Tocolytic Therapy A Meta-Analysis and Decision Analysis David M. Haas, MD, MS, Thomas F. Imperiale, MD, Page R. Kirkpatrick, Robert W. Klein, Terrell W. Zollinger, DrPH, and Alan M. Golichowski, MD, PhD OBJECTIVE: To determine the optimal first-line tocolytic ing prostaglandin inhibitors, only 80 would deliver within agent for treatment of premature labor. 48 hours, compared with 182 for the next-best treatment. METHODS: We performed a quantitative analysis of ran- CONCLUSION: Although all current tocolytic agents domized controlled trials of tocolysis, extracting data on were superior to no treatment at delaying delivery for maternal and neonatal outcomes, and pooling rates for both 48 hours and 7 days, prostaglandin inhibitors were each outcome across trials by treatment. Outcomes were superior to the other agents and may be considered the delay of delivery for 48 hours, 7 days, and until 37 weeks; optimal first-line agent before 32 weeks of gestation to adverse effects causing discontinuation of therapy; absence delay delivery. of respiratory distress syndrome; and neonatal survival. We (Obstet Gynecol 2009;113:585–94) used weighted proportions from a random-effects meta- analysis in a decision model to determine the optimal first-line tocolytic therapy. Sensitivity analysis was per- reterm birth, defined as any birth before the gesta- formed using the standard errors of the weighted propor- Ptional age of 37 weeks, is responsible for most of the 1–3 tions. neonatal morbidity and mortality in the United States and consumes 35% of all U.S. healthcare spending on RESULTS: Fifty-eight studies satisfied the inclusion crite- 4 ria. A random-effects meta-analysis showed that all to- infants. In the United States, 12.7% of infants are born colytic agents were superior to placebo or control groups preterm, totaling more than a half million births in 2 at delaying delivery both for at least 48 hours (53% for 2005. placebo compared with 75–93% for tocolytics) and 7 days To mitigate both maternal and neonatal risks (39% for placebo compared with 61–78% for tocolytics). resulting from preterm birth, current practice is to No statistically significant differences were found for the delay delivery for as long as possible.5 In extremely other outcomes, including the neonatal outcomes of low birth weight infants, a delay of 1 week decreases respiratory distress and neonatal survival. The decision neonatal mortality by 30%6 and allows opportunity to model demonstrated that prostaglandin inhibitors pro- transfer the mother to a tertiary care facility with a vided the best combination of tolerance and delayed neonatal intensive care unit and to administer ante- delivery. In a hypothetical cohort of 1,000 women receiv- natal corticosteroids.1 Tocolytic agents delay births caused by preterm From the Departments of Obstetrics & Gynecology and Internal Medicine, labor. However, no one tocolytic has been identified Division of Gastroenterology, Indiana University School of Medicine; Regenstrief as the best first-line option.1 Risks and benefits of all Institute, Inc.; and Medical Decision Modeling, Inc., Indianapolis, Indiana. tocolytic options for both the fetus and the mother Supported in part by grant K24DK02756 from the National Institutes of Health 7 to Dr. Imperiale. must be considered. Multiple Cochrane systematic 7–11 The authors thank Patrick O. Monahan, PhD, and George Eckert for their reviews exist for individual tocolytic medications, statistical expertise and Ronald Wielage, MPH, for DA programming. but there has been no rigorous, quantitative synthesis Corresponding author: David M. Haas, MD, MS, Department of OB/GYN, of the data comparing tocolytic drug classes. Wishard Memorial Hospital, 1001 West 10th Street, F-5, Indianapolis, IN The objective of this study was to determine the 46202; e-mail: [email protected]. optimal first-line tocolytic agent for the specific ma- Financial Disclosure ternal and neonatal outcomes based on the existing The authors did not report any potential conflicts of interest. literature. The optimal agent would combine the © 2009 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. highest tolerability and the highest proportion of ISSN: 0029-7844/09 delayed delivery. VOL. 113, NO. 3, MARCH 2009 OBSTETRICS & GYNECOLOGY 585 MATERIALS AND METHODS lide, ketorolac, rofecoxib, celecoxib, and mefenamic This project was approved by the Indiana University- acid. Nitrates included nitroglycerin and glyceryl Purdue University Indianapolis-Clarian Institutional trinitrate. We did not control for clinical heterogene- Review Board. We used the Quality of Reporting of ity in the medication dose and schedule. Meta-analyses (QUOROM) statement as a guideline We assessed articles for