The Clinical Issues Surrounding the Use of Terbutaline Sulfate for Preterm Labor

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Clinical Issues Surrounding the Use of Terbutaline Sulfate for Preterm Labor

Volume 53, Number 11
OBSTETRICAL ANO GYNECOLOGICAL SURVEY
Copyright c 1998 by Lippincott Williams & Wilkins

Fung Lam, John Elliott, J. Stephen Jones, Michael Katz, Robert A. Knuppel, John Morrison, Roger Newman, Jeffrey Phelan and Robin Willcourt

California-Pacific Medical Center, San Francisco, California; Good Samaritan Regional Medical Center, Phoenix, Arizona; Carolina Perinatal Obstetrics, GreenviHe, South Carolina; University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey; University of Mississippi, Jackson, Mississippi; Medical University of South Carolina, Charleston, South Carolina; Pomona Valley Medical Center, Pomona, California; and Northern Nevada Medical Center, Reno, Nevada

ß-mimetics have been prescribed by physicians to arrest or prevent premature labor for more than 20 years. Although not approved by the Food and Drug Administration (FDA) for tocolytic use, terbutaline sulfate has been the most widely prescribed beta-mimetic in the United States. Recently,the role of terbutaline in the treatment and prevention of preterm labor has been questioned by the FDA. Because the off-label use of drugs is a formally accepted practice in medicine when scientific studies support such use, we reviewed the currently available clinical literature on terbutaline use in various routes of delivery: intravenous, oral, and subcutaneous via infusion pump. This review describes the clinical evidence that supports the safe and effective use of terbutaline as a tocolytic agent in certain patient populations. Practicing physicians should continue to have unrestricted use of terbutaline for tocolysis as one of the few remaining therapeutic options remaining in the fight against preterm birth.

INTRODUCTION
Prematurity, together with its complications, remains the most common preventable cause of neonatal loss. Preterm delivery occurs in 11 percent of all births in the United States (1) and the complications of prematurity account for more than 60 percent of pefinatal mortality (2). Acute morbidides associated with preterm birth include intraventricular hemorrhage, necrotizing enterocolitis, respiratory distress syndrome, and patent ductus arteriosus (3). Neonatal intensive care units are extremely expensive, often costing at least $3000 per day, and preterm infants who do survive often spend many weeks or months in the hospital. There are also considerable costs for both the parents and the rest of society, particularly if the infant's survival is accompanied by moderate or severe neurodevelopmental handicap. Tocolysis is used to prolong pregnancy in the hope of avoiding or ameliorating the sequelae of prematurity. Delaying delivery can allow time for inutero transfer, enabling the premature infant to be delivered in an obstetric unit experienced in the care of high-risk pregnancies and with supportive neonatal intensive care facilities. Tocolysis may also allow sufficient time for cortico steroid administration to enhance fetal lung maturity. At early gestational ages, even a modest 48- to 72-hour prolongation can be greatly beneficial to the fetus and improve neonatal outcomes. Attention has logically centered on efforts to find safe and effective tocolytic drugs. The drugs most commonly used in the United States for the suppression of preterm labor are the ß-mimetic agents ritodrine and terbutaline, as well as magnesium sulfate. Each of these agents have, in clinical trials, been found to be more effective than either ethanol (4-7) or placebo (6,8,9), and results have been superior to those in a control group (10-13). As of 1990, it was estimated that more than 100,000 women with preterm labor receive ritodrine annually (14), and it is likely that between 2 and 10 times as many are prescribed terbutaline (15,16). Currently, only ritrodrine for intravenous administration is approved by the United States FDA for use in pregnancy as a tocolytic. Because the off-label use of drugs is common among physicians when scientific studies and clinical trails support such use, we undertook a systematic review of the literature for supportive evidence for the safety and efficacy of terbutaline for tocolysis. In addition, we considered the comments and direction offered by regulatory bodies in addressing physician use of terbutaline.

