Skip to main content
Top
Published in: Clinical Pharmacokinetics 4/2019

01-04-2019 | Original Research Article

Comprehensive Measurements of Intrauterine and Postnatal Exposure to Lamotrigine

Authors: Michael Paulzen, Julia C. Stingl, Marc Augustin, Helena Saßmannshausen, Cordula Franz, Gerhard Gründer, Georgios Schoretsanitis

Published in: Clinical Pharmacokinetics | Issue 4/2019

Login to get access

Abstract

Objective

The aim of this study was to measure and investigate correlations of lamotrigine concentrations in maternal as well as umbilical cord blood, amniotic fluid, and breast milk to account for the distribution of the drug.

Methods

Concentrations of lamotrigine were measured in 19 mother–infant pairs at the time of delivery. To account for the penetration ratio into amniotic fluid, cord blood and breast milk, the concentration of lamotrigine in the particular environment was divided by the concentration in maternal serum. A no-intercept model was applied for associations between maternal serum concentrations, amniotic fluid, umbilical cord blood, and breast milk concentrations.

Results

The mean daily dosage of lamotrigine was 351.32 mg (range 50–650 mg). We detected associations between maternal serum and amniotic fluid (β = 0.088, p < 0.001), as well as umbilical cord (β = 0.939, p < 0.001) and breast milk (β = 0.964, p < 0.001). The median penetration ratio into amniotic fluid, cord blood, and breast milk was 0.68, 0.92, and 0.77, respectively.

