Original Article &&&&&&&&&&&&&& A Comparison of Gestational Days Gained with Oral Terbutaline Versus Continuous Subcutaneous Terbutaline in Women with Twin Gestations

Fung Lam, MD rate by 37%.1 This increase is believed in part to be related to the use Niki K. Bergauer, RN of assisted reproductive technologies and the shift toward delayed Suzanne K. Coleman, RNC childbearing. United States birth certificate data for 1996 reveals that Gary J. Stanziano, MD in those with twin gestations the incidence of prematurity was 53%. Debbie Jacques, MPH The incidence of low birth weight for twins was also 53%, which is seven times higher than the overall low birth weight rate of 7.4%.1 The presence of twins, in and of itself, is thus an established risk OBJECTIVE: factor for preterm birth.2 Indeed, multiple births have significant To compare gestational days gained with oral versus subcutaneous impact on perinatal morbidity and mortality. terbutaline for maintenance tocolysis. Parenteral tocolysis has been shown to be successful in delaying delivery for 24 to 48 hours in patients presenting with preterm STUDY DESIGN: labor.3,4 The need for continued tocolysis to prevent recurrent In retrospective fashion 386 women enrolled in an outpatient preterm labor preterm labor after initial stabilization has been a subject of identification program met the following criteria: twin gestation, debate.5±8 The clinical efficacy of maintaining tocolysis is often development of threatened preterm labor resulting in treatment with oral questioned due to lack of evidence that this practice can reduce the terbutaline, and subsequent recurrence of threatened preterm labor overall incidence of preterm birth. Tocolysis is often considered to resulting in treatment with continuous subcutaneous terbutaline. The be a failure if term gestation is not achieved. However, in women primary outcome was gestational days gained with oral terbutaline versus experiencing preterm labor, any additional gestational days gained gain with continuous subcutaneous terbutaline. with tocolysis should be deemed a success as evidenced by a reduction in neonatal morbidity and mortality with each RESULTS: gestational week gained.9,10 There were significantly more days gained during subcutaneous treatment Terbutaline sulfate in oral form is often prescribed for than during oral treatment (34.0‹19.8 versus 19.3‹15.3 days). Thirty- maintenance tocolysis. The efficacy of oral terbutaline is influenced three percent of desired prolongation was achieved with oral terbutaline, by patient compliance and the development of tachyphylaxis related whereas 79% of desired prolongation was achieved with subcutaneous to long-term, high-dose exposure.11 The cardiovascular, renal, terbutaline (p<0.001). Patients gained a mean of 53.4‹21.4 days pulmonary, and metabolic effects of oral and parenteral terbutaline overall with outpatient tocolysis. The mean gestational age at delivery was are considered to be dose- and route-dependent.12 Studies of 35.2‹1.9weeks. continuous subcutaneous terbutaline infusion therapy have suggested a low incidence of cardiovascular side effects, as well as CONCLUSION: efficacy in prolonging pregnancies between 5.4 and 9.2 weeks.13 ± 16 Continuous subcutaneous terbutaline was superior to oral terbutaline in The subcutaneous infusion pump used for this method of delivery is prolonging gestation in women with twin gestations. individually programmed to deliver a continuous administration of Journal of Perinatology 2000; 20:408±413. low-dose terbutaline (basal rate) along with additional scheduled bolus doses that can be coordinated with peak times of uterine INTRODUCTION contractions. Twins occur at a rate of 25.9per 1000 live births. Since 1980,the The purpose of this investigation was to compare gestational overall number of twin pregnancies has risen 47% and the twin birth days gained in a cohort of women with twin gestations receiving oral terbutaline for maintenance tocolysis after an episode of

California - Pacific Medical Center, San Francisco, CA; Matria Healthcare, Inc. Marietta, GA. threatened preterm labor who then received continuous subcutaneous terbutaline after a subsequent episode of preterm Address correspondence and reprint requests to Fung Lam, MD, California Pacific Medical Center, 3838 California Street, San Francisco, CA 94118. labor. Journal of Perinatology 2000; 20:408 ± 413 # 2000 Nature America Inc. All rights reserved. 0743-8346/00 $15 408 www.nature.com/jp Gestational Gain, Terbutaline, and Twin Gestations Lam et al.

