Fetal Risk Summary
Propranolol, a nonselective b-adrenergic blocking agent, has been used for various indications in pregnancy: Maternal hyperthyroidism (1,2,3,4,5,6 and 7) Pheochromocytoma (8) Maternal cardiac disease (6,7,9,10,11,12,13,14,15,16,17,18,19 and 20) Fetal tachycardia or arrhythmia (21,22) Maternal hypertension (7,20,2324,25,26,27,28,29 and 30) Dysfunctional labor (31) Termination of pregnancy (32) Reproduction studies in rats revealed embryotoxicity (increased resorption sites and reduced litter sizes) and reduced neonatal survival at doses up to about 10 times the maximum recommended human dose (MRHD) (33). No embryotoxicity was observed in rabbits at doses up to about 20 times the MRHD. No teratogenicity was noted in either species.
The drug readily crosses the placenta (2,6,12,16,22,29,34,35). Cord serum levels varying between 19% and 127% of maternal serum have been reported (2,16,22,29). Oxytocic effects have been demonstrated following IV, extra-amniotic injections, and high oral dosing (17,31,32,36,37). IV propranolol has been shown to block or decrease the marked increase in maternal plasma progesterone induced by vasopressin or theophylline (38). The pharmacokinetics of propranolol in pregnancy have been described (39). Plasma levels and elimination were not significantly altered by pregnancy.
A number of fetal and neonatal adverse effects have been reported following the use of propranolol in pregnancy. Whether these effects were caused by propranolol, maternal disease, other drugs consumed concurrently, or a combination of these factors is not always clear. Daily doses of 160 mg or higher seem to produce the more serious complications, but lower doses have also resulted in toxicity. Analysis of 23 reports involving 167 liveborn infants exposed to chronic propranolol in utero is shown below (1,2,3 and 4,6,7,9,11,12,13 and 14,20,22,23 and 24,26,27,28 and 29,40,41,42 and 43): No. Cases % Intrauterine growth retardation
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 274 newborns had been exposed to propranolol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 11 (4.0%) major birth defects were observed (12 expected), including (observed/expected) 3/3 cardiovascular defects and 2/1 hypospadias. No anomalies were observed in four other defect categories (oral clefts, spina bifida, polydactyly, and limb reduction defects) for which specific data were available.
Respiratory depression was noted in four of five infants whose mothers were given 1 mg of propranolol IV just before cesarean section (45). None of the five controls in the double-blind study was depressed at birth. The author suggested the mechanism may have been b-adrenergic blockade of the cervical sympathetic discharge that occurs at cord clamping.
Fetal bradycardia was observed in 2 of 10 patients treated with propranolol, 1 mg/minute for 4 minutes, for dysfunctional labor (31). No lasting effects were seen in the babies. In a retrospective study, 8 markedly hypertensive patients (9 pregnancies) treated with propranolol were compared with 15 hypertensive controls not treated with propranolol (25). Other antihypertensives were used in both groups. A significant difference was found between the perinatal mortality rates, with 7 deaths in the propranolol group (78%) and only 5 deaths in the controls (33%). However, a possible explanation for the difference may have been the more severe hypertension and renal disease in the propranolol group than in the controls (46).
Intrauterine growth retardation may be related to propranolol. Several possible mechanisms for this effect, if indeed it is associated with the drug, have been reviewed (47). Premature labor has been suggested as a possible complication of propranolol therapy in patients with pregnancy-induced hypertension (PIH) (42). In nine women treated with propranolol for PIH, three delivered prematurely. The author speculated that these patients were relatively hypovolemic and when a compensatory increase in cardiac output failed to occur, premature delivery resulted. However, another report on chronic propranolol use in 14 women did not observe premature labor (43).
In a randomized, double-blind trial, 36 patients at term were given either 80 mg of propranolol or placebo (48). Fetal heart rate reaction to a controlled sound stimulus was then measured at 1, 2, and 3 hours. The heart rate reaction in the propranolol group was significantly depressed, compared with placebo, at all three time intervals.
The reactivity of nonstress tests (NSTs) was affected by propranolol in two hypertensive women in the 2nd and 3rd trimesters (49). One woman was taking 20 mg every 6 hours and the other 10 mg 3 times daily. Repeated NSTs were nonreactive in both women, but immediate follow-up contraction stress tests were negative. The NSTs became reactive 2 and 10 days, respectively, after propranolol was discontinued.
In summary, propranolol has been used during pregnancy for maternal and fetal indications. The drug is apparently not a teratogen, but fetal and neonatal toxicity may occur. A 1988 review on the use of b-blockers, including propranolol, during pregnancy concluded that these agents are relatively safe (50), but some b-blockers, including propranolol, may cause intrauterine growth retardation and reduced placental weight (e.g., see also Atenolol). Treatment beginning early in the 2nd trimester results in the greatest weight reductions. This toxicity has not been consistently demonstrated in other agents within this class, but the relatively few pharmacologic differences among the drugs suggests that the reduction in fetal and placental weights probably occurs with all at some point. The lack of toxicity documentation may reflect the number and type of patients studied, the duration of therapy, or the dosage used, rather then a true difference among b-blockers. Although growth retardation is a serious concern, the benefits of maternal therapy with b-blockers may, in some cases, outweigh the risks to the fetus and must be judged on a case-by-case basis.
