mp-471 - Medical Policies - Alabama
Acute and Maintenance Tocolysis
Policy Number: MP-471
Latest Review Date: April 2021
Policy Grade: Effective 10/01/2018, Active policy but no longer scheduled for regular literature reviews or updates.
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 considered 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:
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.
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.
Several agents have been used for tocolysis. The calcium channel blocker, Nifedipine, is commonly used for tocolysis. Terbutaline has also been used and is a beta-sympathomimetic that can be administered subcutaneously. Terbutaline has also been administered by continuous subcutaneous infusion via a portable pump for maintenance tocolysis, but should not be used for more than 72 hours. Other tocolytic drugs include magnesium sulfate and nonsteroidal anti-inflammatory drugs.
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.
- 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.)
A literature search was conducted through April 28, 2021.
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."
National Institute for Health and Care Excellence
A 2015 guidance from the National Institute for Health and Care Excellence on preterm labor and birth (updated August 2019) 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.”
1.10.2 “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.
1.10.3 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
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.
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.
Therapeutic prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
Therapeutic, prophylactic or diagnostic injection (specify substance or drug); intravenous push, single or initial substance/drug
Injection, terbutaline sulfate, up to 1 mg
Injection magnesium sulfate, per 500mg
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
- American college of Obstetricians and Gynecologists (ACOG). Management of Preterm Labor, 2012, reaffirmed 2014; www.ncbi.nlm.nih.gov/pubmed/22617615.
- 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).
- 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.
- American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin-List of Titles November 2010.
- 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.
- 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.
- de Haus R, Mulder EJ, Visser GH. Management of preterm labor: atosiban or nifedipine. Int J Women’s Health 2010; 2: 137-42.
- Dodd JM, Crowther CA, Middleton P. Oral betamimetics for maintenance therapy after threatened preterm labor. Cochrane Database Syst Rev 2012; 12: CD003927.
- 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.
- Flenady V, Reinebrant HE, Liley HG, et al. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev. 2014; 6:CD004452.
- Flenady V, Wojcieszek AM, Papatsonis DN, et al. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev. 2014; 6:CD002255.
- Han S, Crowther CA, Moore V. Magnesium maintenance therapy for preventing preterm birth after threatened preterm labor. Cochrane Database Syst Rev 2010; (7):CD000940.
- 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.
- Haas DM, Imperiale TF, Kirkpatrick PR et al. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol 2009; 113(3):585-94.
- 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.
- IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
- King J, Flenady V, Cole S et al. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev 2005; (2):CD001992.
- King J, Flenady V, Papatsonis D et al. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev 2003; (1):CD002255.
- 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.
- 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.
- 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.
- 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.
- 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.
- Papatosinis D, Flenady V, Cole S et al. Oxytocin receptor antagonists for inhibiting preterm labour Cochrane Database Syst Rev 2005; (3):CD004452.
- 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.
- 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.
- 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.
- 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.
- 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.
- Thornton JG. Maintenance tocolysis. BJOG 2005; 112(suppl 1):118-21.
- 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.
- Van Vliet E, Kijkema GH, Schuit E, et al. Nifedipine maintenance tocolysis and perinatal outcome: an individual participant data meta-analysis. BJOG. 2016 Oct;123 (11):1753-60.
- 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.
- Vogel JP, Nardin JM, Dowswell T, et al. Combination of tocolytic agents for inhibiting preterm labour. Cochrane Database Syst Rev. 2014; 7:CD006169.
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.
Medical Policy Group, April 2021 (4): Updates to Description, Key Points, and References. Policy statement updated to remove not medically necessary. No change to policy intent.
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.