MATERIALS AND METHODS threatened recurrent preterm labor occurred was analyzed for the Subjects were identified from a database of women with high-risk oral terbutaline period, and compared to the elapsed time until pregnancies who were enrolled by their physician in a nationally preterm labor resulting in delivery, or discharge at term (36 weeks) available preterm-labor identification program. This outpatient for the subcutaneous terbutaline period. The pregnancy prolongation program included patient education regarding the signs and index was calculated to assess the level of treatment success for each symptoms of preterm labor, home uterine-activity monitoring, and route of tocolysis. Defined as the lag time between onset of treatment telephonic nursing assessment of objective patient data and and discontinuation of treatment divided by the lag time between subjective symptoms. Between January 1992 and December 1997, onset of treatment and 36 weeks, the PPI attempts to create an prospectively collected demographics, pregnancy risk factors, uterine unbiased probability distribution for delivery weighted for gestational activity, subjective symptoms, and pregnancy outcome data were age at start of treatment. The PPI represents the percent of achieved available for 4589women with multiple gestations who received pregnancy prolongation relative to the goal of therapy.17 Other data continuous subcutaneous terbutaline infusion at some time during collected for analysis included maternal demographics, pregnancy their pregnancy. For this study, 386 women met the following history and current pregnancy risk factors, maternal and neonatal inclusion criteria: (1) twin gestation, (2) no prophylactic tocolysis outcomes, and antepartum hospital days. Uterine activity data or diagnosis of preterm labor before enrollment into the program, collected 6 days before and 6 days after initiation of both oral and (3) subsequent development of threatened preterm labor resulting subcutaneous terbutaline was also analyzed. in maintenance tocolysis with oral terbutaline, (4) recurrence of Data were analyzed using McNemar's chi-square or Wilcoxon threatened preterm labor resulting in a change in terbutaline signed rank test statistics for paired samples, using Statistical administration route to continuous subcutaneous infusion, and (5) Package for Social Sciences (SPSS) PC for Windows, version 7.0 no concomitant maintenance tocolysis during either treatment (SPSS, Chicago, IL). All p-values presented are two-tailed and period. Threatened preterm labor was defined as an increase in considered statistically significant if <0.05. uterine contractions above a physician-prescribed threshold (three to four contractions per hour) that led to a change in treatment RESULTS protocol, which included hospitalization or a change in tocolytic medication or route of administration. Exclusions included 689 Demographic characteristics of the study population are described in women with greater than twin gestation, 2389with a preterm-labor Table 1. The mean gestational age at enrollment into the preterm diagnosis before enrollment, and 1125 patients receiving prophy- labor identification program was 25.0‹3.5 weeks. Table 2 shows lactic tocolysis before enrollment or subcutaneous terbutaline historical and current pregnancy risk factors at time of enrollment. therapy without prior exposure to oral terbutaline. At enrollment, The mean gestational age at initiation of oral terbutaline was informed consent was obtained for all participating patients. 27.6‹2.7 weeks with a starting mean dose of 18.7‹8.8 mg/24 hr. The dose, frequency, and route of terbutaline (oral or One hundred seventy-six patients (46.2%) required changes (range subcutaneous infusion) were determined by the physician's 1±4) in the dosage or frequency of their oral terbutaline resulting in prescription. Patient management including antenatal testing, a mean dose of 24.4‹10.7 mg/24 hr. The mean gestational age at additional medications, in-hospital stabilization, recommended initiation of continuous subcutaneous terbutaline infusion was activity level, and timing of delivery were at the discretion of each 30.3‹2.8 weeks at a starting mean dose of 3.3‹1.0 mg/24 hr. The patient's attending physician. 24-hr dose was comprised of a mean continuous basal rate of At initiation of subcutaneous terbutaline therapy, the micro- 0.06‹0.03 mg/hr, and a mean of 7.4‹2.3 scheduled boluses of infusion pump (MiniMed Technologies, Sylmar, CA or Disetronics, 0.25‹0.02 mg. Two hundred thirty-three patients (60%) Minneapolis, MN) was programmed to deliver a continuous basal rate and intermittent bolus doses as was prescribed by the patient's Table 1 Demographics (N=386) physician based on each patient's needs as determined by individual objective and subjective nursing assessments. Patients received Maternal age (years) 29.9‹5.2 Race individualized instruction on infusion pump use, including infusion White (%) 79.0 initiation technique, site selection and care, syringe change, and African-American (%) 12.2 emergency procedures, as well as the procedure for administering an Hispanic (%) 4.7 unscheduled drug bolus if ordered by her physician. Other (%) 4.1 In this retrospective cohort design each patient was used as her Smoker (%) 8.8 Married (%) 89.4 own control to assess individual response to change in medication Primigravida (%) 30.1 route of delivery of terbutaline. The primary outcome variable was Gestational age at service start (weeks) 25.0‹3.5 gestational days gained during each route of terbutaline administration. Elapsed time from start of terbutaline until All data mean‹SD, or expressed as percentage.