randomization allocation for conducting this analysis.12 QUOROM provides a using the Cochrane Collaboration A, B, C criteria. In standardized approach to performing and reporting a an effort to limit selection bias, we included articles meta-analysis. with an allocation score of “A” (the assigned treat- We searched the following computerized databases ment was adequately concealed) or “B” (unclear using the terms “preterm labor,” “tocolytic,” and “ob- whether the treatment assignment was adequately stetric labor, premature”: MEDLINE (1950–present), concealed), and excluded articles with an allocation MEDLINE In-Process (January 2008), EMBASE (1988– score of “C” (assigned treatment was not adequately 13 We did not exclude trials for a lack of 2008), The Cochrane Database of Clinical Trials (4th concealed). investigator-blinding postallocation when comparing quarter 2007), and CINAHL (1982–2008). We limited oral with intravenous tocolytic agents because the the search to articles reporting randomized controlled outcomes were objective in nature and reduced the effect trials in humans. Duplicate trial entries were ex- of bias due to a lack of blinding. To increase the cluded. We performed the search in January 2008. To clinical homogeneity among the study groups, we ensure completeness, we cross-referenced our search excluded studies with a mean gestational age of results with the Cochrane Reviews concerning toco- participants at randomization of less than 28 weeks or lytic medications. We read abstracts of titles that 33 weeks or more. If the mean gestational ages of both appeared relevant and then obtained the full text comparison groups in a study were 28 weeks or more articles of abstracts that appeared to fit the topic. and less than 33 weeks but were statistically signifi- Articles were reviewed by two authors (D.H. and cantly different between the groups, we extracted data P.K.), who read the articles and extracted data from on tocolytic efficacy and adverse effects but not on those that satisfied the study entry criteria. Discor- neonatal outcomes. dance between the two authors was resolved by Two authors independently extracted data, which consensus. Abstracts for articles in non-English lan- included allocation quality, presence of blinding, mean guages were reviewed. If the article seemed relevant gestational ages, interventions compared, use of antena- to the review, the full text was obtained and translated tal corticosteroids, and study entry criteria. Outcomes for possible data extraction. Six articles were trans- data extracted included the numbers of participants who lated (three in Chinese and one each in French, had delivery delayed by 48 hours, by 7 days, and until German, and Spanish). Published abstracts alone 37 weeks of gestation, as well as the number of women were not included because insufficient information who had medication adverse effects severe enough to was provided to conduct the quantitative analysis. discontinue the drug or to switch to another drug. If the We included randomized controlled trials that authors of the trial stated that antenatal corticosteroids reported a comparison between different medications were used, we included neonatal outcomes of the pres- or between a medication and a placebo or usual care. ence of respiratory distress syndrome (RDS) and neona- We included trials comparing tocolytic drugs in the tal death. Because current recommended practice in- same class (ie, two betamimetics like ritodrine com- cludes use of antenatal corticosteroids to accelerate fetal pared with terbutaline) but excluded trials that only lung maturity,14 we believe that neonatal outcomes compared different doses of the same agent. Interven- reported in studies that did not use this therapy tions were grouped into categories of control, betami- would not be applicable to the current standard of metics, calcium-channel blockers, magnesium sulfate, care. To clarify this issue, we attempted e-mail nitrates, oxytocin receptor antagonists, and prosta- contact with the authors of studies that did not glandin inhibitors. Control treatments included pla- contain explicit statements regarding the use of cebo treatments, bed rest, intravenous fluids, and antenatal corticosteroids. If we were unable to usual care. Betamimetic drugs included ritodrine, clarify, neonatal outcomes were not extracted. terbutaline, hexoprenaline, isoxsuprine, nydrilin, sal- Study participants enrolled in the trials were butamol, and fenoterol. Calcium-channel blockers pregnant women diagnosed with preterm labor or included nifedipine and nicardipine. Oxytocin recep- threatened preterm delivery. When results were strat- tor antagonists included only atosiban. Prostaglandin ified based on membrane