Newborn infants of women consuming the drug near delivery should be closely observed during the first 2448 hours after birth for bradycardia, hypoglycemia, and other symptoms of b-blockade. Long-term effects of in utero exposure to b-blockers have not been studied but warrant evaluation.
[*Risk Factor D if used in 2nd or 3rd trimesters.]
Breast Feeding Summary
Propranolol is excreted into breast milk. Peak concentrations occur 23 hours after a dose (12,20,43,51). Milk levels have ranged from 4 to 64 ng/mL, with milk:plasma ratios of 0.21.5 (12,20,29,50). Although such adverse effects as respiratory depression, bradycardia, and hypoglycemia have not been reported, nursing infants exposed to propranolol in breast milk should be closely observed for these symptoms of b-blockade. Long-term effects of exposure to b-blockers from milk have not been studied but warrant evaluation. The American Academy of Pediatrics considers propranolol to be compatible with breast feeding (52).
- Jackson GL. Treatment of hyperthyroidism in pregnancy. Pa Med 1973;76:567.
- Langer A, Hung CT, McA’Nulty JA, Harrigan JT, Washington E. Adrenergic blockade: a new approach to hyperthyroidism during pregnancy. Obstet Gynecol 1974;44:1816.
- Bullock JL, Harris RE, Young R. Treatment of thyrotoxicosis during pregnancy with propranolol. Am J Obstet Gynecol 1975;121:2425.
- Lightner ES, Allen HD, Loughlin G. Neonatal hyperthyroidism and heart failure: a different approach. Am J Dis Child 1977;131:6870.
- Levy CA, Waite JH, Dickey R. Thyrotoxicosis and pregnancy. Use of preoperative propranolol for thyroidectomy. Am J Surg 1977;133:31921.
- Habib A, McCarthy JS. Effects on the neonate of propranolol administered during pregnancy. J Pediatr 1977;91:80811.
- Pruyn SC, Phelan JP, Buchanan GC. Long-term propranolol therapy in pregnancy: maternal and fetal outcome. Am J Obstet Gynecol 1979;135:4859.
- Leak D, Carroll JJ, Robinson DC, Ashworth EJ. Management of pheochromocytoma during pregnancy. Can Med Assoc J 1977;116:3715.
- Turner GM, Oakley CM, Dixon HG. Management of pregnancy complicated by hypertrophic obstructive cardiomyopathy. Br Med J 1968;4:2814.
- Barnes AB. Chronic propranolol administration during pregnancy: a case report. J Reprod Med 1970;5:7980.
- Schroeder JS, Harrison DC. Repeated cardioversion during pregnancy. Am J Cardiol 1971;27:4456.
- Levitan AA, Manion JC. Propranolol therapy during pregnancy and lactation. Am J Cardiol 1973;32:247.
- Reed RL, Cheney CB, Fearon RE, Hook R, Hehre FW. Propranolol therapy throughout pregnancy: a case report. Anesth Analg (Cleve) 1974;53:2148.
- Fiddler GI. Propranolol pregnancy. Lancet 1974;2:7223.
- Kolibash AE, Ruiz DE, Lewis RP. Idiopathic hypertrophic subaortic stenosis in pregnancy. Ann Intern Med 1975;82:7914.
- Cottrill CM, McAllister RG Jr, Gettes L, Noonan JA. Propranolol therapy during pregnancy, labor, and delivery: Evidence for transplacental drug transfer and impaired neonatal drug disposition. J Pediatr 1977;91:8124.
- Datta S, Kitzmiller JL, Ostheimer GW, Schoenbaum SC. Propranolol and parturition. Obstet Gynecol 1978;51:57781.
- Diaz JH, McDonald JS. Propranolol and induced labor: Anesthetic implications. Anesth Rev 1979;6:2932.
- Oakley GDG, McGarry K, Limb DG, Oakley CM. Management of pregnancy in patients with hypertrophic cardiomyopathy. Br Med J 1979;1:174950.
- Bauer JH, Pape B, Zajicek J, Groshong T. Propranolol in human plasma and breast milk. Am J Cardiol 1979;43:8602.
- Eibschitz I, Abinader EG, Klein A, Sharf M. Intrauterine diagnosis and control of fetal ventricular arrhythmia during labor. Am J Obstet Gynecol 1975;122:597600.
- Teuscher A, Boss E, Imhof P, Erb E, Stocker FP, Weber JW. Effect of propranolol on fetal tachycardia in diabetic pregnancy. Am J Cardiol 1978;42:3047.
