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Acute and Maintenance Tocolysis

Policy Number: MP-471

Latest Review Date: September 2018

Category: Pharmacology                                                       

Effective 10/01/2018, Active policy but no longer scheduled for regular literature reviews or updates.

Description of Procedure or Service:

Tocolysis refers to the suppression of preterm labor to delay delivery. A variety of medications are used as tocolytic agents; although none of the currently available options are approved by the U.S. Food and Drug Administration (FDA) for this indication. These medications have also been evaluated as maintenance therapy following successful tocolysis.

Tocolysis

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 the complications of preterm delivery, especially neonatal respiratory distress syndrome. 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 respiratory distress syndrome. 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.

Treatment

Several agents have been used for tocolysis. The only FDA-approved tocolytic drug is ritodrine, a beta-sympathomimetic. Ritodrine is no longer available in the United States and thus only off-label medications are available. Terbutaline, also a beta-sympathomimetic, is an alternative to ritodrine, for acute and maintenance tocolysis. Terbutaline is available as an oral or intravenous medication and, more recently, terbutaline 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 (reaffirmed 2014) by the American College of Obstetricians and Gynecologists (ACOG) summarized the potential adverse effects of common classes of tocolytic agents:

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.)

 

Policy:

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

Maintenance tocolytic therapy (beyond 48-72 hours) with any medication is consideredn not medically necessary and investigational.

On February 17th , 2011, the FDA issued a safety alert with notice of a label change for terbutaline. The safety alert can be found online at: 
https://www.fda.gov/Drugs/DrugSafety/ucm243539.htm

 

Key Points:

Following is a summary of the literature through June 4, 2018.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Acute Tocolysis

Clinical Context and Therapy Purpose

The purpose of acute tocolysis in patients who have preterm labor dis to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does acute tocolysis improve the net health outcome in women with or at risk of preterm labor?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is women experiencing or at risk of preterm labor.

Interventions

The therapy being considered is acute tocolysis. Tocolytic medications include terbutaline sulfate, calcium channel blockers (eg, nifedipine), magnesium sulfate, oxytocin receptor antagonists (eg, atosiban), prostaglandin inhibitors (eg, indomethacin), and nitrates (eg, nitroglycerin)

Comparators

The following practice is currently being used to make decisions about reducing or mitigating the risk and harms of preterm labor: no tocolytic therapy.

Outcomes

The outcomes of interest are the gestational age at birth, morbidity and mortality of the infant, and adverse events of treatment on the mother.

Timing

The timing of therapy is the 24- to 72-hour period during which tocolysis occurs and the gestational age in weeks.

Setting

Therapy is administered in an inpatient care setting by a specialist (eg, obstetrician-gynecologist).

Systematic Reviews

Studies have focused on whether tocolytic agents prevent preterm delivery and thereby reduce associated maternal and neonatal risks. Numerous RCTs on acute tocolysis have been published and Haas et al (2009) conducted a comprehensive systematic review and meta-analysis of RCTs. They included 58 studies that directly compared different tocolytic medications or compared 1 medication with placebo or usual care. Studies were selected if they compared 2 drugs in the same class but excluded if they included 2 doses of the same medication. Participants were women diagnosed with preterm labor or threatened preterm labor. The analysis was limited to studies with fetuses of mean gestational ages between 28 weeks and 32 weeks of gestation. Multiple gestations 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)

Medication Class

48-hour delay

7-day delay

After 37 weeks

No. studies

% (95% CI)

No. studies

% (95% CI)

No. Studies

% 29(95% CI)

Placebo/control

9

53 (45-61)

8

39 (28-49)

3

36 (20-52)

Beta mimetics

29

75 (65-850

26

65 (59-71)

15

46 (36-56)

Calcium channel blockers

17

76 (57-95)

10

63 (56-69)

12

47 (32-62)

Magnesium sulfate

11

89 (85-93)

5

61 (39-84)

7

42 (31-53

Oxytocin receptor antagonists

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)

Medication Class

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 (17-260

6

1 (0-2)

Betamimetcs

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 antagonist

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)

CI= Confidence Interval; RDS=respiratory distress syndrome
Maternal adverse effects are those that required discontinuation of the medication

All tocolytic agents were significantly better than placebo/control at delaying delivery for 48 hours and delaying delivery for seven 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 to 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’ gestation due to a high effectiveness at delaying delivery by at least seven 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 seven days of treatment (relative risk [RR]=0.76; 95% confidence interval [CI], 0.60 to 0.97) and before 34 weeks’ gestation (RR=0.83; 95% CI, 0.69 to 0.99).

