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MP 5.01.07 Acute and Maintenance Tocolysis 

Medical Policy    
Section
Prescription Drugs 
Original Policy Date
11/1/97
Last Review Status/Date
Reviewed with Literature search/10:2014
Issue
10:2014
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description 

General indications for tocolysis, or the suppression of preterm labor, include continued regular uterine contractions associated with cervical changes in a pregnant woman at less than 37 weeks’ gestation. Successful delay of preterm delivery allows further fetal development and precludes potential complications of preterm delivery, especially neonatal respiratory distress syndrome (RDS). Even short-term delay of delivery is thought to be beneficial in that it allows treatment of the patient with corticosteroids, which has proved beneficial in ameliorating the effects of neonatal RDS. In some cases, a short delay in delivery may also allow transport of the pregnant woman to a medical center better equipped to handle premature delivery and neonatal intensive care.

A variety of agents have been used for tocolysis. The only FDA-approved tocolytic drug is ritodrine, a beta-sympathomimetic. Ritodrine is no longer available in the U.S., and thus only off-label medications are available. Terbutaline sulfate, FDA-approved for several non-tocolytic indications, is also a beta-sympathomimetic. Terbutaline is available as an oral or intravenous medication and, more recently, has been administered by continuous subcutaneous infusion via a portable pump for maintenance tocolysis. Other tocolytic drugs include calcium channel blockers (e.g., nifedipine), magnesium sulfate, oxytocin receptor antagonists (e.g., atosiban), prostaglandin inhibitors (e.g., indomethacin), and nitrates (e.g., nitroglycerin).

Tocolytic agents have potential risks as well as potential benefits. A 2012 guideline issued by the American College of Obstetricians and Gynecologists (ACOG) summarized the potential adverse effects of common classes of tocolytic agents (1):

Calcium Channel Blockers

  • Maternal side effects: Dizziness, flushing, and hypotension; suppression of heart rate, contractility, and left ventricular systolic pressure when used with magnesium sulfate; and elevation of hepatic transaminases
  • Fetal or newborn adverse effects: No known adverse effects

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

  • Maternal side effects: Nausea, esophageal reflux, gastritis, and emesis; platelet dysfunction is rarely of clinical significance in patients without underlying bleeding disorder
  • Fetal or newborn adverse effects: In utero constriction of ductus arteriosus*, oligohydramnios*, necrotizing enterocolitis in preterm newborns, and patent ductus arteriosus in newborn†

*Greatest risk associated with use for longer than 48 hours

†Data are conflicting regarding this association

Beta-adrenergic Receptor Agonists

  • Maternal side effects: Tachycardia, hypotension, tremor, palpitations, shortness of breath, chest discomfort, pulmonary edema, hypokalemia, and hyperglycemia
  • Fetal or newborn adverse effects: Fetal tachycardia

Magnesium Sulfate

  • Maternal side effects: Causes flushing, diaphoresis, nausea, loss of deep tendon reflexes, respiratory depression, and cardiac arrest; suppresses heart rate, contractility and left ventricular systolic pressure when used with calcium channel blockers; and produces neuromuscular blockade when used with calcium channel blockers.
  • Fetal or newborn adverse effects: Neonatal depression. (The use of magnesium sulfate in doses and duration for fetal neuroprotection alone does not appear to be associated with an increased risk of neonatal depression when correlated with cord blood magnesium levels.)

Regulatory Status

Ritodrine was approved by the U.S. Food and Drug Administration (FDA) for use as a tocolytic agent. Ritodrine was voluntarily withdrawn from the U.S. market in 1998.

Terbutaline is FDA approved for the prevention and treatment of bronchospasm in patients with asthma and reversible bronchospasm associated with bronchitis and emphysema. Like other tocolytic agents, its use in tocolysis is off-label. In response to a citizen petition in June, 2008, the FDA reviewed safety data on terbutaline sulfate. They issued a safety announcement on February 17, 2011. (2) Based on animal studies, the FDA reclassified terbutaline from pregnancy risk category B to pregnancy risk category C. In addition, the FDA required a boxed warning stating that injectable terbutaline should not be used for prevention or prolonged (beyond 2-3 days) treatment of preterm labor, and oral terbutaline should not be used for acute or maintenance tocolysis. The labeling change is based on a review of postmarketing safety reports submitted to the FDA’s Adverse Event Reporting System (AERS) of maternal death and serious maternal cardiovascular events associated with use of terbutaline.


