Magnesium Sulfate Injections and Terbutaline Pump for Preterm Labor

Number: 0468

Policy

Aetna considers magnesium sulfate injections medically necessary for short-term prolongation of pregnancy (up to 48 hours) in pregnant women who are at risk of preterm delivery within 7 days.

Aetna considers the use of a terbutaline pump for administration of subcutaneous terbutaline experimental and investigational for the prevention or treatment of premature labor becauase its effectiveness has not been established.

See also CPB 0510 - Progestins.

Background

Terbutaline for Preterm Labor

Terbutaline has been used in selected patients to inhibit uterine contractions in preterm labor (tocolysis) in an attempt to prolong pregnancy and prevent preterm birth.  An infusion pump is required for the subcutaneous administration of terbutaline.  Preterm labor often results in preterm births, which significantly contributes to infant morbidity and mortality.

There is no evidence that tocolytics reduces the risk of preterm delivery (Haas, 2007; Nanda et al, 2002; CTAF, 2002).  The incidence of preterm birth has not decreased in the last 2 decades, despite the increased use of tocolytics.

A review of 17 randomized controlled trials (RCTs) that compared a tocolytic with a placebo or no tocolytic for women in preterm labor found that tocolytics were not associated with significant reduction in births before 30 weeks' gestation, before 32 weeks' gestation, or before 37 weeks' gestation.  However, tocolytics were associated with significant decreases in the likelihood of delivery within 24 hours.  Tocolytics reviewed included: isoxuprine, ethanol, terbutaline, ritodrine, indomethacin, magnesium sulfate, and atosiban.  Significant effects on prolongation of pregnancy were found with betamimetics, indomethacin, atosiban, and ethanol, but not with magnesium sulfate.  Only 1 study of indomethacin showed any significant decrease in preterm births.  Tocolytics increased risk of maternal palpitations, nausea, tremor, chorioamnionitis, hyperglycemia, and hypokalemia.  The review concluded that although tocolytics prolong pregnancy, they have not been shown to improve perinatal or neonatal outcomes.

In 1997, the U.S. Food and Drug Administration (FDA) sent a letter to physicians and other health care providers warning them that adequate data establishing the safety and effectiveness of the use of terbutaline as a tocolytic agent have not been submitted to the FDA; that the demonstrated value of tocolytics in general is limited to an initial, brief period of treatment, probably no more than 48 to 72 hours; and that no benefit from prolonged administration has been documented.  In addition, the letter noted that the safety of long-term subcutaneous administration of terbutaline sulfate, especially on an outpatient basis, has not been adequately addressed.  The letter stated that complications of subcutaneous terbutaline administration are similar to that accompanying intravenous administration of terbutaline and other beta-sympathomimetics, including chest pain, tachycardia, dyspnea, pulmonary edema, and death.  The letter noted that the impact of long-term use of subcutaneous terbutaline on maternal glucose metabolism and the risks of prolonged exposure of the fetus are largely unknown.

Guinn and colleagues (1998), reporting on the results of the largest RCT to date of the effectiveness of terbutaline pump for the prevention of preterm delivery, concluded that the terbutaline pump does not prolong gestation in women with suspected preterm labor.  A total of 52 women with suspected preterm labor were randomly assigned to receive either treatment with terbutaline or normal saline solution placebo by subcutaneous infusion pump.  The study found no significant differences between treatment and placebo groups in mean time to delivery and rates of preterm delivery at less than 34 and less than 37 weeks' gestation.

Although there is no evidence of the effectiveness of tocolytics in preventing premature delivery, the literature supports the efficacy of parenteral tocolytic agents in delaying delivery for 24 to 48 hours.  Such a delay may be of benefit by increasing the time to delivery, allowing additional time for the beneficial effects of adjunctive corticosteroid therapy.

Grimes and Nanda (2006) stated that magnesium sulphate tocolysis has no benefit in preventing preterm or very preterm birth.  Moreover, the risk of total pediatric mortality was significantly higher for infants exposed to magnesium sulfate (relative risk 2.8; 95 % confidence interval: 1.2 to 6.6).  Given its lack of benefit, possible harms, and expense, magnesium sulphate should not be used for tocolysis.  The authors stated that any further use of magnesium sulphate for tocolysis should be restricted to formal clinical trials with approval by an institutional review board and signed informed consent for participants.  They noted that should tocolysis be desired, calcium channel blockers, such as nifedipine, seem preferable.

