Acute and Maintenance Tocolysis

POLICY NUMBER

L.5.01.584

Please perform a formulary drug search on your patient’s member ID to ensure the prescription drug is covered under their benefit plan. The medication(s) in this medical policy may not be covered under a specific member’s benefit plan.

DESCRIPTION

Tocolysis refers to the suppression of preterm labor to delay delivery. A variety of medications are used as tocolytic agents, although none are currently approved by the U.S. Food and Drug Administration for the purpose of suppressing labor. 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 of gestation. Successful delay of preterm delivery allows further fetal development and precludes potential 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 has been ritodrine, a beta-sympathomimetic. Ritodrine is no longer available in the United States, 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 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 to increase the risk of adverse events. The 2012 guidelines (reaffirmed 2014) issued by the American College of Obstetricians and Gynecologists summarized the potential adverse events of common classes of tocolytic agents: calcium channel blockers, nonsteroidal anti-inflammatory drugs, β-adrenergic receptor agonists, and magnesium sulfate.

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 events: no known adverse events

Nonsteroidal Anti-inflammatory Drugs

• 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 events: 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 on 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 events: fetal tachycardia

Magnesium Sulfate

• Maternal side effects: flushing, diaphoresis, nausea, loss of deep tendon reflexes, respiratory depression, and cardiac arrest; suppression of 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 events: neonatal depression. (Note: 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.)

Risks Associated with Terbutaline

An FDA-conducted search of its Adverse Event Reporting System identified reports of 16 maternal deaths associated with terbutaline between 1976 and 2009. FDA documents indicate 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 the Adverse Event Reporting System; in 3 cases, subcutaneous terbutaline was specified and, in 5 cases, oral terbutaline was used alone or in addition to subcutaneous terbutaline.

An editorial by Rodier and colleagues examined the human and animal evidence on risks of autism spectrum disorders associated with terbutaline. The commentators concluded that the literature did not support the hypothesis that β₂-adrenergic agonists (including terbutaline) are associated with autism spectrum disorders in offspring.

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

Terbutaline has been approved by the FDA 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 2008 citizen petition, the FDA reviewed safety data on terbutaline sulfate. FDA issued a safety announcement in 2011. 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 to 3 days) treatment of preterm labor, and oral terbutaline should not be used for acute or maintenance tocolysis. The labeling change was based on a review of post-marketing safety reports submitted to the FDA’s Adverse Event Reporting System of maternal death and serious maternal cardiovascular events associated with the use of terbutaline.

Also, see the related medical policy Progesterone Therapy as a Technique to Reduce Preterm Delivery in High-Risk Pregnancies.

POLICY

Acute tocolytic therapy withcalcium 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 of gestational age) labor.

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

POLICY EXCEPTIONS

Federal Employee Program (FEP) Members: Coverage is provided for tocolytic therapy and related services when provided on an inpatient basis during a covered hospital admission or during a covered observation stay.

State Health Plan (State and School Employees): The prescription drug(s) in this medical policy may be covered under a prescription drug benefit plan administered by the State Health Plan’s Pharmacy Benefit Manager. Please perform a formulary drug search at https://www.dfa.ms.gov/cvs-caremark and submit any required Prior Authorization Requests for coverage determination to the Plan’s Pharmacy Benefit Manager. Services related to delivery and/or administration of a medication determined to be not medically necessary will also be considered not medically necessary. Services related to delivery and/or administration of a self-administered drug are not covered.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

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.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

8/1999: Approved by Medical Policy Advisory Committee (MPAC).

2/1/2002: Appeal statement deleted from Policy Exception section.

2/11/2002: Investigational definition added.

5/8/2002: Type of Service and Place of Service deleted.

9/30/2004: Policy title "Tocolytic Therapy for Preterm Labor" renamed "Tocolysis with Intravenous or Subcutaneous Terbutaline," Sources updated.

10/6/2004: Code Reference section updated, CPT code 90782, 90784 deleted, ICD-9 diagnosis code 644.00, 644.10, 644.13, 644.20 added, HCPCS S9349 added.

2/21/2005: Policy reviewed, Description and Policy sections revised to be consistent with BCBSA policy # 5.01.07, non-covered table added, HCPCS S9349 moved to non-covered table.

3/14/2006: Coding updated CPT4 2005 revisions added to policy.

9/18/2007: Policy reviewed, no changes.

06/22/2010: Policy title changed from “Tocolysis with Intravenous or Subcutaneous Terbutaline” to “Acute and Maintenance Tocolysis” as the description and policy statements were broadened to include additional agents in addition to terbutatline. Use in acute tocolysis may be considered medically necessary; use as maintenance is considered investigational. FEP verbiage added to the Policy Exceptions section. Deleted outdated references from the Sources section. Added CPT codes 96372 and 96374; also added HCPCS J3475.

02/23/2011: Policy reviewed; no changes.

08/03/2011: Policy description updated. Replaced "betamimetics" with "parenteral terbutaline" in the first policy statement. Deleted "including but not limited to subcutaneous or intravenous terbutaline" from the investigational policy statement.

01/09/2013: Policy reviewed; no changes.

04/19/2013: Deleted ICD-9 codes 644.20 and 644.21 from the Code Reference section.

11/15/2013: Policy reviewed; no changes.

11/17/2014: Policy reviewed; description updated regarding potential adverse effects of common classes of tocolytic agents. Policy statements unchanged.

08/26/2015: Medical policy revised to add ICD-10 codes. Removed ICD-9 procedure code 99.29 from the Code Reference section.

12/03/2015: Policy description updated. Policy statements unchanged. Policy guidelines updated to add medically necessary and investigative definitions.

05/26/2016: Policy number A.5.01.07 added.

01/16/2017: Policy Exceptions section updated to state that for FEP members, Terbutaline and magnesium sulfate may be considered investigational for tocolysis therapy.

09/13/2017: Policy description updated. Policy statements unchanged.

08/22/2018: Policy description updated regarding risks associated with terbutaline. Policy statements unchanged.

07/29/2020: Policy reviewed and approved by Pharmacy & Therapeutics (P&T) Committee. Policy updated to add statement to perform a formulary drug search on the patient's member ID to ensure the prescription drug is covered under their benefit plan. The medication(s) in this medical policy may not be covered under a specific member's benefit plan.

11/01/2022: Policy number changed from "A.5.01.07" to "L.5.01.584." Policy reviewed. Policy statements unchanged. Policy Exceptions updated for FEP members. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity." Sources updated.

02/01/2023: Policy Exceptions updated to add the following: State Health Plan (State and School Employees): The prescription drug(s) in this medical policy may be covered under a prescription drug benefit plan administered by the State Health Plan’s Pharmacy Benefit Manager. Please perform a formulary drug search at https://www.dfa.ms.gov/cvs-caremark and submit any required Prior Authorization Requests for coverage determination to the Plan’s Pharmacy Benefit Manager. Services related to delivery and/or administration of a medication determined to be not medically necessary will also be considered not medically necessary. Services related to delivery and/or administration of a self-administered drug are not covered.

08/07/2023: Policy reviewed; no changes.

08/20/2024: Policy reviewed; no changes.

SOURCE(S)

1. Blue Cross Blue Shield Association policy # 5.01.07

2. Mayer C, Apodaca-Ramos I. Tocolysis. [Updated 2022 Apr 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK562212/

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.