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Does vitamin K prophylaxis prevent bleeding in neonates exposed to enzyme-inducing antiepileptic drugs in utero?
Massoud Rezvani, MD, ABP, Gideon Koren, MD, FRCPC
One of my epileptic patients takes carbamazepine. She is 36 weeks pregnant and has asked me whether she should start vitamin K to prevent neonatal bleeding. Does current evidence support this practice?
Recent evidence does not support the notion that newborns of women treated with enzyme-inducing anticonvulsant drugs are at increased risk of hemorrhagic disease. Antenatal vitamin K can be prescribed on an individualized basis in certain circumstances, such as imminent premature delivery.
L’une de mes patientes qui est épileptique prend de la carbamazépine. Elle en est à sa 36e semaine de grossesse et m’a demandé si elle devrait commencer à prendre de la vitamine K pour prévenir une hémorragie néonatale. Existe-t-il actuellement des données scientifiques justifiant une telle pratique?
Les données scientifiques récentes ne confirment pas la notion que les nouveau-nés de femmes traitées avec des médicaments anticonvulsivants par induction enzymatique courent un risque accru de troubles hémorragiques. On peut prescrire de la vitamine K sur une base individualisée, dans certaines circonstances, comme un accouchement prématuré imminent.
Epilepsy is the most common major neurologic complication of pregnancy. The prevalence of epilepsy in the general population is between 0.6% and 1%; about 0.5% of all pregnant women have epilepsy.1 Several problems related to both mothers and babies should be considered. One concern is neonatal bleeding secondary to in utero exposure to enzyme-inducing antiepileptic drugs (AEDs). Therapy with enzyme-inducing AEDs has been thought to cause vitamin K deficiency in neonates born to women with epilepsy. More than 40 reports associate neonatal bleeding with maternal anticonvulsant therapy.2-8 The mechanism by which AEDs could cause bleeding in newborns involves alterations in vitamin K metabolism.2,9
Enzyme-inducing AEDs, such as phenobarbital, phenytoin, and carbamazepine, cross the placenta and induce hepatic microsomal enzymes in the fetal liver. These enzymes might induce degradation of vitamin K. Prenatal administration of oral vitamin K to pregnant women with epilepsy taking AEDs is aimed at preventing hemorrhagic disease in newborns during their first day of life. Recommendations to give epileptic mothers vitamin K during the last month of pregnancy have been based on case reports suggesting the offspring of mothers using enzyme-inducing AEDs have vitamin K deficiency.2,9-11 Administration of vitamin K to mothers is in addition to the prophylactic vitamin K given to all infants.12,13 An estimated 24% to 40% of women with epilepsy receive vitamin K prophylaxis during the last month of pregnancy.14,15
Evidence-based reports do not support this practice, however. Kaaja et al16 followed 667 offspring of 452 women using enzyme-inducing AEDs (mostly carbamazepine). Among the 667 fetuses, 528 (78.7%) were exposed to monotherapy, and 142 (21.3%) were exposed to polytherapy. Eighty-five fetuses (12.7%) were also exposed to one or more drugs that were not enzyme inducers (valproate, clonazepam, diazepam, or clobazam). Five infants in this study developed intracranial hemorrhage; 3 of the 5 were born before 34 weeks’ gestation. Another 2 infants had complications known to predispose them to intracranial bleeding, such as intrauterine asphyxia, sepsis, fetal alcohol syndrome, or placental disease. Control subjects were 1324 nonepileptic pregnant women with 1334 neonates matched for maternal age, parity, number of fetuses, and delivery date. None of these mothers received vitamin K during pregnancy. Interestingly, there were also only 5 neonates with bleeding complications among the offspring of these control subjects.
Although this cohort study does not support routine use of antenatal vitamin K, prophylaxis might be worth considering when premature delivery is imminent in women using AEDs.17 There is an obvious need for more studies on the risk of bleeding in newborns exposed to enzyme-inducing AEDs, comparing them with unexposed controls. This clinical question highlights the fact that practice guidelines are sometimes not founded on solid evidence.
- Martin PJ, Millac PA. Pregnancy, epilepsy, management and outcome: a 10-year perspective. Seizure 1993;2:277-80.
- Mountain KR, Hirsh J, Gallus AS. Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy. Lancet 1970;1:265-8.
- Bleyer WA, Skinner AL. Fatal neonatal hemorrhage after maternal anticonvulsant therapy. JAMA 1976;235:626-7.
- Traggis DG, Maunz DL, Baroudy R. Splenic hemorrhage in a neonate of a mother on anticonvulsant therapy. J Pediatr Surg 1984;19:598-9.
- Moslet U, Hansen ES. A review of vitamin K, epilepsy and pregnancy. Acta Neurol Scand 1992;85:39-43.
- Van Creveld S. Nouveaux aspects de la maladie hemorragique du nouveau-né. Arch Fr Pediatr 1958;15(6):721-35.
- Srinivasan G, Seeler RA, Tiruvury A, Pildes RS. Maternal anticonvulsant therapy and hemorrhagic disease of the newborn. Obstet Gynecol 1982;59:250-2.
- Laosombat V. Hemorrhagic disease of the newborn after maternal anticonvulsant therapy: a case report and literature review. J Med Assoc Thai 1988;71:643-8.
- Cornelissen M, Steegers-Theunissen R, Kollee L, Eskes T, Vogels-Mentink G, Motohara K, et al. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol 1993;168(3 Pt 1):923-8.
- Thorp JA, Gaston L, Caspers DR, Pal ML. Current concepts and controversies in the use of vitamin K. Drugs 1995;49:376-87.
- Howe AM, Oakes DJ, Woodman PDC, Webster WS. Prothrombin and PIVKA-II levels in cord blood from newborns exposed to anticonvulsants during pregnancy. Epilepsia 1999;40:980-4.
- Pedley TA. The epilepsies. In: Goldman L, Bennett JC, editors. Cecil textbook of medicine. 21st ed. Philadelphia, Pa: Saunders; 2000. p. 2151-63.
- Quality standards subcommittee of the American Academy of Neurology. Practice parameter. Management issues for women with epilepsy [summary statement]. Neurology 1998;51:944-8.
- Russell AJ, Macpherson H, Cairnie V, Brodie MJ. The care of pregnant women with epilepsy: a survey of obstetricians in Scotland. Seizure 1996;5:271-7.
- Seale CG, Morrell MJ, Nelson L, Druzin ML. Analysis of prenatal and gestational care given to women with epilepsy. Neurology 1998;51:1039-45.
- Kaaja E, Kaaja R, Matila R, Hiilesman V. Enzyme-inducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate. Neurology 2002;58:549-53.
- Thorp JA, Ferrette-Smith D, Gaston LA, Johanson J, Yeast JD, Meyer B. Combined antenatal vitamin K and phenobarbital therapy for preventing intracranial hemorrhage in newborns less than 34 weeks’ gestation. Obstet Gynecol 1995;86:1-8.
Published Motherisk Updates are available on the College of Family Physicians of Canada website (www.cfpc.ca)
Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto, Ont. Dr Rezvani is a member and Dr Koren is Director of the Motherisk Program. Dr Koren is supported by the Research Leadership for Better Pharmacotherapy during Pregnancy and Lactation and, in part, by a grant from the Canadian Institutes of Health Research. He holds the Ivey Chair in Molecular Toxicology at the University of Western Ontario in London.