CLINICAL EFFICACY AND SAFETY OF TERBUTALINE AS A TOCOLYTIC
Efficacy: Intravenous Administration
In 1976, Ingemarsson (9) showed that intravenous terbutaline was effective in treating preterm labor in patients with intact membranes. Pregnancy was maintained to the 37th week in 80 percent of patients receiving terbutaline compared with 20 percent of patients receiving placebo. The mean birth weight of infants in the group receiving terbutaline was 3060 gm compared with 2190 gm for the placebo group. Garcia et al. (17) and Wallace et al. (10) also reported that intravenous terbutaline effectively abolished preterm labor and prolonged pregnancy. Howard et al. (18) instituted a protocol similar to that used by Ingermarsson et al. (9), but failed to show any significant difference in terbutaline's ability to prolong pregnancy or effect infant birth weight, development of respiratory distress syndrome, or infant survival compared with placebo. Caritis et al. (7) reported on a comparison study with ethanol, in which two study groups received either intravenous ethanol or terbutaline, followed by oral terbutaline as maintenance therapy. The intravenous terbutaline group had a mean pregnancy prolongation of 15 days compared with 10 days for the ethanol group. Studies of intravenous terbutaline versus magnesium sulfate for treatment of preterm labor showed equivalency in pregnancy prolongation between the two treatments (19,20). In a comparison of the two most commonly used ß-mimetic agents, Kosasa et al. (21) found that patients treated with intravenous terbutaline gave birth to infants with a mean birth weight of 2588 gm and 60 percent achieved a gestation of 36 weeks. Those receiving intravenous ritodrine gave birth to infants with a mean birth weight of 2392 gm and only 39 percent achieved a gestation of 36 weeks. Kosasa' s study concluded that parturition is more effectively delayed with terbutaline than with ritodrine (21). A meta-analysis of clinical trials comparing ß-mimetics with either placebo or other active treatment was conducted by King et al. (22) in 1988. The authors used the Oxford Database of Perinatal Trials and published clinical reports to obtain data relating to 890 women participating in 16 methodologically acceptable controlled trials for the acute treatment of preterm labor. The ß-mimetics used in the 16 clinical trials included both ritodrine and terbutaline. The authors found that there was an unequivocal effect of ß-mimetics in delaying delivery, resulting in a reduction in the frequency of preterm birth and low birth weight (22).

Efficacy: Oral Administration
A number of clinical trials have compared oral terbutaline with oral ritodrine or placebo for maintenance tocolysis. In a study comparing 120 mg/day ritodrine to 30 mg/day terbutaline for prevention of recurrent preterm labor, Caritis et al. (23) found that terbutaline was more successful in prolonging pregnancy to 37 weeks. Pregnancy was prolonged a mean of 40 days with terbutaline and 22 days with ritodrine (23). In another study comparing oral terbutaline and ritodrine for maintenance therapy, Kopelman et al. (24) found a trend toward more frequent initial treatment failures in the ritodrine group, but no statistically significant differences in efficacy or the frequency of side effects. Brown et al. (25), in a randomized trial of oral terbutaline versus placebo, reported that women receiving 5 mg of oral terbutaline every 6 hours for maintenance therapy had significantly more days gained in utero and greater birth weights than women receiving placebo. Infants born to mothers receiving oral terbutaline also had a lower incidence of idiopathic respiratory distress syndrome. Berg et al. (26) showed that administration of oral terbutaline (5 mg three times a day) in women previously receiving intravenous terbutaline was found to prolong pregnancy for more than 7 days. Alternatively, Parilia et al. (27) determined that oral terbutaline did not reduce the rate of preterm birth after successful treatment with intravenous magnesium sulfate. The prophylactic use of oral terbutaline was also studied in normal twin gestations and it was reported that the mean birth weights were significantly increased compared with those in a similar group of control patients (28). In two relatively recent prospective, randomized, placebo-controlled trials, both Lewis et al. (29) and Rust et al. (30) found that maintenance oral terbutaline therapy was not associated with significant pregnancy prolongation, reduction in the incidence of recurrent preterm labor, or improvement in perinatal outcome.

