Across several outcomes, the evidence favors subcutaneous terbutaline pump as maintenance tocolytic therapy for women with arrested preterm labor. However, our confidence in the validity and reproducibility of this evidence is low. Most of the evidence came from biased observational studies that reported surrogate outcomes only. Furthermore, the safety of the pump therapy remains unclear, largely because studies lacked power to detect differences in outcomes of harm.
A total of 14 unique studies comprised the body of evidence investigating efficacy and harms of SQ terbutaline pump therapy as maintenance tocolysis in women with arrested preterm labor. Evidence from the only two included RCTs was underpowered to detect differences in outcomes of efficacy and harms. Most data came from observational studies, several of which recruited subjects from a single Matria database. These studies were at significant risk of bias and exhibited considerable clinical and methodological diversity.
While a single study demonstrated improvement in neonatal death in women with recurrent preterm labor and twin gestation receiving SQ terbutaline maintenance tocolysis, several studies presented evidence favoring the pump therapy on surrogate outcomes of preterm birth. However, the evidence for important neonatal health outcomes, neonatal harms, and maternal harms was inconclusive because the studies lacked power to detect differences in clinical events. Furthermore, there was no data on the long-term effects of terbutaline infusion on offspring. Although many decisions regarding SQ terbutaline pump are currently made on the assumption that short-term outcomes will correlate well with improved long-term outcomes, rigorous scientific evaluation is needed to confirm whether such factors lead to better outcomes in this population.
These findings are consistent with those of two existing reviews of SQ terbutaline pump 
. As reported by Nanda et al., we found that the available RCT evidence demonstrated non-significant differences between the pump and placebo or oral terbutaline 
. In agreement with another review, we found that the RCT and observational evidence is conflicting 
. We noted that the RCT evidence did not demonstrate any benefit from the pump while cohort studies of limited methodological validity demonstrated statistically significant effects in favor of the pump for several outcomes.
Based on post-marketing surveillance data, the FDA has issued a new warning against the use of terbutaline in general, and particularly as an injection, as maintenance tocolysis (i.e. beyond 48–72 hours) in pregnant women. The warning is a response to several cases of poor maternal outcomes in pregnancies treated with subcutaneous terbutaline. These cases raised concern regarding a potential causative relationship. It is important to consider that the outcomes in question occur infrequently in the pregnant population, even in the absence of terbutaline use. Assessment of the magnitude of the association between terbutaline use and harm continues to be challenging, given the rarity of events and the lack of good quality, well powered studies. Until this relationship is further delineated, use of terbutaline for the prevention of preterm birth should be limited to carefully-controlled study settings.
The evidence base for this review contained several limitations. Most of the evidence originated from observational study designs with significant risk of bias. Important prognostic factors such as race, socioeconomic status, and fetal fibronectin level were not reported and co-interventions, such as administration of corticosteroids, were rarely described. Moreover, it is uncertain how free the available evidence is from confounding imposed by restriction of maternal activity and level of care. While our review of the literature was comprehensive in capturing comparative evidence estimating the magnitude of benefits and harms of pump therapy, one potential and practical limitation was restriction to evidence reported in the English language.
There are several factors of applicability that should be considered by maternity care providers and policymakers when translating the evidence from this review. The majority of available evidence included women with recurrent preterm labor (i.e. those with arrested preterm labor following first-line tocolytic therapy for 48 hours and then presenting with a second episode) and singleton gestation, with some evidence including women with twin gestation and recurrent preterm labor. Several studies included patients from a national proprietary database run by Matria Healthcare, which provides an outpatient perinatal program consisting of 24-hour nursing and pharmacy support, home uterine activity monitoring, individualized education, and provision of tocolytic therapy to women with preterm labor. These women received a high standard of care.
It is notoriously difficult to conduct trials to assess the efficacy of tocolytics. Studies regarding tocolytics have been plagued by the elusive diagnosis of preterm labor as up to 40 percent of women diagnosed with preterm labor may not actually be in labor 
. As such, a significant proportion of women enrolled in clinical trials of tocolytic efficacy may not be destined to deliver preterm. A definitive trial in this domain must include a focus on accurate diagnosis of preterm labor, perhaps, combining stringent clinical criteria with factors such as positive fetal fibronectin and shortened trans-vaginal cervical length. Outcomes to be investigated should go beyond those of prolongation of pregnancy and birthweight to hard clinical endpoints of neonatal morbidity. Furthermore, the trial should include long-term follow-up to assess subsequent childhood outcomes. It is evidence of improvements in clinical effectiveness outcomes that can impact clinical decision making, societal healthcare costs and guideline recommendations.
In conclusion, our systematic review calls into question the evidence base supporting the current practice of using terbutaline pump as a maintenance tocolytic agent. We feel strongly that use of terbutaline infusion for maintenance tocolysis should be restricted to well-designed, carefully-controlled study settings until there is clear evidence supporting its use. Further, decision and policy makers should take into consideration the limitations of the available data, both in terms of benefit and harm, when formulating recommendations.