Effectiveness of Terbutaline Pump for the Prevention of Preterm Birth. A Systematic Review and Meta-Analysis Laura M. Gaudet 1,2,3 , Kavita Singh 1 , Laura Weeks 1 , Becky Skidmore 1 , Alexander Tsertsvadze 1 , Mohammed T. Ansari 1 * 1 Evidence-Based Practice Center, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, 2 Horizon Health Network, Department of Obstetrics and Gynecology, The Moncton Hospital, Moncton, New Brunswick, Canada, 3 University of Ottawa, Ottawa, Ontario, Canada Abstract Background: Subcutaneous terbutaline (SQ terbutaline) infusion by pump is used in pregnant women as a prolonged (beyond 48–72 h) maintenance tocolytic following acute treatment of preterm contractions. The effectiveness and safety of this maintenance tocolysis have not been clearly established. We aimed to systematically evaluate the effectiveness and safety of subcutaneous (SQ) terbutaline infusion by pump for maintenance tocolysis. Methodology/Principal Findings: MEDLINE, EMBASE, CINAHL, the Cochrane Library, the Centre for Reviews and Dissemination databases, post-marketing surveillance data and grey literature were searched up to April 2011 for relevant experimental and observational studies. Two randomized trials, one nonrandomized trial, and 11 observational studies met inclusion criteria. Non-comparative studies were considered only for pump-related harms. We excluded case-reports but sought FDA summaries of post-marketing surveillance data. Non-English records without an English abstract were excluded. Evidence of low strength from observational studies with risk of bias favored SQ terbutaline pump for the outcomes of delivery at ,32 and ,37 weeks, mean days of pregnancy prolongation, and neonatal death. Observational studies of medium to high risk of bias also demonstrated benefit for other surrogate outcomes, such as birthweight and neonatal intensive care unit (NICU) admission. Several cases of maternal deaths and maternal cardiovascular events have been reported in patients receiving terbutaline tocolysis. Conclusions/Significance: Although evidence suggests that pump therapy may be beneficial as maintenance tocolysis, our confidence in its validity and reproducibility is low, suggesting that its use should be limited to the research setting. Concerns regarding safety of therapy persist. Citation: Gaudet LM, Singh K, Weeks L, Skidmore B, Tsertsvadze A, et al. (2012) Effectiveness of Terbutaline Pump for the Prevention of Preterm Birth. A Systematic Review and Meta-Analysis. PLoS ONE 7(2): e31679. doi:10.1371/journal.pone.0031679 Editor: Zulfiqar A. Bhutta, Aga Khan University, Pakistan Received September 22, 2011; Accepted January 16, 2012; Published February 21, 2012 Copyright: ß 2012 Gaudet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This project was funded under Contract No. HHSA-290-2007-10059-I-EPC3 from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services. The funders had no role in study design, data collection and analysis, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: moansari@ohri.ca Introduction Preterm birth is defined as delivery before the completion of the 37th week of gestation and affects 13 percent (542 893 births in 2006) of live births in the United States (http://www.cdc.gov/ nchs/fastats/birthwt.htm) [1]. Approximately 40 percent of preterm births occur after the spontaneous onset of preterm labor [2]. Long-term neonatal sequelae of prematurity such as bron- chopulmonary dysplasia, grade III/IV intraventricular hemor- rhage and retinopathy of prematurity determine the overall quality of life for the child and the family. Terbutaline sulfate has been used off-label in selected patients as a maintenance therapy to inhibit uterine contractions for extended periods of time following primary tocolysis with first-line agents. Terbutaline, a b-sympathomimetic drug, acts to relax smooth muscle in the bronchial tree, blood vessels and myometrium [3]. Maternal side effects are common, and can include serious adverse reactions such as pulmonary edema, myocardial ischemia, cardiac arrhythmias, hypotension, and metabolic alterations [3]. Despite previous reviews which questioned the effectiveness and safety of subcutaneous terbutaline infusion, the use of such therapy is not uncommon in the United States [3,4]. The exact frequency of use of subcutaneous terbutaline infusion for the prevention of preterm birth is not known. This review, commissioned by the Agency for Healthcare Research and Quality through its established stakeholder topic nomination process, aims to systematically review and meta- analyze the evidence examining the efficacy, effectiveness, and harms of SQ terbutaline pump for preventing preterm labor, compared with placebo, conservative treatment, or any other active intervention. We investigated the clinical effectiveness and harms of pump therapy by systematically retrieving, appraising and synthesizing evidence on neonatal health outcomes and outcomes of maternal and neonatal harm. Surrogate outcomes, such as birthweight and prolongation of pregnancy were also examined. The potential confounding effects of maternal activity PLoS ONE | www.plosone.org 1 February 2012 | Volume 7 | Issue 2 | e31679