Efficacy: Subcutaneous Infusion
For women who experience recurrent preterm labor, low dose subcutaneous terbutaline infusion is another therapeutic option. Such patients are treated at home with a continuous low basal dose of terbutaline delivered from a portable infusion pump with additional bolus infusions preprogrammed to coincide with peak periods of uterine contractions. By using periodic bolus doses, subcutaneous terbutaline infusion therapy takes advantage of the concept of intermittent ß-mimetic dosing to avoid myometrial desensitization or tachyphylaxis. This concept has been demonstrated in both basic science (31-33) and clinical literature (34,35). The amount of drug required to be delivered via the subcutaneous route is much less than that delivered either orally or parentally. A typical oral dosage of terbutaline ranges from 30 to 40 mg per day, whereas the typical dosage for subcutaneous terbutaline infusion therapy is approximately 2 to 4 mg per day. It is estimated that subcutaneous delivery affords up to a 10-fold reduction in dosing, given the relative estimated bioavailability of the oral (33-50 percent) and subcutaneous (90-100 percent) forms of terbutaline (36). Terbutaline is preferred to other ß-mimetics such as ritodrine for subcutaneous use because it is more potent and can be administered subcutaneously in smaller volumes (37). It also does not cause the local skin irritation seen with subcutaneous delivery of ritodrine. Subcutaneous terbutaline infusion usually follows initial treatment with intravenous magnesium sulfate rather than by a ß-mimetic, on the hypothesis that tolerance to ß-mimetics may develop after initial high-dose intravenous ß-mimetic therapy which may decrease its efficacy (38,39). When compared with oral dosing, subcutaneous terbutaline infusion therapy provides more precise dosing, a lower required daily dose, reduced desensitization of uterine beta receptors, and improved patient compliance by automatically delivering the required daily drug dosing and avoiding the need for the patient to awake at night to self-medicate. Unlike intravenous infusion, subcutaneous terbutaline pump infusion does not require large fluid volumes, which reduce the risk of fluid overload. In addition, prolonged hospitalization is not necessary because this therapy can be administered at home. Stubblefield et al. (12) described a study of 44 patients receiving intermittent subcutaneous terbutaline therapy followed by oral terbutaline for preterm labor. Terbutaline was given as a 0.25 mg subcutaneous injection and repeated hourly until contractions stopped. This was followed by oral terbutaline therapy (5 mg every 4 hours for 48 hours, then 5 mg four times a day). Eighty-nine percent of patients had their pregnancy prolonged more than 72 hours and 80 percent were delayed more than 1 week, with a mean pregnancy prolongationof 36 days. The authors reported that these results were similar to those obtained with intravenous administration of terbutaline and ritodrine for the management of preterm labor. Lam et al. (40) reported on the use of subcutaneous infusion of terbutaline in nine patients who had previously failed oral terbutaline therapy instead of hospitalization. Patients were managed at home with subcutaneous terbutaline infusion via a portable programmable microinfusion pump that allowed a small basal rate of terbutaline to be administered along with timed bolus doses to coincide with peak uterine contraction activity. Pregnancy was prolonged a mean of 9.2 weeks with patients reporting less side effects than when they were receiving oral terbutaline therapy. In 1988, Lam et al. (41) presented the results of a randomized trial of subcutaneous infusion of terbutaline versus oral terbutaline for long-term tocolysis at the Society of Perinatal Obstetricians annual meeting. Sixty-eight patients stabilized with intravenous tocolysis were randomized to either subcutaneous or oral treatment with terbutaline, and dosages were adjusted according to uterine contraction response. All patients received drug administra tion and uterine contraction monitoring at home. Patients receiving subcutaneous terbutaline infusion had their pregnancies prolonged a mean of 8.6 weeks compared with a mean of 2.4 weeks in the oral terbutaline group. Therapy breakthrough, or recurrent preterm labor, occurred an average of 0. 18 and 0.90 times per patient in the subcutaneous and oral administration groups, respectively. The pregnancy prolongation index (42) was 93 percent for the subcutaneous group and 34 percent for the oral group. The results of a 3-year follow-up study of 1556 obstetric patients were reported by Lam in 1989. Lam et al. (43) reported a reduction in the preterm birth rate in this mostly private patient population from 5.18 percent per year, down to 2.69 percent per year using a protocol including subcutaneous terbutaline infusion therapy. There also was a 40 percent reduction in infants admitted to the neonatal intensive care units. Fisher et al. (44) reported on 19 patients with a confirmed diagnosis of preterm labor treated with subcutaneous terbutaline infusion. The author reported that subcutaneous terbutaline infusion successfully terminated labor in 74 percent of patients and prolonged pregnancy a mean of 43 days. Mean gestational age at delivery was 36.9 weeks and the mean birth weight was 2960 gm. Three patients reported side effects associated with subcutaneous in fusion of terbutaline with one patient discontinuing therapy. Allbert et al. (45) reported a matched control study in which patients receiving subcutaneous terbutaline infusion therapy for recurrent preterm labor were compared with patients receiving oral terbutaline therapy for the same indication. Patients receiving subcutaneous terbutaline were more likely to reach term than patients receiving oral therapy and had a greater achieved pregnancy prolongation index than those receiving oral terbutaline. Only 13 percent of patients on subcutaneous terbutaline infusion therapy failed tocolytic therapy or had ruptured membranes, compared with 38 percent on oral therapy. Giano poulos et al. (46) studied 31 preterm labor patients who had failed oral ß-mimetic therapy or had medical problems that precluded the use of oral ß-mimetics at high doses necessary to stop contractions. Subcutaneous terbutaline infusion therapy was started at an average gestational age of 28.8 weeks, and pregnancy was prolonged a mean of 5.4 weeks, with an average gestational age at delivery of 34.2 weeks. Thirty-three percent of patients delivered at 36 weeks or beyond. No significant maternal complications attributable to subcutaneous infusion therapy were reported.
Jones et al. (47) analyzed 50 consecutive patients that were treated with subcutaneous terbutaline infusion therapy for prevention of recurrent preterm labor. All patients received intensive inpatient parental tocolysis before starting outpatient subcutaneous terbutaline infusion. The mean gestational age at entry was 28.3 weeks and the mean pregnancy prolongation was 6.3 weeks. Three inpatients, all with risk factors, but no outpatients, developed pulmonary edema. The authors concluded that outpatient subcutaneous terbutaline infusion therapy may be beneficial. Weinbaum et al. (48) reported on 202 patients at risk for recurrent preterm delivery receiving subcutaneous terbutaline infusion therapy and uterine contraction monitoring in the home. Mean pregnancy prolongation was 4.9 weeks, with only 9.6 percent of patients requiring further hospitalization for tocolysis. The mean gestational age at delivery was 36.2 weeks, with 70 percent of patients completing 35 weeks. The authors concluded that subcutaneous terbutaline infusion therapy rapidly and effectively decreased mean uterine activity and sustained this delaying effect for a clinically significant period. Allbert et al. (49) reported on 992 singleton and twin gestations at high risk for preterm delivery who were prescribed subcutaneous terbutaline infusion therapy for tocolysis. Tocolytic dosing was individualized according to the patient's volume of distribution and clearance. Daily dosing was adjusted on the basis of uterine activity obtained from home uterine activity monitoring. Subcutaneous terbutaline infusion therapy extended gestation a mean of 38 days and the average gestational age at delivery was 36.3 weeks, with a mean birth weight of 2759 gm. In the largest study of its kind, the authors confirmed earlier reports that subcutaneous terbutaline infusion can be beneficial for women at very high risk for preterm delivery. Moise et al. (50) reported on 13 patients receiving subcutaneous terbutaline infusion for treatment of refractory preterm labor. In three patients, subcutaneous infusion was regarded completely successful with a mean prolongation of 52.7 days and a gestational age at delivery of 37.1 weeks. In six patients, subcutaneous infusion was partially successful, with a mean prolongation of 42.2 days and a mean gestational age at delivery of 33.8 weeks, including two triplet pregnancies. In four patients, subcutaneous infusion therapy was stopped because of maternal side effects. Adkins et al. (51) reported on 51 patients with preterm labor who received subcutaneous terbutaline therapy after stabilization with intravenous magnesium sulfate. Subcutaneous administration of terbutaline was successful in 98 percent of patients, prolonging pregnancy a mean of 6.6 weeks. Mean gestational age at delivery was 37 weeks and the mean infant birth weight was 3035 gm, with 85 percent of neonates weighing >2500 gm. Only 22 percent of infants went to the neonatal intensive care units, with a mean stay of 7 days. Three patients reported adverse effects and had their bolus dosages decreased. No serious adverse events were reported. Allbert et al. (52) reported on 32 patients with recurrent preterm labor who were subsequently treated with subcutaneous terbutaline infusion therapy. Patients using subcutaneous terbutaline infusion were more likely to reach term than those receiving oral therapy (66 percent vs. 16 percent). This pregnancy prolongation index for the subcutaneous infusion group was higher than for the oral group (0.86 vs. 0.72). Thirteen percent of patients on subcutaneous terbutaline infusion therapy failed tocolytic therapy or had ruptured membranes, compared with 38 percent on oral therapy. There were 123 unscheduled visits to the hospital in the oral group compared with 82 in the subcutaneous group. The number of patients experiencing recurrent preterm labor was lower in the subcutaneous infusion group as compared with those receiving oral drug (8 vs. 19). Wenstrom et al. (53) enrolled 42 patients during a 4-year period having the diagnosis of preterm labor to evaluate subcutaneous infusion therapy. In this three-ann study, patients were randomized to receive either oral terbutaline, subcutaneous terbutaline infusion, or subcutaneous saline infusion. Subcutaneous drug therapy was not adjusted for weight or volume of distribution, but boluses were adjusted for patient reported contractions. Electronic home uterine contraction monitoring was not used. Patients were permitted to cross over between treatment arms if initial therapy failed. Outcomes for patients were compared only by the treatment group to which patients were originally assigned. Mean gestational age at delivery and neonatal outcomes were the same for all three study groups. Elliott et al. (54) reported on subcutaneous terbutaline infusion therapy use in high-order multiple gestations. Fifteen triplet and six quadruplet pregnancies were treated by subcutaneous terbutaline infusion with individualized dosing protocols. Triplet patients remained on infusion therapy for 58 days and delivered at a mean gestational age of 33 weeks. Quadruplet patients were on subcutaneous infusion for 77 days and delivered at a mean gestational age of 33 weeks. Only 2 of 15 (13 percent) of triplets and 1 of 6 (17 percent) of quadruplets were delivered be cause of tocolytic failure. In 1998, Lam et al. (55) reported on the efficacy of subcutaneous terbutaline infusion therapy in singleton pregnancies at high risk for preterm birth. A total of 256 patients experiencing a recurrent episode of preterm labor while on oral terbutaline were switched to subcutaneous terbutaline infusion therapy in the home. Patients were given individualized bolus dosing on the basis of home uterine contraction activity. Pregnancy prolongation was found to be greater for subcutaneous versus oral administration of terbutaline (4.4 vs. 2.7 weeks). The pregnancy prolongation index for subcutaneous therapy was 74 percent compared with 31 percent for oral therapy. The authors concluded that subcutaneous infusion of terbutaline was superior to oral administration for prolonging gestation in high-risk pregnancies complicated by recurrent preterm labor.

