Fetal Risk Summary
Terbutaline is a b-sympathomimetic indicated for the prevention and reversal of bronchospasm. During pregnancy it is primarily used as a tocolytic agent. No reports linking the use of terbutaline with congenital defects have been located. However, the tocolytic use of this drug is confined to the late 2nd and early 3rd trimesters. Published reports describing the use of terbutaline as a bronchodilator during early pregnancy have not been found.
Reproduction studies in mice, rats, and rabbits at doses up to 1500 times the SC maximum recommended human daily dose of 0.1 mg/kg have revealed no evidence of impaired fertility or fetal harm (1).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 149 newborns had been exposed to terbutaline during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of seven (4.7%) major birth defects were observed (six expected), including three cardiovascular defects (two expected) and one oral cleft (none expected). No anomalies were observed in four other categories of defects (spina bifida, polydactyly, limb-reduction defects, and hypospadias) for which specific data were available. These data do not support an association between the drug and congenital defects.
Terbutaline rapidly crosses the placenta to the fetus (2). In seven women given 0.25 mg IV during the second stage of labor, cord blood levels 760 minutes after the dose ranged from 12% to 55% (mean 36%) of maternal serum.
Terbutaline has been used as a tocolytic agent since the early 1970s (3,4). The incidence of maternal side effects is usually low (e.g., 5% or less) but may be severe (3,5,6,7,8 and 9). A 1983 review listed the more serious side effects of parenteral b-sympathomimetic therapy (e.g., terbutaline, ritodrine) as pulmonary edema, myocardial ischemia, cardiac arrhythmias, cerebral vasospasm, hypotension, hyperglycemia, and miscellaneous metabolic alterations (hypokalemia, increased serum lactate, and a decrease in measured hemoglobin concentration) (10). The more serious adverse effects are seen with continuous infusions of these drugs. Avoidance of this route of administration as well as careful selection of patients, appropriate dosing, and close monitoring of patient status may help to prevent serious maternal effects.
Terbutaline may cause fetal and maternal tachycardia (3,5,6 and 7). Fetal rates are usually less than 175 beats/minute (6). As mentioned previously, maternal hypotension may occur, especially in the bleeding patient (10). More commonly, increases in systolic pressure and decreases in diastolic pressure occur with no reduction in mean arterial pressure and, thus, do not adversely affect the fetus (7,10,11).
Like all b-mimetics, terbutaline may cause transient maternal hyperglycemia followed by an increase in serum insulin levels (3,12,13). Sustained neonatal hypoglycemia may be observed if maternal effects have not terminated before delivery (12). Maternal glucose intolerance was observed at 1 hour in 19 of 30 patients receiving oral terbutaline for at least 1 week (14). Although macrosomia was not observed, the birth weights (after adjustment for gestational age) of infants from terbutaline-treated mothers had a tendency to be greater than those of babies from comparable controls (14).
Sudden, unexplained intrapartum death in a fetus at 30 weeks' gestation occurred 5 hours after the start of an IV infusion of terbutaline for premature labor (15). No evidence of uterine, placental, or fetal anomalies was discovered.
Myocardial necrosis in a newborn was reported in 1991 (16). A continuous SC infusion of terbutaline (initial dose 0.5 mg/hour) was started at 25 weeks' gestation for premature labor in a 22-year-old woman with gestational diabetes. Therapy was continued until delivery at 37 weeks' of a 2850-g male infant. Tachypnea (80100 breaths/minute) developed shortly after birth and chest radiography demonstrated mild cardiomegaly with increased pulmonary vascularity (16). A right ventricular biopsy obtained during cardiac catheterization showed marked myocardial fiber degeneration and focal bizarre nuclear dysmorphism (16). These findings were believed to be caused by catecholamine excess. Normal electrocardiogram and echocardiogram were found on examination at 1 month of age.
Maternal liver impairment was reported in a patient after 1 week of continuous IV administration of terbutaline (17). Therapy was stopped and 1 week later a healthy newborn was delivered without signs of liver toxicity.
A paradoxical reaction to terbutaline was observed in a patient after 0.25 mg IV produced marked uterine hypertonus and subsequent severe fetal bradycardia (<50 beats/minute) (18). A healthy baby was delivered by emergency cesarean section.
