Research on Terbutaline

And Other Beta-Adrenergics Used to Treat Preterm Labor

Updated 4/14/99

Heart and Lung Complications

Studies go back to at least 1980 with reports of heart and lung complications in women taking beta-adrenergics, including terbutaline and ritodrine, for preterm labor.

• In a 1980 case report (The Journal of the American Medical Association, Vol. 244, pp. 692-693), an 18-year-old woman experienced severe chest pain when she was treated with terbutaline for preterm labor. The woman had taken terbutaline intravenously and then was started on an oral dose of 5 mg every six hours. She experienced the pain after the second pill. She had no history of premature heart disease.

• A 1981 study (American Journal of Obstetrics and Gynecology, Vol. 139, pp. 605-608) reported a 5 percent incidence of severe cardiovascular complications among women taking terbutaline. Among women taking terbutaline with multiple gestations, the incidence of severe complications was 50 percent.

• In a 1981 study (European Journal of Obstetrical Gynecology, Vol. 11, pp. 371-378), the incidence of severe cardiovascular complications was 5.3 percent among women taking terbutaline. Among those women with multiple gestations who were taking terbutaline by IV, the rate of serious cardiovascular symptoms was *43 percent.* The study, done at the University of California Medical Center, San Francisco, reviewed the records of 343 patients who had taken terbutaline or isoxsuprine for preterm labor.

• In a 1983 study (Obstetrics & Gynecology, Vol. 61, p. 10S), 2 percent of patients treated with intravenous ritodrine for preterm labor developed cardiovascular complications and had to discontinue the drug. The patients had all been screened for pre-existing heart conditions, so these problems were unexpected. Diagnoses: arrhythmia, myocardial ischemia, cardiomyopathy and congenital cardiac malformation.

• In a 1986 study (The Lancet, Vol. 2, p. 917-918), 15 women suffering from preterm labor were monitored with EKGs before and during administration of intravenous ritodrine. Significant ST segment depression readings, which are "highly suggestive" of myocardial ischemia, were recorded on the EKGs of 73 percent of these women (11 patients). This diagnosis was reconfirmed in three of four patients who received echocardiograms. The study says: "Silent ischaemia could contribute to the cardiomyopathy that has been reported after prolonged ritodrine treatment.

• In a 1984 case report (American Journal of Obstetrics and Gynecology, Vol. 148, pp. 821-823), a 32-year-old woman experienced chest pain and shortness of breath during treatment with terbutaline. She had been treated twice in the hospital with subcutaneous terbutaline and was switched to an oral dose of 5 mg every four hours. Eighteen days after discharge, she experienced the symptoms. She was diagnosed with an asymptomatic congenital abnormality that was aggravated by drug-induced stress.

• In a 1988 case report (American Journal of Obstetrics and Gynecology, Vol. 169, pp. 332-333), a 34-year-old Israeli woman developed pulmonary edema after 28 days on ritodrine. After delivering her baby, an echocardiogram showed evidence of a dilated cardiomyopathy. The case report's authors characterized it as "underlying."

• In a 1988 study (Obstetrics & Gynecology, Vol 71, p. 361-364), 10 out of 30 women (33 percent) developed cardiovascular symptoms during treatment with intravenous ritodrine. The "unsuspected events" picked up by a Holter monitor included: severe tachycardia, premature ventricular contractions, and supraventricular premature contractions.

• Researchers in 1989 reviewed 58 case reports of pulmonary edema associated with the use of preterm labor drugs (Annals of Internal Medicine, Vol 110, No.9, p. 714-718). In 41 percent of these cases, terbutaline had been used, followed by isoxsuprine (33%), ritodrine (17%) and salbutamol (10%). All of these drugs are in the same beta-adrenergic family as terbutaline. Twin gestations were involved in 24 percent of the cases.

• In a 1993 study (American Journal of Obstetrics and Gynecology, Vol. 168, pp. 493-495), 4 out of 15 cases of peripartum dilated cardiomyopathy involved women who had taken terbutaline for at least four weeks.

• In a 1996 study (American Journal of Obstetrics and Gynecology, Vol. 175, pp. 847-852), 5 of 7 pregnant rabbits who were put on terbutaline pumps exhibited periodic arrhythmias and mechanical alterans versus 1 of 7 pregnant rabbits receiving a saline solution.

