Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015, 159(4):569-575 | DOI: 10.5507/bp.2015.055

Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight

Ivana Kacirovaa,b, Milan Grundmanna, Hana Brozmanovaa,b
a Department of Clinical Pharmacology, Faculty of Medicine, University of Ostrava, Czech Republic
b Department of Clinical Pharmacology, Department of Laboratory Diagnostics, University Hospital Ostrava

Aims: The data on the valproic acid transplacental transfer and risk to the fetus of exposure, remain sparse and only a limited number of studies have reported umbilical cord blood levels.

Materials and Methods: Maternal and umbilical cord serum levels were analyzed at delivery in a cohort of 58 women, between the years 1991 - 2013. The request forms for routine therapeutic drug monitoring were used as the data source. Maternal levels and dosing information were used for estimating the maternal apparent oral clearance and the paired umbilical cord and maternal levels for estimation of umbilical cord/maternal level ratios.

Results: The levels varied from 5.3 - 59.5 mg/L in maternal and 5.4 - 72.1 mg/L in umbilical cord serum. The umbilical cord/maternal level ratios ranged from 0.64 - 2.49. Significant correlation was found between maternal and umbilical cord levels. Significant inverse correlations were found between birth length, and both maternal and umbilical cord levels in monotherapy.

Conclusions: There were large individual variations in umbilical cord/maternal level ratios of valproic acid. Neonatal length and weight were inversely related to maternal and umbilical cord levels, but not to dose. Therefore, therapeutic drug monitoring in mothers is more useful than the given dose for the estimation of fetal exposure and minimization of the risk of fetal effects.

Keywords: delivery, epilepsy, birth length, therapeutic drug monitoring, valproic acid

Received: May 20, 2015; Accepted: October 16, 2015; Prepublished online: October 27, 2015; Published: December 3, 2015  Show citation

