Comparative Effectiveness Review Number 35 Ef fective Health Care Program

Terbutaline Pump for the Prevention of Preterm Birth Executive Summary

Background Effective Health Care Program Preterm birth is defined as delivery before The Effective Health Care Program the completion of the 37th week of was initiated in 2005 to provide valid gestation, and it affects 13 percent of live evidence about the comparative births in the United States. 1 According to effectiveness of different medical the 2010 National Vital Statistics report, interventions. The object is to help there were 542,893 preterm births in the consumers, health care providers, and United States in 2006. 2 Rates of preterm others in making informed choices birth result in a significant disease burden among treatment alternatives. Through to the health care system. Although overall its Comparative Effectiveness Reviews, rates of neonatal mortality continue to the program supports systematic decline, infants born too early are at risk appraisals of existing scientific for long-term morbidity. 3 evidence regarding treatments for Tocolytics are drugs used to delay or high-priority health conditions. It also inhibit contractions during the labor promotes and generates new scientific process. Several tocolytics are available to evidence by identifying gaps in prevent preterm birth. These agents may be existing scientific evidence and administered as primary therapy to control supporting new research. The program acute episodes of preterm labor or as puts special emphasis on translating maintenance therapy to prevent subsequent findings into a variety of useful episodes. Maintenance tocolysis is usually formats for different stakeholders, provided for prolonged periods beyond 48 including consumers. to 72 hours after arrest of acute preterm The full report and this summary are labor to inhibit the process of parturition available at www.effectivehealthcare. until full term. While several studies have ahrq.gov/reports/final.cfm. examined these agents for the control of acute episodes of preterm labor, the evidence to support their safety and The ß -agonist agent, terbutaline sulfate, has efficacy as maintenance therapy is limited. been used orally and subcutaneously as maintenance tocolytic therapy in women following acute treatment and arrest of

Effective Health Care confirmed preterm labor. As with all other performing an up-to-date search of the literature, contemporary tocolytics, the use of terbutaline for synthesizing evidence in the context of specific maintenance tocolysis is off-label. The Food and Drug populations of women, addressing confounding by level Administration (FDA) has approved terbutaline for the of maternal activity and level of care, and grading the management of acute and chronic obstructive strength of evidence for important outcomes to help pulmonary disease only. When administered through decisionmakers develop evidence-based the subcutaneous (SQ) route, terbutaline may be recommendations and policies. administered by a pump that provides a steady continuous infusion with allowance for boluses. Objectives Compared with the oral route of administration, the SQ terbutaline pump uses lower doses (usual basal rate is The objectives of this review were to examine the 0.03–0.05 mg/hr with an intermittent bolus of 0.25 mg efficacy, effectiveness, and safety of the SQ terbutaline every 4 to 6 hours) and has less potential for pump as prolonged maintenance tocolysis for inhibiting tachyphylaxis. 4 progression of parturition in women with arrested acute preterm labor. The SQ terbutaline pump was compared The effectiveness and safety of the SQ terbutaline pump with placebo, conservative treatment, or any other for maintenance tocolytic therapy was examined in two active intervention in the following specific systematic reviews. One review, which was based on populations: women delivering at various gestational two small randomized controlled trials (RCTs), ages, classified as extremely preterm (<28 weeks of concluded that the SQ terbutaline pump offers no gestation), very preterm (28 weeks to 31 weeks of advantages compared with the saline pump or oral gestation), preterm (32 weeks to 33 weeks of gestation), 4 terbutaline. The second review found contradictory and later preterm (34 weeks to 36 weeks of gestation); results among RCTs and observational studies; the women with multiple gestation; women of different RCTs found no difference between the SQ terbutaline racial or ethnic backgrounds; women with previous pump and comparators, although the observational preterm birth; women with history of preeclampsia; and studies demonstrated positive effect estimates in favor women with recurrent preterm labor (RPTL) during the 5 of the pump. same pregnancy. Clinical endpoints, which included Despite previous systematic reviews, uncertainty neonatal health outcomes and maternal/neonatal harms, surrounding the use of terbutaline and other tocolytics were assessed in addition to several surrogate as maintenance therapy to prevent recurrent episodes of outcomes, such as birth weight and prolongation of preterm labor still exists. No clear first-line pregnancy. The potential confounding effects of maintenance tocolytic therapy has yet emerged. The maternal activity and maternal care on the above possibility of maternal side effects and unclear evidence endpoints were explored. Lastly, the pump device was on perinatal outcomes contribute to the ambiguity of evaluated by examining the incidence of pump-related terbutaline’s role in obstetrical practice. Moreover, in a outcomes, such as missed doses, dislodgment, and recent cost analysis of four tocolytic agents, overdose. 6 subcutaneous terbutaline had the highest cost. The These objectives were framed in the following Key expense is due not only to the device, but also to the Questions: need for increased monitoring and management of adverse events associated with this therapy. 6 In women with arrested preterm labor, does treatment with an SQ infusion of terbutaline Given the importance and associated uncertainty about delivered by a pump, in comparison with placebo, the appropriateness of ongoing use of the terbutaline conservative treatment, or other interventions: pump for maintenance tocolysis for clinicians, patients, and policymakers, a review about the effectiveness and Key Question 1: improve neonatal health outcomes, safety of SQ terbutaline pump was commissioned by including bronchopulmonary dysplasia, neonatal the Agency for Healthcare Research and Quality death, death within initial hospitalization, significant (AHRQ) to address six Key Questions. This evidence intraventricular hemorrhage (grade III/IV), report will add to previous systematic reviews by necrotizing enterocolitis, periventricular

