Abstract
An increased risk of seizures during and immediately after labour has been observed in epileptic women, and it is recognized that serum levels of antiepileptic drugs may decrease in pregnancy. Several studies have suggested that total valproate levels fall, but that free fractions increase during pregnancy. Recent findings suggest that the actual metabolism of valproate is not altered by pregnancy and that the changes of the plasma clearance are due primarily to decreased protein binding. The levels of free drug will not change significantly as pregnancy advances. However, dose reduction after delivery may be necessary to avoid toxicity. Valproate and its metabolites undergo placental transfer. In the foetus the plasma level of valproate and the protein binding are higher than in maternal plasma, and the halflife of valproate following placental transfer is considerably longer than in adults. Only small amounts of valproate appear in breast milk and those are not likely to cause any problems. During pregnancy and the first month after delivery preferably both total and free valproate serum levels should be closely monitored to determine the lowest effective dose.
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Schmidt D, Beck-Mannagetta G, Janz D, Koch S. The effect of pregnancy on the course of epilepsy: a prospective study. In: Janz D, Bossi L, Dam M, Helge H, Richens A, Schmidt D, eds. Epilepsy, pregnancy, and the child. New York: Raven Press, 1982:39–49.
Yerby M. Problems and management of the pregnant woman with epilepsy. Epilepsia 1987;28 Suppl 3:S29–37.
Philbert A, Dam M. Antiepileptic drug disposition during pregnancy: review of the litterature. In: Janz D, Bossi L, Dam M, Helge H, Richens A, Schmidt D, eds. Epilepsy, pregnancy, and the child. New York: Raven Press, 1982:109–14.
Levy RH, Yerby MS. Effects of pregnancy on antiepileptic drug utilization. Epilepsia 1985;26 Suppl 1:S52–7.
Robert E. Valproic acid and spina bifida: a preliminary report — France. MMRR 1982;31:565–6.
Bourgeois B, Beaumanoir A, Blajev B, De la Cruz N, Despland PA, Egli M, et al. Monotherapy with valproate in primary generalized epilepsies. Epilepsia 1987;28 Suppl 2:S8–11.
Nau H, Kuhnz W, Egger H-J, Rating D, Helge H. Anticonvulsants during pregnancy and lactation. Transplacental, maternal and neonatal pharmacokinetics. Clin Pharmacokinet 1982;7:508–43.
Krauer B, Krauer F. Drug kinetics in pregnancy. In: Gibaldi M, Prescott L, eds. Handbook of clinical pharmacokinetics. Balgowlah: Adis Press, 1983:1–17.
Zaccara G, Messori A, Moroni F. Clinical pharmacokinetics of valproic acid — 1988. Clin Pharmacokinet 1988;15:367–89.
Sabers A, Dam M. Pregnancy, delivery, and puerperium. In: Dam M, Gram L, eds. Comprehensive epileptology. New York: Raven Press, 1991:299–307.
Leppik IE. Pharmacokinetics of antiepileptic drugs during pregnancy. Semin Neurol 1988;8(3):240–6.
Wittfodt W, Nau H, Rating D, Helge H.13C-labeled valproic acid pulse dosing during steady state antiepileptic therapy for pharmacokinetic studies during pregnancy. In: Schmidt HL, Förstel H, Heinzinger K, eds. Stable isotopes. Amsterdam: Elsevier, 1982:265–70.
Notarianni LJ. Plasma protein binding of drugs in pregnancy and in neonates. Clin Pharmacokinet 1990; 18(1):20–36.
Nau H, Schmidt-Gollwitzer M, Kuhnz W, Koch S, Helge H, Rating D. Antiepileptic disposition, protein binding, and estradiol/progesterone serum concentration ratios during pregnancy. In: Porter R, Mattson R, Ward A, Dam M, eds. Advances in epileptology. New York: Raven Press, 1984:239–49.
Riva R, Albani F, Contin M, Baruzzi A, Altomare M, Merlini GP, et al. Mechanism of altered drug binding to serum proteins in pregnant women: studies with valproic acid. Ther Drug Monit 1984;6:25–30.