ACS AIP APA ASA Harvard Chicago IEEE ISO690 MLA NLM Turabian Vancouver
Kacirova, I., Grundmann, M., & Brozmanova, H. (2015). Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight. Biomedical papers, 159(4), 569-575. doi: 10.5507/bp.2015.055
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. EURAP. An International Antiepileptic Drugs and Pregnancy Registry. Interim Report November 2014. Available at: www.eurapinternational.org.
    2. Tomson T, Battino D, Bonizzoni E, Craig JJ, Lindhout D, Perucca E, Sabers A, Thomas SV, Vajda F; EURAP Study Group. Antiepileptic drugs and intrauterine death: A prospective observational study from EURAP. Neurology 2015 Jul 17.pii:10.1212/WNL.0000000000001840. Go to original source... Go to PubMed...
    3. Kacirova I, Grundmann M, Koristkova B, Brozmanova H. Development of a treatment of pregnant women suffering from epilepsy in the region of Ostrava between the years 1991 and 2006. Ces slov Farm 2010;59:172-8.
    4. Philbert A, Pedersen B, Dam M. Concentration of valproate during pregnancy, in the newborn and in breast milk. Acta Neurol Scand 1985;72:460-3. Go to original source... Go to PubMed...
    5. Sabers A,Tomson T. Managing antiepileptic drugs during pregnancy and lactation. Curr Opin Neurol 2009;22:157-1. Go to original source... Go to PubMed...
    6. Brachet-Liermain A, Demarquez JL. Pharmacokinetics of dipropyl acetate in infants and young children. Pharm Weekblad 1977;112:293-7.
    7. Dickinson RG, Harland RC, Lynn RK, Smith WB, Gerber N. Transmission of valproic acid (Depakene) across the placenta: half life of the drug in mother and baby. J Pediatr 1979;94:832-5. Go to original source... Go to PubMed...
    8. Ishizaki T, Yokochi K, Chiba K, Tabuchi T, Wagatsuma T. Placental transfer of anticonvulsants (phenobarbital, phenytoin, valproic acid) and the elimination from neonates. Pediatr Pharmacol 1981;1:291-303.
    9. Nau H, Rating D, Koch S, Häuser I, Helge H. Valproic acid and its metabolites: placenta transfer, neonatal pharmacokinetics, transfer via mother´s milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther 1981;219:768-7. Go to PubMed...
    10. 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;104:627-4. Go to original source... Go to PubMed...
    11. Von Unruh GE, Froescher W, Hoffman F, Niesen M. Valproic acid in breast milk. How much is really there? Ther Drug Monit 1984;6:272-6. Go to original source... Go to PubMed...
    12. Meyer FP, Quednow B, Potrafki A, Walther H. Zur Pharmakokinetik von antiepileptika in der perinatalperiode. Zent bl Gynäkol 1988;110:1195-205.
    13. Fröscher W, Herrmann R, Niesen M, Bülau P, Penin H, Hildenbrand G. Untersuchungen zum Schwangerschaftsverlauf und zur Teratogenität der Antiepileptika bei 66 Epilepsie-Patientinnen. Schweizer Archiv für Neurologie und Psychiatrie 1991;142:389-407. Go to PubMed...
    14. Tanaka H, Takeda A, Izumi M, Okada H, Ishikawa S. Effects of antiepileptic drugs on delivery and early childhood-comparison among mono-therapies of valproic acid, phenytoin, carbamazepine and phenobarbital. Rinsho Shinkeigaku 1991;31:266-9. Go to PubMed...
    15. Takeda A, Okada H, Tanaka H, Izumi M, Ishikawa S, Noro T. Protein binding of four antiepileptic drugs in maternal and umbilical cord serum. Epilepsy Res 1992;13:147-1. Go to original source... Go to PubMed...
    16. Koch S, Jäger-Roman E, Lösche G, Nau H, Rating D, Helge H. Antiepileptic drug treatment in pregnancy: drug side effects in the neonate and neurological outcome. Acta Paediatr1996;85:739-6. Go to original source... Go to PubMed...
    17. Ornoy A.Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod Toxicol 2009;28:1-10. Go to original source... Go to PubMed...
    18. Sharony R, Garber A, Viskochil D. Preaxial ray reduction defects as part of valproic acid embryopathy. Prenat Diagn 1993;13:909-8. Go to original source... Go to PubMed...
    19. Holmes LB. The teratogenicity of anticonvulsant drugs: a progress report. J Med Genet 2002; 39:245-7. Go to original source... Go to PubMed...
    20. Eadie MJ. Treating epilepsy in pregnant women. Expert Opin Pharmacother 2014;15(6):841-50. Go to original source... Go to PubMed...
    21. Vajda FJ, O'Brien TJ, Graham J, Lander CM, Eadie MJ. Associations between particular types of fetal malformation and antiepileptic drug exposure in utero. Acta Neurol Scand 2013;128(4):228-4. Go to original source... Go to PubMed...