- Gladstone GR, Hordof A, Gersony WM. Propranolol administration during pregnancy: Effects on the fetus. J Pediatr 1975;86:9624.
- Tcherdakoff PH, Colliard M, Berrard E, Kreft C, Dupry A, Bernaille JM. Propranolol in hypertension during pregnancy. Br Med J 1978;2:670.
- Lieberman BA, Stirrat GM, Cohen SL, Beard RW, Pinker GD, Belsey E. The possible adverse effect of propranolol on the fetus in pregnancies complicated by severe hypertension. Br J Obstet Gynaecol 1978;85:67883.
- Eliahou HE, Silverberg DS, Reisin E, Romen I, Mashiach S, Serr DM. Propranolol for the treatment of hypertension in pregnancy. Br J Obstet Gynaecol 1978;85:4316.
- Bott-Kanner G, Schweitzer A, Schoenfeld A, Joel-Cohen J, Rosenfeld JB. Treatment with propranolol and hydralazine throughout pregnancy in a hypertensive patient: a case report. Isr J Med Sci 1978;14:4668.
- Bott-Kanner G, Reisner SH, Rosenfeld JB. Propranolol and hydralazine in the management of essential hypertension in pregnancy. Br Obstet Gynaecol 1980;87:1104.
- Taylor EA, Turner P. Anti-hypertensive therapy with propranolol during pregnancy and lactation. Postgrad Med J 1981;57:42730.
- Serup J. Propranolol for the treatment of hypertension in pregnancy. Acta Med Scand 1979;206:333.
- Mitrani A, Oettinger M, Abinader EG, Sharf M, Klein A. Use of propranolol in dysfunctional labour. Br J Obstet Gynaecol 1975;82:6515.
- Amy JJ, Karim SMM. Intrauterine administration of 1-noradrenaline and propranolol during the second trimester of pregnancy. J Obstet Gynaecol Br Commonw 1974;81:7583.
- Product information. Inderal. Wyeth-Ayerst Laboratories, 1997.
- Smith MT, Livingstone I, Eadie MJ, Hooper WD, Triggs EJ. Metabolism of propranolol in the human maternal-placental-foetal unit. Eur J Clin Pharmacol 1983;24:72732.
- Erkkola R, Lammintausta R, Liukko P, Anttila M. Transfer of propranolol and sotalol across the human placenta. Acta Obstet Gynecol Scand 1982;61:314.
- Barden TP, Stander RW. Myometrial and cardiovascular effects of an adrenergic blocking drug in human pregnancy. Am J Obstet Gynecol 1968;101:919.
- Wansbrough H, Nakanishi H, Wood C. The effect of adrenergic receptor blocking drugs on the human fetus. J Obstet Gynaecol Br Commonw 1968;75:18998.
- Fylling P. Dexamethasone or propranolol blockade of induced increase in plasma progesterone in early human pregnancy. Acta Endocrinol (Copenh) 1973;72:56972.
- Smith MT, Livingstone I, Eadie MJ, Hooper WD, Triggs EJ. Chronic propranolol administration during pregnancy: maternal pharmacokinetics. Eur J Clin Pharmacol 1983;25:48190.
- O’Connor PC, Jick H, Hunter JR, Stergachis A, Madsen S. Propranolol and pregnancy outcome. Lancet 1981;2:1168.
- Caldroney RD. Beta-blockers in pregnancy. N Engl J Med 1982;306:810.
- Goodlin RC. Beta blocker in pregnancy-induced hypertension. Am J Obstet Gynecol 1982;143:237.
- Livingstone I, Craswell PW, Bevan EB, Smith MT, Eadie MJ. Propranolol in pregnancy: three year prospective study. Clin Exp Hypertens (B) 1983;2:34150.
- Duminy PC, Burger P du T. Fetal abnormality associated with the use of captopril during pregnancy. S Afr Med J 1981;60:805.
- Tunstall ME. The effect of propranolol on the onset of breathing at birth. Br J Anaesth 1969;41:792.
- Rubin PC. Beta-blockers in pregnancy. N Engl J Med 1981;305:13236.
- Redmond GP. Propranolol and fetal growth retardation. Semin Perinatol 1982;6:1427.
- Jensen OH. Fetal heart rate response to a controlled sound stimulus after propranolol administration to the mother. Acta Obstet Gynecol Scand 1984;63:199202.
- Margulis E, Binder D, Cohen AW. The effect of propranolol on the nonstress test. Am J Obstet Gynecol 1984;148:3401.
- Frishman WH, Chesner M. Beta-adrenergic blockers in pregnancy. Am Heart J 1988;115:14752.
- Karlberg B, Lundberg O, Aberg H. Excretion of propranolol in human breast milk. Acta Pharmacol Toxicol (Copenh) 1974;34:2224.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.