Conclusions

Lamotrigine concentrations in amniotic fluid, cord blood, and breast milk give evidence that the fetus/newborn is constantly exposed to lamotrigine. Maternal serum concentrations predicted exposure via amniotic fluid, umbilical cord, and breast milk. Data suggest that therapeutic drug monitoring can be recommended as part of the clinical routine in psychopharmacotherapy for pregnant or breastfeeding women.
Literature
1.
go back to reference Graham RK, Tavella G, Parker GB. Is there consensus across international evidence-based guidelines for the psychotropic drug management of bipolar disorder during the perinatal period? J Affect Disord. 2017;12(228):216–21. Graham RK, Tavella G, Parker GB. Is there consensus across international evidence-based guidelines for the psychotropic drug management of bipolar disorder during the perinatal period? J Affect Disord. 2017;12(228):216–21.
2.
go back to reference Patel N, Viguera AC, Baldessarini RJ. Mood-stabilizing anticonvulsants, spina bifida, and folate supplementation: commentary. J Clin Psychopharmacol. 2018;38(1):7–10.PubMed Patel N, Viguera AC, Baldessarini RJ. Mood-stabilizing anticonvulsants, spina bifida, and folate supplementation: commentary. J Clin Psychopharmacol. 2018;38(1):7–10.PubMed
3.
go back to reference Schaefer C. Drug safety in pregnancy: utopia or achievable prospect? Risk information, risk research and advocacy in Teratology Information Services. Congenit Anom (Kyoto). 2011;51(1):6–11.CrossRef Schaefer C. Drug safety in pregnancy: utopia or achievable prospect? Risk information, risk research and advocacy in Teratology Information Services. Congenit Anom (Kyoto). 2011;51(1):6–11.CrossRef
6.
go back to reference Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ. A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry. 2010;67(10):1012–24.PubMedPubMedCentralCrossRef Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ. A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry. 2010;67(10):1012–24.PubMedPubMedCentralCrossRef
7.
go back to reference Dayan J, Creveuil C, Marks MN, Conroy S, Herlicoviez M, Dreyfus M, et al. Prenatal depression, prenatal anxiety, and spontaneous preterm birth: a prospective cohort study among women with early and regular care. Psychosom Med. 2006;68(6):938–46.PubMedCrossRef Dayan J, Creveuil C, Marks MN, Conroy S, Herlicoviez M, Dreyfus M, et al. Prenatal depression, prenatal anxiety, and spontaneous preterm birth: a prospective cohort study among women with early and regular care. Psychosom Med. 2006;68(6):938–46.PubMedCrossRef
8.
go back to reference Diego MA, Field T, Hernandez-Reif M, Schanberg S, Kuhn C, Gonzalez-Quintero VH. Prenatal depression restricts fetal growth. Early Hum Dev. 2009;85(1):65–70.PubMedCrossRef Diego MA, Field T, Hernandez-Reif M, Schanberg S, Kuhn C, Gonzalez-Quintero VH. Prenatal depression restricts fetal growth. Early Hum Dev. 2009;85(1):65–70.PubMedCrossRef
9.
go back to reference Paulzen M, Gründer G, Orlikowsky T, Graf CM, Hoeltzenbein M, Veselinovic T. Suicide attempt during late pregnancy with quetiapine: nonfatal outcome despite severe intoxication. J Clin Psychopharmacol. 2015;35(3):343–4.PubMedCrossRef Paulzen M, Gründer G, Orlikowsky T, Graf CM, Hoeltzenbein M, Veselinovic T. Suicide attempt during late pregnancy with quetiapine: nonfatal outcome despite severe intoxication. J Clin Psychopharmacol. 2015;35(3):343–4.PubMedCrossRef
10.
go back to reference Eshkoli T, Sheiner E, Ben-Zvi Z, Feinstein V, Holcberg G. Drug transport across the placenta. Curr Pharm Biotechnol. 2011;12(5):707–14.PubMedCrossRef Eshkoli T, Sheiner E, Ben-Zvi Z, Feinstein V, Holcberg G. Drug transport across the placenta. Curr Pharm Biotechnol. 2011;12(5):707–14.PubMedCrossRef
11.
go back to reference Hutson JR, Garcia-Bournissen F, Davis A, Koren G. The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clin Pharmacol Ther. 2011;90(1):67–76.PubMedCrossRef Hutson JR, Garcia-Bournissen F, Davis A, Koren G. The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clin Pharmacol Ther. 2011;90(1):67–76.PubMedCrossRef
12.
go back to reference Giaginis C, Theocharis S, Tsantili-Kakoulidou A. Current toxicological aspects on drug and chemical transport and metabolism across the human placental barrier. Expert Opin Drug Metab Toxicol. 2012;8(10):1263–75.PubMedCrossRef Giaginis C, Theocharis S, Tsantili-Kakoulidou A. Current toxicological aspects on drug and chemical transport and metabolism across the human placental barrier. Expert Opin Drug Metab Toxicol. 2012;8(10):1263–75.PubMedCrossRef