2 leukomalacia, retinopathy of prematurity, seizures, e. multiple gestation? sepsis, and stillbirth for the following subgroups: f. racial or ethnic subgroups? a. women <28 weeks of gestation (extremely g. women with previous preterm birth? preterm)? h. women with history of preeclampsia? b. women between 28 weeks and 31 weeks of gestation (very preterm)? i. women with RPTL and women without RPTL? c. women between 32 weeks and 33 weeks of Key Question 3: increase the maternal harms of gestation (preterm)? arrhythmia, heart failure, hyperglycemia, hypokalemia, maternal mortality, myocardial d. women between 34 weeks and 36 weeks of infarction, pulmonary edema, or refractory gestation (later preterm)? hypotension, or result in an increased rate of e. multiple gestation? maternal discontinuation of therapy or maternal f. racial or ethnic subgroups? withdrawal due to adverse effects (Withdrawal-AE)? g. women with previous preterm birth? Key Question 4: increase the neonatal terbutaline- related harms of hypoglycemia, hypocalcemia, and h. women with history of preeclampsia? ileus? i. women with RPTL and women without RPTL? Key Question 5: Can the differences in the outcomes Key Question 2: improve other surrogate outcomes, above be partially explained by the differences in including gestational age at delivery, incidence of level of care (e.g., frequency of followup, nurse visits, delivery at various gestational ages (<28 weeks, < 32 concomitant treatment, etc.) and level of activity weeks, <34 weeks, <37 weeks), mean prolongation of (e.g., other children in the home, marital/support pregnancy (days), birth weight, ratio of birth status, working status, bedrest, etc.) between the weight/gestational age at delivery, pregnancy terbutaline pump group and the comparator group? prolongation index, need for assisted ventilation, Key Question 6: What is the incidence of failure of need for oxygen per nasal cannula, and neonatal the pump device used for terbutaline infusion, intensive care unit (NICU) admission for the including missed doses, dislodgment, and overdose? following subgroups: a. women <28 weeks of gestation (extremely Analytic Framework preterm)? We developed an analytic framework depicting links b. women between 28 weeks and 31 weeks of between the intervention and related clinical and gestation (very preterm)? intermediate efficacy and harms outcomes and other c. women between 32 weeks and 33 weeks of unintended adverse effects (Figure A). In the framework gestation (preterm)? below, the key questions of interest can be seen to encompass a holistic inquiry of the topic. d. women between 34 weeks and 36 weeks of gestation (later preterm)?

3 Figure A. Analytical framework of terbutaline pump for maintenance tocolysis

Surrogate Outcomes • Gestational age at delivery (KQ1) • Incidence of delivery (<28, <32, <34, <37 weeks) Pregnant women with arrest (KQ2) • Mean prolongation of of preterm labor (24-36 pregnancy (days) Neonatal Outcomes* weeks’ gestation) • Birthweight • Bronchopulmonary dysplasia • Ratio of birthweight/ • Neonatal death Treatment with gestational age at delivery • Death within intial terbutaline pump as • Pregnancy prolongation hospitalization compared with index • Grade III/IV Intraventricular placebo, conservative • Need for assisted ventilation hemorrhage (KQ3, KQ4) treatment, or other • Need for oxygen per nasal • Necrotizing enterocolitis interventions cannula • Periventricular leukomalacia • NICU admission • Retinopathy of prematurity Maternal Side Effects • Seizures

4 • Arrhythmia • Sepsis • Heart failure (KQ6 ) • Stillbirth • Hyperglycemia *Contributors to morbidity and • Hypokalemia mortality of infants born • Maternal mortality Pump Failure preterm • Myocardial infarction • Pulomonary edema • Hypotension (KQ5) • Maernal discontinuation of therapy Important Subgroups: • Withdrawl-AE KQ1a, KQ2a: <28 weeks’ gestation Confounders (level of care, Neonatal Side Effects level of activity and KQ1a, KQ2b: <32 weeks’ gestation • Hypoglycemia cointerventions) KQ1c, KQ2c: <34 weeks’ gestation • Hypocalcemia KQ1d, KQ2d: <37 weeks’ gestation • Ileus KQ1e, KQ2e: multiple gestation KQ1f, KQ2f: racial or ethnic subgroups KQ1g, KQ2g: history of preterm birth KQ1h, KQ2h: history of preeclampsia KQ1i, KQ2i: RPTL Methods Study Selection Two reviewers screened abstracts and full-text reports Input From Stakeholders with conflicts resolved by consensus or third-party We formulated the population, intervention, adjudication. Studies were included if they met the comparator, outcome, timing, setting (PICOTS) following criteria: evaluated pregnant women between conceptual framework and Key Questions in 24 and 36 weeks’ gestation having had acute preterm consultation with key informants during a topic labor arrested with primary tocolytic therapy; contained refinement stage. The public was invited to provide at least one group that was administered the SQ comments on the Key Questions. During the review terbutaline pump; and assessed one of the specified process, we followed a research protocol we developed outcomes listed in the key questions or described a with the clinical and methodological input of a long-term childhood outcome. Noncomparative studies technical expert panel. The protocol followed the (i.e., case series) were assessed only for pump-related Effective Health Care Program’s Methods Guide for harms outcomes, such as incidence of pump failure, Effectiveness and Comparative Effectiveness Reviews. 7 missed doses, or overdose. Non-English records without an English abstract were excluded. We also Data Sources and Searches excluded case reports, but in a post hoc decision sought FDA summaries of postmarketing data highlighting We developed a peer-reviewed search strategy and serious harms. searched the following databases: MEDLINE In- Process & Other Non-Indexed Citations and MEDLINE Data Extraction and Risk of Bias Assessment (1950 to April 1, 2011); Embase (1980 to April 1, 2011); Cumulative Index to Nursing and Allied Health One reviewer extracted data into a standardized Literature (CINAHL) via EBSCOhost (1985 to electronic form and assessed study risk of bias and December 7, 2009), the Cochrane Library via the Wiley applicability. Extraction items included general study interface (April 1, 2011) (including CENTRAL, characteristics (e.g., year of publication, study design), Cochrane Database of Systematic Reviews, Database of population characteristics (e.g., inclusion/exclusion Abstracts of Reviews of Effects – DARE, Health criteria, age, race, level of activity), intervention Technology Assessment – HTA, and the National characteristics (e.g., dose, duration, details about Health Service Economic Evaluation Database – NHS comparators, level of care), and outcomes with their EED), and the Centre for Reviews and Dissemination estimates. A second reviewer verified outcomes data (CRD) databases (January 2, 2010). Appendix A and study risk of bias assessments. Ratings for level of provides details of the search strategies. We hand- activity, level of care, and assessments of applicability searched the bibliographies and text of review articles, were verified by a clinical expert. Level of activity and letters to editors, and commentaries and the reference level of care were rated based on composite lists of included studies for additional references. We assessments across preidentified variables. also reviewed grey literature sources and information We assessed study risk of bias given the study design, received from pharmaceutical companies (see by outcome, using generic items to assess confounding Appendixes B and C), and sought unpublished and various types of bias (e.g., selection, performance, information from Matria (now called Alere) Healthcare detection bias, attrition bias). Selected items from the about their perinatal program and associated database. McMaster Quality Assessment Scale of Harms were In February 2011, the FDA issued new warnings also incorporated into the risk of bias assessment for against the use of terbutaline to treat preterm labor, so harm-related outcomes. 8 Certain criteria were specific we also accessed a summary of the FDA postmarketing to particular study designs (e.g., allocation generation surveillance results. This decision was made post hoc. and concealment applied only to RCTs). We rated each relevant outcome in a study with an overall risk of bias rating designated as high, medium, or low. Outcomes were rated as high risk of bias if there was an apparent