Policy 

Acute tocolytic therapy with calcium channel blockers, magnesium sulfate, prostaglandin inhibitors, and parenteral terbutaline may be considered medically necessary for the induction of tocolysis in patients with preterm (<37 weeks’ gestational age) labor.

Maintenance (beyond 48-72 hours) tocolytic therapy with any medication is considered investigational.


Policy Guidelines

Patient selection criteria for induction of tocolysis include regular uterine contractions associated with cervical changes. Induction of tocolysis typically requires hospitalization to monitor for incipient delivery.


Benefit Application
BlueCard/National Account Issues  

Continuous infusion of terbutaline for maintenance therapy via a subcutaneous pump (HCPCS code E0781) may be offered as part of the management protocols of high-risk pregnancies offered by carve-out networks, such as Matria. However, as noted above, this therapy is considered investigational.


Rationale

An initial literature search was performed in 1997. The policy was updated regularly with a literature review using MEDLINE. Most recently, the literature was reviewed through September 2, 2014. Following is a summary of the literature to date:

Acute tocolysis

Studies have focused on the ability of tocolytic agents to prevent preterm delivery and thereby reduce associated maternal and neonatal risks. A comprehensive meta-analysis of randomized controlled trials (RCTs) on acute tocolysis was published by Haas et al. in 2009. (3) Haas and colleagues included 58 studies that directly compared different tocolytic medications or compared 1 medication to placebo or usual care. Studies were included if they compared 2 drugs in the same class but excluded if they included 2 doses of the same medication. Participants were women who were diagnosed with preterm labor or had threatened preterm labor. The analysis was limited to studies with fetuses of mean gestational ages between 28 and 32 weeks’ gestation. Multiple gestation was not an exclusion criterion, but if trials stratified on this variable, only data on singleton pregnancies were used. Data were extracted for each outcome and combined by drug class to calculate a weighted mean and standard error for proportions of successful events; proportions were weighted based on the number of participants in each study. Primary efficacy and safety outcomes are as follows in Tables 1 and 2:

Table 1. Effect of tocolytics on delaying birth (weighted % of women experiencing outcome)

 

48-hour delay

7-day delay

After 37 weeks

 

No. Studies

% (95% CI)

No. Studies

% (95% CI)

No. Studies

% (95% CI)

Placebo/control

9

53 (45-61)

8

39 (28-49)

3

36 (20-52)

Betamimetics

29

75 (65-85)

26

65 (59-71)

15

46 (36-56)

Calcium channel blockers

17

76 (57-95)

10

62 (56-69)

12

47 (32-62)

Magnesium sulfate

11

89 (85-93)

5

61 (39-84)

7

42 (31-53)

Oxytocin receptor antag.

8

86 (80-91)

6

78 (68-88)

No data

 

Prostaglandin inhibitors

8

93 (90-95)

3

76 (67-85)

4

43 (6-79)

CI=confidence interval

Table 2. Adverse maternal and neonatal effects associated with tocolytics (weighted % of women/neonates experiencing outcome)

 

Maternal adverse effects

Neonates with RDS

Neonatal death

 

No. Studies

% (95% CI)

No. Studies

% (95% CI)

No. Studies

% (95% CI)

Placebo/control

6

(0-2)

3

21 (17-26)

6

1(0-2)

Betamimetics

32

14 (9-18)

17

13 (8-18)

32

14 (9-18)

Calcium channel blockers

16

1 (0-3)

11

19 (4-33)

16

1 (0-3)

Magnesium sulfate

16

3 (1-6)

9

16 (11-20)

16

3 (1-6)

Oxytocin receptor antag.