In an another review published in 2012, Haas et al conducted a systematic review and network meta-analysis in which direct and indirect evidence on relative impacts of tocolytics on health outcomes were pooled simultaneously. 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, four included nitrates and five 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 three 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%.

Fifty-eight 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, at 70% probability, and calcium channel blockers at 15%.

Overall, prostaglandin inhibitors and calcium channel blockers had the highest probability of being the best classes of medication based on all four outcome measures: delivery delayed by 48 hours, neonatal mortality, neonatal respiratory distress syndrome and maternal side effects.

Several systematic reviews and meta-analyses have focused on a single tocolytic class or agent. A Cochrane review by Flenady et al (2014) identified 38 trials evaluating calcium channel blockers for tocolysis (total N=3550 women). The calcium channel blocker was nifedipine in 35 trials and nicardipine in the other 3. Thirty-five trials used other tocolytic agents as the comparator (19 used betamimetics), one compared doses of nifedipine, and the other two compared calcium channel blockers with placebo or no intervention. Only 1 trial was double-blinded. Reviewers 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 events (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. Reviewers noted that the quality of studies (eg, lack of blinding, limited placebo controls) limited the ability to draw firm conclusions about the efficacy of calcium channel blockers compared with other tocolytic agents.

An updated Cochrane review by Flenady et al (2014) identified 14 trials on oxytocin inhibitors (total N=2485 women). The control intervention was a 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 that oxytocin inhibitors are not approved by the Food and Drug Administration for use in the United States).

Another 2014 Cochrane review identified 37 trials with a total of 3571 women. 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.

Conde-Agudelo et al (2011) reviewed trials on nifedipine. They identified 26 randomized trials (total N=2179 women) comparing nifedipine with placebo, no treatment, or a different tocolytic agent. Twenty- three trials evaluated acute tocolysis and 3 evaluated maintenance tocolysis. Findings were mixed. Pooled analyses of trials comparing nifedipine with 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 of gestation (5 trials; RR=0.77; 95% CI, 0.66 to 0.91), but no significant differences in the rates 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 of 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 both small, making it difficult to draw conclusions about comparative efficacy.

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 ten of the trials. Only one 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’ 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. 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 seven different comparisons met the review’s inclusion criteria; two 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: Acute Tocolysis

Multiple RCTs and meta-analyses have found tocolytics to be effective at decreasing rates of preterm birth in women with preterm labor, e.g., delaying delivery for seven days and/or decreasing rates of delivery before 34 or 37 weeks’ gestation. The optimal first-line medication is not certain. A 2012 network meta-analyses suggest 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

Clinical Context and Therapy Purpose

The purpose of maintenance of tocolysis in patients who have had preterm labor is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does maintenance with tocolytic agents improve the net health outcome in women who have had successful tocolytic therapy for preterm labor?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is women treated successfully with tocolytic agents for preterm labor.

Interventions

The therapy being considered is maintenance tocolysis. Tocolytic medications include terbutaline sulfate, calcium channel blockers (eg, nifedipine), magnesium sulfate, oxytocin receptor antagonists (eg, atosiban), prostaglandin inhibitors (eg, indomethacin), and nitrates (eg, nitroglycerin).

Comparators

The following practice is currently being used to make decisions about use of maintenance tocolysis to prevent recurrence of preterm labor: no tocolytic therapy.

Outcomes

The outcomes of interest are the gestational age at birth, morbidity and mortality of the infant, and adverse effects of treatment on the mother.

Timing

The timing is up to 37 weeks gestation.

Setting

Therapy is administered in an inpatient care setting by a specialist (eg, obstetrician-gynecologist).