5 and major flaw in the study that would invalidate Analyses) diagram below depicts the flow of records results. from identification to inclusion (Figure B). Most Appendix D of the full report provides the data records were excluded at full-text screening (n=197) extraction, risk of bias, and applicability forms. based on the reasons listed in the diagram. Appendix E provides a list of excluded studies, and Appendix F Data Synthesis and Analysis provides individual-level study data.

We meta-analyzed the RCTs with a random effects Study Characteristics model, following a DerSimonian and Laird approach, when they were clinically and methodologically similar. Table A presents general summary characteristics of the To assess statistical heterogeneity and the magnitude of included studies. Most studies were observational and heterogeneity, we used Cochran’s Q ( a=0.10 ) and the I 2 included cohorts and case series. Two studies were statistic respectively. Odds ratios (ORs) were calculated RCTs, and one was a nonrandomized trial. Sample for dichotomous outcomes and mean differences for sizes ranged from 9 to 1,366, but greater than 70 continuous outcomes. All analyses were performed percent of studies included at least 200 participants using Comprehensive Meta Analysis version 2.2.046 or (average 291 ± 395). All studies were from the United version 2.2.055 (New Jersey, USA). We did not meta- States, and participants were recruited either from analyze observational studies because of potential single-center study sites or from a national proprietary differences in confounders, nor did we combine studies database run by Matria Healthcare. The Matria database of singleton and multiple pregnancies. Synthesis of provides an outpatient perinatal program consisting of evidence from observational studies was, therefore, 24-hour nursing and pharmacy support, home uterine undertaken qualitatively. Due to the small number of activity monitoring, individualized education, and studies, we could not perform any meta-regression to provision of tocolytic therapy to women with preterm explore statistical heterogeneity in effect estimates. labor. Because five studies originated in the Matria database, and not all reported geographic region and/or Strength of Evidence and Applicability years over which participants were recruited, the question of overlap in participants across these studies Based on published guidance for the Effective Health was an important concern of reviewers. Through the 9 Care Program, two reviewers graded the strength of Scientific Resource Center (SRC), we requested this evidence using the four primary domains (i.e., risk of missing information from Matria (now called Alere) bias, consistency, directness, and precision) for the Healthcare but did not receive a response. Therefore, following outcomes: incidence of delivery at various where appropriate, we report this risk of double- gestational ages (<28 weeks, <32 weeks, <34 weeks, counting of participants. <37 weeks), mean prolongation of pregnancy, bronchopulmonary dysplasia, significant Several studies included women with RPTL and intraventricular hemorrhage (grade III/IV), neonatal singleton gestation. Comparator groups included death, death within initial hospitalization, and maternal placebo, no treatment, oral terbutaline, oral nifedipine, withdrawal due to adverse effects (Withdrawal-AE). We and mixed oral tocolytics. The definition of labor was described population, intervention, comparison, unclear in 36 percent of the included studies. The outcome, timing, and setting characteristics to remaining studies included women with persistent summarize the applicability of the body of evidence. contractions and cervical change.

Results

Study Selection

We screened 427 citations and included 14 unique records in the review. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-

6 Figure B. PRISMA diagram

Articles identified Articles identified through database Articles nominated through search of searching after by TEP members grey literature duplicates (n=5) (n=94) removed (n=255)

Artcles FDA drug safety Total number of articles (n=431) unavailable communication n (n=4) o i t a c i f i t n e d I

Articles identified Articles screened at Articles excluded from reviews/ Level 1(n=427) (n=215) commentaries/letters and reference lists of g included studies Full text articles excluded, with reasons n i (n=197) n (n=77) e

e 61: SQ tertubaline pump was not given as r

c maintenance tocolytic therapy in at least one

S pump 51: Review article, letter to editor, commentary, or newspaper article 25: Study of maternal/neonatal outcomes or Full text assessed for harms with no comparison group (including eligibility at Levels 2 and 3 studies where women served as their own (n=212) controls) 18: Single or multiple (individual) case report 13: Miscellaneous (no patient data, clearly not y t relevant to the pump, betamimetic treatment i l i not specified) b i 12: Non-English abstract or full-text/insufficient g i

l information provided in abstract (full-text not

E in Englsih) 7: Full-text unavailable 4: Did not include women with arrested preterm Included studies labor (n=15) 3: Did not assess one of the specified outcomes 2: Companion article with no additional data 1: Study design did not allow for evaluation of SQ terbutaline pump as the sole maintenance tocolytic therapy d e d u l c FDA summary

n Independent Companion I studies article of post- (n=14) (n=1) marketing data

7 Table A. Summary characteristics of the included studies Number of Characteristic Studies References

Study Design RCT 2 10,11 Nonrandomized trial 1 12 Prospective cohort 2 13,14 Retrospective cohort 7 15-21 Case series 2 22,23

