Phenytoin Pregnancy and Breastfeeding Warnings
Phenytoin Pregnancy Warnings
Features of the fetal hydantoin syndrome include both craniofacial and distal limb abnormalities. The specific facial features include a broad nasal bridge, wide fontanel, epicanthic folds, short upturned nose, hypertelorism, ocular abnormalities, prominent and low set ears, wide mouth, cleft lip or palate, prominent lips and variations in the size and shape of the head. The specific distal limb abnormalities include hypoplasia of the distal phalanges, fingerlike thumbs, small or absent nails, and altered palmar creases. Recent studies have suggested that in utero exposure to phenytoin may result in significantly lower IQ scores. Some clinicians have recommended that the need for anticonvulsant therapy be reevaluated prior to pregnancy if possible. If a need is clearly present, consideration may be given to the use of alternative anticonvulsants (such as carbamazepine) which may pose a smaller risk. If phenytoin therapy is deemed necessary, close observation for clinical and laboratory evidence of altered phenytoin effect is indicated throughout the course of pregnancy. Pregnancy results in a number of changes in the pharmacokinetic disposition of phenytoin. The plasma clearance is increased (with a peak just before or in the first weeks after delivery). The plasma protein binding is decreased. Some of the changes in the pharmacokinetic disposition of phenytoin may be related to increases in the hepatic metabolism of the drug. Some women who must take phenytoin during pregnancy may require dose increases in order to maintain seizure control. To provide information regarding the effects of in utero exposure to phenytoin, physicians are advised to recommend that pregnant patients taking phenytoin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
Phenytoin has been assigned to pregnancy category D by the FDA. An increased risk of congenital malformations and other adverse developmental outcomes have been associated with the use of anticonvulsant agents (including phenytoin) in epileptic women during pregnancy. Increased frequencies of major malformations (including orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or 2 to 3 fold higher than that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed in utero to phenytoin. This drug condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Women who are or may become pregnant while taking phenytoin should be apprised of the potential harm to the fetus. Phenytoin should only be given during pregnancy when there are no alternatives and benefit outweighs risk.
Phenytoin Breastfeeding Warnings
Phenytoin is excreted into human milk in small amounts. Typical doses given to a nursing mother would be expected to result in very small infant doses (less than 5% of a typical dose for most infants). Breast-feeding is considered contraindicated by the manufacturer. The American Academy of Pediatrics classifies phenytoin as a drug which is "usually compatible with breast-feeding". The Academy notes one case of methemoglobinemia as a cause of possible concern.
References for pregnancy information
- Monson RR, Rosenberg L, Hartz SC, et al "Diphenylhydantoin and selected congenital malformations." N Engl J Med 289 (1973): 1049-52
- Eadie MJ, McKinnon GE, Dickinson RG, et al "Phenytoin metabolism during pregnancy." Eur J Clin Pharmacol 43 (1992): 389-92
- Page RL "Treatment of arrhythmias during pregnancy." Am Heart J 130 (1995): 871-6
- Scolnik D "Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy." JAMA 271 (1994): 767-70
- Paulson GW, Paulson RB "Teratogenic effects of anticonvulsants." Arch Neurol 38 (1981): 140-3
- Dean M, Stock B, Patterson RJ, Levy G "Serum protein binding of drugs during and after pregnancy in humans." Clin Pharmacol Ther 28 (1980): 253-61
- Knott C, Williams CP, Reynolds F "Phenytoin kinetics during pregnancy and the puerperium." Br J Obstet Gynaecol 93 (1986): 1030-7
- Tomson T, Lindbom U, Ekqvist B, Sundqvist A "Disposition of carbamazepine and phenytoin in pregnancy." Epilepsia 35 (1994): 131-5
- Scolnik D, Nulman I, Rovet J, Gladstone D, Czuchta D, Gardner HA, Gladstone R, Ashby P, Weksberg R, Einarson T, Koren G "Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy." JAMA 271 (1994): 767-70
- Koren G, Pastuszak A, Ito S "Drugs in pregnancy." N Engl J Med 338 (1998): 1128-37
- Kochenour NK, Emery MG, Sawchuk RJ "Phenytoin metabolism in pregnancy." Obstet Gynecol 56 (1980): 577-82
- Waters CH, Belai Y, Gott PS, Shen P, Degiorgio CM "Outcomes of pregnancy associated with antiepileptic drugs." Arch Neurol 51 (1994): 250-3
- Jick SS, Terris BZ "Anticonvulsants and congenital malformations." Pharmacotherapy 17 (1997): 561-4
- Tomson T, Lindbom U, Ekqvist B, Sundqvist A "Epilepsy and pregnancy - a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin." Epilepsia 35 (1994): 122-30
- "Teratogenic risks of antiepileptic drugs." Br Med J 283 (1981): 515-6
- Lander CM, Smith MT, Chalk JB, et al "Bioavailability and pharmacokinetics of phenytoin during pregnancy." Eur J Clin Pharmacol 27 (1984): 105-10
- Dam M, Christiansen J, Munck O, Mygind KI "Antiepileptic drugs: metabolism in pregnancy." Clin Pharmacokinet 4 (1979): 53-62
References for breastfeeding information
- Roberts RJ, Blumer JL, Gorman RL, et al "American Academy of Pediatrics Committee on Drugs: Transfer of drugs and other chemicals into human milk." Pediatrics 84 (1989): 924-36
- Steen B, Rane A, Lonnerholm G, Falk O, Elwin CE, Sjoqvist F "Phenytoin excretion in human breast milk and plasma levels in nursed infants." Ther Drug Monit 4 (1982): 331-4
- Committee on Drugs, 1992 to 1993 "The transfer of drugs and other chemicals into human milk." Pediatrics 93 (1994): 137-50
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