To obtain information on the transport of valproic acid from mothers to colostrum and breastfed infants, in this cohort study, valproic acid concentrations in maternal serum (90 subjects), colostrum and the serum of breastfed infants were analyzed in years 1993-2018, between the 2nd and 5th postnatal days. Valproic acid concentrations ranged from 4.3 to 66.5 mg/L (mean 31.2 ± 13.6 mg/L) in maternal serum, from 0.5 to 5.9 mg/L (mean 1.1 ± 1.2 mg/L) in milk, and from 0.5 to 42.9 mg/L (mean 15.4 ± 9.4 mg/L) in infant serum. The milk/maternal serum concentration ratio ranged from 0.01 to 0.22 (mean 0.04 ± 0.04), and the infant/maternal serum concentration ratio ranged from 0.01 to 1.61 (mean 0.51 ± 0.28). A significant correlation was found between serum concentrations of breastfed infants and milk concentrations, maternal serum concentrations, maternal daily dose, and dose related to maternal body weight. Valproic acid concentrations in milk and infant serum did not reach the lower limit of the reference range used for the general epileptic population, and three-quarters of the concentrations in milk were lower than the lower limit of quantification. Routine monitoring of serum concentrations of breastfed infants is not necessary. If signs of potential adverse reactions are noted, serum concentrations of the infants should be measured.

Department of Clinical Pharmacology Faculty of Medicine University of Ostrava 70300 Ostrava Czech Republic

Department of Laboratory Medicine Institute of Clinical Pharmacology University Hospital Ostrava 70852 Ostrava Czech Republic

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Weston J., Bromley R., Jackson C.F., Adab N., Clayton-Smith J., Greenhalgh J., Hounsome J., McKay A.J., Smith C.T., Marson A.G. Monotherapy treatment of epilepsy in pregnancy: Congenital malformation outcomes in the child. Cochrane Database Syst. Rev. 2016;11:CD010224. doi: 10.1002/14651858.CD010224.pub2. PubMed DOI PMC

Christensen J., Pedersen L.H., Sun Y., Dreier J.W., Brikell I., Dalsgaard S. Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs with Risk for Attention-Deficit/Hyperactivity Disorder in Offspring. JAMA Netw. Open. 2019;2:e186606. doi: 10.1001/jamanetworkopen.2018.6606. PubMed DOI PMC

Elkjær L.S., Bech B.H., Sun Y., Laursen T.M., Christensen J. Association Between Prenatal Valproate Exposure and Performance on Standardized Language and Mathematics Tests in School-aged Children. JAMA Neurol. 2018;75:663–671. doi: 10.1001/jamaneurol.2017.5035. PubMed DOI PMC

Andersson K., Ozanne A., Bolin K., Tomson T., Zelano J. Valproic acid and socioeconomic associations in Swedish women with epilepsy 2010–2015. Acta Neurol. Scand. 2021;143:383–388. doi: 10.1111/ane.13397. PubMed DOI

New Measures to Avoid Valproate Exposure in Pregnancy Endorsed. [(accessed on 15 October 2021)]. Available online: https://www.ema.europa.eu/en/medicines/human/referrals/valproate-related-substances-0.

Irelli E.C., Morano A., Cocchi E., Casciato S., Fanella M., Albini M., Avorio F., Basili L.M., Fisco G., Barone F.A., et al. Doing without valproate in women of childbearing potential with idiopathic generalized epilepsy: Implication on seizure outcome. Epilepsia. 2020;61:107–114. doi: 10.1111/epi.16407. PubMed DOI

Tomson T., Battino D., Bonizzoni E., Craig J., Lindhout D., Perucca E., Sabers A., Thomas S.V., Vajda F., EURAP Study Group Declining malformation rates with changed antiepileptic drug prescribing: An observational study. Neurology. 2019;93:e831–e840. doi: 10.1212/WNL.0000000000008001. PubMed DOI

Vajda F.J.E., O’Brien T., Graham J.E., Hitchcock A.A., Lander C.M., Eadie M.J. Pregnancy after valproate withdrawal—Fetal malformations and seizure control. Epilepsia. 2020;61:944–950. doi: 10.1111/epi.16505. PubMed DOI

Kacirova I., Grundmann M. Trend analysis of the utilization of antiepileptic drugs in pregnant women with epilepsy in Mo-ravian-Silesian region of the Czech Republic. Klin. Farmakol. Farm. 2016;30:23–28.