Side Effects: Intravenous and Oral Administration
Terbutaline, like other beta-mimetics, stimulates ß-adrenergic receptors that are distributed through out the body (23,56,57). ß-adrenergic receptor agonists can cause palpitations, tremor, nausea, vomiting, headaches, nervousness, anxiety, chest pain, and shortness of breath (37,58-61). Ingemarsson et al. (62) reviewed a 5-year institutional experience with 330 patients receiving intravenous terbutaline for tocolysis and reported only 2.7% of patients discontinuing therapy because of any of these side effects. The most common reason for discontinuation of ther apy was nausea and vomiting (62). The most serious complication of ß-adrenergic agonist therapy is pulmonary edema (63), although this is not unique to ß-adrenergic tocolytics (64). Clinical circumstances associated with the development of pulmonary edema with intravenous terbutaline or other ß-mimetic use include multifetal gestation, excessive fluid administration, use of physiologic saline solutions, and prolonged therapy. The risk of pulmonary edema can be minimized by limiting fluids, avoiding saline solutions, and using as little ß-agonist as necessary. The incidence of pulmonary edema is low when such precautions are taken (23,62). In the most recent and largest ß-mimetic trial, ritodrine use was associated with a 0.3 percent incidence of pulmonary edema (65). Metabolic and cardiovascular effects have been found to be dose related and are thus more commonly seen with the intravenous form of terbutaline therapy (58,66-70). With prudent fluid management and dosing, contemporary administration of ß-mimetics for tocolysis seems to be relatively safe and associated with a low incidence of undesirable side effects. Developmental outcomes assessed 1 to 9 years after exposure to ß-mimetic drugs in utero are not significantly different from preterm controls (23,57,71-76). No significant alterations in growth, head circumference, neurologic development, or psychomotor or social development have been associated with ß-mimetic use. Nor have there been any reports of congenital defects caused by maternal use of terbutaline for tocolysis or asthma relief. In a 2-year study of infants surviving prematurity, the incidence of short- or long-term adverse effects of terbutaline treatment was found to be no higher than that of infants born to mothers who had not received tocolysis (73). Seven maternal deaths have been reported in the literature in patients receiving ß-mimetic tocolytic therapy; of these, two are reported in patients receiving terbutaline (77-80). In none of these patients has it been concluded that maternal death was caused by ß-mimetic therapy. Many of these patients had a history of cardiac disease or pulmonary hypertension. Thirteen maternal deaths have been reported to the FDA in patients receiving terbutaline tocolysis according to FDA proceedings (15,16). Not all of these deaths have been reported in the literature. Because an estimated 260,000 women per year have been prescribed terbutaline during pregnancy, during the past 10 years, it can be projected that approximately 2.6 million women have been exposed to terbutaline during pregnancy (16). This suggests an estimated maternal mortality of 0.00050 percent. This compares favorably with the worldwide maternal mortality for ritodrine, the only FDA-approved ß-mimetic, of 21 deaths in 4 million exposures or 0.00052 percent (15).