Systematic Reviews

A Cochrane review by Papatsonis et al (2013), evaluating maintenance therapy with oxytocin antagonists, identified only 1 trial. This trial, by Valenzuela et al (2000), did not find that atosiban reduced the rate of preterm birth after threatened preterm birth compared with placebo.

Another Cochrane review, conducted by Naik Gaunekar et al (2013), identified 6 RCTs on maintenance therapy with calcium channel blockers. 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.  The authors identified 13 RCTs; some of these had more than two arms. There were ten comparisons of a betamimetic and placebo or no treatment, one comparison of a betamimetic and indomethacin, one comparison between two different betamimetics and three 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 six 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 to placebo or no treatment, there were not statistically significant differences between groups in birthweight (seven studies, mean difference: 4.13, 95% CI: -91.89 to 100.16), risk of perinatal mortality (six studies, RR: 2.41, 95% CI: 0.86 to 6.74) and risk of respiratory distress syndrome in the infant (six 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’ gestation.  A meta-analysis of two studies (total n=99) that compared magnesium therapy to 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 to an alternative treatment. In this analysis, the combined risk ratio was 0.99 (95% CI: 0.57 to 1.72).

The 2011 Conde-Agudelo et al systematic review, described earlier, included three studies evaluating the calcium channel blocker nifedipine for maintenance tocolysis. A pooled analysis of these three trials (total n=215) did not find a significant difference in the rate of preterm birth before 37 weeks’ gestation with nifedipine compared to 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.  However, for the outcomes prevention of preterm birth before 34 weeks’ or 37 weeks’ gestation, there were only a sufficient number of trials to conduct pooled analyses for two comparisons. Neither of the analyses found a statistically significant benefit of tocolysis. In a pooled analysis comparing magnesium maintenance therapy to other tocolytic agents, the combined relative risk was 0.98 (95% CI: 0.56 to 1.72). In addition, a pooled analysis of four trials (total n=384) did not find a significant benefit of oral betamimetics compared to placebo or no treatment for preventing pre-term birth before 37 weeks’ gestation. The combined relative risk was 1.08 (95% CI: 0.88 to 1.22).

Nonrandomized Studies

Follow-up data from the APOSTEL II trial were reported by van Vliet et al (2016) on maintenance tocolysis using nifedipine. Two-year outcomes data from this RCT were available for 135 (52.5%) of 276 participants. Outcomes were mixed for infants of women in the nifedipine maintenance group compared with the placebo group. Those on nifedipine maintenance doses had a higher incidence of fine motor problems (22% vs 8%, odds ratio, 3.43; 95% CI, 1.29 to 9.14) and a lower incidence of poor problem-solving ability (22% vs 29%; odds ratio, 0.27; 95% CI, 0.08 to 0.95).

Section Summary: Maintenance of Tocolysis

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

Summary of Evidence

For individuals who preterm labor or threatened preterm labor who receive acute tocolytic therapy, the evidence includes multiple randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are overall survival, morbid events, functional outcomes, and treatment-related morbidity. Overall, the body of evidence found that the commonly used tocolytic agents presented here are effective at inducing tocolysis in patients with preterm labor or threatened preterm labor. Data have suggested 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. The evidence is sufficient to determine quantitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals who have successful acute tocolysis for preterm labor who receive maintenance tocolytic therapy, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, morbid events, functional outcomes, and treatment-related morbidity. Studies have generally not found that maintenance tocolysis lowers the rate of preterm birth or perinatal mortality, or increases the birthweight. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines, and Position Statements

American College of Obstetricians and Gynecologists (ACOG)

The American College of Obstetricians and Gynecologists (2016) updated its practice bulletin on the management of preterm labor. The 2016 bulletin contained the following relevant 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 seven 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 short-term 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.”

National Institute for Health and Care Excellence

A 2015 guidance from the National Institute for Health and Care Excellence on preterm labor and birth made the following recommendations on tocolysis:

1.8.2 “Consider nifedipine for tocolysis for women between 24+0 and 25+6 weeks of pregnancy who have intact membranes and are in suspected preterm labour.

