Quinidine in pregnancy and breastfeeding

Quinidine]]>

Risk Factor: CM
Class: Cardiovascular drugs/ Cardiac drugs

Contents of this page:
Fetal Risk Summary
Breast Feeding Summary
References

Fetal Risk Summary

No reports linking the use of quinidine with congenital defects have been located. Animal reproduction studies have apparently not been conducted with quinidine.

Quinidine has been in use as an antiarrhythmic drug for more than 100 years (1) and in pregnancy, at least back to the 1920s (2,3,4,5,6,7 and 8). Eighth cranial nerve damage has been associated with high doses of the optical isomer, quinine, but not with quinidine (4). Neonatal thrombocytopenia has been reported after maternal use of quinidine (5).

Quinidine crosses the placenta and achieves fetal serum levels similar to maternal levels (1,6,7 and 8). In a 1979 case, a woman taking 600 mg every 8 hours plus an additional dose of 300 mg (2100 mg/day) had serum and amniotic fluid levels of 5.8 and 10.6 g/mL, respectively, 10 days before term (6). Three days later, 10 hours after the last dose, a healthy male infant was delivered by elective cesarean section. Quinidine concentrations in the serum, cord blood, and amniotic fluid were 3.4, 2.8, and 9.3 g/mL, respectively (6). The cord blood:serum ratio was 0.82. The cord blood levels were greater than those measured in three other reports (1,7,8).

In a 1984 study, three women maintained on quinidine, 300 mg every 6 hours, and digoxin had serum levels of quinidine at delivery ranging from 0.7 to 2.1 g/mL (7). A quinidine level in one amniotic fluid sample was 0.9 g/mL, whereas cord blood levels ranged from
In a 1985 report, a woman taking quinidine, 400 mg every 6 hours, plus digoxin and propranolol was electively delivered by cesarean section 18 hours after the last dose (8). The quinidine concentration in the cord blood was 0.8 g/mL.

One case involved a woman in whom quinidine doses were escalated during a 6-day interval from 300 mg every 6 hours to 1500 mg every 6 hours (1). On day 8, the dosage was reduced to 1500 mg every 8 hours, then to 1200 mg every 8 hours on day 9, and then stopped on day 10. Amniotic fluid levels of quinidine and the metabolite, 3-hydroxyquinidine, on day 10 were 2.2 and 9.7 g/mL, respectively. At delivery 2 days later, cord blood contained 0.5 g/mL of quinidine and 0.7 g/mL of the metabolite.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 17 newborns had been exposed to quinidine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (5.9%) major birth defect was observed (one expected). No anomalies were observed in six defect categories (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.

The drug has been used in combination with digoxin to treat fetal supraventricular and reciprocating atrioventricular tachycardia (7,8). The authors of one of these reports consider quinidine to be the drug of choice after digoxin for the treatment of persistent fetal tachyrhythmias (8). A 1990 report described an unsuccessful attempt of maternal transplacental cardioversion with quinidine for a rare case of fetal ventricular tachycardia associated with nonimmune hydrops fetalis at 30 weeks’ gestation (9). A dose of 200 mg quinidine 4 times daily was given for 3 days before worsening preeclampsia with breech presentation required delivery by cesarean section. The newborn died 5 hours after birth.

A 33-year-old woman with new-onset, sustained ventricular tachycardia was treated with metoprolol, 50 mg twice daily, at 22 weeks’ gestation (10). Because of recurrent palpitations, quinidine (dose not specified) was added to the regimen at 26 weeks’ gestation, and with the attainment of a therapeutic quinidine level, the combination was successful in controlling the ectopic beats. Combination therapy was continued until term when a healthy, growth-retarded, 4-lb 15-oz (approximately 2240-g) infant was delivered. Intrauterine growth retardation apparently developed after maternal combination therapy was initiated, but a discussion of its cause was not included in the Reference, nor were maternal blood pressures given.

A mother treated with quinidine for a fetal supraventricular tachycardia developed symptoms of quinidine toxicity consisting of severe nausea and vomiting, diarrhea, light-headedness, and tinnitus (1). Electrocardiographic changes were consistent with quinidine toxicity. Her dosage had been increased during an interval of 6 days in a manner described above, producing serum quinidine levels of 1.43.3 g/mL (therapeutic range in the author’s laboratory was 1.55.0 g/mL) (1). At the highest dose, her serum level was 2.3 g/mL. Levels of the metabolite, 3-hydroxyquinidine, rose from 1.1 to 6.8 g/mL during the 6-day interval, eventually reaching 9.7 g/mL 1 day after quinidine was discontinued. The 3-hydroxyquinidine:quinidine ratio varied from 0.8 (on day 2) to 3.7 (on day 10). These ratios were much higher than those observed in previously reported patients (1). Because the fetal heart rate continued to be elevated, with only occasional reductions to 120130 beats/minute, and fetal lung maturity had been demonstrated, labor was induced, resulting in the delivery of a 3540-g infant with hydrops fetalis. The infant required pharmacologic therapy to control the supraventricular tachycardia. The maternal toxicity was attributed to the elevated levels of 3-hydroxyquinidine, because concentrations of quinidine were in the low to mid-therapeutic range (1).