Side Effects: Subcutaneous Infusion
Few complications have been reported with subcutaneous terbutaline therapy. In a study of 992 patients, Allbert reported that maternal side effects, such as tachycardia, headache, and nervousness, were generally not seen (49). Perry et al. (80) found that subcutaneous terbutaline infusion for women with stabilized preterm labor is associated with much fewer adverse effects than previously reported for intravenous ß-adrenergic agonist therapy. In a review of 8709 women receiving subcutaneous terbutaline infusion therapy for maintenance tocolysis, cardiac events including chest pain, EKG changes, arrhythmias, and cardiac arrest occurred with an incidence of 0.22 percent. Pulmonary edema developed in 0.32 percent of patients. Maternal heart irregular ities were the reason for discontinuing subcutaneous terbutaline therapy in approximately one-fifth of the pregnancies in the study by Moise et al. (50), although it was noted by the authors that some of these women had been given large doses of oral terbutaline before beginning subcutaneous therapy. There is one report of myocardial necrosis in a newborn after prolonged subcutaneous terbutaline infusion (81), but as noted by Bey et al. (82), the doses received by the mother were nearly 10~fold higher than doses typically used via the subcutaneous infusion route. In another case of a quadruplet pregnancy, three infants developed cardiovascular decompensation with bradycardia, metabolic acidosis, poor tissue perfusion, and decreased urine output. The authors speculated this was caused by prolonged subcutaneous terbutaline therapy (83). Hudgens et al. (79) reported on a case of sudden maternal death occurring in a twin pregnancy while on subcutaneous terbutaline infusion therapy. The cause of death, although undetermined, was speculated by the authors to be caused by cardiac arrhythmia, the origin of which was probably multifactorial. This case, along with one other, was later reviewed by Perry et al. (80) and the cause of death was determined to be not related to ß-agonist therapy. No other cases of maternal mortality have been reported in the literature in patients receiving subcutaneous terbutaline infusion therapy in pregnancy. Concerns regarding metabolic side effects of subcutaneous terbutaline infusion therapy focus on thepotential of ß-mimetics to induce gestational diabetes in women receiving prolonged therapy. This has been previously demonstrated in pregnant patients receiving oral terbutaline maintenance therapy (84,85). Lindenbaum et al. (86) found that the incidence of gestational diabetes is not increased in otherwise normal patients receiving terbutaline via the subcutaneous pump. The study reported a 5 percent incidence of gestational diabetes in patients receiving subcutaneous terbutaline compared with an incidence of 11 percent in those on oral terbutaline therapy and an incidence of 6 percent in normal controls (86). A single case report of diabetic ketoacidosis was reported by Tibaldi et al. (87) in a pregnant woman with a 15-year history of diabetes who was treated with subcutaneous terbutaline infusion therapy for uterine contractions. Regenstein et al. (88) found a higher incidence of gestational diabetes in pregnant women receiving oral or subcutaneous terbutaline therapy compared with a control group. The authors stated that their subcutaneous treatment group differed from that of Lindenbaum et al. (86) in which patients all had a normal glucose tolerance test before terbutaline therapy, which was not the case in their own investigation (88).