Participant Single center sites 9 10-14,20-23 Recruitment Matria database 5 15-19

Funding Industry 2 10,22 Nonindustry 3 14,20,21 Not reported 9 11-13,15-19,23

Comparator* Oral nifedipine 3 15-17 Oral terbutaline 4 11,12,20,21 Oral tocolytics 3 14,18,1 Placebo (saline pump) 2 10,11 No treatment 1 13 No comparison group 2 22,23

Primary Tocolytic IV magnesium sulfate only 1 23 Treatments IV magnesium sulfate and/or 5 10-13,22 other agents Not reported 8 14-21

Gestation Singletons only 6 10,12,13,15,17,18 Twins only 2 16,19 Singletons and twins 2 11,22 Not reported 4 14,20,21,23

Definition of Labor Not reported 5 15,17-19,21

Risk of Bias** Low 1 10 Medium 7 12,16,17,19,20,22,23 High 7 11-15,18,21

By Key Question Key Question 1 6 10,11,13,17-19 Key Question 2 12 10-21 Key Question 3 6 10,12,13,18,19,21 Key Question 4 1 11 Key Question 6 3 11,22,23

RCT=randomized controlled trial; IV=intravenous * One study contained two comparison groups. 11 **Risk of bias of one study differed by outcome. 12

8 Risk of Bias Assessment such as compliance, adequacy of sample size, and selective outcome reporting, were unclear. 22,23 We rated studies as low, medium, or high risk of bias for the relevant reported outcomes. Although the Neonatal Health Outcomes (Key Question 1) randomization procedures in the two RCTs were appropriate, we rated one RCT as low risk of bias10 Strength of evidence is insufficient for and the second RCT as high risk of bias because more bronchopulmonary dysplasia, death within initial than 90 percent of eligible participants declined to hospitalization, and significant intraventricular participate, the study was underpowered, and blinding hemorrhage (grade III/IV). Based on one retrospective was ineffective. 11 cohort of medium risk of bias, the strength of evidence favoring the SQ terbutaline pump compared with oral The single nonrandomized trial was high risk of bias tocolytics for neonatal death in women with twin for the outcomes of birth weight and gestational age at gestation and RPTL is low (Table B). This study delivery due to potential prognostic imbalances in investigated women from the Matria database and groups. However, we did not anticipate that such reported a statistically significant difference in neonatal imbalances would impact the outcome of maternal death in favor of SQ terbutaline pump (OR = 0.09, 95% hyperglycemia, which we rated as medium risk of bias, CI: 0.01, 0.70).19 Sparse evidence from underpowered due to insufficient information to assess several other studies addressed necrotizing enterocolitis, retinopathy 12 criteria. of prematurity, and sepsis with inconclusive results. 11,13 We rated most of the cohort studies as high risk of bias No data were available for periventricular leukomalacia because there were important group imbalances in and seizures. 13-15,18,21 baseline characteristics or prognostic factors. The Three retrospective cohort studies from the Matria other cohort studies we rated as medium risk of bias; database reported stillbirths in women with RPTL and although these studies had no identifiable flaws, several single or twin gestation. 17-19 All three studies found criteria could not be assessed due to incomplete nonsignificant differences between the SQ terbutaline 16,17,19,20 reporting. pump and oral tocolytics. However, these studies were Lastly, we rated the two case series as medium risk of likely underpowered to detect a difference in still birth, bias because neither study provided clear definitions for given the small number of events (<1%). the pump-related harm outcomes, and several criteria,