Patel IH, Levy RH. Valproic acid binding to human serum albumin and determination of free fraction in the presence of anticonvulsants and free fatty acids. Epilepsia 1979;20:85–90.
Hunter J. Enzyme induction and inhibition in human pregnancy. In: Richens A, Woodford FP, eds. Anticonvulsant drugs and enzyme induction. Amsterdam: Elsevier, 1976:131–3.
Nau H, Löscher W. Valproic acid and metabolites. Pharmacological and toxicological studies. Epilepsia 1984;25 Suppl 1:S14–22.
Schobben F, Van der Kleijn E, Gabreels PJM. Pharmacokinetics of di-N-propylacetate in epileptic patients. Eur J Clin Pharmacol 1975;8:97–105.
Sackellares C, Sato S, Dreifuss FE, Penry JK. Reduction of steady-state valproate levels by other antiepileptic drugs. Epilepsia 1981;22:437–41.
Oxley J, Hedges A, Makki KA, Monks A, Richens A. Lack of enzyme inducing effects of sodium valproate. Br J Clin Pharmacol 1979;8:189–90.
Henriksen O, Johannessen SI. Clinical and pharmacokinetic observations on sodium valproate. A five-year follow-up study of 100 children with epilepsy. Acta Neurol Scand 1982;65:504–23.
Philbert A, Dam M. The epileptic mother and her child. Epilepsia 1982;23:85–99.
Nau H, Helge H, Luck W. Valproic acid in the perinatal period: decreased maternal serum protein binding results in fetal accumulation and neonatal displacement of the drug and some metabolites. J Pediatr 1984;104:627–34.
Koerner M, Yerby M, Friel P, McCormick K. Valproic acid disposition and protein binding in pregnancy. Ther Drug Monit 1989;11:228–30.
Bardy AH, Hiilesmaa VK, Teramo K, Neuvonen PJ. Protein binding of antiepileptic drugs during pregnancy, labor, and puerperium. Ther Drug Monit 1990;12:40–6.
Atkinson HC, Begg EJ, Darlow BA. Drugs in human milk. Clinical pharmacokinetic considerations. Clin Pharmacokinet 1988;14:217–40.
Knott C, Reynolds F. Therapeutic drug monitoring in pregnancy. Rationale and current status. Clin Pharmacokinet 1990;19(6):425–33.
Choonara IA, Rane A. Therapeutic drug monitoring of anticonvulsants. State of art. Clin Pharmacokinet 1990;18(4):318–28.
Cramer JA, Matsson RH. Valproic acid:in vitro plasma protein binding and interaction with phenytoin. Ther Drug Monit 1979;23:307–13.
Levy RH, Bowdle TA, Patel IH, Wilensky AJ. Variability in valproate binding and clearance: implications in therapeutic monitoring. Epilepsia 1981;22:240–1.
Levy RH. Monitoring of free valproic acid levels? Ther Drug Monit 1980;2:199–201.
Farrell K, Abbott FS, Orr JM, Applegarth A, Jan JE, Wong PK. Free and total serum valproate concentrations: their relationship to seizure control, liver enzymes and plasma ammonia in children. Can J Neurol Sci 1986;13:252–5.
Kilpatrick CJ, Fullinfaw RO, Burg RW, Moulds RFW. Plasma concentrations of unbound valproate and management of epilepsy. Aust NZ J Med 1987;17:574–7.
Barre J, Didey F, Delion F, Tillement J-P. Problems in therapeutic monitoring. Free drug level monitoring. Ther Drug Monitor 1988;10:133–43.
Johannessen SI, Løyning Y, Munthe-Kaas AW. IX. Medical treatment. General aspects. In: Dam M, Gram L, eds. Comprehensive epileptology. New York: Raven Press, 1991:505–24.
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Johannessen, S.I. Pharmacokinetics of valproate in pregnancy: Mother-foetus-newborn. Pharmaceutisch Weekblad Scientific Edition 14, 114–117 (1992). https://doi.org/10.1007/BF01962699
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DOI: https://doi.org/10.1007/BF01962699