In an in vitro study using plasma from 16 normal pregnant women, quinidine concentrations between 0.5 and 5.0 g/mL were shown to inhibit plasma pseudocholinesterase activity (11). Inhibition varied from 29% (0.5 g/mL) to 71% (5.0 g/mL). Pseudocholinesterase is responsible for the metabolism of succinylcholine and ester-type local anesthetics (e.g., procaine, tetracaine, cocaine, and chloroprocaine) (11). The quinidine-induced inhibition of this enzyme, which is already significantly decreased by pregnancy itself, could potentially result in toxicity if these agents were used in a mother maintained on quinidine.

A 21-year-old woman in premature labor at 31 weeks’ gestation was treated with IV quinidine and exchange transfusion for severe, apparently chloroquine-resistant, malaria (12). Parasitemia with Plasmodium falciparum greater than 12% was shown on blood smears before treatment and then fell to 1% after treatment. Initial therapy with 1 g oral chloroquine was unsuccessful and approximately 12 hours later, she was given an IV loading dose of quinidine, 10 mg base/kg during 2 hours, followed by a continuous infusion of 0.02 mg/kg/min and exchange transfusion. No potentiation of labor was observed during quinidine therapy, although the mother was receiving IV magnesium sulfate for tocolysis. Because of fetal distress, thought to be caused by uteroplacental insufficiency as a result of maternal parasitemia or fever, a cesarean section was performed to deliver a 1570-g male infant with Apgar scores of 5 and 7 at 1 and 5 minutes, respectively. Except for respiratory difficulty during the first 6 hours, the infant had an uneventful hospital course, including a negative blood smear for malaria.

The use of quinidine during pregnancy has been classified in reviews of cardiovascular drugs as relatively safe for the fetus (13,14,15 and 16). In therapeutic doses, the oxytocic properties of quinidine have been rarely observed, but high doses can produce this effect and may result in abortion (15,17).

Breast Feeding Summary

Quinidine is excreted into breast milk (6). A woman taking 600 mg every 8 hours had milk and serum concentrations determined on the 5th postpartum day, 3 hours after a dose (6). Levels in the two samples were 6.4 and 9.0 g/mL, respectively, a milk:serum ratio of 0.71. A quinidine level of 8.2 g/mL was noted in a milk sample on the preceding day (time relationship to the dose not specified) but a simultaneous serum concentration was not determined. The infant in this case did not breast-feed. The American Academy of Pediatrics considers quinidine to be compatible with breast feeding (18).

References

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  1. Killeen AA, Bowers LD. Fetal supraventricular tachycardia treated with high-dose quinidine: toxicity associated with marked elevation of the metabolite, 3(S)-3-hydroxyquinidine. Obstet Gynecol 1987;70:4459.
  2. Meyer J, Lackner JE, Schochet SS. Paroxysmal tachycardia in pregnancy. JAMA 1930;94:19014.
  3. McMillan TM, Bellet S. Ventricular paroxysmal tachycardia: report of a case in a pregnant girl of sixteen years with an apparently normal heart. Am Heart J 1931;7:708.
  4. Mendelson CL. Disorders of the heartbeat during pregnancy. Am J Obstet Gynecol 1956;72:12681301.
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  8. Guntheroth WG, Cyr DR, Mack LA, Benedetti T, Lenke RR, Petty CN. Hydrops from reciprocating atrioventricular tachycardia in a 27-week fetus requiring quinidine for conversion. Obstet Gynecol 1985;66(Suppl):29S33S.
  9. Sherer DM, Sadovksy E, Menashe M, Mordel N, Rein AJJT. Fetal ventricular tachycardia associated with nonimmunologic hydrops fetalis: a case report. J Reprod Med 1990;35:2924.
  10. Braverman AC, Bromely BS, Rutherford JD. New onset ventricular tachycardia during pregnancy. Int J Cardiol 1991;33:40912.
  11. Kambam JR, Franks JJ, Smith BE. Inhibitory effect of quinidine on plasma pseudocholinesterase activity in pregnant women. Am J Obstet Gynecol 1987;157:8979.
  12. Wong RD, Murthy ARK, Mathisen GE, Glover N, Thornton PJ. Treatment of severe Falciparum malaria during pregnancy with quinidine and exchange transfusion. Am J Med 1992;92:5612.
  13. Rotmensch HH, Elkayam U, Frishman W. Antiarrhythmic drug therapy during pregnancy. Ann Intern Med 1983;98:48797.
  14. Tamari I, Eldar M, Rabinowitz B, Neufeld HN. Medical treatment of cardiovascular disorders during pregnancy. Am Heart J 1982;104:135763.
  15. Rotmensch HH, Rotmensch S, Elkayam U. Management of cardiac arrhythmias during pregnancy: current concepts. Drugs 1987;33:62333.
  16. Ward RM. Maternal drug therapy for fetal disorders. Semin Perinatol 1992;16:1220.
  17. Bigger JT, Hoffman BF. Antiarrhythmic drugs. In Gilman AG, Goodman LS, Gilman A, eds. The Pharmacological Basis of Therapeutics. 6th ed. New York, NY: Macmillan, 1980:768.
  18. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.

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