1.8.3 Offer nifedipine for tocolysis to women between 26+0 and 33+6 weeks of pregnancy who have intact membranes and are in suspected or diagnosed preterm labour.

1.8.4 If nifedipine is contraindicated, offer oxytocin receptor antagonists for tocolysis.

1.8.5 Do not offer betamimetics for tocolysis.”

1.9.1 “For women between 23+0 and 23+6 weeks of pregnancy who are in suspected or established preterm labour, are having a planned preterm birth or have P-PROM [preterm prelabour rupture of membranes] … discuss with the woman (and her family members or carers as appropriate) the use of maternal corticosteroids in the context of her individual circumstances.

1.9.2 Consider maternal corticosteroids for women between 24+0 and 25+6 weeks of pregnancy who are in suspected or established preterm labour, are having a planned preterm birth or have P-PROM.

1.9.3 Offer maternal corticosteroids to women between 26+0 and 33+6 weeks of pregnancy who are in suspected, diagnosed or established preterm labour, are having a planned preterm birth or have P-PROM.

1.9.4 Consider maternal corticosteroids for women between 34+0 and 35+6 weeks of pregnancy who are in suspected, diagnosed or established preterm labour, are having a planned preterm birth or have P-PROM.”

1.10.1 “Offer intravenous magnesium sulfate for neuroprotection of the baby to women between 24+0 and 29+6 weeks of pregnancy who are:

  • in established preterm labour or

  • having a planned preterm birth within 24 hours.

1.10.2 Consider intravenous magnesium sulfate for neuroprotection of the baby for women between 30+0 and 33+6 weeks of pregnancy who are:

  • in established preterm labour or

  • having a planned preterm birth within 24 hours.”

U.S. Preventive Services Task Force Recommendations

No relevant recommendations were found.

 

Key Words:

Tocolytic, acute tocolytic therapy, maintenance tocolytic therapy, betamimetics, calcium channel blockers, magnesium sulfate, and prostaglandin inhibitors, terbutaline

 

Approved by Governing Bodies:

Ritodrine was approved by the FDA for use as a tocolytic agent, but was voluntarily withdrawn from the U.S. market in 1998.

Terbutaline sulfate 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. Based on animal studies, the FDA reclassified terbutaline sulfate 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 to 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 post-marketing 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.

 

Benefit Application:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply.
FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

 

Coding: 

CPT Codes:

96372              Therapeutic prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

96374              Therapeutic, prophylactic or diagnostic injection (specify substance or drug); intravenous push, single or initial substance/drug

HCPCS Codes:

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

 

References:

  1. American college of Obstetricians and Gynecologists (ACOG).  Management of Preterm Labor, 2012, reaffirmed 2014; www.ncbi.nlm.nih.gov/pubmed/22617615.

  2. American College of Obstetricians and Gynecologists (ACOG). Management of preterm labor. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2003 May. 9 p. (ACOG Practice Bulletin; No. 43).

  3. American College of Obstetricians Gynecologists, Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin no. 127: Management of preterm labor. Obstet Gynecol. Jun 2012;119(6):1308-1317.

  4. American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin-List of Titles November 2010.

  5. Conde-Agudelo A, Pomero R, Kusanovic JP.  Nifedipine in the management of preterm labor: a systematic review and meta-analysis.  Am J Obstet Gynocol 2011: 204(2):134 e131.

  6. 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.

  7. de Haus R, Mulder EJ, Visser GH.   Management of preterm labor: atosiban or nifedipine.  Int J Women’s Health 2010; 2: 137-42.

  8. Dodd JM, Crowther CA, Middleton P.  Oral betamimetics for maintenance therapy after threatened preterm labor.  Cochrane Database Syst Rev 2012; 12: CD003927.

  9. FDA drug safety communication: New warnings against use of terbutaline to treat preterm labor.  February 17, 2011.  www.fda.gov/drugs/drugsafety/ucm243539.htm. Last accessed July 22, 2018.

  10. Flenady V, Reinebrant HE, Liley HG, et al. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev. 2014; 6:CD004452.

  11. Flenady V, Wojcieszek AM, Papatsonis DN, et al. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev. 2014; 6:CD002255.