16.
go back to reference Chen H, Yang K, Choi S, Fischer JH, Jeong H. Up-regulation of UDP-glucuronosyltransferase (UGT) 1A4 by 17beta-estradiol: a potential mechanism of increased lamotrigine elimination in pregnancy. Drug Metab Dispos. 2009;37(9):1841–7.PubMedPubMedCentralCrossRef Chen H, Yang K, Choi S, Fischer JH, Jeong H. Up-regulation of UDP-glucuronosyltransferase (UGT) 1A4 by 17beta-estradiol: a potential mechanism of increased lamotrigine elimination in pregnancy. Drug Metab Dispos. 2009;37(9):1841–7.PubMedPubMedCentralCrossRef
20.
go back to reference Deshmukh U, Adams J, Macklin EA, Dhillon R, McCarthy KD, Dworetzky B, et al. Behavioral outcomes in children exposed prenatally to lamotrigine, valproate, or carbamazepine. Neurotoxicol Teratol. 2016;54:5–14.PubMedPubMedCentralCrossRef Deshmukh U, Adams J, Macklin EA, Dhillon R, McCarthy KD, Dworetzky B, et al. Behavioral outcomes in children exposed prenatally to lamotrigine, valproate, or carbamazepine. Neurotoxicol Teratol. 2016;54:5–14.PubMedPubMedCentralCrossRef
21.
go back to reference Petersen I, McCrea RL, Sammon CJ, Osborn DP, Evans SJ, Cowen PJ, et al. Risks and benefits of psychotropic medication in pregnancy: cohort studies based on UK electronic primary care health records. Health Technol Assess. 2016;20(23):1–176.PubMedPubMedCentralCrossRef Petersen I, McCrea RL, Sammon CJ, Osborn DP, Evans SJ, Cowen PJ, et al. Risks and benefits of psychotropic medication in pregnancy: cohort studies based on UK electronic primary care health records. Health Technol Assess. 2016;20(23):1–176.PubMedPubMedCentralCrossRef
22.
go back to reference Paulzen M, Goecke TW, Stickeler E, Gründer G, Schoretsanitis G. Sertraline in pregnancy—therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood. J Affect Disord. 2017;1(212):1–6.CrossRef Paulzen M, Goecke TW, Stickeler E, Gründer G, Schoretsanitis G. Sertraline in pregnancy—therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood. J Affect Disord. 2017;1(212):1–6.CrossRef
23.
go back to reference Paulzen M, Goecke TW, Kuzin M, Augustin M, Gründer G, Schoretsanitis G. Pregnancy exposure to quetiapine—therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood and obstetrical outcomes. Schizophr Res. 2018;195:252–7.PubMedCrossRef Paulzen M, Goecke TW, Kuzin M, Augustin M, Gründer G, Schoretsanitis G. Pregnancy exposure to quetiapine—therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood and obstetrical outcomes. Schizophr Res. 2018;195:252–7.PubMedCrossRef
24.
go back to reference Paulzen M, Goecke TW, Stingl JC, Janssen G, Stickeler E, Gründer G, et al. Pregnancy exposure to citalopram—therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood. Prog Neuropsychopharmacol Biol Psychiatry. 2017;79(Pt B):213–9.PubMedCrossRef Paulzen M, Goecke TW, Stingl JC, Janssen G, Stickeler E, Gründer G, et al. Pregnancy exposure to citalopram—therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood. Prog Neuropsychopharmacol Biol Psychiatry. 2017;79(Pt B):213–9.PubMedCrossRef
25.
go back to reference Paulzen M, Lammertz SE, Veselinovic T, Goecke TW, Hiemke C, Gründer G. Lamotrigine in pregnancy—therapeutic drug monitoring in maternal blood, amniotic fluid, and cord blood. Int Clin Psychopharmacol. 2015;30(5):249–54.PubMedCrossRef Paulzen M, Lammertz SE, Veselinovic T, Goecke TW, Hiemke C, Gründer G. Lamotrigine in pregnancy—therapeutic drug monitoring in maternal blood, amniotic fluid, and cord blood. Int Clin Psychopharmacol. 2015;30(5):249–54.PubMedCrossRef
26.
go back to reference Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1–02):9–62.PubMed Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1–02):9–62.PubMed
27.
go back to reference Kacirova I, Grundmann M, Brozmanova H. Serum levels of lamotrigine during delivery in mothers and their infants. Epilepsy Res. 2010;91(2–3):161–5.PubMedCrossRef Kacirova I, Grundmann M, Brozmanova H. Serum levels of lamotrigine during delivery in mothers and their infants. Epilepsy Res. 2010;91(2–3):161–5.PubMedCrossRef
28.
go back to reference Fotopoulou C, Kretz R, Bauer S, Schefold JC, Schmitz B, Dudenhausen JW, et al. Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Res. 2009;85(1):60–4.PubMedCrossRef Fotopoulou C, Kretz R, Bauer S, Schefold JC, Schmitz B, Dudenhausen JW, et al. Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Res. 2009;85(1):60–4.PubMedCrossRef
29.