Journal of Perinatology 2000; 20:408 ± 413 409 Lam et al. Gestational Gain, Terbutaline, and Twin Gestations

Table 2 Pregnancy History and Current Risk Factors at Enrollment each period hospitalized. Only 15 patients (4%) in the study group Twin gestation (%) 100 were hospitalized for an extended period ( >14 days) while History of PTL in previous pregnancy (%) 17.1 receiving oral and/or subcutaneous terbutaline. History of PTD (%) 11.1 Uterine activity for 6 days before and after oral terbutaline Uterine activity with cervical change (%)* 31.3 initiation, 6 days before and after change to the subcutaneous route, Uterine activity without cervical change (%)* 38.3 and for 6 days before delivery is illustrated in Figure 2. This suggests Cervical incompetence with cerclage (%)* 7.0 Uterine abnormality (%) 0.8 a rise in mean uterine contractions per hour before each acute episode of preterm labor, with a stabilization of uterine activity the Data expressed as percentage. PTL=preterm labor; PTD=preterm delivery. week following either initiation of oral, or change to subcutaneous *With current pregnancy. terbutaline. Six days before initiation of oral terbutaline, women experienced changes in the dosage or frequency of their experienced a mean of 2.3‹1.7 (median 2.0) uterine contractions subcutaneous terbutaline resulting in a mean dose of 4.0‹1.2 mg/ per monitored hour, this increased to 4.4‹3.3 (median 3.5) on the 24 hr before delivery or discontinuation of treatment. day before oral-therapy start. There again was a progressive increase Pregnancy prolongation data are summarized in Figure 1. in uterine activity per monitored hour in the 6 days before recurrence Desired prolongation was calculated as the time (in days and of preterm labor and initiation of subcutaneous therapy for a mean weeks) from gestational age at start of treatment to 36 weeks. While of 3.1‹2.1 (median 3.0) at 6 days prior, to 4.8‹3.2 (median 4.5) receiving oral terbutaline women achieved a mean pregnancy on the day before subcutaneous start. prolongation of 19.3‹15.3 vs. 34.0‹19.8 days while receiving Pregnancy outcome data are displayed on Table 3. A total of 452 subcutaneous terbutaline ( p<0.001). The pregnancy prolongation infants (58.5%) delivered at less than 36.0 weeks' gestation. A total index was applied to assess the level of treatment success for each of 473 infants (61.8%) were of low birth weight (less than 2500 administration route of terbutaline. Patients achieved significantly gm). The reasons for delivery are presented on Table 4. Tocolytic greater pregnancy prolongation on subcutaneous terbutaline (SQT) breakthrough and recurrent preterm labor resulting in delivery than on oral (PO) terbutaline. While receiving oral terbutaline occurred in 104 women. Five women experienced the loss of one women only achieved 33% (0.33‹.21) of desired pregnancy twin. There were two stillborn infants and three neonatal deaths, all prolongation, compared with 79% (0.79‹.26) accomplishing of which occurred at gestational ages less than 35 weeks. All neonatal desired prolongation while receiving subcutaneous therapy deaths occurred at less than 24 hours of age and were related to ( p<0.001). Overall, these pregnancies achieved a total of 20,609 multiple congenital anomalies, hypoplastic lungs, or Trisomy-13. days gained (mean 53.4‹21.4 days per patient) with the One intrauterine fetal death occurred in a pregnancy complicated combination of oral and subcutaneous terbutaline. 93.7% (19,305) with PIH. The other intrauterine death was in a fetus diagnosed with of these days were outpatient. One hundred fifty-four (39.9%) Downs Syndrome. women had antepartum hospital days while receiving oral terbutaline, vs. 164 (42.5%) women with antepartum hospital days during subcutaneous terbutaline treatment ( p=0.510). The COMMENT proportion of hospital days to tocolytic treatment days was equal for The purpose of this investigation was to compare gestational days the oral and subcutaneous phases with women spending 6.3% of gained by route of terbutaline administration (oral or subcutaneous

Figure 1. Pregnancy prolongation: desired versus actual weeks/days gained.

410 Journal of Perinatology 2000; 20:408 ± 413 ora fPerinatology of Journal Gestations Twin and Terbutaline, Gain, Gestational 00 048±413 ± 20:408 2000;

Figure 2. Uterine activity during treatment phases. a tal. et Lam 411 Lam et al. Gestational Gain, Terbutaline, and Twin Gestations

Table 3 Pregnancy Outcome (N=772) receiving oral therapy achieved 72% desired prolongation >Gestational age at service stop 34.9‹2.0 compared to 86% desired prolongation for subcutaneous therapy. Gestational age at delivery 35.2‹2.1 A descriptive analysis of 992 very high-risk patients, including 206 <37.0 wk (%) 80.8 twin pregnancies, receiving continuous subcutaneous terbutaline <36.0 wk (%) 58.5 infusion, also by Allbert et al.,15 showed a mean pregnancy <35.0 wk (%) 39.1 prolongation of 38‹23 days. Elliott et al.,25 reported success in <32.0 wk (%) 7.8 Birth weight (gm) (N=767) 2333.5‹499 utilizing prophylactic subcutaneous terbutaline infusion in 21 <2500 gm (%) 61.8 patients with high-order multiple gestations. Moise et al.,26 <2000 gm (%) 24.7 reported on 13 patients given continuous subcutaneous terbutaline <1500 gm (%) 4.7 using pump after failure of other tocolytic regimens. Though he Admission to NICU (%) 36.4 considered his findings to reflect only limited success, patients Nursery length of stay (N=767) 10.0‹13 gained an average of 35 days. Adkins et al.,16reported on 51 7 day (%) 65.6 14 day (%) 79.8 patients, including four with twins, prescribed continuous 21 day (%) 88.3 subcutaneous terbutaline as treatment for their first episode of Delivery type preterm labor. He reported a success rate of 98%, with pregnancies Vaginal (%) 39.1 prolonged an average of 6.6 weeks. Cesarean (%) 60.9 Wenstrom et al.,18 randomized 42 women with singleton and Perinatal mortality rate 6/1000 twin pregnancies, who were stable on parenteral tocolysis, into All data mean‹SD, or expressed as percentage. three groups: terbutaline pump, saline pump, or oral terbutaline. NICU=Neonatal intensive care unit. There were no differences noted between the groups in birth outcomes. It should be noted that patients received only a mean infusion). We have shown that in women with twin gestations who of 1.5‹2.4 scheduled boluses per day in the terbutaline pump experienced recurrent threatened preterm labor, pregnancy was group, which is considerably less than standard practice, and prolonged 57% longer when terbutaline was administered through considerably less than patients in our present study who received a continuous subcutaneous infusion than when administered orally. mean of 7.4‹2.3 boluses. In addition, all patients were given a This was achieved in spite of a six times lower daily dose of basal rate of 0.05 mg/hr, which was not titrated to level of terbutaline when compared to oral administration. Overall, patients uterine irritability exhibited. Most importantly, crossover between gained a mean of 7.6 weeks' gestation with oral and subcutaneous groups occurred as patients who failed one route of therapy were terbutaline. This gain is significantly greater than the 4- and 5-week switched to another group. Fifty percent of the patients in the gains achieved with placebo recently reported 18,19 and is consistent placebo group ultimately received either continuous subcutaneous with previous reports on women utilizing subcutaneous terbutaline terbutaline, or intravenous tocolytics. Based on intent to treat therapy. Furthermore, we observed that uterine activity increases analysis, this study concluded that terbutaline by pump, saline by before the onset of preterm labor in women with twin gestations. This pump, and oral terbutaline were equally efficacious. The authors is supportive of the works of Nageotte et al.,20 Katz et al.,21 and Garite reported no serious complications related to terbutaline pump et al.,22 who showed a surge, or crescendo, of uterine activity 3 days therapy. before the onset of spontaneous labor. Most recently, Guinn et al.,19 randomized 52 women with In the literature there are other reported experiences with singleton gestation to either terbutaline or placebo through continuous subcutaneous terbutaline infusion. Lam et al.,14 reported subcutaneous infusion. Overall, there was only a 1-day difference in on nine patients successfully treated with continuous subcutaneous pregnancy prolongation between the groups with the terbutaline terbutaline after failed oral tocolysis. Pregnancies were prolonged an average of 9.2 weeks with subcutaneous therapy. More recently, Lam et al.,23 reported on 256 women with singleton gestations comparing Table 4 Reasons for Delivery pregnancy prolongation with oral versus subcutaneous terbutaline in patients with recurrent preterm labor. Women achieved an average of Term (36.0 weeks) 160 (41.4%) Preterm labor 104 (26.9%) 2.7 weeks with oral terbutaline versus 4.4 weeks with subcutaneous Physician preference/elective PTD 50 (12.9%) terbutaline. Combined mean pregnancy prolongation with progres- PPROM 31 (8%) sive tocolysis was 7.14 weeks. PIH 29(7.5%) Allbert et al.,24 in a matched case design, compared 32 patients Fetal indications 8 (2.1%) receiving continuous subcutaneous terbutaline infusion to patients Chorioamnionitis 3 ( <1%) receiving oral therapy. He concluded that the terbutaline pump Vaginal bleeding 1 ( <1%) appeared to be more successful in prolonging gestation than oral PTD=preterm delivery, pPROM=preterm premature rupture of membranes, PIH= therapy. Utilizing the pregnancy prolongation index, women pregnancy induced hypertension.

412 Journal of Perinatology 2000; 20:408 ± 413 Gestational Gain, Terbutaline, and Twin Gestations Lam et al.

group achieving a 28.8‹22.0-day prolongation. It is not specified in 9. Copper RL, Goldenberg RL, Creasy RK, et al. A multicenter study of preterm the study if treatment was initiated at the first episode of preterm birth weight and gestational age-specific neonatal mortality. Am J Obstet labor, or at a recurrent episode. Patients did not receive daily nursing Gynecol 1993;168:78±84. contact or home uterine-activity monitoring as is generally 10. McCormick MC. The contribution of low birth weight to infant mortality and prescribed in obstetric practice for women receiving continuous childhood morbidity. N Engl J Med 1985;312:82±90. subcutaneous terbutaline infusion. It must be noted that the cervix in 11. Berg G, Andersson RGG, Ryden G. Beta-adrenergic receptors in human myometrium during pregnancy: changes in the number of receptors after 50% of the patients in this study was 3 cm or more dilated and at beta-mimetic treatment. Am J Obstet Gynecol 1985;85:313±317. least 50% effaced, at start. Patients were enrolled at a mean of 31 12. Wischnik A. Risk±benefit assessment of tocolytic drugs. Drug Saf weeks, which made the predicted 6-week prolongation impossible, 1991;6:371±381. and were not treated for recurrent preterm labor occurring after 34 13. Perry KG, Morrison JC, Rust OA, Sullivan CA, Martin RW, Naef RW. Incidence weeks. Also, dosing was not individualized or titrated to uterine of adverse cardiopulmonary effects with low-dose continuous terbutaline activity, all women received a standard basal rate of 0.05 mg/hr and infusion. Am J Obstet Gynecol 1995;173:1273±1277. five scheduled boluses. The standard bolus schedule allowed for a 7- 14. Lam F, Gill PJ, Smith M, Kitzmiller JL, Katz M. Use of subcutaneous hour lapse during the nighttime hours, a period where there is a terbutaline pump for long-term tocolysis. Obstet Gynecol 1988;72:810±813. likelihood of increased uterine activity.27 15. Allbert JR, Wise CA, Lou CH, et al. Subcutaneous tocolytic infusion therapy This current study was not designed to determine the overall for patients at high risk for preterm birth. J Perinatol 1992;12:28±31. efficacy or safety of maintenance tocolysis and did not compare to a 16. Adkins RT, Van Hooydonk JE, Bressman PL, et al. Prevention of preterm control group of patients who did not receive tocolysis. While the birth: early detection and aggressive treatment with terbutaline. South Med J 1993;86:157±164. debate over tocolytic efficacy persists, many physicians will continue 17. Omer H, Palti Z, Freidlander D. Evaluating treatments for preterm labor: to prescribe maintenance tocolysis. Our goal was to analyze two possible solutions for some methodological problems. Eur J Obstet Gynecol routes of terbutaline delivery, oral and subcutaneous, and compare Reprod Biol 1986;22:229±236. overall time gained in utero for each treatment. As such, we found 18. Wenstrom KD, Weiner CP, Merrill D, Neibyl J. A placebo-controlled that in women with twin gestations who received terbutaline orally, randomized trial of the terbutaline pump for prevention of preterm delivery. J then subcutaneously, greater pregnancy prolongation was achieved Perinatol 1997;14:87±91. with subcutaneous administration. 19. Guinn DA, Goepfert AR, Owen J, Wenstrom KD, Hauth JC. Terbutaline pump maintenance therapy for prevention of preterm delivery: a double-blind trial. Am J Obstet Gynecol 1998;179:874±878. References 20. Nageotte MP, Dorchester W, Porto M, Keegan KA Jr, Freeman RK. 1. Ventura SJ, Martin JA, Curtin SC, Mathews TJ. Report of final natality Quantitation of uterine activity preceding preterm, term, and postterm labor. statistics, 1996. Monthly Vital Statistics Report. Vol. 46, No. 11, Supp. Am J Obstet Gynecol 1988;156:1254±1259. Hyattsville, Maryland: National Center for Health Statistics, 1998. 21. Katz M, Newman RB, Gill PJ. Assessment of uterine activity in ambulatory 2. Goldenberg RL, Iams JD, Miodovnik M, et al. NICHHDMFMUN. The preterm patients at risk for preterm labor and delivery. Am J Obstet Gynecol prediction study: risk factors in twin gestations. Am J Obstet Gynecol 1996; 1986;154:44±47. 175:1047±1053. 22. Garite TJ, Bentley DL, Hamer CA, Porto ML. Uterine activity characteristics in 3. The Canadian Preterm Labor Investigators Group. Treatment of preterm multiple gestations. Obstet Gynecol 1990;76(suppl):56S±59S. labor with the beta-agonist ritodrine. N Engl J Med 1992;327:308±312. 23. Lam F, Bergauer NK, Stanziano GJ, Jacques D. Pregnancy prolongation and 4. Chau AC, Gabert HA, Miller JM. A prospective comparison of terbutaline and route of tocolytic administration inpatients with singleton gestation. Am J magnesium for tocolysis. Obstet Gynecol 1992;80:847±851. Obstet Gynecol 1998;178:180. 5. Rust OA, Bofill JA, Arriola RM, Andrew ME, Morrison JC. The clinical efficacy 24. Allbert JR, Johnson C, Roberts WE, et al. Tocolysis for recurrent preterm labor of oral tocolytic therapy. Am J Obstet Gynecol 1996;175:838±842. using a continuous subcutaneous infusion pump. J Reprod Med 6. How HY, Hughes SA, Vogel RI, Gall SA, Spinnato JA. Oral terbutaline in the 1994;39:614±618. outpatient management of preterm labor. Am J Obstet Gynecol 25. Elliott JP, Flynn MJ, Kaemmerer EL, Radin TG. Terbutaline pump tocolysis in 1995;173:1518±1522. high-order multiple gestation. J Reprod Med 1997;42:687±694. 7. Macones GA, Berlin M, Berlin JA. Efficacy of oral beta-agonist 26. Moise KJ Jr, Sala DJ, Zurawin RK, Cano LE, Hesketh DE, Carpenter RJ. maintenance therapy in preterm labor: a meta-analysis. Obstet Gynecol Continuous subcutaneous terbutaline pump for premature labor: safety and 1995;85:313±317. efficacy. South Med J 1992;85:255±260. 8. Lewis R, Mercer BM, Salama M, Walsh MA, Sibai BM. Oral terbutaline after 27. Moore TR, Iams JD, Creasy RK, Burau KD, Davidson AL. Diurnal and parenteral tocolysis: a randomized, double-blind, placebo-controlled trial. gestational patterns of uterine activity in normal human pregnancy. Obstet Am J Obstet Gynecol 1996;175:834±837. Gynecol 1994;83:517±523.

Journal of Perinatology 2000; 20:408 ± 413 413