arrest of premature labor. A preliminary report. J Reprod Med 1982;27:348–51.
49.Morales WJ, Smith SG, Angel JL, O’Brien WF, Knuppel RA. Efficacy and safety of indomethacin versus ritodrine in the management of preterm labor: a randomized study. Obstet Gynecol 1989;74:567–72.
50.Moutquin JM, Sherman D, Cohen H, Mohide PT, Hochner-Celnikier D, Fejgin M, et al. Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study. Am J Obstet Gynecol 2000;182:1191–9.
51.Papatsonis DN, Van Geijn HP, Ader HJ, Lange FM, Bleker OP, Dekker GA. Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial. Obstet Gynecol 1997;90:230–4.
52.Raymajhi R, Pratap K. A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour. Kathmandu Univ Med J (KUMJ) 2003;1:85–90.
53.Shim JY, Park YW, Yoon BH, Cho YK, Yang JH, Lee Y, et al. Multicentre, parallel group, randomised, single-blind study of the safety and efficacy of atosiban versus ritodrine in the treatment of acute preterm labour in Korean women. BJOG 2006;113:1228–34.
54.Surichamorn P. The efficacy of terbutaline and magnesium sulfate in the management of preterm labor. J Med Assoc Thai 2001;84:98–104.
55.Weerakul W, Chittacharoen A, Suthutvoravut S. Nifedipine versus terbutaline in management of preterm labor. Int J Gynaecol Obstet 2002;76:311–3.
56.Wilkins IA, Lynch L, Mehalek KE, Berkowitz GS, Berkowitz RL. Efficacy and side effects of magnesium sulfate and ritodrine as tocolytic agents. Am J Obstet Gynecol 1988;159:685–9.
57.Zhu B, Fu Y. Treatment of preterm labor with ritodrine [in Chinese]. Zhonghua Fu Chan Ke Za Zhi 1996;31:721–3.
58.Ferguson JE 2nd, Dyson DC, Schutz T, Stevenson DK. A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome. Am J Obstet Gynecol 1990;163:105–11.
59.Fan L, Wu L, Huang X. The effect of calcium entry blocker on the management of preterm labor: a randomized controlled study [in Chinese]. Chin J Pract Gynecol Obstet 2003;19:87–9.
60.Floyd RC, McLaughlin BN, Perry KG, Martin RW, Sullivan CA, Morrison JC. Magnesium sulfate or nifedipine hydrochloride for acute tocolysis of preterm labor: efficacy and side effects. J Matern Fetal Invest 1995;5:25–9.
61.Glock JL, Morales WJ. Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study. Am J Obstet Gynecol 1993;169:960–4.
62.Kashanian M, Akbarian AR, Soltanzadeh M. Atosiban and nifedipine for the treatment of preterm labor. Int J Gynaecol Obstet 2005;91:10–4.
63.Larmon JE, Ross BS, May WL, Dickerson GA, Fischer RG, Morrison JC. Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor. Am J Obstet Gynecol 1999;181:1432–7.
64.Lyell DJ, Pullen K, Campbell L, Ching S, Druzin ML, Chitkara U, et al. Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial. Obstet Gynecol 2007;110:61–7.
65.Borna S, Saeidi FM. Celecoxib versus magnesium sulfate to arrest preterm labor: randomized trial. J Obstet Gynaecol Res 2007;33:631–4.
66.El-Sayed YY, Riley ET, Holbrook RH Jr, Cohen SE, Chitkara U, Druzin ML. Randomized comparison of intravenous nitroglycerin and magnesium sulfate for treatment of preterm labor. Obstet Gynecol 1999;93:79–83.
67.Lorzadeh N, Kazemirad S, Lorzadrh M, Dehnori A. A comparison of human chorionic gonadotropin with magnesium sulphate in inhibition of preterm labor. J Med Sci 2007;7:640–4.
68.McWhorter J, Carlan SJ, OLeary TD, Richichi K, OBrien WF. Rofecoxib versus magnesium sulfate to arrest preterm labor: a randomized trial [published erratum appears in Obstet Gynecol 2004;104:200]. Obstet Gynecol 2004;103:923–30.