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11 Other Surrogate Outcomes (Key Question 2) Prolongation of pregnancy. The strength of evidence favoring SQ terbutaline pump compared with oral Studies reported surrogate outcomes of preterm labor tocolytics or no treatment is insufficient or low for much more frequently than neonatal or maternal women with twin gestation and/or RPTL (difference in clinical endpoints. However, none of the included means range 5.50–25.30, 95% CI range: 0.79–16.77, studies examined incidence of delivery < 28 weeks 8.72–33.83) (Table B). 13,15-18 This evidence came from (strength of evidence is insufficient, Table B), need for five cohort studies of medium to high risk of bias, oxygen per nasal cannula, or ratio of birth mostly from the Matria database. Two small RCTs weight/gestational age at delivery. (n=52 and n=42), which did not pertain to any of the Incidence of delivery at various gestational ages . populations of interest, showed nonsignificant Incidence of delivery < 32 weeks: The strength of differences between SQ terbutaline pump and evidence favoring SQ terbutaline pump compared with placebo. 10,11 either oral tocolytics or no treatment is low for women In one Matria-based cohort study, more women in the with RPTL and those additionally with twin gestation SQ terbutaline pump group had pregnancy prolonged (OR range = 0.04–0.52, 95% CI range: 0.00–0.35, > 7 days compared with women who received oral 0.50–0.76) (Table B). The evidence originated in six, nifedipine (OR = 7.84, 95% CI: 3.59, 17.12). 15 Other mostly Matria-based, cohort studies of medium to high Matria-based studies reported statistically significant 13,15-19 risk of bias. benefits in favor of the pump compared with oral Incidence of delivery < 34 weeks: The strength of tocolytics for prolongation > 14 days (OR range = evidence for this outcome is insufficient (Table B). One 1.93–3.47, 95% CI range: 0.87–2.34, 2.65–5.15). 15-19 small RCT (n=52) that did not address any of the Birth weight . Cohort studies of women with RPTL and populations of interest, showed a nonsignificant single or twin gestation demonstrated statistically difference between SQ terbutaline pump and placebo in significant differences in mean birth weight in favor of 10 women with singleton gestation. SQ terbutaline pump compared with oral tocolytics or Incidence of delivery < 37 weeks: The strength of no treatment (range of mean difference in grams = evidence favoring SQ terbutaline pump compared with 136–721, 95% CI range: 83–355, 189–1087). 13,16-19 oral tocolytics or no treatment is insufficient or low for Aside from one study, all were from the Matria women with RPTL (Table B). Four of five cohort database. 16-19 Two small RCTs (n=52 and n=42), which studies of medium to high risk of bias, mostly from the did not pertain to any of the populations of interest, Matria database, reported statistically significant reported nonsignificant differences between SQ differences in favor of SQ terbutaline pump (OR range terbutaline pump and placebo. 10,11 = 0.04–0.75, 95% CI range: 0.01–0.58, Incidence of low birth weight (< 2500 g) and very low 13,15,17,18,20 0.23–1.20). birth weight (< 1500 g) were reported in cohort studies. Mean gestational age at delivery . Larger cohort Most of these studies originated from the Matria studies of medium to high risk of bias in women with database. All studies that reported low birth weight RPTL and single or twin gestation demonstrated found statistically significant differences in favor of SQ consistent benefit of SQ terbutaline pump compared terbutaline pump compared with no treatment or oral with oral tocolytics or no treatment (RPTL and tocolytics (OR range = 0.24–0.64, 95% CI range: singleton gestation: difference in means range = 0.06–0.51, 0.62–0.96). 13,15-19 Most studies also found 0.70–3.40 weeks, 95% CI range: 0.28–1.80 weeks, statistically significant differences in favor of the pump 0.98–5.00 weeks; RPTL and twin gestation: difference for incidence of very low birth weight (OR range = in means = 0.70 weeks, 95% CI range: 0.43–0.48 0.22-0.46, 95% CI range: 0.07–0.29, 0.60–1.06). 16-19 13,15-19 weeks, 0.92–0.97 weeks). Most participants in the Pregnancy prolongation index . Pregnancy cohort studies came from the Matria database. RCT prolongation index was reported in two cohort evidence not directly addressing the populations of studies. 13,20 Both found statistically significant interest yielded a nonsignificant effect estimate between differences in favor of the SQ terbutaline pump the pump and placebo (n=52 and n=42). 10,11

12 compared with either no treatment or oral terbutaline retrospective cohort and a nonrandomized trial, (mean difference = 0.41, 95% CI: 0.26, 0.56; and 0.14, demonstrated nonsignificant differences between the 95% CI: 0.02–0.26). SQ terbutaline pump and oral terbutaline in the Need for assisted ventilation . One cohort study from incidence of gestational diabetes, though type II error the Matria database reported a nonsignificant difference cannot be excluded. No data were available on heart between the SQ terbutaline pump and oral tocolytics in failure, myocardial infarction, refractory hypotension, requirement for ventilator among infants with NICU and hypokalemia. admission. 18 Until 2009, 16 maternal deaths and 12 cases of NICU admission . Incidence of NICU Admission: maternal cardiovascular events (hypertension, Statistically significant differences in favor of the SQ myocardial infarction tachycardia, arrhythmias, and terbutaline pump compared with oral tocolytics or no pulmonary edema) in association with terbutaline treatment were reported in cohort studies of women tocolysis were reported to the FDA. Of these, at least with RPTL and single or twin gestation (OR range three maternal deaths and three cardiovascular adverse events were clearly reported to be in association with 0.28–0.72, 95% CI range: 0.08–0.58, 0.63–0.97). 13,15-19 the use of the SQ terbutaline pump. 24 Again, most of these studies were Matria-based. 15-19 One small RCT (n=52), which did not pertain to any of the Neonatal Harms (Key Question 4) populations of interest, reported a nonsignificant difference between the SQ terbutaline pump and Neonatal harms data were very sparse. Neonatal placebo. 10 hypoglycemia was reported in only one RCT that compared the SQ terbutaline pump with placebo and NICU length of stay: Statistically significant oral terbutaline. 11 Differences between the SQ differences in favor of the SQ terbutaline pump terbutaline pump and placebo or oral terbutaline were compared with oral tocolytics or no treatment were also nonsignificant. However, given the small number of reported for NICU length of stay in mostly Matria- events and limited sample size (n=42), the RCT was based cohort studies of women with RPTL and single underpowered and the results are inconclusive. No or twin gestation (range of mean difference in days: studies reported neonatal hypocalcemia or ileus. -3.50 to -17.90, 95% CI range: -5.26 to -32.88, -1.74 to 13,15,18,19 -3.54). Another small RCT (n=42), which did not Assessment of Confounding by Level of address any of the subgroups of interest, reported a Activity and Level of Care (Key Question 5) nonsignificant difference between the SQ terbutaline pump and placebo or oral terbutaline. 11 Only a small number of studies could be rated for level of activity and level of care. Therefore, we could not Maternal Harms (Key Question 3) carry out meta-regressions to explore the effect of these variables on maternal and neonatal outcomes. The strength of evidence is insufficient for Withdrawal- Furthermore, we could not even explore the impact of AE (Table B). One prospective cohort in women with level of activity on effect estimates in a qualitative singleton gestation and RPTL demonstrated highly manner because all studies that could be rated were unreliable odds favoring no treatment compared with designated as having “low” level of activity. No the pump for tachycardia/nervousness (OR=25.48, 95% apparent trends in effect estimates according to level of CI:1.23, 526.6). 13 Underpowered studies demonstrated care based on qualitative assessments were observed. indeterminate results for the outcomes of mortality, pulmonary edema, and therapy discontinuation (i.e., type II error cannot be excluded). 10,18,19 Two studies, a

13 Incidence of Pump Failure (KQ6) Applicability

Two case series and one RCT reported outcomes related In Table C below, we summarize the overall to the pump device. 11,22,23 In a case series of 51 women, applicability of the evidence base, according to the one participant had dislodgment of catheter (2 percent, domains of population, intervention, comparison, exact central CI: 0.5%, 10%) and there was one pump outcomes, timing, and setting. that malfunctioned (2 percent, exact central CI: 0.5%, 10%). 22 No infusion site infections or mechanical failures were observed in a case series of nine women. 23 An underpowered RCT demonstrated indeterminate results for the outcomes of local pain and local skin irritation. 11 No data were available for missed doses or overdoses.

