Clinical Policy Bulletin: Terbutaline Pump for Preterm Labor
Aetna considers the use of a terbutaline pump for administration of subcutaneous terbutaline experimental and investigational for the prevention or treatment of premature labor becauase its effectiveness has not been established.
Terbutaline has been used in selected patients to inhibit uterine contractions in preterm labor (tocolysis) in an attempt to prolong pregnancy and prevent preterm birth. An infusion pump is required for the subcutaneous administration of terbutaline. Preterm labor often results in preterm births, which significantly contributes to infant morbidity and mortality.
There is no evidence that tocolytics reduces the risk of preterm delivery (Haas, 2007; Nanda et al, 2002; CTAF, 2002). The incidence of preterm birth has not decreased in the last 2 decades, despite the increased use of tocolytics.
A review of 17 randomized controlled trials (RCTs) that compared a tocolytic with a placebo or no tocolytic for women in preterm labor found that tocolytics were not associated with significant reduction in births before 30 weeks' gestation, before 32 weeks' gestation, or before 37 weeks' gestation. However, tocolytics were associated with significant decreases in the likelihood of delivery within 24 hours. Tocolytics reviewed included: isoxuprine, ethanol, terbutaline, ritodrine, indomethacin, magnesium sulfate, and atosiban. Significant effects on prolongation of pregnancy were found with betamimetics, indomethacin, atosiban, and ethanol, but not with magnesium sulfate. Only 1 study of indomethacin showed any significant decrease in preterm births. Tocolytics increased risk of maternal palpitations, nausea, tremor, chorioamnionitis, hyperglycemia, and hypokalemia. The review concluded that although tocolytics prolong pregnancy, they have not been shown to improve perinatal or neonatal outcomes.
In 1997, the U.S. Food and Drug Administration (FDA) sent a letter to physicians and other health care providers warning them that adequate data establishing the safety and effectiveness of the use of terbutaline as a tocolytic agent have not been submitted to the FDA; that the demonstrated value of tocolytics in general is limited to an initial, brief period of treatment, probably no more than 48 to 72 hours; and that no benefit from prolonged administration has been documented. In addition, the letter noted that the safety of long-term subcutaneous administration of terbutaline sulfate, especially on an outpatient basis, has not been adequately addressed. The letter stated that complications of subcutaneous terbutaline administration are similar to that accompanying intravenous administration of terbutaline and other beta-sympathomimetics, including chest pain, tachycardia, dyspnea, pulmonary edema, and death. The letter noted that the impact of long-term use of subcutaneous terbutaline on maternal glucose metabolism and the risks of prolonged exposure of the fetus are largely unknown.
Guinn and colleagues (1998), reporting on the results of the largest RCT to date of the effectiveness of terbutaline pump for the prevention of preterm delivery, concluded that the terbutaline pump does not prolong gestation in women with suspected preterm labor. A total of 52 women with suspected preterm labor were randomly assigned to receive either treatment with terbutaline or normal saline solution placebo by subcutaneous infusion pump. The study found no significant differences between treatment and placebo groups in mean time to delivery and rates of preterm delivery at less than 34 and less than 37 weeks' gestation.
Although there is no evidence of the effectiveness of tocolytics in preventing premature delivery, the literature supports the efficacy of parenteral tocolytic agents in delaying delivery for 24 to 48 hours. Such a delay may be of benefit by increasing the time to delivery, allowing additional time for the beneficial effects of adjunctive corticosteroid therapy.
Grimes and Nanda (2006) stated that magnesium sulphate tocolysis has no benefit in preventing preterm or very preterm birth. Moreover, the risk of total pediatric mortality was significantly higher for infants exposed to magnesium sulfate (relative risk 2.8; 95 % confidence interval: 1.2 to 6.6). Given its lack of benefit, possible harms, and expense, magnesium sulphate should not be used for tocolysis. The authors stated that any further use of magnesium sulphate for tocolysis should be restricted to formal clinical trials with approval by an institutional review board and signed informed consent for participants. They noted that should tocolysis be desired, calcium channel blockers, such as nifedipine, seem preferable.
An assessment of the terbutaline pump for prevention of preterm birth prepared for the Agency for Healthcare Research and Quality (AHRQ) (Gaudet, et al., 2011) found that the evidence base consists of a small number of biased studies. The report stated that a substantial body of evidence originated from one proprietary database. The report concluded that, although evidence suggests that pump therapy is beneficial as maintenance tocolysis, confidence in its validity and reproducibility is low. The report noted that postmarketing surveillance has detected cases of serious harms, and safety of the therapy remains unclear.
