Fetal Risk Summary
No reports linking digitalis or the various digitalis glycosides with congenital defects have been located. Animal studies have failed to show a teratogenic effect (1).
Rapid passage to the fetus has been observed after digoxin and digitoxin (2,3,4,5,6,7,8 and 9). One group of investigators found that the amount of digitoxin recovered from the fetus was dependent on the length of gestation (2). In the late 1st trimester, only 0.05%0.10% of the injected dose was recovered from three fetuses. Digitoxin metabolites accounted for 0.18%0.33%. At 34 weeks of gestation, digitoxin recovery was 0.85% and metabolite recovery was 3.49% from one fetus. Average cord concentrations of digoxin in three reports were 50%, 81%, and 83% of the maternal serum (3,4,9). The highest fetal concentrations of digoxin in the second half of pregnancy were found in the heart (5). The fetal heart has only a limited binding capacity for digoxin in the first half of pregnancy (5). In animals, amniotic fluid acts as a reservoir for digoxin, but no data are available in humans after prolonged treatment (5). The pharmacokinetics of digoxin in pregnant women have been reported (10,11).
Digoxin has been used for both maternal and fetal indications (e.g., congestive heart failure and supraventricular tachycardia) during all stages of gestation without causing fetal harm (12,13,14,15,16,17,18,19,20,21,22,23,24 and 25). Direct administration of digoxin to the fetus by periodic IM injections has been used to treat supraventricular tachycardia when indirect therapy via the mother failed to control the arrhythmia (26).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 34 newborns had been exposed to digoxin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (2.9%) major birth defect was observed (one expected), an oral cleft. Although the number of exposures is small, these data are supportive of previous experience for a lack of association between the drug and congenital defects.
Fetal toxicity resulting in neonatal death has been reported after maternal overdose (27). The mother, in her 8th month of pregnancy, took an estimated 8.9 mg of digitoxin as a single dose. Delivery occurred 4 days later. The baby demonstrated digitalis cardiac effects until death at age 3 days from prolonged intrauterine anoxia.
In a series of 22 multiparous patients maintained on digitalis, spontaneous labor occurred more than 1 week earlier than in 64 matched controls (28). The first stage of labor in the treated patients averaged 4.3 hours vs. 8 hours in the control group. In contrast, others found no effect on duration of pregnancy or labor in 122 patients with heart disease (29).
Breast Feeding Summary
Digoxin is excreted into breast milk. Data for other cardiac glycosides have not been located. Digoxin milk:plasma ratios have varied from 0.60.9 (4,7,30,31). Although these amounts seem high, they represent very small amounts of digoxin due to significant maternal protein binding. No adverse effects in the nursing infant have been reported. The American Academy of Pediatrics considers digoxin to be compatible with breast feeding (32).
- Shepard TH. Catalog of Teratogenic Agents. 3rd ed. Baltimore, MD:Johns Hopkins University Press, 1980:1167.
- Okita GT, Plotz EF, Davis ME. Placental transfer of radioactive digitoxin in pregnant women and its fetal distribution. Circ Res 1956;4:37680.
- Rogers MC, Willserson JT, Goldblatt A, Smith TW. Serum digoxin concentrations in the human fetus, neonate and infant. N Engl J Med 1972;287:10103.
- Chan V, Tse TF, Wong V. Transfer of digoxin across the placenta and into breast milk. Br J Obstet Gynaecol 1978;85:6059.
- Saarikoski S. Placental transfer and fetal uptake of 3H-digoxin in humans. Br J Obstet Gynaecol 1976;83:87984.
- Allonen H, Kanto J, Lisalo E. The foeto-maternal distribution of digoxin in early human pregnancy. Acta Pharmacol Toxicol 1976;39:47780.
- Finley JP, Waxman MB, Wong PY, Lickrish GM. Digoxin excretion in human milk. J Pediatr 1979;94:33940.
- Soyka LF. Digoxin: placental transfer, effects on the fetus, and therapeutic use in the newborn. Clin Perinatol 1975;2:2335.
- Padeletti L, Porciani MC, Scimone G. Placental transfer of digoxin (beta-methyl-digoxin) in man. Int J Clin Pharmacol Biopharm 1979;17:823.