FDA REGULATORY STATUS OF TOCOLYTICS IN THE UNITED STATES
Presently, only ritodrine is approved by the FDA for use as a tocolytic. Ritodrine (Yutopar, Astra Pharmaceuticals) was approved for use in preterm labor in 1980. During the ensuing 18 years, no other drug has been approved for use as a tocolytic by FDA. After an FDA Fertility and Maternal Drug Advisory Committee meeting in October 1992, oral ritodrine for maintenance therapy was removed from the United States market after the presentation of one clinical trial, the Canadian Ritodrine Trial (65), to the FDA at the October 1992 meeting. However, the negative conclusions regarding ritodrine in this study were not without criticism (89-92). A majority of eligible patients were excluded, a third of enrolled patients had ruptured membranes, and treatment was only given for 5 days. Previous randomized, double blind studies demonstrated that oral maintenance therapy with ritodrine was successful in preventing recurrent preterm labor (21,23,93). Regardless, the manufacturer of ritodrine was advised by the FDA to perform more studies to validate ritodrine's efficacy for maintenance use at a higher than originally approved oral dose (94). Rather than bear the tremendous financial burden of further FDA clinical trials, the manufacturer removed oral ritodrine for maintenance tocolysis from the United States market, leaving physicians with no FDA-approved drug for tocolytic maintenance therapy. Terbutaline is currently FDA-approved only for the treatment of asthma. However, terbutaline has now replaced oral ritodrine for use as a maintenance tocolytic in the United States. Terbutaline is thus used off-label and can be administered in oral and subcutaneous forms. Terbutaline is much less expensive than ritodrine, costing approximately 10 times less on an milligram to milligram basis (95). Terbutaline, with other commonly prescribed ß-mimetic tocolytics such as ritodrine, salbutamol, fenoterol, and hexo prenaline, have been approved for use in many countries outside of the United States. Currently approved FDA labeling for terbutaline contains warnings or precautions against use in preterm labor that are not found outside the United States. In early 1998, Astra Pharmaceuticals removed the only remaining available form of ritodrine (Yutopar; intravenous injection) from the United States market. This action completed the manufacturer's total withdrawal from supplying physicians in this country with an FDA-approved tocolytic. On April 20, 1998, the FDA Advisory Committee for Reproductive Health Drugs met to discuss a new drug application for the tocolytic drug Antocin (atosiban) for use in the management of preterm labor. The sponsor of this new drug application was the R.W. Johnson Pharmaceutical Research Institute, a division of Johnson & Johnson. The study results presented to the FDA Committee represented the 10-year effort of Johnson & Johnson to obtain FDA approval. A total of 1150 patients from more than 60 academic medical centers were enrolled in two pivotal trials (acute and maintenance). Johnson & John son also presented to the FDA the results of three randomized, controlled trials of atosiban conducted for approvals outside the United States. The total development cost for this drug has been estimated to be in excess of 200 million dollars. In the acute treatment study, patients receiving atosiban had similar days of prolongation as patients receiving placebo drug. However, significantly more patients receiving atosiban remained undelivered at 48 hours than those receiving placebo. In the maintenance study, the atosiban treated group had more days to reoccurrence of preterm labor, more pregancy prolongation, than did the placebo group. The FDA also found that the drug was safe for mothers. The sponsor asked for FDA approval of atosiban for "the acute treatment of preterm labor for up to 48 hours." This indication was denied by the Committee who stated that because no benefit to infant outcomes could be demonstrated with atosiban use, there was not enough evidence to support approval and that, although the secondary outcome of remaining undelivered at 48 hours was supportive, it was not the primary study endpoint and therefore could not be used for approval. In addition, the FDA discounted the three European and Canadian clinical trials that showed that atosiban was beneficial in the acute treatment of preterm labor patients and had an excellent safety profile. The Committee recommended that Johnson & Johnson perform another large multicenter study (96). Given the tens of millions of dollars and years that would be required to perform another study, this is unlikely to occur. As a result, a promising new drug for treatment of preterm labor, and the first drug submitted to the FDA for this indication in more than 20 years, will not be avail- able for physician use in the United States.