An assessment of the terbutaline pump for prevention of preterm birth prepared for the Agency for Healthcare Research and Quality (AHRQ) (Gaudet, et al., 2011) found that the evidence base consists of a small number of biased studies. The report stated that a substantial body of evidence originated from one proprietary database. The report concluded that, although evidence suggests that pump therapy is beneficial as maintenance tocolysis, confidence in its validity and reproducibility is low. The report noted that postmarketing surveillance has detected cases of serious harms, and safety of the therapy remains unclear.

In summary, although tocolytic agents, including the terbutaline pump, have been shown to be of benefit in managing acute episodes of preterm labor in the hospital, there is no evidence that the use of any of these agents as “maintenance” medications provides any clinical benefit.  On the other hand, tocolytics have known adverse effects on women in preterm labor.  Further investigation on the use of tocolytics in improving perinatal, neonatal and maternal outcomes is needed in order to establish their effectiveness.

Terbutaline is sometimes used off-label for acute obstetric uses, including treating preterm labor and treating uterine hyper-stimulation.  It has also been used off-label over longer periods of time to prevent recurrent preterm labor.  There are multiple generic versions of terbutaline oral tablets and injectable formulations available.  On February 17, 2011, the FDA warned the public that injectable terbutaline should not be used in pregnant women for prevention or prolonged treatment (beyond 48 to 72 hours) of preterm labor in either the hospital or outpatient setting because of the potential for serious maternal heart problems and death.  The agency is requiring the addition of a Boxed Warning and Contraindication to the terbutaline injection label to warn against this use.  In addition, oral terbutaline should not be used for prevention or any treatment of preterm labor because it has not been shown to be effective and has similar safety concerns.  The agency is requiring the addition of a boxed warning and contraindication to the terbutaline tablet label to warn against this use.

Although it may be clinically deemed appropriate based on the healthcare professional's judgment to administer terbutaline by injection in urgent and individual obstetrical situations in a hospital setting, the prolonged use of this drug to prevent recurrent preterm labor can result in maternal heart problems and death.  Terbutaline should not be used in the outpatient or home setting.  The decision to require the addition of a boxed warning and contraindication is based on new safety information received and reviewed by the FDA.  Specifically, the FDA has reviewed post-marketing safety reports of terbutaline used for obstetrical indications, as well as data from the medical literature.  These label changes are consistent with statements from the American College of Obstetricians and Gynecologists (ACOG, 2003) discouraging use of terbutaline for preventing preterm labor.

In a Cochrane review, Chawanpaiboon et al (2014) determined the effectiveness of terbutaline pump maintenance therapy after threatened preterm labor in reducing adverse neonatal outcomes.  These investigators searched the Cochrane Pregnancy and Childbirth Group's Trials Register (January 31, 2014) and reference lists of retrieved studies.  Randomized controlled trials comparing terbutaline pump therapy with alternative therapy, placebo, or no therapy after arrest of threatened preterm labor were selected for analysis.  Two review authors independently assessed the studies for inclusion and then extracted data as eligible for inclusion in qualitative and quantitative synthesis (meta-analysis).  A total of 4 studies were included with a total of 234 women randomized.  The overall methodological quality of the included studies was mixed; 2 studies provided very little information on study methods, there was high sample attrition in 1 study and in 3 studies the risk of performance bias was high.  These researchers found no strong evidence that terbutaline maintenance therapy offered any advantages over saline placebo or oral terbutaline maintenance therapy in reducing adverse neonatal outcomes by prolonging pregnancy among women with arrested preterm labor.  The mean difference (MD) for gestational age at birth was -0.14 weeks (95 % confidence interval [CI]: -1.66 to 1.38) for terbutaline pump therapy compared with saline placebo pump for 2 trials combined.  One trial reported a risk ratio (RR) of 1.17 (95 % CI: 0.79 to 1.73) for preterm birth (less than 37 completed weeks) and a RR of 0.97 (95 % CI: 0.51 to 1.84) of very preterm birth (less than 34 completed weeks) for terbutaline pump compared with saline placebo pump.  These investigators found no evidence that terbutaline pump therapy was associated with statistically significant reductions in infant respiratory distress syndrome, or neonatal intensive care unit admission compared with placebo.  Compared with oral terbutaline, the authors found no evidence that pump therapy increased the rate of therapy continuation, or reduced the rate of infant complications or maternal hospital re-admissions.  One study suggested that pump therapy resulted in significantly increased weekly cost/woman, $580 versus $12.50 (p < 0.01).  No data were reported on long-term infant outcomes.  The authors concluded that they found no evidence that terbutaline pump maintenance therapy decreased adverse neonatal outcomes.  Taken together with the lack of evidence of benefit, its substantial expense and the lack of information on the safety of the therapy do not support its use in the management of arrested preterm labor.  They stated that future use should only be in the context of well-conducted, adequately powered RCTs.