6

2 (0-5)

5

14 (8-21)

6

2 (0-5)

Prostaglandin inhibitors

6

0 (0-2)

4

2 (0-4)

6

0 (0-2)

Maternal adverse effects are those that required discontinuation of the medication
CI: confidence interval; RDS, respiratory distress syndrome

All tocolytic agents were significantly better than placebo/control at delaying delivery for 48 hours and delaying delivery for 7 days. None were significantly better than placebo/control at delaying delivery until after 37 weeks’ gestation. The rate of discontinuation due to adverse effects was significantly higher for
betamimetics compared with placebo/control but not for any of the other categories of medication.

As part of their review, the investigators also conducted a decision analysis to determine the optimal medication based on the balance of benefits and risks. The decision analysis model found that prostaglandin inhibitors might be the superior agent up to 32 weeks of gestation due to a high effectiveness at delaying delivery by at least 7 days and a low rate of adverse effects. Calcium channel blockers were the superior agent for delaying delivery until 37 weeks. Compared with other tocolytics, calcium channel blockers reduced the incidence of birth within 7 days of treatment (relative risk [RR], 0.76; 95% confidence interval [CI], 0.60 to 0.97) and before 34 weeks of gestation (RR=0.83; 95% CI, 0.69 to 0.99).

In an additional study published in 2012, Haas et al conducted a network meta-analysis in which direct and indirect evidence on relative impacts of tocolytics on health outcomes were pooled simultaneously.(4) Consequently, the analysis was not limited to the comparisons in head-to-head trials that the research
team had addressed in 2009. The investigators identified a total of 95 RCTs; 25 contained a placebo arm, 60 included betamimetics, 29 included magnesium sulfate, 29 included calcium channel blockers, 18 included prostaglandin inhibitors, 13 included oxytocin receptor blockers, 4 included nitrates, and 5
included “other” drugs. The authors assumed that all drugs in the same class had a similar effect.

Fifty-five studies were included in the network analysis for the primary efficacy outcome, delivery delayed by 48 hours. All active classes were found to be superior to placebo. The analysis also suggested that prostaglandin inhibitors had a greater beneficial effect than any other active class of medication, and
calcium channel blockers and magnesium sulfate had a greater beneficial effect than oxytocin receptor blockers, nitrates and betamimetics. Prostaglandin inhibitors had an 83% probability of being the “best” class of active medications. The probability of being ranked among the 3 most efficacious classes was
96% for prostaglandin inhibitors, 63% for magnesium sulfate, 57% for calcium channel blockers, 33% for betamimetics, 24% for nitrates, and 14% for oxytocin receptor blockers.

Forty trials were included in the network analysis for the outcome neonatal mortality. There was no clear evidence for any class of medication being superior to placebo. Calcium channel blockers were found to be the “best” class, but the probability of this was only 41%, which reflects the considerable uncertainty in the estimate. Prostaglandin inhibitors had a 28% chance of being the “best” class, which was the second highest probability of any class. Similarly, calcium channel blockers was the “best” class for reducing neonatal respiratory distress syndrome (RDS), but the probability of being the best was only 47%. Fiftyeight trials were included in the network analysis for the outcome all-cause maternal side effects. Other than placebo, prostaglandin inhibitors had a 79% chance of being the drug class with the fewest maternal side effects. This was followed by oxytocin receptor blockers, which had a 70% probability of the class with the lowest rate of maternal side effects. Calcium channel blockers had a 15% chance of being included in the top 3 drug classes for the fewest maternal side effects. Overall, prostaglandin inhibitors and calcium channel blockers had the highest probability of being the best classes of medication based
on all 4 outcome measures: delivery delayed by 48 hours, neonatal mortality, neonatal RDS and maternal side effects.

There are also meta-analyses on acute tocolysis, focusing on a single tocolytic class or agent. In 2011, Conde-Agudelo et al reviewed trials on nifedipine, a calcium channel blocker.(5) The investigators identified 26 randomized trials with a total of 2179 women comparing nifedipine with placebo, no treatment, or a different tocolytic agent. Twenty-three of the trials evaluated acute tocolysis and 3 evaluated maintenance tocolysis (maintenance tocolysis is discussed later in the Rationale section). Findings were mixed. Pooled analyses of trials comparing nifedipine and beta-agonists found significantly lower rates of delivery within 7 days of treatment (10 trials; RR=0.82; 95% CI, 0.70 to 0.97) and preterm birth before 34 weeks’ gestation (5 trials; RR=77; 95% CI, 0.66 to 0.91) but no significant difference in the rate of preterm delivery within 48 hours of treatment (13 trials, RR: 0.84, 95% CI, 0.68 to 1.05) or preterm delivery before 37 weeks’ gestation (9 trials; RR=0.97; 95% CI, 0.87 to 1.08). There were no significant differences in any of the preterm delivery variables when nifedipine was compared with magnesium sulfate, but the number of trials and total sample sizes were small, making it difficult to draw conclusions about comparative efficacy.

Several Cochrane reviews on a single type of tocolytic agent are available and are described briefly next:

A 2014 review identified 38 trials evaluating calcium channel blockers for tocolysis, with a total of 3550 women.(6) The calcium channel blocker was nifedipine in 35 trials and nicardipine in the other 3. Thirty-five trials used other tocolytic agents as the comparison intervention (19 used betamimetics), 1 compared doses of nifedipine and the remaining 2 compared calcium channel blockers with placebo or no intervention. Only 1 trial was double-blinded. The authors evaluated several primary and secondary outcomes and conducted pooled analyses when sufficient data were available. Findings were mixed
among primary outcomes, but several favored calcium channel blockers over betamimetics. There was a significantly lower rate of “very preterm birth” before 34 weeks of gestation with calcium channel blockers compared with betamimetics (6 trials; RR=0.78; 95% CI, 0.66 to 0.93) and a significantly lower rate of
maternal adverse effects (15 trials; RR=0.36; 95% CI, 0.24 to 0.53). The incidence of birth less than 48 hours after trial entry and the rate of perinatal mortality did not differ significantly between calcium channel blockers and other tocolytic agents. Among secondary outcome measures, there was a significantly lower rate of preterm birth before completion of 37 weeks of gestation with calcium channel blockers compared with betamimetics (13 trials; RR=0.89; 95% CI, 0.80 to 0.98), and there were too few studies to compare with other tocolytic agents The authors noted that the quality of studies eg, lack of blinding and limited placebo controls, limited the ability for firm conclusions to be drawn about the efficacy of calcium channel blockers compared with other tocolytic agents.

A Cochrane review, updated in 2014, identified 14 trials on oxytocin inhibitors, with a total of 2485 women.(7) The control intervention was placebo in 4 trials, betamimetics in 8 trials and a calcium channel blocker in 2 studies. Pooled analyses did not demonstrate the superiority of oxytocin receptor antagonists
over betamimetics or placebo in terms of reduction in preterm birth or adverse neonatal outcomes. (Note: Oxytocin inhibitors are not approved by FDA for use in the United States.)

Another 2014 Cochrane review identified 37 trials with a total of 3571 women.(8) Comparison interventions included other tocolytic drugs, predominantly betamimetics, nitroglycerine, human chorionic gonadotropin, saline, and dextrose. No placebo-controlled trials were identified. Pooled analyses found no statistically significant differences between magnesium sulfate and comparison interventions for outcomes including birth less than 48 hours after trial entry, serious infant adverse events, and preterm birth before 37 weeks of gestation.

A 2005 Cochrane review by King et al included 13 trials on cyclo-oxygenase (COX) inhibitors, with a total of 713 women; indomethacin was used in 10 of the trials.(9) Only 1 trial compared COX inhibitors with placebo. Pooled analysis of studies comparing COX inhibitors with other tocolytics found a significant
reduction in the incidence of birth before 37 weeks of gestation (RR=0.53; 54 women). The authors noted that numbers were small, and thus estimates were imprecise and not definitive.