Kinney M.O., Morrow J., Patterson C.C., Campbell E., Russell A., Smithson H.W., Parsons L., Morrison P.J., Bromley R., Liggan B., et al. Changing antiepilepsy drug-prescribing trends in women with epilepsy in the UK and Ireland and the impact on major congenital malformations. J. Neurol. Neurosurg. Psychiatry. 2018;89:1320–1323. doi: 10.1136/jnnp-2017-317368. PubMed DOI

Seshachala B.B., Jose M., Lathikakumari A.M., Murali S., Kumar A.S., Thomas S.V. Valproate usage in pregnancy: An audit from the Kerala Registry of Epilepsy and Pregnancy. Epilepsia. 2021;62:1141–1147. doi: 10.1111/epi.16882. PubMed DOI

Halani S., Tshering L., Bui E., Clark S.J., Grundy S.J., Pem T., Lhamo S., Dema U., Nirola D.K., Dorji C., et al. Contraception, pregnancy, and peripartum experiences among women with epilepsy in Bhutan. Epilepsy Res. 2017;138:116–123. doi: 10.1016/j.eplepsyres.2017.10.012. PubMed DOI PMC

Krauss G., Sandy S., Corbin D.O., Bird-Compton J., Jack F., Nelson B., Jalonen T.O., Ali A., Fortuné T., Clarke D., et al. Epilepsy care in the southern Caribbean. Epilepsy Behav. 2015;51:267–272. doi: 10.1016/j.yebeh.2015.07.011. PubMed DOI

Kacirova I., Grundmann M., Brozmanova H. Serum levels of valproic acid during delivery in mothers and in umbilical cord—Correlation with birth length and weight. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 2015;159:569–575. doi: 10.5507/bp.2015.055. PubMed DOI

Kacirova I., Grundmann M., Brozmanova H. Valproic acid concentrations in nursing mothers, mature milk, and breastfed infants in monotherapy and combination therapy. Epilepsy Behav. 2019;95:112–116. doi: 10.1016/j.yebeh.2019.04.002. PubMed DOI

Patsalos P.N., Spencer E.P., Berry D.J. Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update. Ther. Drug Monit. 2018;40:526–548. doi: 10.1097/FTD.0000000000000546. PubMed DOI

Birnbaum A.K., Meador K.J., Karanam A., Brown C., May R.C., Gerard E.E., Gedzelman E.R., Penovich P.E., Kalayjian L.A., Cavitt J., et al. Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers with Epilepsy. JAMA Neurol. 2020;77:441–450. doi: 10.1001/jamaneurol.2019.4443. PubMed DOI PMC

Keizer R.J., Jansen R.S., Rosing H., Thijssen B., Beijnen J.H., Schellens J.H.M., Huitema A.D.R. Incorporation of concentration data below the limit of quantification in population pharmacokinetic analyses. Pharmacol. Res. Perspect. 2015;3:e00131. doi: 10.1002/prp2.131. PubMed DOI PMC

Johnson E.L., Stowe Z.N., Ritchie J.C., Newport D.J., Newman M.L., Knight B., Pennell P.B. Carbamazepine clearance and seizure stability during pregnancy. Epilepsy Behav. 2014;33:49–53. doi: 10.1016/j.yebeh.2014.02.011. PubMed DOI PMC

Von Unruh G.E., Froescher W., Hoffmann F., Niesen M. Valproic Acid in Breast Milk: How Much Is Really There? Ther. Drug Monit. 1984;6:272–276. doi: 10.1097/00007691-198409000-00003. PubMed DOI

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;104:627–634. doi: 10.1016/S0022-3476(84)80567-3. PubMed DOI

Piontek C.M., Baab S., Peindl K.S., Wisner K.L. Serum valproate levels in 6 breastfeeding mother-infant pairs. J. Clin. Psychiatry. 2000;61:170–172. doi: 10.4088/JCP.v61n0304. PubMed DOI

Nau H., Rating D., Koch S., Häuser I., Helge H. Valproic acid and its metabolites: Placental transfer, neonatal pharmacoki-netics, transfer via mother’s milk and clinical status in neonates of epileptic mothers. J. Pharmacol. Exp. Ther. 1981;219:768–777. PubMed

Froescher W., Eichelbaum M., Niesen M. Antiepileptic Therapy with Carbamazepine and Valproic Acid During Pregnancy and Lactation Period. In: Dam M., editor. Advances in Epileptology: XIIth Epilepsy International Symposium. Raven Press; New York, NY, USA: 1981. pp. 581–588.

