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.
See also CPB 0510 - ProgestinsBackground
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.
In a Cochrane review, Chawanpaiboon et al (2014) determined the effectiveness of terbutaline pump maintenance therapy after threatened preterm labor in reducing adverse neonatal outcomes. These investigators searched the Cochrane Pregnancy and Childbirth Group's Trials Register (January 31, 2014) and reference lists of retrieved studies. Randomized controlled trials comparing terbutaline pump therapy with alternative therapy, placebo, or no therapy after arrest of threatened preterm labor were selected for analysis. Two review authors independently assessed the studies for inclusion and then extracted data as eligible for inclusion in qualitative and quantitative synthesis (meta-analysis). A total of 4 studies were included with a total of 234 women randomized. The overall methodological quality of the included studies was mixed; 2 studies provided very little information on study methods, there was high sample attrition in 1 study and in 3 studies the risk of performance bias was high. These researchers found no strong evidence that terbutaline maintenance therapy offered any advantages over saline placebo or oral terbutaline maintenance therapy in reducing adverse neonatal outcomes by prolonging pregnancy among women with arrested preterm labor. The mean difference (MD) for gestational age at birth was -0.14 weeks (95 % confidence interval [CI]: -1.66 to 1.38) for terbutaline pump therapy compared with saline placebo pump for 2 trials combined. One trial reported a risk ratio (RR) of 1.17 (95 % CI: 0.79 to 1.73) for preterm birth (less than 37 completed weeks) and a RR of 0.97 (95 % CI: 0.51 to 1.84) of very preterm birth (less than 34 completed weeks) for terbutaline pump compared with saline placebo pump. These investigators found no evidence that terbutaline pump therapy was associated with statistically significant reductions in infant respiratory distress syndrome, or neonatal intensive care unit admission compared with placebo. Compared with oral terbutaline, the authors found no evidence that pump therapy increased the rate of therapy continuation, or reduced the rate of infant complications or maternal hospital re-admissions. One study suggested that pump therapy resulted in significantly increased weekly cost/woman, $580 versus $12.50 (p < 0.01). No data were reported on long-term infant outcomes. The authors concluded that they found no evidence that terbutaline pump maintenance therapy decreased adverse neonatal outcomes. Taken together with the lack of evidence of benefit, its substantial expense and the lack of information on the safety of the therapy do not support its use in the management of arrested preterm labor. They stated that future use should only be in the context of well-conducted, adequately powered RCTs.
Also, an UpToDate review on “Management of pregnant women after inhibition of acute preterm labor” (Caritis and Simhan, 2015) states that “A systematic review of four randomized trials (n = 234 women) comparing terbutaline pump therapy with alternative therapy, placebo, or no therapy found no evidence that terbutaline pump maintenance therapy decreased adverse neonatal outcomes. The US Food and Drug Administration concluded that the risk of serious adverse events from prolonged terbutaline therapy of preterm labor (beyond 48 to 72 hours) outweighs any potential benefit. The Agency for Healthcare Research and Quality reviewed available data and found that terbutaline pump therapy could be beneficial for maintenance tocolysis, but most studies were biased so there was low confidence in this conclusion; in addition, the safety of this therapy was unclear”.
|CPT Codes / HCPCS Codes / ICD-10 Codes|
|Information in the [brackets] below has been added for clarification purposes.  Codes requiring a 7th character are represented by "+":|
|ICD-10 codes will become effective as of October 1, 2015:|
|CPT codes covered if selection criteria are met :|
|99601||Home infusion/specialty drug administration, per visit (up to 2 hours);|
|+ 99602||each additional hour (List separately in addition to code for primary procedure)|
|HCPCS codes covered if selection criteria are met [exception basis only]:|
|J3105||Injection, terbutaline sulfate, up to 1 mg|
|E0779||Ambulatory infusion pump, mechanical, reusable, for infusion 8 hours or greater|
|E0780||Ambulatory infusion pump, mechanical, reusable, for infusion less than 8 hours|
|E0781||Ambulatory infusion pump, single or multiple channels, electric or battery operated, with administrative equipment, worn by patient|
|S9208||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)|
|S9349||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-10 codes covered if selection criteria are met:|
|O60.02 - O60.03||Preterm labor without delivery [after 22 weeks but before 37 weeks]|