Antiarrhythmic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
The limited human pregnancy experience includes only one case in which flecainide was used in the 1st trimester. Although the animal data suggest moderate risk, the human data are too limited to allow a complete assessment of risk to the embryo. However, the fetal risk from treatment of refractory fetal arrhythmias appears to be low.
FETAL RISK SUMMARY
Flecainide is an antiarrhythmic agent that is structurally related to encainide and procainamide. In one breed of rabbits, flecainide produced dose-related teratogenicity and embryotoxicity at approximately four times the usual human dose (1). Structural defects observed were club paws, sternebrae and vertebrae abnormalities, and pale hearts with contracted ventricular septum. Similar toxic effects and malformations were not observed in a second breed of rabbits, or in mice and rats, but dose-related delayed sternebral and vertebral ossification was observed in rat fetuses (1).
Two 1988 reports of human use of flecainide during pregnancy may have described a single incidence of exposure to the drug (2,3). IV flecainide was given to a pregnant woman at 30 weeks’ gestation for persistent fetal supraventricular tachycardia resistant to digoxin (2,3). The fetal heart rate pattern quickly converted to a sinus rhythm and the mother was maintained on oral flecainide, 100 mg 3 times daily, until delivery was induced at 38 weeks’ gestation. The 3450-g female infant had no cardiac problems during the 10 days of observation. Flecainide concentrations in the cord blood and maternal serum at delivery 5 hours after the last dose were 533 and 833 ng/mL, respectively, a ratio of 0.63 (2).
Flecainide 100 mg twice daily, combined with the β-blocker sotalol, was used throughout gestation in one woman for the treatment of ventricular tachycardia and polymorphous ventricular premature complexes associated with an aneurysm of the left ventricle (4). A cesarean section was performed at approximately 37 weeks’ gestation. Flecainide concentrations in umbilical cord and plasma samples at delivery, 11 hours after the last dose, were 0.394 and 0.455 mcg/mL, respectively, a ratio of 0.86. No adverse effects, including bradycardia, were observed in the fetus or newborn, who was growing normally at 1 year of age.
A 22-year-old woman at approximately 31 weeks’ gestation was treated with flecainide, 100 mg every 8 hours, for fetal arrhythmia associated with fetal hydrops unresponsive to therapeutic levels of digoxin (5). Therapeutic levels of flecainide were measured in the mother over the next 4 days, during which time the fetal heart rate (FHR) converted to a normal sinus rhythm of 120 beats/minute. Approximately 2 days later, a nonreactive nonstress test was documented and flecainide and digoxin were discontinued, but the FHR returned to pretreatment levels within 36 hours. Flecainide was restarted at 150 mg every 12 hours, and within 30 minutes of the first dose, the FHR converted to normal. This dose was continued for 4 days, during which time the FHR remained normal at 120 beats/minute, but with a nonreactive nonstress test. Gradual reduction of the dose to 50 mg every 12 hours maintained a normal FHR with return of a reactive nonstress test and normal beat-to-beat variability. Fetal ascites was completely resolved after 10 days of therapy. A normal 3480-g infant, Apgar scores of 9 and 10 at 1 and 5 minutes, respectively, was delivered vaginally at 41 weeks’ gestation. Maternal and fetal serum trough levels at delivery were 0.2 and 0.1 mcg/mL, respectively (5). A postnatal echocardiogram performed on the newborn was normal.
A 1991 report described the experimental use of flecainide, 300–400 mg/day orally, in 14 women at a mean gestational age of 31 weeks (range 23–36 weeks) to treat fetal hydrops and ascites secondary to supraventricular tachycardias or atrial flutter (6). The duration of treatment ranged from 2 days to 5 weeks. Although specific data were not given, the cord:maternal plasma ratio at birth was approximately 0.80, and all fetuses had flecainide concentrations within the usual therapeutic range (400–800 mcg/L). Twelve of the fourteen newborns were alive and well at the time of the report, and one infant, not under treatment at the time, died of sudden infant death syndrome at 4.5 months of age. One intrauterine death occurred after 3 days of therapy and may have been caused by either a flecainide-induced arrhythmia or fetal blood sampling (6).