    22. Campbell E, Kennedy F, Russell A, Smithson WH, Parsons L, Morrison PJ, Liggan B, Irwin B, Delanty N, Hunt SJ, Craig J, Morrow J. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol Neurosurg Psychiatry 2014;85(9):1029-4. Go to original source... Go to PubMed...
    23. Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy. J Neurol 2014;261(3):579-8. Go to original source... Go to PubMed...
    24. Mountain KR, Hirsch J, Gallus AS. Neonatal coagulation defect due to anticonvulsantdrug treatment in pregnancy. Lancet 1970:256-68. Go to original source... Go to PubMed...
    25. Dalens B, Raynaud EJ, Gaulme J. Teratogenicity of valproic acid. J Pediatr 1980;97:332-3. Go to original source... Go to PubMed...
    26. Vert P, Deblay MF, Andre M. Follow-up study on growth and neurologic development of chidren born to epileptic mothers. In: Janz D, Dam M, Richens A (editors). Epilepsy, Pregnancy and the Child. New York: Raven Press; 1982. p. 433-436.
    27. Leguis E, Jaeken J, Eggermont E. Sodium valproate, pregnancy and infantile fatal liver failure. Lancet 1987;2:1518-9. Go to original source...
    28. Webster WS, Howe AM, Lipson AH. The role of vitamin K in prenatal development. Teratology 1995;15:285.
    29. Pennell PB, Klein AM, Browning N, Baker GA, Clayton-Smith J, Kalayjian LA, Liporace JD, Privitera M, Crawford T, Loring DW, Meador KJ; NEAD Study Group. Differential effects of antiepileptic drugs on neonatal outcomes. Epilepsy Behav 2012;24(4):449-6. Go to original source... Go to PubMed...
    30. Bantz EW. Valproic acid and congenital malformations: a case report. Clin Pediatr 1984;23:352-3. Go to original source... Go to PubMed...
    31. Jäger-Roman E, Deichi A, Jakob S, Hartmann AM, Koch S, Rating D, Steldinger R, Nau H, Helge H. Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 1986;108:997-4. Go to original source... Go to PubMed...
    32. Winter RM, Donnai D, Burn J, Tucker SM. Fetal valproate syndrome: Is there a recognizable phenotype? J Med Genet 1987;24:692-5. Go to original source... Go to PubMed...
    33. Ardinger HH, Atkins JF, Blackson DR, Elsas LJ, Clarren SK, Livingstone S, Flannery DB, Pellock JM, Harrod MJ, Lammer EJ. Verification of the fetal valproate syndrome phenotype. Am J Med Genet 1988;29:171-85. Go to original source... Go to PubMed...
    34. Pennell PB, Hovinga CA. Antiepileptic drug therapy in pregnancy I: gestation-induced effects on AED pharmacokinetics. Int Rev Neurobiol 2008;83:227-40. Go to original source... Go to PubMed...
    35. Brozmanova H, Grundmann M. First experiences with therapeutic monitoring of antiepileptics. (Article in Czech). Cesk Fysiol 1985;34:416.
    36. Budakova L, Brozmanova H, Grundmann M, Fischer J. Simultaneous determination of antiepileptic drugs and two active metabolites by HPLC. J Separ Sci 2008;31:1-8. Go to original source... Go to PubMed...
    37. Reisinger TL, Newman M, Loring DW, Pennell PB, Meador KJ. Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy. Epilepsy Behav 2013 Oct; 29(1):13-8. Go to original source... Go to PubMed...
    38. Neels HM, Sierens AC, Naelaerts K, Scharpé SL, Hatfield GM, Lambert WE. Therapeutic drug monitoring of old and newer anti-epileptic drugs. Clin Chem Lab Med 2004;42:1228-55. Go to original source... Go to PubMed...
    39. Nakamura H, Ushigome F, Koyabu N, Satoh S, Tsukimori K, Nakano H, Ohtani H, Sawada Y. Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles. Pharm Res 2002;19:154-1. Go to original source... Go to PubMed...
    40. Kaneko S, Battino D, Andermann E. Congenital malformations due to antiepileptic drugs. Epilepsy Res 1999;33:145-58. Go to original source... Go to PubMed...
    41. Atkinson DE, Brice-Bennett S, D'Souza SW. Antiepileptic medication during pregnancy: Does fetal genotype affect outcome? Pediatr Res 2007;62:120-7. Go to original source... Go to PubMed...
    42. Meador KJ, Baker GA, Finnell RH, Kalayjian LA, Liporace JD, Loring DW, Mawer G, Pennell PB, Smith JC, Wolff MC; NEAD Study Group. In utero antiepileptic drug exposure: Fetal death and malformations. Neurology 2006;67:407-2. Go to original source...
    43. Tomson T, Marson A, Boon P, Canevini MP, Covanis A, Gaily E, Kälviäinen R, Trinka E. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia 2015;56(7):1006-19. Go to original source... Go to PubMed...

    Return to the content