FDA REGULATORY ACTIONS REGARDING TERBUTALINE
The off-label utility of terbutaline as a tocolytic agent has been known to clinicians for more than 20 years (9,97). During this time, terbutaline was studied and evaluated by the medical community in numerous investigations and clinical trials. As a result of physician acceptance and comfort in prescribing terbutaline, it is now estimated that at least 260,000 women per year receive terbutaline during pregnancy and that it is the most popular prescribed ß-mimetic for tocolysis (15,16). Until May of 1993, the FDA did not comment on this off-label prescription of terbutaline for treatment of preterm labor by physicians. The FDA appeared to be following its long-standing policy on the use of approved drugs for nonlabeled indications as being entirely appropriate on the basis of medical advances reported in the literature (98). During the October 29, 1992 meeting of the FDA Fertility and Maternal Drug Advisory Committee on ritodrine, it became apparent to the FDA that the ß-mimetic tocolytic of choice in this country was not the FDA-approved ritodrine, but rather terbutaline, used in an off-label prescribing manner. On May 21, 1993, the FDA Fertility and Maternal Health Drug Advisory Committee met to discuss terbutaline. After lengthy discussion and review of the existing literature, the Committee unanimously agreed that terbutaline in certain dosage forms was safe and effective to treat preterm labor. Because there were no substantial data indicating that any warning or precaution should be included in the labeling concerning tocolytic use, the Committee advised the FDA to ask the manufacturers of terbutaline to remove any warnings or precautions against terbutaline use in preterm labor. The Committee agreed that data in the literature showed that intravenous terbutaline is safe and effective for tocolysis and that the FDA should solicit a new drug application for its use as a tocolytic. The Committee agreed that between 8 and 10 times more terbutaline is used for a pregnancy-related diagnosis than the FDA-approved drug ritodrine and that terbutaline is considerably less expensive for patients. The Committee also agreed that oral terbutaline may also be effective as a tocolytic agent and that more data were required to substantiate its effectiveness and establish an optimal dose. The Committee voted that subcutaneous and intramuscular routes of administration and longer durations of use should be studied because some promise has been shown. During the meeting, the FDA expressed the possibility of a literature-only based new drug application from the manufacturer for approval of terbutaline use as a tocolytic (99). The manufacturer has thus far declined to make this submission to FDA.
Since the May 1993 FDA Committee meeting on terbutaline, the FDA has convened no additional advisory or scientific panel meetings or discussions regarding terbutaline use in preterm labor. However, several clinical studies were subsequently published on the safety and efficacy of subcutaneous terbutaline. In 1994, Allbert et al. (52) compared oral administration of terbutaline with subcutaneous delivery via infusion pump. Terbutaline pump was reported to be more successful in prolonging pregnancies to term than did oral terbutaline. In 1995, Perry et al. (80) reviewed hospital records of 8709 women receiving subcutaneous infusion of terbutaline for recurrent preterm labor and found that continuous terbutaline infusion for women with stabilized preterm labor is associated with fewer adverse effects than previous literature regarding intravenous ß-agonist therapy suggested. The authors also reviewed two maternal deaths in this population and concluded that these deaths were not caused by ß-agonist therapy. In 1997, Wenstrom et al. (53) and Elliott et at. (54) published reports on the efficacy of subcutaneous terbutaline infusion therapy. Wenstrom et at. (53) concluded that terbutaline by pump, saline by pump, and oral terbutaline seem to be equivalent in the prevention of preterm delivery. Elliott et al. (54) concluded that terbutaline pump tocolysis provides safe and effective tocolytic therapy in a select group of high-order mutifetal gestations. Lam et al. (55), in 1998, demonstrated in 256 patients that subcutaneous terbutaline infusion therapy was superior to oral terbutaline therapy in prolonging gestation in high-risk pregnancies complicated by recurrent pre term labor. On November 13, 1997, the FDA Associate Commissioner for Health Affairs, Smart Nightingale, issued a "Dear Colleague" letter to medical societies and or ganizations regarding subcutaneous administration of terbutaline for tocolysis. The letter stated that the FDA had concerns about the subcutaneous administration of terbutaline for the treatment and prevention of preterm labor. In the letter, Nightingale explained that "in the absence of data establishing the effectiveness and safety of the drug/device, FDA is alerting practitioners, home health care agencies, insurance carriers, and others that continuous subcutaneous administration of terbutaline has not been demonstrated to be effective and is potentially dangerous." This letter came as a shock to the medical community, insurance companies, and scientists alike, be cause the FDA had apparently reversed its stance set forth in the May 1993 terbutaline Advisory Committee meeting. There was no publication of new data since the May 1993 meeting indicating any concerns for safety regarding subcutaneous use of terbutaline as a tocolytic, no publication of new reports of maternal deaths since the 1993 meeting indicating a potentially dangerous situation developing with the use of terbutaline therapy, no publication of new safety or efficacy data or presentation in public forum by the manufacturers of terbutaline questioning the safety or efficacy of subcutaneous therapy, and no publication of a new body of data indicating that subcutaneous terbutaline as a tocolytic is not effective in certain patient populations.