  12. Han S, Crowther CA, Moore V. Magnesium maintenance therapy for preventing preterm birth after threatened preterm labor. Cochrane Database Syst Rev 2010; (7):CD000940.

  13. Haas DM, Caldwell DM, Kirkpatrick P, McIntosh JJ, Welton NJ.  Tocolytic therapy for preterm delivery:  systematic review and network meta-analysis.  BMJ 2012; 345:e6226. 

  14. Haas DM, Imperiale TF, Kirkpatrick PR et al. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol 2009; 113(3):585-94.

  15. Honest H, Forbes CA, Durée KH et al. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling. Health Technol Assess 2009; 13(43):1-627.

  16. King J, Flenady V, Cole S et al. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev 2005; (2):CD001992.

  17. King J, Flenady V, Papatsonis D et al. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev 2003; (1):CD002255.

  18. Klauser CK, Briery CM, Keiser SD, Martin RW, Kosek MA, Morrison JC . Effect of Antenatal Tocolysis on Neonatal Outcomes. J Matern Fetal Neonatal Med. 2012.

  19. Lyell DJ, Pullen KM, Mannan J et al. Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial. Obstet Gynecol 2008; 112(6):1221-6.

  20. 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.

  21. Nasser AH, Aoun J, Usta IM.  Calcium channel blocker for the management of preterm birth: a review.  Am J Pernatol 2011; 28(1):57-66.

  22. National Institute for Health and Care Excellence (NICE). Preterm labour and birth [NG25]. 2015; https://www.nice.org.uk/guidance/ng25. Accessed July 22, 2018.

  23. Papatosinis D, Flenady V, Cole S et al. Oxytocin receptor antagonists for inhibiting preterm labour Cochrane Database Syst Rev 2005; (3):CD004452.

  24. 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.

  25. Rodier P, Miller RK, Brent RL.  Does treatment of premature labor with terbutaline increase the risk of autism spectrum disorders?  Am J Obstet Gynecol 2011; 204(2):91-4.

  26. Roos C, Spaanderman ME, Schuit E, Bloemenkamp KW et al.  Effect of maintenance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes:  a randomized controlled trial.  JAMA.  2013; 309(1):41-7.

  27. Royal College of Obstetricians and Gynecologists Green-top Guideline 1b.  Tocolysis for women in preterm labor. February 2011.  www.rcog.org.uk/womens-health/clinical-guidance/tocolytic-drugs-women-preterm-labour-green-top-1b.

  28. Sanchez-Ramos L, Kaunitz AM, Gaudier FL et al. Efficacy of maintenance therapy after acute tocolysis: a meta-analysis. Am J Obstet Gynecol 1999; 181(2):484-90.

  29. Thornton JG. Maintenance tocolysis. BJOG 2005; 112(suppl 1):118-21.

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  31. van Vliet E, Seinen L, Roos C, et al. Maintenance tocolysis with nifedipine in threatened preterm labour: 2-year follow up of the offspring in the APOSTEL II trial. BJOG. Aug 27 2015.

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Policy History:

Medical Policy Group, April 2011(2)
Medical Policy Administration Committee, April 2011
Available for comment April 25 – June 13, 2011
Medical Policy Panel, September 2012
Medical Policy Group, May 2013 (4): Updated Key Points and References, No changes to the policy at this time.
Medical Policy Panel, September 2013
Medical Policy Group, October 2013 (2): Policy updated with literature review.  No change to policy statement.  Description, Key Points, and References updated to reflect information found in literature search.
Medical Policy Panel, October 2014
Medical Policy Group, October 2014 (3):  2014 Updates to Key Points & References; no change to policy statement
Medical Policy Panel, October 2015
Medical Policy Group, October 2015 (4): Updates to Key Points and References.  No change to policy statement.
Medical Policy Panel, August 2017
Medical Policy Group, August 2017 (4): Updates to Description and Key Points.  No change to policy statement.
Medical Policy Panel, September 2018
Medical Policy Group, September 2018 (4): Updates to Description, Policy, Key Points, and References. Removed coverage information prior to June 14, 2011 from policy section. No change in policy statements.

 

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.