In addition to these reviews on single agents, in 2014 Vogel et al published a Cochrane review on combinations of tocolytic agents for preventing preterm labor.(10) The investigators searched for RCTs comparing any combination of tocolytic agents with any other treatment (including other combinations,
single tocolytic agents, no intervention, or placebo). Eleven trials evaluating 7 different comparisons met the review’s inclusion criteria; 2 of these did not report relevant outcome data. Thus, few studies with small combined sample sizes were available for analysis, and the authors were not able to pool data or
draw conclusions about the safety and efficacy of any combination of tocolytics versus any comparison intervention.

Section Summary

Multiple RCTs and meta-analyses have found tocolytics to be effective at decreasing rates of preterm birth in women with preterm labor, eg, delaying delivery for 7 days and/or decreasing rates of delivery before 34 or 37 weeks of gestation. The optimal first-line medication is not certain. A 2012 network metaanalyses suggests that prostaglandin inhibitors and calcium channel blockers may have greater efficacy and fewer adverse effects than other classes of medication. However, there was considerable uncertainty in the estimates of which class of medication was the “best” for each of the outcomes. Cochrane reviews of various tocolytic agents have not found that any agent is clearly superior to any other agent.

Maintenance of Tocolysis

Several meta-analyses of the published literature have been published. The 2011 Conde-Agudelo et al meta-analysis, described earlier,(5) included 3 studies evaluating the calcium channel blocker nifedipine for maintenance tocolysis. A pooled analysis of these 3 trials (total N=215) did not find a significant difference in the rate of preterm birth before 37 weeks of gestation with nifedipine compared with placebo or no treatment (RR=0.87; 97% CI, 0.69 to 1.08). There were insufficient data to conduct pooled analyses on other pregnancy outcome variables.

In 2009, a Health Technology Assessment from the U.K. addressed a wider range of maintenance tocolytic agents.(11) However, for the outcomes prevention of preterm birth before 34 weeks’ or 37 weeks of gestation, there were only a sufficient number of trials to conduct pooled analyses for 2 comparisons.
Neither of the analyses found a statistically significant benefit of tocolysis. In a pooled analysis of magnesium maintenance therapy to other tocolytic agents, the combined RR was 0.98 (95% CI, 0.56 to 1.72). In addition, a pooled analysis of 4 trials (total N=384) did not find a significant benefit of oral
betamimetics compared with placebo or no treatment for preventing preterm birth before 37 weeks’ gestation. The combined relative risk was 1.08 (95% CI, 0.88 to 1.22).

Several Cochrane reviews have addressed specific agents used for maintenance therapy and are described briefly next.

A 2014 Cochrane review of maintenance therapy with oxytocin antagonists identified only 1 trial.(12) This trial, published in 2000 by Valenzuela et al, did not find that atoisiban reduced the rate of preterm birth after threatened preterm birth compared with placebo.(13)

Another 2014 Cochrane review identified 6 RCTs on maintenance therapy with calcium channel blockers.(14) Nifedipine was used in all trials and a total of 794 women were included. The comparison intervention was placebo in 3 trials and no treatment in the other 3 trials. Pooled analyses did not find that
calcium channel blockers significantly reduced the rate of preterm birth before 37 weeks (5 trials; RR=0.97; 95% CI, 0.87 to 1.09) or 34 weeks (3 trials; RR=1.07; 95% CI, 0.88 to 1.30). A pooled analysis of 2 trials did not find significant differences between calcium channel blockers and controls for the outcome birth within 48 hours of treatment. There were insufficient data to draw conclusions about other outcomes.

In 2012, Dodd et al published a Cochrane review on oral betamimetics for maintenance tocolysis after threatened preterm labor.(15) The authors identified 13 RCTs; some of these had more than 2 arms. There were 10 comparisons of a betamimetic and placebo or no treatment, 1 comparison of a betamimetic and indomethacin, 1 comparison between 2 different betamimetics and 3 comparisons between a betamimetic and magnesium. Data could not be pooled for all outcomes due to a shortage of studies on a particular comparison. In a pooled analysis of 6 studies, there was not a statistically significant difference in the rate of preterm birth before 37 weeks in patients receiving a maintenance betamimetic versus placebo or no treatment (RR=1.11; 95% CI, 0.91 to 1.35). In other pooled analysis of findings from studies comparing maintenance betamimetics with placebo or no treatment, there were not statistically significant differences between groups in birthweight (7 studies; mean difference, 4.13; 95% CI, -91.89 to 100.16), risk of perinatal mortality (6 studies; RR=2.41; 95% CI, 0.86 to 6.74) and risk of RDS in the infant (6 studies; RR=1.10; 95% CI, 0.61 to 1.98).

A 2010 review by Han et al evaluated magnesium maintenance therapy and did not find a statistically significant effect of magnesium maintenance therapy on prevention of preterm birth before 37 weeks of gestation.(16) A meta-analysis of 2 studies (total N=99) that compared magnesium therapy with placebo or no treatment found a combined risk ratio of 1.05 (99% CI, 0.80 to 1.40). Two studies (total N=100) were also available for a meta-analysis of studies comparing magnesium therapy with an alternative treatment. In this analysis, the combined RR was 0.99 (95% CI, 0.57 to 1.72).

Section Summary

There are fewer RCTs on maintenance tocolysis compared with acute tocolysis. RCTs and metaanalyses on maintenance tocolysis have generally found that tocolytic agents do not significantly improve health outcomes. Moreover, there are insufficient data from placebo-controlled trials.

Risks Associated With terbutaline

An FDA-conducted search of its Adverse Event Reporting System (AERS) identified reports of 16 maternal deaths associated with terbutaline between 1976 and 2009.(2) FDA documents stated that in 3 cases, it was specified that terbutaline was administered by a subcutaneous pump, and in 9 cases oral
terbutaline was used instead of or in addition to injectable or subcutaneous terbutaline. (Presumably, in the remaining cases, the mode of administration was not reported.) Moreover, between 1998 and July 2009, 12 cases of serious maternal cardiovascular events associated with terbutaline were submitted to

AERS; in 3 cases, use of subcutaneous terbutaline was specified and in 5 cases, it was reported that oral terbutaline was used alone or in addition to subcutaneous terbutaline.

A 2011 commentary examined the human and animal evidence on risks of autism spectrum disorders associated with terbutaline.(17) The authors concluded that the literature does not support the hypothesis that β²-adrenergic agonists including terbutaline are associated with autism spectrum disorders in the
offspring.

Clinical Input Received From Physician Specialty Societies and Academic Medical Centers

In response to requests, input was received through 2 physician specialty societies and 4 academic medical centers while this policy was under review in 2012. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this
process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. There was consensus that acute tocolysis may be considered medically necessary for the induction of tocolysis in patients with preterm labor and near-consensus that preterm should be defined as “<37 weeks” gestational age. There was mixed input on the investigational policy statement on maintenance tocolysis (beyond 48-72 hours).

Summary of Evidence

There is sufficient evidence that the commonly used tocolytic agents presented here are effective at inducing tocolysis in patients with preterm labor or threatened preterm labor. Thus, these agents are considered medically necessary for the acute prevention of preterm delivery. There are data suggesting
that oral terbutaline is associated with more adverse events than parenteral terbutaline for acute tocolysis. Each medication has a different risk/benefit profile, and there is no clear first-line tocolytic agent. There are fewer studies on medications to maintain tocolysis. The available evidence does not suggest that maintenance tocolysis improves health outcomes, and therefore maintenance tocolysis is considered investigational.

