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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