• In a 1997 study (Kidney International, Vol. 51, pp. 1867-1875), 3 of 14 women being monitored for cardiac rhythm developed arrhythmias while taking ritodrine or terbutaline. No woman in the control group (N=12) developed these arrhythmias. This study also found terbutaline and ritodrine induced profound hypokalemia in women being treated with these drugs.

• In a 1997 study (American Journal of Obstetrics and Gynecology, Vol. 176, pp. 182-188), 2 out of 28 women who developed peripartum dilated cardiomyopathy had been treated with multiple tocolytics.

• A 1995 study found an association between the use of beta-adrenergics for respiratory illnesses and the incidence of idiopathic (of unknown origin) dilated cardiomyopathy in these same patients (American Journal of Epidemiology, Vol. 142, pp. 395-403). Patients diagnosed with respiratory illnesses were compared with neighborhood controls. The study's authors reported: "The results of this study suggest, but do not prove, that use of beta-agonists has an etiologic role in idiopathic dilated cardiomyopathy."

Deaths

• At least two women's deaths have been linked to their use of terbutaline. One of the deaths, in 1993, involved a woman pregnant with twins who was found dead after complaining of chest discomfort. She died of pulmonary edema and cardiac arrhythmia, which are two serious side effects of terbutaline (American Journal of Obstetrics and Gynecology, Vol. 169, pp. 120-121). The second death involved a 26-year-old woman pregnant with a singleton. She had been taking terbutaline for preterm labor (5 mg every 6 hours). She developed chest pain and had a heart attack. An emergency C-Section was performed, and a male infant delivered at 30 weeks. But the woman died. An autopsy revealed she had a coronary artery dissection due to type IV Ehlers-Danlos Syndrome (a genetic connective tissue disorder). The authors of the case study (American Journal of Perinatology, 1996, Vol. 13, pp. 181-183) concluded that the "inotropic properties of betamimetic tocolytics may increase the shear force of the blood column in fragile vessels, which may predispose them to dissection or rupture."

• In a 1980 case report, a 27-year-old French woman was treated as an outpatient with ritodrine and then with multiple tocolytics including ritodrine in the hospital for preterm labor (European Journal of Obstetrical Gynecology and Reproductive Biology, 1980, Vol. 11, pp. 95-100). After giving birth to a premature baby at 35 weeks, she developed signs of pulmonary edema. Upon further tests, she was diagnosed with tachycardia, cardiomegaly (enlarged heart) and left ventricle dilation. She was discharged after 19 days in the hospital. She died suddenly at home 60 days after delivery.

• In a 1987 case report, an Israeli woman pregnant with twins and suffering from pre-eclampsia (The Journal of Reproductive Medicine, Vol. 32, pp. 793-797) was treated with ritodrine for premature labor. After delivering her twins, she developed peripartum congestive cardiomyopathy and endocardial fibroelastosis (thickening of the endocardium). She was treated for her heart condition but died suddenly at home 4.5 months after delivery of her twins.

• A 1998 study (American Journal of Obstetrics and Gynecology, Vol. 179, pp. 874-878) found no statistically significant difference in mean time to delivery in groups of women taking terbutaline by pump versus groups of women on a saline solution by pump. This study was randomized, double-blind and involved 52 women at less than 34 weeks gestation who were experiencing preterm labor. All the women had their contractions arrested by magnesium sulfate before the trials began. There were no differences in the rates of preterm delivery; neonatal outcomes were similar.

• A 1998 study (American Journal of Perinatology, Vol. 15, pp. 177-181), found that 75 women who took tocolytics for preterm labor did not have a better preterm delivery rate or better perinatal outcomes than 81 women in a control group who took no tocolytics and were observed. Most of the women taking magnesium sulfate and/or terbutaline were older patients with commercial insurance, while most of the control group were younger women on public assistance.

• Four studies in 1996 and 1997 cast doubts on terbutaline's efficacy. When compared to a placebo, terbutaline fared no better in prolonging women's pregnancies to any statistically significant degree (American Journal of Obstetrics and Gynecology, 1996, Vol. 175, pp. 834-837; American Journal of Obstetrics and Gynecology, 1997, Vol. 177, pp. 814-818; American Journal of Perinatology, 1997, Vol. 14, pp. 404-409; American Journal of Perinatology, 1997, Vol. 14, pp. 87-91). Three of these studies were randomized; two were randomized, double-blind studies.