Practice Guidelines and Position Statements

  • American College of Obstetricians and Gynecologists
    The American College of Obstetricians and Gynecologists’ Management of preterm labor practice bulletin (2012)(1) contains the following recommendations based on “good and consistent” scientific evidence:
  • “A single course of corticosteroids is recommended for pregnant women between 24 weeks of gestation and 34 weeks of gestation who are at risk of preterm delivery within 7 days.
  • Accumulated available evidence suggests that magnesium sulfate reduces the severity and risk of cerebral palsy in surviving infants if administered when birth is anticipated before 32 weeks of gestation. Hospitals that elect to use magnesium sulfate for fetal neuroprotection should develop uniform and specific guidelines for their departments regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.
  • The evidence supports the use of first-line tocolytic treatment with beta-adrenergic agonist therapy, calcium channel blockers, or non-steroidal anti-inflammatory drugs (NSAIDs) for shortterm prolongation of pregnancy (up to 48 hours) to allow for the administration of antenatal steroids.
  • Maintenance therapy with tocolytics is ineffective for preventing preterm birth and improving neonatal outcomes and is not recommended for this purpose.
  • Antibiotics should not be used to prolong gestation or improve neonatal outcomes in women with pre-term labor and intact membranes.”

Royal College of Obstetricians and Gynecologists

The Royal College of Obstetricians and Gynecologists evidence-based guideline (updated in February 2011)(18) on use of tocolysis for women in preterm labor included the following conclusions relevant to this policy:

  • There is no clear evidence that tocolytic drugs improve outcome and therefore it is reasonable not to use them. However, tocolysis should be considered if the few days gained would be put to good use, such as completing a course of corticosteroids or in utero transfer.
  • Nifedipine and atosiban have comparable effectiveness in delaying birth for up to seven days.
  • Compared with beta-agonists, nifedipine is associated with improvement in neonatal outcome, although there are no long-term data.
  • Beta-agonists have a high frequency of adverse effects. Nifedipine, atosiban and the COX inhibitors have fewer types of adverse effects, and they occur less frequently than for betaagonists but how they compare with each other is unclear.
  • There is insufficient evidence for any firm conclusions about whether or not tocolysis leads to benefit in preterm labor in multiple pregnancy.
  • There is insufficient evidence for any firm conclusion about whether or not maintenance tocolytic therapy following threatened preterm labor is worthwhile. Thus, maintenance therapy is not recommended.

U.S. Preventive Services Task Force Recommendations
No relevant recommendations were found.

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

 References:
  1. American College of Obstetricians and Gynecologists (ACOG) . Management of Preterm Labor. 2012.
  2. FDA drug safety communication: New warnings against use of terbutaline to treat preterm labor.; February 17, 2011.
  3. Haas DM, Imperiale TF, Kirkpatrick PR et al . Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol. 2009;113(3):585-94.
  4. Haas DM, Caldwell DM, Kirkpatrick P et al . Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. BMJ. 2012;345:e6226.
  5. Conde-Agudelo A, Romero R, Kusanovic JP . Nifedipine in the management of preterm labor: a systematic review and metaanalysis. Am J Obstet Gynecol. 2011;204(2):134 e1-20.
  6. Flenady V, Wojcieszek AM, Papatsonis DN, et al. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev. 2014;6:CD002255. PMID 24901312
  7. Flenady V, Reinebrant HE, Liley HG, et al. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev. 2014;6:CD004452. PMID 24903678
  8. Crowther CA, Brown J, McKinlay CJ, et al. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev. 2014;8:CD001060. PMID 25126773
  9. King J, Flenady V, Cole S, et al. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev. 2005(2):CD001992. PMID 15846626
  10. Vogel JP, Nardin JM, Dowswell T, et al. Combination of tocolytic agents for inhibiting preterm labour. Cochrane Database Syst Rev. 2014;7:CD006169. PMID 25010869
  11. Honest H, Forbes CA, Duree KH, et al. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling. Health Technol Assess. Sep 2009;13(43):1-627. PMID 19796569
  12. Papatsonis DN, Flenady V, Liley HG. Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour. Cochrane Database Syst Rev. 2013;10:CD005938. PMID 24122673
  13. Valenzuela GJ, Sanchez-Ramos L, Romero R, et al. Maintenance treatment of preterm labor with the oxytocin antagonist atosiban. The Atosiban PTL-098 Study Group. Am J Obstet Gynecol. May 2000;182(5):1184-1190. PMID 10819856
  14. Naik Gaunekar N, Raman P, Bain E, et al. Maintenance therapy with calcium channel blockers for preventing preterm birth after threatened preterm labour. Cochrane Database Syst Rev. 2013;10:CD004071. PMID 24173691
  15. Dodd JM, Crowther CA, Middleton P. Oral betamimetics for maintenance therapy after threatened preterm labour. Cochrane Database Syst Rev. 2012;12:CD003927. PMID 23235600
  16. Han S, Crowther CA, Moore V. Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour. Cochrane Database Syst Rev. 2010(7):CD000940. PMID 20614423
  17. Rodier P, Miller RK, Brent RL. Does treatment of premature labor with terbutaline increase the risk of autism spectrum disorders? Am J Obstet Gynecol. Feb 2011;204(2):91-94. PMID 21284962
  18.  Royal College of Obstetricians and Gynecologists Green-top Guideline 1b. Tocolysis for women in preterm labor. February 2011; http://www.rcog.org.uk/womens-health/clinical-guidance/tocolytic-drugs-women-preterm-labourgreen-top-1b. Accessed August, 2014.

Codes

Number

Description

CPT 

96372

Therapeutic, prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

 

96374

Intravenous push, single or initial substance/drug

ICD-9 Procedure 

99.29 

Injection or infusion of other therapeutic or prophylactic substance 

ICD-9 Diagnosis 

644.00 - 644.03

Early or threatened labor 

HCPCS 

J3105 

Injection, terbutaline sulfate, up to 1 mg 

  J3475 Injection, magnesium sulfate, per 500mg

 

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-CM (effective 10/1/15) O47.00-O47.9 False labor code range (includes threatened labor)
   O60.00-O60.03 Preterm labor without delivery code range
ICD-10-PCS (effective 10/1/15)    ICD-10-PCS codes are only used for inpatient services.
There is no specific ICD-10-PCS code for this procedure.

Type of Service 

Obstetrics 

Place of Service 

Inpatient 
Home
 


Index

Terbutaline Tocolysis
Tocolysis, Terbutaline  


Policy History

Date

Action

Reason

11/01/1997

Add to Prescription Drug section

New policy

07/12/2002

Replace policy

Policy updated; title changed to include tocolytics other than terbutaline; policy statement unchanged

12/17/03

Replace policy

Literature review update; policy regarding intravenous and subcutaneous terbutaline unchanged. Policy retitled to focus on intravenous or subcutaneous terbutaline therapy; policy no longer addresses oral terbutaline

04/1/05

Replace policy

Policy updated with literature review; no change in policy statement

12/05

Replace policy – coding update only

CPT codes updated

03/7/06

Replace policy

Policy updated with literature review for the period of October 2004 through January 2006; no change in policy statement. Reference #7 added.

09/18/07

Replace policy

Policy updated with literature review up to July 2007; no change in policy statement.   Reference number 8 added. 
09/2009 Policy Archived  
12/2009   Policy updated with literature review through October 2009; new reference numbers 1-5 and 9-10 added. Policy broadened, and policy title changed, to include additional agents in addition to terbutatline. Use in acute tocolysis may be considered medically necessary, use as maintenance is considered investigational.  Policy remains archived
12/09/10 Replace policy returned to active status- Policy updated with literature review through October 2010; no change in policy statement. Reference numbers 2, 7 and 8 added; other references re-numbered or removed.
4/14/11 Replace policy Policy updated with literature review through February 2011. Policy statement on acute tocolysis changed to state that parenteral terbutaline, rather than all betaminetics, may be considered medically necessary. Time frame (beyond 48-72 hours) added to maintenance tocolysis policy statement and mention of specific medications was removed. Reference numbers 3, 5, 9-10, 14-15 added; other references renumbered/removed.
9/13/12 Replace policy Policy updated with literature review through July 2012. Clinical input added. Reference numbers 4 and 11 added; other references renumbered/removed.
9/12/13 Replace policy Policy updated with literature review through July 12, 2013. Reference numbers 1, 3, 11 and 12 added; other references renumbered/removed. No change to policy statements.
10/09/14 Replace policy Policy updated with literature review through September 2, 2014 References 6-8, 10, 12, and 14. No change to policy statements.