Philbert A., Pedersen B., Dam M. Concentration of valproate during pregnancy, in the newborn and in breast milk. Acta Neurol. Scand. 1985;72:460–463. doi: 10.1111/j.1600-0404.1985.tb00901.x. PubMed DOI

Meyer F.P., Quednow B., Potrafki A., Walther H. The perinatal pharmacokinetics of anticonvulsant drugs. Zent. Gynakol. 1988;110:1195–1205. PubMed

Birnbaum C.S., Cohen L.S., Bailey J.W., Grush L.R., Robertson L.M., Stowe Z.N. Serum concentrations of antidepressants and benzodiazepines in nursing infants: A case series. Pediatrics. 1999;104:e11. doi: 10.1542/peds.104.1.e11. PubMed DOI

Tsuru N., Maeda T., Tsuruoka M. Three Cases of Delivery under Sodium Valproate—Placental Transfer, Milk Transfer and Probable Teratogenicity of Sodium Valproate. Jpn. J. Psychiatry Neurol. 1988;42:89–96. doi: 10.1111/j.1440-1819.1988.tb01960.x. PubMed DOI

Wisner K., Perel J.M. Serum Levels of Valproate and Carbamazepine in Breastfeeding Mother-Infant Pairs. J. Clin. Psychopharmacol. 1998;18:167–169. doi: 10.1097/00004714-199804000-00009. PubMed DOI

Dickinson R.G., Harland R.C., Lynn R.K., Smith W.B., Gerber N. Transmission of valproic acid (Depakene) across theplacenta: Half-life of the drug in mother and baby. J. Pediatr. 1979;94:832–835. doi: 10.1016/S0022-3476(79)80172-9. PubMed DOI

Alexander F.W. Sodium valproate and pregnancy. Arch. Dis. Child. 1979;54:240. doi: 10.1136/adc.54.3.240. PubMed DOI PMC

Bardy A.H., Granstrom M.L., Hiilesmaa V.K. Valproic Acid and Breast-Feeding. In: Janz D., Bossi L., Dam M., Helge H., Richens A., Schmidt D., editors. Epilepsy, Pregnancy and The Child. Raven Press; New York, NY, USA: 1982. pp. 359–360.

Espir M.L.E., Benton P., Will E. Sodium Valproate (Epilim)-Some Clinical and Pharmacological Aspects. In: Legg N.J., editor. Clinical and Pharmacological Aspects of Sodium Valproate in The Treatment of Epilepsy: Proceedings of a Symposium. MCS Consultants; Tunbridge Wells, UK: 1976. pp. 145–151.

Stahl M.M., Neiderud J., Vinge E. Thrombocytopenic purpura and anemia in a breast-fed infant whose mother was treated with valproic acid. J. Pediatr. 1997;130:1001–1003. doi: 10.1016/S0022-3476(97)70292-0. PubMed DOI

Kacirova I., Grundmann M., Brozmanova H. Umbilical Cord, Maternal Milk, and Breastfed Infant Levetiracetam Concentrations Monitoring at Delivery and during Early Postpartum Period. Pharmaceutics. 2021;13:398. doi: 10.3390/pharmaceutics13030398. PubMed DOI PMC

Kacirova I., Grundmann M., Brozmanova H., Koristkova B. Monitoring topiramate concentrations at delivery and during lactation. Biomed. Pharmacother. 2021;138:111446. doi: 10.1016/j.biopha.2021.111446. PubMed DOI

Jani M., Ambrus C., Magnan R., Tauberné K., Erzsébet J., Zolnerciks J.K., Krajcsi P. Structure and function of BCRP, a broad specificity transporter of xenobiotics and endobiotics. Arch. Toxicol. 2014;88:1205–1248. doi: 10.1007/s00204-014-1224-8. PubMed DOI

Groneberg D.A., Döring F., Theis S., Nickolaus M., Fischer A., Daniel H. Peptide transport in the mammary gland: Expression and distribution of PEPT2 mRNA and protein. Am. J. Physiol. Endocrinol. Metab. 2002;282:E1172–E1179. doi: 10.1152/ajpendo.00381.2001. PubMed DOI

García-Lino A.M., Álvarez-Fernández I., Blanco-Paniagua E., Merino G., Álvarez A.I. Transporters in the Mammary Gland—Contribution to Presence of Nutrients and Drugs into Milk. Nutrients. 2019;11:2372. doi: 10.3390/nu11102372. PubMed DOI PMC