Also, an UpToDate review on “Management of pregnant women after inhibition of acute preterm labor” (Caritis and Simhan, 2015) states that “A systematic review of four randomized trials (n = 234 women) comparing terbutaline pump therapy with alternative therapy, placebo, or no therapy found no evidence that terbutaline pump maintenance therapy decreased adverse neonatal outcomes.  The US Food and Drug Administration concluded that the risk of serious adverse events from prolonged terbutaline therapy of preterm labor (beyond 48 to 72 hours) outweighs any potential benefit.  The Agency for Healthcare Research and Quality reviewed available data and found that terbutaline pump therapy could be beneficial for maintenance tocolysis, but most studies were biased so there was low confidence in this conclusion; in addition, the safety of this therapy was unclear”.

Magnesium Sulfate for Preterm Labor

In a meta-analysis, Zeng and colleagues (2016) evaluated safety and effectiveness of magnesium sulfate (MgSO4) on neuroprotection for preterm infants who had exposure in uteri. These investigators searched electronic databases and bibliographies of relevant papers to identify studies comparing MgSO4 with placebo or other treatments in patients at high-risk of preterm labor and reporting safety and effectiveness of MgSO4 for antenatal infants.  This meta-analysis was carried out based on PRISMA guidelines.  The primary outcomes included fatal death, cerebral palsy (CP), intra-ventricular hemorrhage, and peri-ventricular leukomalacia.  Secondary outcomes included various neonatal and maternal outcomes.  A total of 10 studies including 6 RCTs and 5 cohort studies, and involving 18,655 preterm infants were analyzed.  For the rate of moderate-to-severe CP, MgSO4 showed the ability to reduce the risk and achieved statistically significant difference (odd ratio [OR] 0.61, 95 % CI: 0.42 to 0.89, p = 0.01).  The comparison of mortality rate between the MgSO4 group and the placebo group only presented small difference clinically, but reached no statistical significance (OR 0.92, 95 % CI: 0.77 to 1.11, p = 0.39).  The analysis of adverse effects on babies showed no margin (p > 0.05).  Yet for mothers, MgSO4 exhibited obvious side-effects, such as respiratory depression and nausea, but there existed great heterogeneity.  Magnesium sulfate administered to women at high-risk of preterm labor could reduce the risk of moderate-to-severe CP, without obvious adverse effects on babies.  Although there existed many unfavorable effects on mothers, yet they may be lessened through reduction of the dose of MgSO4 and could be tolerable for mothers.  The authors concluded that MgSO4 is both safe and beneficial for use as a neuro-protective agent for premature infants before a valid alternative is discovered.