go back to reference Newport DJ, Pennell PB, Calamaras MR, Ritchie JC, Newman M, Knight B, et al. Lamotrigine in breast milk and nursing infants: determination of exposure. Pediatrics. 2008;122(1):e223–31.PubMedPubMedCentralCrossRef Newport DJ, Pennell PB, Calamaras MR, Ritchie JC, Newman M, Knight B, et al. Lamotrigine in breast milk and nursing infants: determination of exposure. Pediatrics. 2008;122(1):e223–31.PubMedPubMedCentralCrossRef
30.
go back to reference Liporace J, Kao A, D’Abreu A. Concerns regarding lamotrigine and breast-feeding. Epilepsy Behav. 2004;5(1):102–5.PubMedCrossRef Liporace J, Kao A, D’Abreu A. Concerns regarding lamotrigine and breast-feeding. Epilepsy Behav. 2004;5(1):102–5.PubMedCrossRef
31.
go back to reference Blanca Sanchez M, Herranz JL, Leno C, Arteaga R, Oterino A, Valdizan EM, et al. UGT2B7_-161C>T polymorphism is associated with lamotrigine concentration-to-dose ratio in a multivariate study. Ther Drug Monit. 2010;32(2):177–84.PubMed Blanca Sanchez M, Herranz JL, Leno C, Arteaga R, Oterino A, Valdizan EM, et al. UGT2B7_-161C>T polymorphism is associated with lamotrigine concentration-to-dose ratio in a multivariate study. Ther Drug Monit. 2010;32(2):177–84.PubMed
32.
go back to reference Strassburg CP, Strassburg A, Kneip S, Barut A, Tukey RH, Rodeck B, et al. Developmental aspects of human hepatic drug glucuronidation in young children and adults. Gut. 2002;50(2):259–65.PubMedPubMedCentralCrossRef Strassburg CP, Strassburg A, Kneip S, Barut A, Tukey RH, Rodeck B, et al. Developmental aspects of human hepatic drug glucuronidation in young children and adults. Gut. 2002;50(2):259–65.PubMedPubMedCentralCrossRef
33.
go back to reference Veiby G, Bjork M, Engelsen BA, Gilhus NE. Epilepsy and recommendations for breastfeeding. Seizure. 2015;28:57–65.PubMedCrossRef Veiby G, Bjork M, Engelsen BA, Gilhus NE. Epilepsy and recommendations for breastfeeding. Seizure. 2015;28:57–65.PubMedCrossRef
34.
go back to reference Dalili H, Nayeri F, Shariat M, Asgarzadeh L. Lamotrigine effects on breastfed infants. Acta Medica Iran. 2015;53(7):393–4. Dalili H, Nayeri F, Shariat M, Asgarzadeh L. Lamotrigine effects on breastfed infants. Acta Medica Iran. 2015;53(7):393–4.
35.
go back to reference de Haan GJ, Edelbroek P, Segers J, Engelsman M, Lindhout D, Devile-Notschaele M, et al. Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology. 2004;63(3):571–3.PubMedCrossRef de Haan GJ, Edelbroek P, Segers J, Engelsman M, Lindhout D, Devile-Notschaele M, et al. Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology. 2004;63(3):571–3.PubMedCrossRef
38.
go back to reference Prakash C, Hatters-Friedman S, Moller-Olsen C, North A. Maternal and fetal outcomes after lamotrigine use in pregnancy: a retrospective analysis from an urban maternal mental health centre in New Zealand. Psychopharmacol Bull. 2016;46(2):63–9.PubMedPubMedCentral Prakash C, Hatters-Friedman S, Moller-Olsen C, North A. Maternal and fetal outcomes after lamotrigine use in pregnancy: a retrospective analysis from an urban maternal mental health centre in New Zealand. Psychopharmacol Bull. 2016;46(2):63–9.PubMedPubMedCentral
39.
go back to reference Cunnington M, Tennis P, International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology. 2005;64(6):955–60.PubMedCrossRef Cunnington M, Tennis P, International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology. 2005;64(6):955–60.PubMedCrossRef
40.
go back to reference Dolk H, Wang H, Loane M, Morris J, Garne E, Addor MC, et al. Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. Neurology. 2016;86(18):1716–25.PubMedPubMedCentralCrossRef Dolk H, Wang H, Loane M, Morris J, Garne E, Addor MC, et al. Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. Neurology. 2016;86(18):1716–25.PubMedPubMedCentralCrossRef
41.
go back to reference Panchaud A, Garcia-Bournissen F, Csajka C, Kristensen JH, Taddio A, Ilett KF, et al. Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine exposure. Clin Pharmacol Ther. 2011;89(6):830–6.PubMedCrossRef Panchaud A, Garcia-Bournissen F, Csajka C, Kristensen JH, Taddio A, Ilett KF, et al. Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine exposure. Clin Pharmacol Ther. 2011;89(6):830–6.PubMedCrossRef
Metadata
Title
Comprehensive Measurements of Intrauterine and Postnatal Exposure to Lamotrigine
Authors
Michael Paulzen
Julia C. Stingl
Marc Augustin
Helena Saßmannshausen
Cordula Franz
Gerhard Gründer
Georgios Schoretsanitis
Publication date
01-04-2019
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 4/2019
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-018-0713-y

Other articles of this Issue 4/2019

Clinical Pharmacokinetics 4/2019 Go to the issue