Table C. Overall applicability of the body of evidence

Population The majority of evidence pertained to women with recurrent preterm labor and singleton gestation in the United States. Very little information was reported about the study populations’ demographic and clinical characteristics. Nine of 14 studies (64 percent) included women judged to be in labor on account of persistent contractions and cervical change. The definition of labor was unclear in other studies. Among the studies that suggested that the pump was efficacious, 50 percent reported cervical change and contractions as part of the definition of labor while 50 percent did not report how labor was defined. Intervention Although there were gaps in reporting, the intervention generally did not pose any serious limitations to applicability. Very few details were reported on cointerventions that could modify the effectiveness of therapy, such as administration of corticosteroids. In several studies, participants received specialized outpatient services from Matria Healthcare. Comparison Comparators included oral tocolytics, no treatment, and placebo. Outcomes Surrogate outcomes were the most commonly reported. Data on clinical outcomes, neonatal/maternal harms, and pump-related outcomes were sparse. Long-term outcomes have not been reported at all. Timing of Outcomes The absence of followup beyond delivery is a major limitation because important long- Measurement term outcomes have not been evaluated. Setting All studies were from the United States and participant data were acquired from a national database (Matria) or from single center sites. Women from the Matria database generally received a high level of care from an outpatient perinatal program. However, the distribution of regions from which patient data were included into the national database is unknown and information about the standards followed by the individual practice sites that provided obstetrical care was not reported. Similarly, for those studies that took place at single center sites, the standards of care followed at these sites are unclear.

14 Discussion not so unexpected in any adult population—pregnant women may experience these adverse events in the In this small review of 14 studies, most data came from absence of terbutaline therapy due to other reasons. observational designs, and several studies analyzed data Observational studies of medium to high risk of bias, from the Matria database. Aside from two RCTs, the primarily from the Matria database, showed benefit of studies exhibited considerable clinical and SQ terbutaline pump compared with oral tocolytics or methodological heterogeneity. For the gradable no treatment for other surrogate outcomes, such as birth outcomes, the available evidence addressed only two weight and NICU admission, for women with twin specific populations of interest—women with RPTL or gestation and/or RPTL. In contrast, two small RCTs that those additionally with twin gestation. The strength of did not address any of the populations of interest, evidence favoring the SQ terbutaline pump compared reported nonsignificant differences for several surrogate with oral tocolytics for neonatal death in women with outcomes. twin gestation and RPTL is low (OR = 0.09, 95% CI: 0.01, 0.70). While this result is striking in the presence The evidence base for this review contained several of insufficient findings on other neonatal health limitations. Most evidence came from observational outcomes summarized below, it is apparent that it stems designs of medium to high risk of bias. Several from the largest of studies contributing data on neonatal outcomes revealed nonsignificant results that could be health outcomes with more than 700 patients. As such, it attributed to type II error. Type II error is a statistical is the only outcome that appears to be adequately term that implies inability of studies to find a difference powered to reach statistical significance. Strength of when it might truly exist because of their small sample evidence favoring terbutaline pump compared to oral size (false negative). Many important variables, such as tocolytics or no treatment is also low for women with race, socioeconomic status, and fetal fibronectin level twin gestation and/or RPTL for the surrogate outcomes were not reported. Furthermore, cointerventions, such as of pregnancy prolongation. For bronchopulmonary administration of corticosteroids, were rarely described. dysplasia, significant intraventricular hemorrhage, death None of the included studies assessed long-term within initial hospitalization, and Withdrawal-AE, childhood outcomes, such as childhood development, strength of evidence is insufficient. The evidence was neurobehavioral testing, long-term lung function, and inconclusive for all other neonatal health outcomes, long-term vision. Our review comprehensively reviewed neonatal harms, maternal harms, and pump-related the literature and selected reports based on well-defined outcomes. inclusion and exclusion criteria. However, one potential limitation of our review process is that we excluded Based on postmarketing surveillance data, the FDA has potentially relevant non-English publications. Also, we issued a new warning against the use of terbutaline in could not investigate the impact of publication bias. general, and as an injection in particular, as maintenance However, in completing this review, we undertook an tocolysis (i.e., beyond 48–72 hours) in pregnant extensive grey literature search. Further, we requested women. 24 Although meriting transparent disclosure in the relevant scientific information from the industry and had form of a warning, evidence emerging from case reports many experts in the field participate in the review is usually regarded as noncomparative and hypothesis process. Despite this thorough process, the number of generating signal rather than a hypothesis testing identified studies was very small—we had too few confirmation. 25 Furthermore, case reports are useful in studies per outcome to perform statistical assessment of identifying rare and unexpected adverse events—the publication bias. We believe that all relevant data rarer the adverse event, the stronger is the effect size, regarding the use of subcutaneous terbutaline for the and the magnitude of effect size is an important criterion prevention of preterm labor is captured in this review. that increases our confidence in an estimate. 9 However, Any exaggerated positive findings are more likely due to adverse events such as death, hypertension, myocardial the medium to high risk of bias detected in infarction, tachycardia, arrhythmias, and pulmonary observational studies than publication bias. edema that were reported with the use of terbutaline are