COMMENT
A clinical review of the existing scientific literature on terbutaline as a tocolytic agent finds it generally efficacious for acute and maintenance tocolysis. Evidence to date clearly demonstrates a low incidence of cardiac, metabolic, and other side effects associated with its use. Benefits of terbutaline for tocolysis clearly outweigh the minimal risks to mother and fetus. Proper monitoring and surveillance of patients on terbutaline tocolysis is warranted, especially in situations where maternal fluid overload is a possibility, such as in multiple gestations. Low-dose subcutaneous infusion of terbutaline for tocolysis appears to be a viable option for treatment of patients with recurrent preterm labor. Patients refractory to oral ß-mimetic therapy or other tocolytics can benefit from low dose basal and intermittent bolus dosing of subcutaneous terbutaline. Clinical studies indicate that significant pregnancy prolongation is possible with this type of dosing because of a decreased tendency for patients to de velop tachyphylaxis and subsequent drug breakthrough. Current reports regarding the safety of subcutaneous terbutaline therapy indicate that serious side effects are rare and usually multi-factorial in origin. As with the administration of any tocolytic, prudent management of the patient' s fluid status and concurrent medical condition is advised. ß-mimetic drug therapy for preterm labor is not perfect. As with all medications, physicians must remain vigilant about the risks and benefits to mother and fetus. All currently available tocolytic alternatives are also less than optimal. Other drugs currently used off-label as tocolytics, such as nifedipine and indomethacin, have minimal clinical evidence for efficacy and safety. On the other hand, numerous studies conducted during the past 20 years support the use of terbutaline as a tocolytic and report clinical safety parameters are well within the tolerances established by the FDA-approved ß-mimetic ritodrine. At a time where national expenditures for treating preterm birth rise above 5 billion dollars annually and the United States continues to have one of the worst preterm delivery rates among industrialized nations, physicians have increasingly fewer treatment options available, primarily because of decisions set forth by our regulatory agencies. The FDA has further complicated this situation by the issuance of the November 1997 "Dear Colleague" letter which cast doubt on one of the few remaining treatment options available. Physicians should not be restricted or made liable for continuing to use ß-mimetic agents such as terbutaline or ritodrine for the treat ment of preterm labor in all currently available routes of administration when the clinical and scientific literature supports such use.

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