In summary, although tocolytic agents, including the terbutaline pump, have been shown to be of benefit in managing acute episodes of preterm labor in the hospital, there is no evidence that the use of any of these agents as “maintenance” medications provides any clinical benefit. On the other hand, tocolytics have known adverse effects on women in preterm labor. Further investigation on the use of tocolytics in improving perinatal, neonatal and maternal outcomes is needed in order to establish their effectiveness.
Terbutaline is sometimes used off-label for acute obstetric uses, including treating preterm labor and treating uterine hyper-stimulation. It has also been used off-label over longer periods of time to prevent recurrent preterm labor. There are multiple generic versions of terbutaline oral tablets and injectable formulations available. On February 17, 2011, the FDA warned the public that injectable terbutaline should not be used in pregnant women for prevention or prolonged treatment (beyond 48 to 72 hours) of preterm labor in either the hospital or outpatient setting because of the potential for serious maternal heart problems and death. The agency is requiring the addition of a Boxed Warning and Contraindication to the terbutaline injection label to warn against this use. In addition, oral terbutaline should not be used for prevention or any treatment of preterm labor because it has not been shown to be effective and has similar safety concerns. The agency is requiring the addition of a boxed warning and contraindication to the terbutaline tablet label to warn against this use.
Although it may be clinically deemed appropriate based on the healthcare professional's judgment to administer terbutaline by injection in urgent and individual obstetrical situations in a hospital setting, the prolonged use of this drug to prevent recurrent preterm labor can result in maternal heart problems and death. Terbutaline should not be used in the outpatient or home setting. The decision to require the addition of a boxed warning and contraindication is based on new safety information received and reviewed by the FDA. Specifically, the FDA has reviewed post-marketing safety reports of terbutaline used for obstetrical indications, as well as data from the medical literature. These label changes are consistent with statements from the American College of Obstetricians and Gynecologists (ACOG, 2003) discouraging use of terbutaline for preventing preterm labor.
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met :
HCPCS codes covered if selection criteria are met [exception basis only]:
Injection, terbutaline sulfate, up to 1 mg
Ambulatory infusion pump, mechanical, reusable, for infusion 8 hours or greater
Ambulatory infusion pump, mechanical, reusable, for infusion less than 8 hours
Ambulatory infusion pump, single or multiple channels, electric or battery operated, with administrative equipment, worn by patient
Home management of preterm labor, including administrative services, professional pharmacy services, care coordination, and all necessary supplies or equipment (drugs and nursing visits coded separately), per diem (do not use this code with any home infusion per diem code)
Home infusion therapy, tocolytic infusion therapy; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
ICD-9 codes covered if selection criteria are met:
Threatened premature labor, premature labor after 22 weeks, but before 37 completed weeks of gestation without delivery
Other ICD-9 codes related to the CPB:
Supervision of pregnancy with history of pre-term labor
The above policy is based on the following references:
Gyetvai K, Hannah ME, Hodnett ED, et al. Tocolytics for preterm labor: A systematic review. Obstet Gynecol. 1999;94(5)(part 2):869-877.
Gonik B, Creasy RK. Preterm labor: Its diagnosis and management. Am J Obstet Gynecol. 1986;154(1):3-8.
Von Der Pool, BA. Preterm labor: Diagnosis and treatment. Am Fam Physician. 1998;57(10):2457-64.
American Academy of Pediatrics (AAP) and American College of Obstetricians and Gynecologists (ACOG). Guidelines for Perinatal Care. 5th ed. Elk Grove Village, IL: AAP; 2002.
Macones GA, Berlin M, Berlin JA. Efficacy of oral beta-agonist maintenance therapy in preterm labor: A meta-analysis. Obstet Gynecol. 1995;85(2):313-317.
American College of Obstetricians and Gynecologists (ACOG). Preterm labor. Technical Bulletin No. 206. Washington, DC: ACOG; 1995.
Nightingale SL. From the Food and Drug Administration. JAMA. 1998;280(21):1817.
Lam F, Elliott J, Jones JS, et al. Clinical issues surrounding the use of terbutaline sulfate for preterm labor. Obstet Gynecol Surv. 1998;53(11 Suppl):S85-S95.
Guinn DA, Goepfert AR, Owen J, et al. Terbutaline pump maintenance therapy for prevention of preterm delivery: A double-blind trial. Am J Obstet Gynecol. 1998;179(4):874-878.
Guinn DA, Goepfert AR, Owen J, et al. Management options in women with preterm uterine contractions: A randomized clinical trial. Am J Obstet Gynecol. 1997;177(4):814-818.
Elliott JP, Flynn MJ, Kaemmerer EL, et al. Terbutaline pump tocolysis in high-order multiple gestation. J Reprod Med. 1997;42(11):687-694.
Allbert JR, Johnson C, Roberts WE, et al. Tocolysis for recurrent preterm labor using a continuous subcutaneous infusion pump. J Reprod Med. 1999;39(8):614-618.
Moise KJ Jr, Sala DJ, Zurawin RK, et al. Continuous subcutaneous terbutaline pump therapy for premature labor: Safety and efficacy. South Med J. 1992;85(3):255-260.
Letter from Stuart L. Nightengale, M.D., Associate Commissioner for Health Affairs, Food and Drug Administration, regarding subcutaneous administration, via infusion pump, of terbutaline sulfate for the treatment and prevention of preterm labor (tocolytic therapy), Rockville, MD: FDA; November 13, 1997. Available at: http://www.fda.gov/medwatch/safety/1997/terbut.htm. Accessed April 13, 2001.
Institute for Clinical Systems Improvement (ICSI). Tocolytic therapy for preterm labor. ICSI Technology Assessment No. 49. Bloomington, MN: ICSI; March 2000.
Lam F, Bergauer NK, Jacques D, et al. Clinical and cost-effectiveness of continuous subcutaneous terbutaline versus oral tocolytics for treatment of recurrent preterm labor in twin gestations. J Perinatol. 2001;21(7):444-450.
Elliott JP, Bergauer NK, Jacques DL, et al. Pregnancy prolongation in triplet pregnancies. Oral vs. continuous subcutaneous terbutaline. J Reprod Med. 2001;46(11):975-982.
Hofmeyr GJ, Kulier R. Tocolysis for preventing fetal distress in second stage of labour. Cochrane Database Syst Rev. 1996;(1):CD000037.
Berkman ND, Thorp JM, Hartmann KE, et al. Management of preterm labour. Volume 1: Evidence report and appendixes; Volume 2: Evidence tables. Evidence Report/Technology Assessment No. 18. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2000.
Nanda K, Cook LA, Gallo MF, Grimes DA. Terbutaline pump maintenance therapy after threatened preterm labor for preventing preterm birth. Cochrane Database Syst Rev. 2002;(4):CD003933.
Morrison JC, Chauhan SP, Carroll CS Sr, et al. Continuous subcutaneous terbutaline administration prolongs pregnancy after recurrent preterm labor. Am J Obstet Gynecol. 2003;188(6):1460-1465; discussion 1465-1467.
California Technology Assessment Forum (CTAF). Maintenance tocolytic therapy with oral terbutaline or subcutaneous terbutaline infusion by pump for prevention of preterm delivery. Technology Assessment. San Francisco, CA: CTAF; June 12, 2002. Available at: http://ctaf.org/ass/viewfull.ctaf?id=6048341338. Accessed July 12, 2005.
Anotayanonth S, Subhedar NV, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev. 2004;(4):CD004352.
Yamasmit W, Chaithongwongwatthana S, Tolosa JE, et al. Prophylactic oral betamimetics for reducing preterm birth in women with a twin pregnancy. Cochrane Database Syst Rev. 2005;(3):CD004733.
Dodd JM, Crowther CA, Dare MR, Middleton P. Oral betamimetics for maintenance therapy after threatened preterm labour. Cochrane Database Syst Rev. 2006;(1):CD003927.
Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev. 2002;(4):CD001060.
Grimes DA, Nanda K. Magnesium sulfate tocolysis: Time to quit. Obstet Gynecol. 2006;108(4):986-989.
Whitworth Melissa, Quenby Siobhan. Prophylactic oral betamimetics for preventing preterm labour in singleton pregnancies. Cochrane Database Syst Rev. 2008;(1):CD006395.
Mawaldi L, Duminy P, Tamim H. Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor. Int J Gynaecol Obstet. 2008;100(1):65-68.
Haas DM, Imperiale TF, Kirkpatrick PR, et al. Tocolytic therapy: A meta-analysis and decision analysis. Obstet Gynecol. 2009;113(3):585-594.
American College of Obstetricians and Gynecologists (ACOG). ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologist. No. 43. Management of preterm labor. Obstet Gynecol. 2003;101(5 Pt 1):1039-1047.
U.S. Food and Drug Administration. FDA drug safety communication: New warnings against use of terbutaline to treat preterm labor. February 17, 2011. Food and Drug Administraion: Silver spring, MD. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm243539.htm. Accessed February 23, 2011.
Gaudet L, Singh K, Weeks L, et al. Terbutaline pump for the prevention of preterm birth. Comparative Effectiveness Review No. 35. Prepared by the University of Ottawa Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ) under Contract No. HHSA 290 2007 10059 I. AHRQ Publication No. 11-EHC068-EF. Rockville, MD: AHRQ; September 2011.
Gaudet LM, Singh K, Weeks L, et al. Effectiveness of terbutaline pump for the prevention of preterm birth: A systematic review and meta-analysis. PLoS ONE. 2012;7(2):e31679.
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