15 In conclusion, the available evidence suggests that should be placebo controlled and include blinding of pump therapy is beneficial as maintenance tocolysis. study participants, care providers, and study personnel. However, our confidence in the validity and Consideration should be given to employing multiple reproducibility of this evidence is low. While treatment arms in order to evaluate the pump against postmarketing surveillance has detected cases of serious other tocolytic agents and conservative management. harms, safety of the therapy remains unclear. Furthermore, the level of care provided to participants (i.e., nursing assessments, home uterine monitoring, Future Research education, telephone support, and restriction of Although cohort studies have provided a glimpse of the activities) should be practical, feasible, and likely to be potential for the SQ terbutaline pump to improve short- adopted in routine practice. Important cointerventions, term neonatal outcomes for fetuses at risk for preterm such as administration of corticosteroids, should be birth, the answers to several important questions remain reported. A full accounting of the number of women unanswered. Most importantly, it remains to be seen approached but not enrolled should be included to whether SQ terbutaline pump therapy alters long-term allow users to assess the impact of respondent bias. The development or systemic impairment of offspring, and analysis should be “intent to treat,” where all neonatal/maternal morbidity and mortality. The participants assigned by randomization to each group limitations of the available data must also be are included in the primary comparisons, regardless of recognized. Most of the cohort studies were medium to whether the assigned medication was received. high risk of bias. In addition, several of the cohort Outcomes to be examined should go beyond those of studies investigated participants from a single prolongation of pregnancy and birth weight to hard proprietary database (Matria), which raises concerns clinical endpoints of neonatal morbidity, such as regarding double-counting of patients and common bronchopulmonary dysplasia, necrotizing enterocolitis, biases. Therefore, results showing effectiveness should significant intraventricular hemorrhage (grade III/IV), be interpreted with caution, especially in light of the retinopathy of prematurity, sepsis, stillbirth, and most recent FDA warning recommending against the neonatal death. Lastly, there should be long-term use of terbutaline for maintenance tocolysis. followup to assess subsequent childhood outcomes. Pharmacodynamic and pharmacokinetic outcome Information is lacking on the effectiveness and safety of measures can additionally be studied to understand SQ terbutaline pump as a maintenance tocolytic inter-individual differences in effectiveness and toxicity treatment in specific populations, including women and avoidance of ß-agonist related tachyphylaxis. who deliver at specific gestational ages, women of different racial or ethnic backgrounds, and women with Conducting RCTs to assess the efficacy of tocolytics in previous preterm birth or preeclampsia. Future studies, general is notoriously difficult. A definitive trial in this whether observational or experimental in design, should domain must include a focus on accurate diagnosis of focus on garnering evidence for these specific preterm labor (perhaps combining stringent clinical populations. criteria with factors such as positive fetal fibronectin and shortened transvaginal cervical length). Emphasis Below we provide some specific recommendations for must also be placed on securing funding and the conduct of RCTs and observational studies to maintaining followup for an appropriate duration of further elucidate the potential benefits and harms of SQ time to allow assessment of long-term childhood terbutaline pump for maintenance tocolysis. outcomes, including neurobehavioral testing and Randomized trials . We recommend that an adequately developmental assessment. powered randomized controlled and pragmatic clinical Observational studies . Although the RCT is the ideal trial that assesses the SQ terbutaline pump as a study design for evaluating the efficacy of maintenance tocolytic be conducted. A pragmatic RCT interventions, it may not be feasible for a number of is designed to have broad applicability so that the reasons, such as a prohibitive sample size requirements 26 results can guide decisions about practice. Such a trial and ethical considerations. We realize that collecting

16 RCT evidence on clinically important outcomes may Applicability : The relevance of the evidence base to an not be possible because a large number of patients will external population. need to be recruited to detect rare events, such as Bias : A systematic error, arising from participant maternal deaths. Therefore, we additionally propose: selection or outcome measurement that produces an • Well-designed, well powered cohort studies erroneous effect estimate. examining clinical outcomes. These studies should include a representative and inception cohort of all References patients with arrested preterm labor. Since observational studies are susceptible to the effects 1. Behrman R, Butler A. Preterm Birth: Causes, Consequences, and Prevention. Washington, DC: of confounding, future observational studies National Academies Press; 2007. should measure, report, and adjust for potential 2. Centers for Disease Control and Prevention. confounders such as fetal fibronectin, cervical Birthweight and Gestation. Available at: length/dilation, cerclage, maternal characteristics www.cdc.gov/nchs/fastats/birthwt.htm. Accessed (e.g., age, race), level of care and activity, and May 12, 2010. concomitant medications. Propensity scores based 3. Mathews TJ, MacDorman MF. Infant mortality statistics on these variables may be considered. Other from the 2006 period linked birth/infant death data set. considerations about power, multiple comparison Natl Vital Stat Rep 2010 Apr 30;58(17):1-31. PMID: groups, level of care, reporting of cointerventions, 20815136. and long-term followup are the same as for RCTs. 4. Nanda K, Cook LA, Gallo MF, et al. Terbutaline pump • Record linkage studies in which mothers’ prenatal maintenance therapy after threatened preterm labor for preventing preterm birth. Cochrane Database Syst Rev and infants’ NICU and childhood developmental 2002 Dec;(4): electronic health records are linked may be a more practical research proposition for the near future 5. HAYES, Inc. Continuous subcutaneous terbutaline infusion for treatment of preterm labor (Structured with improvements in quality and accessibility of abstract). Lansdale, Pa: Hayes, Inc 2006; electronic patient records. NICU registries in 6. Hayes E, Moroz L, Pizzi L, et al. A cost decision which prenatal data of mothers are available can analysis of 4 tocolytic drugs. Am J Obstet Gynecol be a very valuable source. However, such linkage 2007 Oct;197(4):383-6. PMID: 17904969. based studies may also be impacted by biases not 7. Agency for Healthcare Research and Quality. Methods uncommon to cohort study designs, especially Guide for Effectiveness and Comparative Effectiveness confounding because of unmeasured or Reviews [Draft]. AHRQ Publication No. 10(11)- unrecorded variables with important prognostic EHC063-EF. Available at: implications. www.effectivehealthcare.ahrq.gov/ehc/products/60/318/ MethodsGuide_Prepublication_Draft_20110824.pdf. Glossary Rockville, MD: 2011. 8. Santaguida, P and Raina, P. McMaster Quality Preterm birth : Delivery before completion of the 37th Assessment Scale of Harms (McHarm) for primary week of gestation. studies: Manual for use of the McHarm. Available at: http://hiru.mcmaster.ca/epc/mcharm.pdf. Accessed Tocolytic : An agent that inhibits labor by slowing or December 22, 2010. halting uterine contractions. 9. Owens DK, Lohr KN, Atkins D, et al. AHRQ series Strength of evidence : The strength of evidence grading paper 5: grading the strength of a body of evidence reflects a global assessment of the evidence base. when comparing medical interventions--agency for Strength of evidence may be designated as insufficient, healthcare research and quality and the effective health- care program. J Clin Epidemiol 2010 May;63(5):513- low, moderate or high based on the domains of study 23. PMID: 19595577. risk of bias, consistency, directness, and precision.