• A 1982 study (Military Medicine, Vol. 147, pp. 305-307) of 33 women found no statistically significant difference between those women (N=15) treated with terbutaline and those treated with a placebo (N=18). The women treated with terbutaline received it by IV, then through a subcutaneous pump for 24 hours, then orally. This was a double-blind, randomized study.

• A 1984 study (The Journal of Reproductive Medicine, Vol. 29, No. 2, pp. 92-97), failed to find any significant difference in success between treatments of magnesium sulfate, terbutaline and a placebo in delaying labor for at least 48 hours. This was a randomized, double-blind study.

• A 1993 study (American Journal of Obstetrics and Gynecology, Vol. 169, pp. 965-969) found the use of oral terbutaline after successful intravenous tocolysis with magnesium sulfate failed to reduce the rate of preterm birth. This was a randomized study that compared 28 women on terbutaline to 27 who did not receive terbutaline and were solely on bed rest.

• In a 1995 study (American Journal of Obstetrics and Gynecology, Vol. 173, pp. 1518-1522), long-term oral terbutaline failed to improve patients' pregnancy outcome when compared to a control groups just on bed rest. All the women had been treated and stabilized with magnesium sulfate in the hospital. They were divided into two trial and two control groups based on the amount of cervical change (rated as a Bishop's score).

• The University of Manitoba teaching hospitals (American Journal of Perinatology, Vol. 9, No. 5/6, pp. 394-397) have not used tocolytics since 1985 to treat preterm labor because of concerns about tocolytic safety and efficacy. Researchers reviewed the records of 364 women who delivered between Nov. 1, 1986 and June 30, 1987 at their hospitals to see if any women would have been eligible for tocolytic therapy. Only 9 percent would have qualified, using published guidelines for tocolytics.

• In a 1991 study (American Journal of Obstetrics and Gynecology, Vol. 167, pp. 873-879), researchers found a two-fold increase in the incidence of neonatal periventricular hemorrhage among the babies of women who had taken beta-adrenergics for preterm labor. This was a retrospective study of 2827 women, and the data were adjusted for type of tocolytic agent, race, infant sex, gestational age, birth weight, health care center, route of delivery, indication for delivery, intrapartum fetal distress, respiratory distress syndrome, and neonatal sepsis.

• In a 1991 case report (American Journal of Obstetrics and Gynecology, Vol. 165, pp. 1401-1404), a baby whose mother had taken a high dose of terbutaline for preterm labor developed congestive heart failure and cardiomyopathy. A cardiac catheterization was done that revealed myocardial injury in the right ventricle of the heart caused by catecholamine excess (which can be caused by terbutaline). Infectious and metabolic causes of cardiomyopathy were ruled out. The baby recovered by the 12th day after his birth. The baby's mother was on the terbutaline pump and was receiving a dose 10 times higher than the usual amount.

• In a 1992 study (American Journal of Obstetrics and Gynecology, Vol. 167, pp. 1059-1063), a single dosage of indomethacin or terbutaline increased fetal breathing movements by 103% and 78% respectively.

• A 1985 study (American Journal of Perinatology, Vol. 2, No. 4, pp. 338-346) found that when mongrel dogs were treated with these agents and another tocolytic (hexaprenaline)for 19 hours, the most severe cardiovascular side effects were seen in the dogs taking terbutaline. Cardiac arrhythmias were responsible for a 50 percent death rate in the group of 4 dogs taking terbutaline, and for a 50 percent death rate in the group of 4 dogs taking ritodrine and bethamethasone. "Terbutaline-treated animals developed arrhythmias during more treatment cycles (50%) and at lower drug concentrations."

• Two reviews of existing studies have concluded that terbutaline and other beta-adrenergists should not be used for preterm labor because of the risk of serious side effects to the mother and fetus. (American Journal of Obsetrics and Gynecology, 1993, Vol. 168, pp. 1247-59; Obstetrical Gynecology 1995, Vol. 85, pp. 313-317)

• In a 1985 study (American Journal of Obstetrics and Gynecology, Vol. 1553, pp. 854-859), terbutaline caused so many side effects that the Univeristy of Southern California School of Medicine and Women's Hospital decided to stop prescribing it for preterm labor. Terbutaline, ritodrine and magnesium sulfate were compared in effectiveness and side effects. "No differences in efficacy were found between the drugs." Terbutaline had to be discontinued because of serious side effects in 60 percent of the women who took it. The rate of discontinuation because of serious side effects was 38 percent for ritodrine and 2 percent for magnesium sulfate.