Terbutaline has been used frequently to treat intrapartum fetal distress (19,20,21,22 and 23). The mechanism of the beneficial effects on fetal pH and heart rate is thought to be caused by relief of the ischemia produced by uterine contractions on the placental circulation.
Although maternal complications may occur, few direct adverse effects, other than transient tachycardia and hypoglycemia, and the single report of myocardial necrosis, have been observed in the fetus or newborn. In many studies, neonatal complications are minimal or nonexistent (24,25,26,27 and 28). Compared with controls, prophylactic terbutaline in low-risk patients with twin gestations has produced significant gains in birth weights caused by longer gestational times (27). In addition, terbutaline decreases the incidence of neonatal respiratory distress syndrome in a manner similar to other b-mimetics (29). Long-term evaluation of infants exposed to terbutaline in utero has been reported (30,31 and 32) . No harmful effects in the infants (224 months) have been found.
In summary, terbutaline has been used as a tocolytic since the early 1970s. Only rare reports of serious toxicity in the fetus or newborn have appeared, and although maternal adverse effects are much more common, toxicity in both are no more frequent than with other b-mimetics used for the treatment of premature labor. Avoidance of continuous terbutaline infusions lessens the chance of serious maternal effects. The manufacturer has now categorized the drug as not indicated for the management of preterm labor, but this was apparently done for regulatory concerns as published information does not support the reclassification.
Breast Feeding Summary
Terbutaline is excreted into breast milk (33,34). In two mothers with chronic asthma about 68 weeks postpartum, 5 mg 3 times daily produced mean maternal plasma levels of 1.94.8 ng/mL, whereas milk concentrations ranged between 2.5 and 3.8 ng/mL (33). The nursing infants ingested approximately 0.2% of the maternal dose, and the drug could not be detected in their plasma. In the second report, two mothers, both at 3 weeks postpartum and both with chronic asthma, were treated with 2.5 mg 3 times a day (34). Plasma levels varied between 0.97 and 3.07 ng/mL, whereas mean milk levels were 2.763.91 ng/mL. Peak milk concentrations occurred at about 4 hours. The milk:plasma ratios of 1.42.9 are indicative of ionic trapping in the milk (34). Concentrations of terbutaline were highest in the fat fraction of the milk. Based on calculations, the infants were ingesting approximately 0.7% of the maternal dose.
No symptoms of adrenergic stimulation were observed in the four infants and all exhibited normal development. Long-term effects of this exposure, however, have not been studied. The American Academy of Pediatrics considers terbutaline to be compatible with breast feeding (35).
- Product information. Brethine. Novartis Pharmaceuticals, 2000.
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- Haller DL. The use of terbutaline for premature labor. Drug Intell Clin Pharm 1980;14:75764.
- Ingemarsson I. Cardiovascular complications of terbutaline for preterm labor. Am J Obstet Gynecol 1982;142:117.
- Andersson KE, Bengtsson LP, Gustafson I, Ingermarsson I. The relaxing effect of terbutaline on the human uterus during term labor. Am J Obstet Gynecol 1975;121:6029.
- Ingermarrson I. Effect of terbutaline on premature labor. A double-blind placebo-controlled study. Am J Obstet Gynecol 1976;125:5204.
- Ravindran R, Viegas OJ, Padilla LM, LaBlonde P. Anesthetic considerations in pregnant patients receiving terbutaline therapy. Anesth Analg (Cleve) 1980;59:3912.
- Katz M, Robertson PA, Creasy RK. Cardiovascular complications associated with terbutaline treatment for preterm labor. Am J Obstet Gynecol 1981;139:6058.
- Ingemarsson I, Bengtsson B. A five-year experience with terbutaline for preterm labor: low rate of severe side effects. Obstet Gynecol 1985;66:17680.
- Benedetti TJ. Maternal complications of parenteral b-sympathomimetic therapy for premature labor. Am J Obstet Gynecol 1983;145:16.
- Vargas GC, Macedo GJ, Amved AR, Lowenberg FE. Terbutaline, a new uterine inhibitor. Ginecol Obstet Mex 1974;36:7588.