- Marzo A, Lo Cicero G, Brina A, Zuliani G, Ghirardi P, Pardi G. Preliminary data on the pharmacokinetics of digoxin in pregnancy. Boll Soc Ital Biol Sper 1980;56:21923.
- Luxford AME, Kellaway GSM. Pharmacokinetics of digoxin in pregnancy. Eur J Clin Pharmacol 1983;25:11721.
- Lingman G, Ohrlander S, Ohlin P. Intrauterine digoxin treatment of fetal paroxysmal tachycardia: case report. Br J Obstet Gynaecol 1980;87:3402.
- Kerenyi TD, Gleicher N, Meller J, Brown E, Steinfeld L, Chitkara U, Raucher H. Transplacental cardioversion of intrauterine supraventricular tachycardia with digitalis. Lancet 1980;2:3934.
- Harrigan JT, Kangos JJ, Sikka A, Spisso KR, Natarajan N, Rosenfeld D, Leiman S, Korn D. Successful treatment of fetal congestive heart failure secondary to tachycardia. N Engl J Med 1981;304:1527-9.
- Diro M, Beydoun SN, Jaramillo B, O'Sullivan MJ, Kieval J. Successful pregnancy in a woman with a left ventricular cardiac aneurysm: a case report. J Reprod Med 1983;28:55963.
- Heaton FC, Vaughan R. Intrauterine supraventricular tachycardia: cardioversion with maternal digoxin. Obstet Gynecol 1982;60:74952.
- Simpson PC, Trudinger BJ, Walker A, Baird PJ. The intrauterine treatment of fetal cardiac failure in a twin pregnancy with an acardiac, acephalic monster. Am J Obstet Gynecol 1983;147:8424.
- Spinnato JA, Shaver DC, Flinn GS, Sibai BM, Watson DL, Marin-Garcia J. Fetal supraventricular tachycardia: in utero therapy with digoxin and quinidine. Obstet Gynecol 1984;64:7305.
- Bortolotti U, Milano A, Mazzucco A, Valfre C, Russo R, Valente M, Schivazappa L, Thiene G, Gallucci V. Pregnancy in patients with a porcine valve bioprosthesis. Am J Cardiol 1982;50:10514.
- Rotmensch HH, Rotmensch S, Elkayam U. Management of cardiac arrhythmias during pregnancy: current concepts. Drugs 1987;33:62333.
- Tamari I, Eldar M, Rabinowitz B, Neufeld HN. Medical treatment of cardiovascular disorders during pregnancy. Am Heart J 1982;104:135763.
- Dumesic DA, Silverman NH, Tobias S, Golbus MS. Transplacental cardioversion of fetal supraventricular tachycardia with procainamide. N Engl J Med 1982;307:112831.
- Gleicher N, Elkayam U. Cardiac problems in pregnancy. II. Fetal aspects: advances in intrauterine diagnosis and therapy. JAMA 1984;252:7880.
- Golichowski AM, Caldwell R, Hartsough A, Peleg D. Pharmacologic cardioversion of intrauterine supraventricular tachycardia. A case report. J Reprod Med 1985;30:13944.
- Reece EA, Romero R, Santulli T, Kleinman CS, Hobbins JC. In utero diagnosis and management of fetal tachypnea. A case report. J Reprod Med 1985;30:2214.
- Weiner CP, Thompson MIB. Direct treatment of fetal supraventricular tachycardia after failed transplacental therapy. Am J Obstet Gynecol 1988;158:5703.
- Sherman JL Jr, Locke RV. Transplacental neonatal digitalis intoxication. Am J Cardiol 1960;6:8347.
- Weaver JB, Pearson JF. Influence of digitalis on time of onset and duration of labour in women with cardiac disease. Br Med J 1973;3:51920.
- Ho PC, Chen TY, Wong V. The effect of maternal cardiac disease and digoxin administration on labour, fetal weight and maturity at birth. Aust NZ J Obstet Gynaecol 1980;20:247.
- Levy M, Granit L, Laufer N. Excretion of drugs in human milk. N Engl J Med 1977;297:789.
- Loughnan PM. Digoxin excretion in human breast milk. J Pediatr 1978;92:101920.
Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.