A woman in the 3rd trimester was initially treated with flecainide 100 mg orally twice daily, then decreased to 50 mg twice daily, for fetal tachycardia that resolved within 4 days (7). The fetal ascites and polyhydramnios also resolved around this time. Approximately 6 weeks after treatment was begun, she gave birth to a 3320-g, male infant. The cord blood:maternal serum ratio of the drug was 0.97 (235.4/241.2 ng/mL), but the flecainide concentration in the amniotic fluid was 6426.5 ng/mL, about 27 times the level in the fetus.
Other publications have described the successful use of flecainide for the treatment of fetal tachycardia (8–14), and in one of these, flecainide and digoxin were considered the drugs of choice for this condition (8). However, flecainide is superior to digoxin for the treatment of tachycardia in hydropic fetuses (9,10).
The loss of FHR variability and accelerations was described in a case of supraventricular tachycardia treated with 300 mg/day of flecainide during the 3rd trimester (11). The heart rate of the 3690-g male infant returned to a reactive pattern 5 days after delivery. One day later, the infant’s serum concentration of flecainide was below the detection level. A general review of drug therapy used for the treatment of fetal arrhythmias was published in 1994 (12). Flecainide has also been used to treat new-onset maternal ventricular tachycardia presenting during the 3rd trimester (15).
Conjugated hyperbilirubinemia thought to be caused by flecainide was described in a 1995 reference (16). Flecainide, 150 mg twice daily, was started at about 28 weeks’ gestation for the treatment of fetal supraventricular tachycardia after a trial of digoxin and adenosine had failed to halt the arrhythmia. Other fetal complications, in addition to the arrhythmia, were polyhydramnios, ascites, pericardial effusion, cardiomegaly, and tricuspid and mitral valve regurgitation. Successful conversion to a sinus rhythm occurred within 24 hours. The mother discontinued the therapy 1 week later, and a second course of flecainide was started when the fetal tachycardia and ascites reoccurred. The 2843-g, male infant, delivered vaginally at 36 weeks, developed transient conjugated hyperbilirubinemia within a few days of birth. The authors attributed the hyperbilirubinemia to flecainide because no other cause of the toxicity could be found and the drug is known to produce a similar condition in adults. Follow-up of the infant at 2 months of age revealed that the liver toxicity had resolved and, at 28 months of age, the child was continuing to do well (16).
BREASTFEEDING SUMMARY
Flecainide is concentrated in breast milk (4,17), but no reports of infant exposure to the drug from nursing have been located. A woman was treated throughout gestation and in the postpartum period with flecainide, 100 mg twice daily, and sotalol (see Sotalol) (4). Simultaneous samples of milk and plasma were drawn 3 hours after the second daily dose on the 5th and 7th days postpartum. Flecainide concentrations on day 5 were 0.891 and 0.567 mcg/mL, respectively, and 1.093 and 0.500 mcg/mL, respectively, on day 7. Milk:plasma ratios were 1.57 and 2.18, respectively. The infant was not breastfed (4).
Eleven healthy women volunteers who intended not to breastfeed were given flecainide 100 mg orally every 12 hours for 5.5 days starting on postpartum day 1 (17). The breasts were emptied by a mechanical breast suction pump every 3–4 hours during the study. Peak milk levels of the drug occurred at 3–6 hours after a dose with a mean half-life of elimination of 14.7 hours. The highest daily average concentration of the drug ranged from 270 to 1529 ng/mL, with milk:plasma ratios on days 2, 3, 4, and 5 of 3.7, 3.2, 3.5, and 2.6, respectively. An estimated maximum steady-state concentration of flecainide in an infant consuming approximately 700 mL of milk per day (assumed to be the total milk production) was 62 ng/mL, an apparently nontoxic level. Based on this, the investigators concluded that the risk of adverse effects in a nursing infant whose mother was consuming flecainide was minimal (17). The American Academy of Pediatrics classifies flecainide as compatible with breastfeeding (18).
References
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