- Epstein MF, Nicholls RN, Stubblefield PG. Neonatal hypoglycemia after beta-sympathomimetic tocolytic therapy. J Pediatr 1979;94:44953.
- Westgren M, Carlsson C, Lindholm T, Thysell H, Ingemarsson I. Continuous maternal glucose measurements and fetal glucose and insulin levels after administration of terbutaline in term labor. Acta Obstet Gynecol Scand 1982;Suppl 108:635.
- Main EK, Main DM, Gabbe SG. Chronic oral terbutaline tocolytic therapy is associated with maternal glucose intolerance. Am J Obstet Gynecol 1987;157:6447.
- Lenke RR, Trupin S. Sudden, unforeseen fetal death in a woman being treated for premature labor: a case report. J Reprod Med 1984;29:8724.
- Fletcher SE, Fyfe DA, Case CL, Wiles HB, Upshur JK, Newman RB. Myocardial necrosis in a newborn after long-term maternal subcutaneous terbutaline infusion for suppression of preterm labor. Am J Obstet Gynecol 1991;165:14014.
- Suzuki M, Inagaki K, Kihira M, Matsuzawa K, Ishikawa K, Ishizuka T. Maternal liver impairment associated with prolonged high-dose administration of terbutaline for premature labor. Obstet Gynecol 1985;66:14S15S.
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- Tejani NA, Verma UL, Chatterjee S, Mittelmann S. Terbutaline in the management of acute intrapartum fetal acidosis. J Reprod Med 1983;28:85761.
- Barrett JM. Fetal resuscitation with terbutaline during eclampsia-induced uterine hypertonus. Am J Obstet Gynecol 1984;150:895.
- Ingemarsson I, Arulkumaran S, Ratnam SS. Single injection of terbutaline in term labor. I. Effect on fetal pH in cases with prolonged bradycardia. Am J Obstet Gynecol 1985;153:85965.
- Ingemarsson I, Arulkumaran S, Ratnam SS. Single injection of terbutaline in term labor. II. Effect on uterine activity. Am J Obstet Gynecol 1985;153:8659.
- Mendez-Bauer C, Shekarloo A, Cook V, Freese U. Treatment of acute intrapartum fetal distress by b2-sympathomimetics. Am J Obstet Gynecol 1987;156:63842.
- Stubblefield PG, Heyl PS. Treatment of premature labor with subcutaneous terbutaline. Obstet Gynecol 1982;59:45762.
- Caritis SN, Carson D, Greebon D, McCormick M, Edelstone DI, Mueller-Heubach E. A comparison of terbutaline and ethanol in the treatment of preterm labor. Am J Obstet Gynecol 1982;142:18390.
- Kaul AF, Osathanondy R, Safon LE, Frigoletto FD Jr, Friedman PA. The management of preterm labor with the calcium channel-blocking agent nifedipine combined with the b-mimetic terbutaline. Drug Intell Clin Pharm 1985;19:36971.
- O'Leary JA. Prophylactic tocolysis of twins. Am J Obstet Gynecol 1986;154:9045.
- Arias F, Knight AB, Tomich PB. A retrospective study on the effects of steroid administration and prolongation of the latent phase in patients with preterm premature rupture of the membranes. Am J Obstet Gynecol 1986;154:105963.
- Bergman B, Hedner T. Antepartum administration of terbutaline and the incidence of hyaline membrane disease in preterm infants. Acta Obstet Gynecol Scand 1978;57:21721.
- Wallace R, Caldwell D, Ansbacher R, Otterson W. Inhibition of premature labor by terbutaline. Obstet Gynecol 1978;51:38793.
- Svenningsen NW. Follow-up studies on preterm infants after maternal b-receptor agonist treatment. Acta Obstet Gynecol Scand 1982;Suppl 108:6770.
- Karlsson K, Krantz M, Hamberger L. Comparison of various b-mimetics on preterm labor, survival and development of the child. J Perinat Med 1980;8:1926.
- Lonnerholm G, Lindstrom B. Terbutaline excretion into breast milk. Br J Clin Pharmacol 1982;13:72930.
- Boreus LO, de Chateau P, Lindberg C, Nyberg L. Terbutaline in breast milk. Br J Clin Pharmacol 1982;13:7312.
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