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.
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