69.Mittendorf R, Covert R, Boman J, Khoshnood B, Lee KS, Siegler M. Is tocolytic magnesium sulphate associated with increased total paediatric mortality? Lancet 1997;350:1517–8.
70.Morales WJ, Madhav H. Efficacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor: a randomized study. Am J Obstet Gynecol 1993;169:97–102.
71.Schorr SJ, Ascarelli MH, Rust OA, Ross EL, Calfee EL, Perry KG Jr, et al A comparative study of ketorolac (Toradol) and magnesium sulfate for arrest of preterm labor. South Med J 1998;91:1028–32.
72.Rasanen J, Jouppila P. Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labor: a randomized study. Am J Obstet Gynecol 1995;173:20–5.
73.Sawdy RJ, Lye S, Fisk NM, Bennett PR. A double-blind randomized study of fetal side effects during and after the short-term maternal administration of indomethacin, sulindac, and nimesulide for the treatment of preterm labor. Am J Obstet Gynecol 2003;188:1046–51.
74.Crowley P. Prophylactic corticosteroids for preterm birth. The Cochrane Database of Systematic Reviews 2000, Issue 2 Art. No.: CD000065. DOI: 10.1002/14651858.CD000065.pub2.
75.Norton ME, Merrill J, Cooper BA, Kuller JA, Clyman RI. Neonatal complications after the administration of indomethacin for preterm labor. N Engl J Med 1993;329:1602–7.
76.Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000;342:1500–7.
77.Macones GA, Bader TJ, Asch DA. Optimising maternal-fetal outcomes in preterm labour: a decision analysis. Br J Obstet Gynaecol 1998;105:541–50.
78.Ferriols Lisart R, Nicolas Pico J, Alos Alminana M. Pharmacoeconomic assessment of two tocolysis protocols for the inhibition of premature delivery [in Spanish]. Farm Hosp 2005;29:18–25.
79.Myers ER, Alvarez JG, Richardson DK, Ludmir J. Cost-effectiveness of fetal lung maturity testing in preterm labor. Obstet Gynecol 1997;90:824–9.
80.Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replacement [published erratum appears in JAMA 1995;273:288]. JAMA 1994;271:1780–5.
81.Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum 1990;33:1449–61.
82.Bravata DM, Sanders L, Huang J, Krumholz HM, Olkin I, Gardner CD, et al. Efficacy and safety of low-carbohydrate diets: a systematic review. JAMA 2003;289:1837–50.
83.Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 2005;331:897–900.
This article has been cited 9 time(s).
American Journal of PerinatologyNifedipine Pharmacokinetics Are Influenced by CYP3A5 Genotype When Used as a Preterm Labor TocolyticAmerican Journal of Perinatology
Ultrasound in Obstetrics & GynecologyHotelling's test, multiple t-tests, and uterine artery Doppler evaluation ReplyUltrasound in Obstetrics & Gynecology
American Family Physician
American Family Physician, 81(4):
Journal of Maternal-Fetal & Neonatal MedicineMedical therapy in the management of preterm birthJournal of Maternal-Fetal & Neonatal Medicine
Emergency Medicine Clinics of North AmericaComplications in Late PregnancyEmergency Medicine Clinics of North America
Deutsches Arzteblatt InternationalThe Prevention, Diagnosis and Treatment of Premature LaborDeutsches Arzteblatt International
Obstetrics & GynecologyTocolytic Therapy: A Meta-Analysis and Decision AnalysisObstetrics & Gynecology
Obstetrics & GynecologyTocolytic Therapy: A Meta-Analysis and Decision AnalysisObstetrics & Gynecology
Obstetrics & GynecologyEvidence-Based Medicine Under AttackObstetrics & Gynecology
© 2009 by The American College of Obstetricians and Gynecologists.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Looking for ABOG articles? Visit our ABOG MOC II collection. The selected Green Journal articles are free through the end of the calendar year.
ACOG MEMBER SUBSCRIPTION ACCESS
If you are an ACOG Fellow and have not logged in or registered to Obstetrics & Gynecology, please follow these step-by-step instructions to access journal content with your member subscription.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read