17 10. Guinn DA, Goepfert AR, Owen J, et al. Terbutaline 21. Regenstein AC, Belluomini J, Katz M. Terbutaline pump maintenance therapy for prevention of preterm tocolysis and glucose intolerance. Obstet Gynecol 1993 delivery: a double-blind trial.[see comment]. Am J May;81(5 ( Pt 1):739-41. PMID: 8469464. Obstet Gynecol 1998 Oct;179(4):874-8. PMID: 22. Adkins RT, Van Hooydonk JE, Bressman PL, et al. 9790362. Prevention of preterm birth: early detection and 11. Wenstrom KD, Weiner CP, Merrill D, et al. A placebo- aggressive treatment with terbutaline.[see comment]. controlled randomized trial of the terbutaline pump for South Med J 1993 Feb;86(2):157-64. PMID: 8240475. prevention of preterm delivery. Am J Perinatol 1997 23. Lam F, Gill P, Smith M, et al. Use of the subcutaneous Feb;14(2):87-91. PMID: 9259905. terbutaline pump for long-term tocolysis. Obstet 12. Lindenbaum C, Ludmir J, Teplick FB, et al. Maternal Gynecol 1988 Nov;72(5):810-3. PMID: 3173932. glucose intolerance and the subcutaneous terbutaline 24. U.S. Food and Drug Administration. FDA Drug Safety pump. Am J Obstet Gynecol 1992 Mar;166(3):925-8. Communication: New warnings against use of PMID: 1550166. terbutaline to treat preterm labor. Available at: 13. Morrison JC, Chauhan SP, Carroll CS, Sr., et al. www.fda.gov/Drugs/DrugSafety/ucm243539.htm. Continuous subcutaneous terbutaline administration Accessed April 7, 2011. prolongs pregnancy after recurrent preterm labor. Am J 25. Chou R, Aronson N, Atkins D, et al. AHRQ series Obstet Gynecol 2003 Jun;188(6):1460-5. PMID: paper 4: assessing harms when comparing medical 12824979. interventions: AHRQ and the effective health-care 14. Morrison JC, Allbert JR, Floyd RC, et al. Interval to program. J Clin Epidemiol 2010 May;63(5):502-12. delivery in high-risk patients: Do tocolytic agents really PMID: PM:18823754. work? Int J Gynaecol Obstet 1992;38(3):189-93. PMID: 26. Zwarenstein M, Treweek S, Gagnier JJ, et al. 1992210309. Improving the reporting of pragmatic trials: an 15. Flick AA, de la Torre L, Roca LE, et al. An extension of the CONSORT statement. BMJ examination of the clinical benefits and cost- 2008;337:a2390. PMID: 19001484. effectiveness of tocolytic replacement following recurrent preterm labor. Am J Perinatol 2010 Full Report Jan;27(1):53-9. PMID: 19823965. 16. de la Torre L, Istwan NB, Desch C, et al. Management This executive summary is part of the following of recurrent preterm labor in twin gestations with document: Gaudet L, Singh K, Weeks L, Skidmore B, nifedipine tocolysis. Am J Perinatol 2008 Tsouros S, Tsertsvadze A, Daniel R, Doucette S, Oct;25(9):555-60. PMID: 18773381. Walker M, Ansari MT. Terbutaline Pump for the 17. Fleming A, Bonebrake R, Istwan N, et al. Pregnancy Prevention of Preterm Birth. Comparative Effectiveness and economic outcomes in patients treated for recurrent Review No. 35. (Prepared by the University of Ottawa preterm labor. J Perinatol 2004 Apr;24(4):223-7. PMID: Evidence-based Practice Center under Contract No. 14999214. HHSA290-2007-10059I.) AHRQ Publication No. 18. Lam F, Istwan NB, Jacques D, et al. Managing 11-EHC068-EF. Rockville, MD: Agency for Healthcare perinatal outcomes: the clinical benefit and cost- Research and Quality. September 2011. Available at: effectiveness of pharmacologic treatment of recurrent preterm labor. Managed Care 2003 Jul;12(7):39-46. www.effectivehealthcare.ahrq.gov/reports/final.cfm. PMID: 12891954. 19. Lam F, Bergauer NK, Jacques D, et al. Clinical and For More Copies cost-effectiveness of continuous subcutaneous terbutaline versus oral tocolytics for treatment of For more copies of Terbutaline Pump for the Prevention recurrent preterm labor in twin gestations. J Perinatol of Preterm Birth: Executive Summary No. 35 (AHRQ 2001 Oct;21(7):444-50. PMID: 11894512. Pub. No 11-EHC068-1), please call the AHRQ 20. Allbert JR, Johnson C, Roberts WE, et al. Tocolysis for Clearinghouse at 1–800–358–9295 or email recurrent preterm labor using a continuous [email protected]. subcutaneous infusion pump. J Reprod Med 1994 Aug;39(8):614-8. PMID: 7996525.

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