Warnings Against Using Terbutaline for Preterm Labor

• The 1998 Physicians' Desk Reference says of terbutaline (both pills and subcutaneous injection):
  "Terbutaline should not be used for tocolysis. Serious adverse reactions may occur after administration of terbutaline sulfate to women in labor. In the mother, these include increased heart rate, transient hyperglycemia, hypokalemia, cardiac arrhythmias, pulmonary edema, and myocardial ischemia. Increased fetal heart rate and neonatal hypoglycemia may occur as a result of maternal administration."

• Mosby's GenRx: The Complete Reference for Generic and Brand Drugs, St. Louis, 1998, says:
  "Terbutaline sulfate is not indicated and should not be used for the management of preterm labor. Serious adverse reactions have been reported following administration of terbutaline sulfate to women in labor. These reports have included transient hypokalemia, pulmonary edema (sometimes after delivery), and hypoglycemia in the mother and/or neonatal child. Maternal death has been reported with terbutaline sulfate and other drugs of this class."

• In a 1997 study (Obstetrical Gynecology, Vol. 90, pp. 880-883), women who were treated with terbutaline and betamethasone ran a "significantly" higher risk of developing gestational diabetes than the control group.

• In a 1983 study (American Journal of Obstetrics and Gynecology, Vol. 150, pp. 7-14), women who were treated with terbutaline were "significantly more likely" to have a serum glucose level in excess of 140 mg/dl in comparison with women who were treated with ritodrine.

• In a 1993 study (American Journal of Obstetrics and Gynecology, Vol. 168, pp. 100-105), women treated with terbutaline developed a dose-dependent, terbutaline-induced glucose intolerance.

• In a 1987 study (American Journal of Obstetrics and Gynecology, Vol. 157, pp. 644-647), researchers concluded that treatment with terbutaline "appears to be associated with impairment of glucose tolerance in pregnancy."

Terbutaline, Liver Complications

• In a 1985 study (Obstetrical Gynecology, Vol. 66, pp 14S-15S), a woman who took terbutaline first in pill form, later through an IV, developed severe liver impairment that improved upon delivery of her baby.

• In a 1994 case report (American Journal of Gastroenterology, Vol. 89, No. 5, pp. 781-784), two women developed hepatitis that could not be traced to any other source than the terbutaline they were taking for preterm labor. Both women recovered quickly after the terbutaline was discontinued.

Terbutaline, Massive Vulvar Edema

• In a 1996 case report (The Journal of Reproductive Medicine, Vol. 41, No. 2, pp. 121-124), a woman pregnant with twins who was taking terbutaline for preterm labor developed a massive vulvar edema, a potentially fatal condition. Her edema resolved after her feet were elevated in her hospital bed..

Terbutaline, Cerebral Ischemia

• In a 1982 case report (American Journal of Obstetrics and Gynecology, Vol. 143, pp. 405-407), two patients with a history of migraine headaches developed signs of cerebral ischemia while being treated with subcutaneous terbutaline. One woman received the terbutaline for asthma, the other for preterm labor.

Effectiveness of Ritodrine

• In a 1992 study (The New England Journal of Medicine, Vol. 327, pp. 308-312), Canadian researchers compared ritodrine to a placebo in a randomized, controlled, multicenter trial involving 708 women. They found ritodrine "had no significant beneficial effect on perinatal mortality, the frequency of prolongation of pregnancy to term, or birth weight."

• A 1992 New England Journal of Medicine Editorial (Vol. 327, pp. 349-351) urged the FDA to "reappraise the vanishingly small neonatal benefits in the light of substantial maternal risks of ritodrine given in an attempt to forestall preterm labor."

Ritodrine vs. Nifedipine

• A 1995 study comparing the use of ritodrine to nifedipine for treating preterm labor found that nifedipine prolonged pregnancies two weeks longer than ritodrine and resulted in fewer maternal side effects (Journal of Perinatal Medicine, Vol. 23, pp. 409-415). Maternal side effects occurred in 74 percent of the 32 patients receiving ritodrine, versus in 24 percent of the 29 patients receiving nifedipine.

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