In a multi-center RCT, Kamyar and associates (2016) evaluated the neuroprotective effect of MgSO4 in preterm children exposed to chorioamnionitis.  Antenatal MgSO4 was administered to women at risk of preterm birth for the prevention of cerebral palsy (CP).  Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at greater than or equal to 24 weeks of gestation, were selected.  Cases were exposed to antepartum MgSO4 ; controls received placebo.  All data were analyzed by intention to treat; uni-variate and multi-variate analyses were performed.  Primary outcome was a composite of still-birth, death by the age of 1 year, or moderate or severe CP by the age of 2 years.  Secondary outcomes included a composite neonatal outcome as well as neurodevelopmental delay, defined as Bayley II mental and psychomotor developmental indices of less than 70 at the age of 2 years.  Subgroup analysis assessed these outcomes in children born at less than 28 weeks of gestation.  A total of 396 children were included, with 192 (48.5 %) randomized to MgSO4.  Maternal and delivery characteristics were similar between the groups.  The primary outcome occurred in 14.1 % of children exposed to MgSO4 and 12.7 % of children exposed to placebo (RR 1.29; 95 % CI: 0.70 to 2.38).  Rates of still-birth, death, moderate-severe CP, and neurodevelopmental delay did not differ between groups.  In the subgroup analysis of children born at less than 28 weeks of gestation, there was no difference in the rates of the primary outcome, nor in the secondary outcomes assessed.  The authors concluded that among children at risk for early preterm delivery exposed to chorioamnionitis, antenatal administration of MgSO4 was not associated with improved neurodevelopmental outcome.  These investigators did not recommend any change in the guidelines on the administration of MgSO4 for neuroprotection based on this study.  These investigators stated that chorioamnionitis and intra-uterine inflammation are significant risk factors for adverse neurodevelopmental outcome after preterm birth.  Currently, there is insufficient understanding of effective neuroprotective strategies in this high‐risk subgroup.  The effect of MgSO4 among subgroups of preterm children, especially those at increased risk for adverse outcome, needs to be an area of concerted research focus.  This information may provide mechanistic insights for magnesium neuroprotection, and may inform future clinical trials of neuroprotective strategies in preterm children.  These researchers noted that there is inadequate data to alter the prescribing pattern for MgSO4, and recommended its use for neuroprotection in all infants at risk for preterm delivery of less than 32 weeks of gestation, with or without chorioamnionitis.

Edwards and colleagues (2018) examined the effects of magnesium on premature neonatal outcomes complicated by chorioamnionitis.  These researchers conducted a secondary analysis of data from the BEAM Trial, an RCT to determine if antenatal magnesium decreases the incidence of CP in preterm birth.  They compared the effect of MgSO4 by the presence or absence of chorioamnionitis.  Outcomes examined include broncho-pulmonary dysplasia (BPD), CP, intra-ventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC), assessments of mental and motor disability.  Logistic regression was used to estimate adjusted ORs of each outcome.  Approximately 1,944 women were included in this analysis of which 228 were diagnosed with chorioamnionitis.  Demographic characteristics were similar between women randomized to receive MgSO4 or placebo.  Magnesium therapy demonstrated no significant reduction in CP in the presence of chorioamnionitis (OR 0.76, CI: 0.19 to 2.76); but did demonstrate benefit in the absence of chorioamnionitis (OR 0.52, CI: 0.31 to 0.86).  The authors concluded that antenatal MgSO4 did not show a clear neuroprotective effect in the setting of chorioamnionitis.

Magnesium Sulfate Use in Obstetrics

In a Committee Opinion Summary on “magnesium sulfate use in obstetrics”, the ACOG and the Society for Maternal-Fetal Medicine (SMFM) (2016) support the short-term (usually less than 48 hours) use of magnesium sulfate in obstetric care for appropriate conditions and for appropriate durations of treatment, which include the following:

• Prevention and treatment of seizures in women with preeclampsia or eclampsia.
• Fetal neuroprotection before anticipated early preterm (less than 32 weeks of gestation) delivery.
• Short-term prolongation of pregnancy (up to 48 hours) to allow for the administration of antenatal corticosteroids in pregnant women who are at risk of preterm delivery within 7 days.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met :
99601	Home infusion/specialty drug administration, per visit (up to 2 hours);
+ 99602	each additional hour (List separately in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met [exception basis only]:
E0779	Ambulatory infusion pump, mechanical, reusable, for infusion 8 hours or greater
E0780	Ambulatory infusion pump, mechanical, reusable, for infusion less than 8 hours
E0781	Ambulatory infusion pump, single or multiple channels, electric or battery operated, with administrative equipment, worn by patient
J3105	Injection, terbutaline sulfate, up to 1 mg
J3475	Injection, magnesium sulfate, per 500 mg
S9208	Home management of preterm labor, including administrative services, professional pharmacy services, care coordination, and all necessary supplies or equipment (drugs and nursing visits coded separately), per diem (do not use this code with any home infusion per diem code)
S9349	Home infusion therapy, tocolytic infusion therapy; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
ICD-10 codes covered if selection criteria are met:
O60.02 - O60.03	Preterm labor without delivery [after 22 weeks but before 37 weeks]

The above policy is based on the following references: