Original article 249
Lamotrigine in pregnancy – therapeutic drug monitoring in maternal blood, amniotic fluid, and cord blood Michael Paulzena, Sarah E. Lammertza, Tanja Veselinovica, Tamme W. Goeckeb, Christoph Hiemkec and Gerhard Gründera This study is the first to measure and correlate lamotrigine concentrations in maternal blood, amniotic fluid, and umbilical cord blood and account for distribution of the drug between these three compartments. Concentrations of lamotrigine were measured in six mother–infant pairs at the time of delivery. Daily doses of lamotrigine ranged between 200 and 650 mg. Daily doses were correlated with maternal serum and umbilical cord blood concentrations, and serum levels were correlated with levels in amniotic fluid. Lamotrigine levels in serum correlated strongly with the lamotrigine levels in amniotic fluid (r = + 0.986, P < 0.001) and cord blood (r = + 0.928, P = 0.008). The penetration ratio into amniotic fluid was in a range between 0.31 and 0.75 (mean 0.58, SD 0.17); the penetration ratio into the fetal circulation, calculated on the basis of umbilical cord blood levels, was found to be in a range between 0.48 and 1.27 (mean 0.81, SD 0.28). Lamotrigine concentrations in amniotic fluid provided evidence that maternally administered lamotrigine is accessible to the fetus in a manner not previously
Introduction The use of psychotropic drugs during pregnancy is increasing (Thomas and Yates, 2012; Kallen et al., 2013), but pregnant women and prescribers are rightly concerned about potential adverse effects on the fetus. This is because of the fact that for the majority of psychotropic drugs, clinical experience is still insufficient with respect to their safety in pregnancy (Schaefer, 2011). Accordingly, the treatment of psychiatric and/or neurologic diseases during pregnancy using psychotropic drugs is always complicated by the concern for the safety of the mother and the unborn child. By balancing the risks, one has to take into account that every pregnancy outcome is influenced by the natural course of the untreated disease such as epilepsy, depression, or psychosis on the one hand or by potential negative effects of drug intake on the other. Leaving epilepsy untreated during pregnancy appears to be disadvantageous from the standpoint of seizure control, but does not seem to reduce the risk of fetal malformation unless one avoids valproate (Vajda et al., 2014). Children of mothers with untreated or inadequately treated psychiatric diseases such as depression or psychosis might be at risk of future psychopathology (Nulman et al., 2012), intrauterine growth retardation (Grote et al., 2010; Uguz et al., 2011), or even at risk for maternal suicidal behavior because of uncontrolled symptomatology (Klys et al., 2007). When the thalidomide scandal occurred in the early 1960s, it became obvious that the placenta is not able to 0268-1315 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
appreciated. Furthermore, the penetration ratio into umbilical cord blood calculated here is in line with the largest study carried out so far to explore transplacental transfer. Int Clin Psychopharmacol 30:249–254 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. International Clinical Psychopharmacology 2015, 30:249–254 Keywords: amniotic fluid, cord blood, epilepsy, lamotrigine, mood stabilizer, pharmacokinetics, placental transfer, pregnancy, therapeutic drug monitoring a Department of Psychiatry, Psychotherapy and Psychosomatics and JARA – Translational Brain Medicine, bDepartment of Gynaecology and Obstetrics, RWTH Aachen University, Aachen and cDepartment of Psychiatry and Psychotherapy, Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany
Correspondence to Michael Paulzen, MD, Department of Psychiatry, Psychotherapy and Psychosomatics and JARA – Translational Brain Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany Tel: + 49 241 80 89508; fax: + 49 241 80 82401; e-mail: [email protected] Received 25 March 2015 Accepted 19 May 2015
provide a fully protected environment for the fetus (Eshkoli et al., 2011). However, the placenta constitutes the sole structural barrier at the maternal–fetal interface (Ganapathy et al., 2000) and separates the maternal and fetal circulations. It performs many functions that support the maintenance of pregnancy and the normal development of the fetus, but various factors can influence placental transfer, including the physicochemical properties of a drug (Hutson et al., 2011). Passive diffusion of drugs across the human placental barrier mainly depends on properties related to the chemical structure of the drugs and compartmental pH, being also influenced by pharmacokinetic parameters and physiological conditions such as protein binding, volume of distribution, renal plasma flow, and glomerular filtration rate. Moreover, the placenta expresses a multitude of transporters such as p-glycoprotein, multidrug-resistance proteins, and others facilitating or preventing the passage of xenobiotics (Giaginis et al., 2012). Through enzyme activity such as cytochromes or uridine 5′-diphosphoglucuronosyltransferase (UGT), the human placenta can metabolize a large diversity of pharmacologically active molecules eliciting or inhibiting fetotoxic effects (Reimers et al., 2011; Giaginis et al., 2012). Quantification of the extent of placental passage or knowledge of the accumulation of a drug in amniotic fluid as another route of fetal exposure (Loughhead et al., 2006) can facilitate medication selection on the basis of DOI: 10.1097/YIC.0000000000000088
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250 International Clinical Psychopharmacology 2015, Vol 30 No 5
the extent of fetal drug exposure and ultimately provide insight into whether or not neonatal complications are directly related to medication exposure with measurable drug levels in amniotic fluid or fetal circulation. Accumulating evidence suggests an association between prenatal exposure to antiepileptic drugs and increased risk of both physical anomalies and neurodevelopmental impairment (Bromley et al., 2014). Hence, any decision for or against a psychopharmacological treatment with antiepileptic drugs detached from the indication of treating epilepsy or for the treatment of bipolar disorder or depression requires a careful balance between the risks for the mother and the unborn child. The difficulty of a drug therapy using antiepileptic drugs during pregnancy is to find a balance between minimal fetal drug exposure and maximum maternal relapse prevention or seizure control in the case of epilepsy. Lamotrigine, an antiepileptic drug of the phenyltriazine class, is chemically unrelated to other existing antiepileptic drugs (Glaxosmithkline, 2014). It is used for the adjunctive treatment of partial seizures in epilepsy and generalized seizures of Lennox–Gastaut syndrome. In psychiatry, lamotrigine is recommended in bipolar disorder maintenance when depression is prominent (Reid et al., 2013). It is believed to exert its anticonvulsant effect by stabilizing presynaptic neuronal membranes; however, the mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder or depression have not been established. Lamotrigine inhibits sodium currents by selectively binding to the inactivated state of the sodium channel and subsequently suppresses the release of the excitatory amino acid glutamate. Lamotrigine is metabolized primarily through the liver by glucuronidation (Cohen et al., 1987; Green et al., 1995). UGT1A4 catalyzes 90% of lamotrigine conjugation and the major metabolite, lamotrigine-2-N-glucuronide, is excreted through the kidneys (Green et al., 1995). Estradiol upregulates the expression of UGT1A4, which increases lamotrigine clearance associated with increasing estrogen levels during pregnancy (Chen et al., 2009). Furthermore, decreasing levels of lamotrigine during pregnancy might be a result of placental expression of UGT1A isozymes facilitating the lamotrigine metabolism (Reimers et al., 2011). In terms of increasing the risk for major congenital malformations, lamotrigine seems to be unsuspicious (Kallen et al., 2013) and only one study found a dosedependent increase in the malformation rate (2% at < 300 mg/day and 4.5% at ≥ 300 mg/day) (Tomson et al., 2011). However, correlations between drug levels in maternal serum, amniotic fluid, or umbilical cord blood and malformation rates have never been investigated. The ‘International Lamotrigine Pregnancy Registry’ did not detect an appreciable increase in major congenital malformations frequency following first-trimester lamotrigine monotherapy exposure (Cunnington et al., 2011)
and fetal exposure was not associated with neurocognitive deficits in early childhood (Meador et al., 2012). The aim of our study was to analyze the distribution pattern of lamotrigine in maternal serum, amniotic fluid, and umbilical cord blood, to account for the relation between the applied daily doses of lamotrigine and the serum as well as the umbilical cord blood concentrations and concentrations in amniotic fluid at the time of delivery in patients with epilepsy under naturalistic/ clinical conditions. To account for the placental penetration, the correlation between maternal serum concentrations of lamotrigine and the cord blood concentration was calculated. Furthermore, the correlation between maternal serum and amniotic fluid was computed to account for the impact of drug accumulation in amniotic fluid as one way of fetal exposure.
Materials and methods Patients
This investigation is part of an observational study examining the distribution pattern of different psychotropic drugs in maternal blood, amniotic fluid, and umbilical cord blood in pregnant women at the time of delivery. It has been carried out as a collaboration between the Department of Psychiatry, Psychotherapy, and Psychosomatics, and the Department of Gynaecology and Obstetrics – Perinatalcenter Level I, at the University Hospital of RWTH Aachen University, Germany, since November 2012. The study protocol was approved by the local Ethics Committee. Data of six pregnant women, ranging in age from 19 to 35 years (mean age = 28.8 ± 6; median = 29.5), and six newborns are presented. Women were treated throughout their pregnancies with lamotrigine in fixed daily doses between 200 and 650 mg. The last dose adaptations were performed more than 2 weeks before delivery. Two patients were comedicated with 25 mg clobazam per day at the time of delivery for seizure control (started some days before delivery) and one patient received 3000 mg levetiracetam additionally throughout the entire pregnancy. All patients were diagnosed with localizationrelated idiopathic epilepsy and epileptic syndromes with seizures of localized onset according to ICD-10, G44.0. All six mother–infant pairs provided maternal serum levels, amniotic fluid levels, and umbilical cord levels at delivery. Methods
The present study is a naturalistic prospective investigation of lamotrigine concentrations in maternal serum and amniotic fluid in six women and umbilical cord blood of their six newborns. Blood was taken at the same time as delivery under steady-state conditions with respect to the ingested drug, but because of clinical circumstances not as trough levels. As an indicator for drug levels in blood, we used serum concentrations. Serum was
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– 0.59 2.4 0.68 2.8 1.17 4.1
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LAM, lamotrigine; LDR, level-to-dose ratio. a All patients had epilepsy and lamotrigine was used in this particular indication. b LDR is calculated by the formula: lamotrigine level (µg/ml) × 100/prescribed daily lamotrigine dose (mg). c Patient 1 delivered two infants with two pregnancies within 16 months.
350 10/10/10 Female 62th 3395 Section 34 6
38 + 4
Clobazam 0.77 4.8 0.45 2.8 1.55 6.20 400 10/10/10 Male 59th 2600 Section 19 5
33 + 4
– 0.48 1.4 0.31 0.9 0.58 2.9 500 9/10/10 Male 44th 3270 Section 27 4
38 + 1
31 3
34 + 1
Section
2440
56th
Male
7/9/9
200
1.1
0.55
0.75
0.68
1.4
1.27
–
Normal Hyponatriaemia, hyperbilirubinemia Respiratory distress syndrome, hyperbilirubinemia DiGeorge syndrome, interrupted aortic arc type B, ventricle septal defect Slow feeding of newborn Normal Clobazam Levetiracetam 0.95 0.80 6.2 2.65 0.58 0.75 3.8 2.47 1.00 0.55 6.53 3.31 650 600
LDR
b
APGAR
9/10/10 9/9/9 Male Female 10th 78th 2900 3170 Section Spontanous 38 + 6 35 + 6 35 26
Ratio amniotic fluid LAM amniotic fluid (µg/ml) LAM maternal serum (µg/ml) Daily dose of LAM (mg) Patient numbera
Obstetrical outcome data, and data on daily doses, serum, amniotic fluid, and cord blood concentrations of lamotrigine are shown in Table 1. Obstetrical outcome data are available for all six infants. Obstetrical complications included two of six preterm deliveries (i.e. < 37 weeks’ gestational age). One infant had a prenatally diagnosed DiGeorge syndrome with an interrupted aortic arc type B and a ventricle septal defect, one infant showed signs of a respiratory distress syndrome, and one infant showed a slow feeding syndrome. These three infants were temporarily admitted to the ICU. With respect to the weight, only one infant had a low birth weight (i.e. < 2.5 kg); all six were within a range between the 10th and the 78th percentile. The average daily dose of lamotrigine was 458.3 mg (SD 162.5, range 200–650 mg), applied twice daily. Maternal serum levels of lamotrigine were in a range between 1.1 and 6.5 µg/ml (mean 4.0 µg/ml, SD 2.1 µg/ml, recommended therapeutic drug concentration range 3–14 µg/ml) (Hiemke et al., 2011). In amniotic fluid, lamotrigine levels ranged between 0.8 and 3.8 µg/ml (mean 2.3 µg/ml, SD 1.2 µg/ml) and in the cord
Gestational age at delivery Maternal age (weeks) Mode of delivery Weight (g) Percentile Infant sex
Results
Patients’ characteristics and clinical characteristics of six mothers taking lamotrigine during pregnancy and their infants
Correlations were computed to assess the relation between the level of drug concentrations in maternal serum, amniotic fluid, and cord blood, as well as the relation of these concentrations with the daily dose of lamotrigine. Because of the small sample size, nonparametric tests were used to analyze data. Statistical analyses were carried out using SPSS (version 21; IBM Corp., Armonk, New York, USA).
Table 1
To account for the range of doses of lamotrigine received by the patients, we divided the serum, amniotic fluid, and cord blood levels of lamotrigine by the applied dose of lamotrigine (applied twice daily), resulting in a levelby-dose-ratio of lamotrigine for serum, amniotic fluid, and cord blood, respectively. In addition, the penetration ratio into the amniotic fluid and cord blood of lamotrigine was calculated. For this purpose, the levels of lamotrigine in amniotic fluid as well as cord blood were divided by their counterpart levels in the maternal serum, reflecting the penetration ratio into amniotic fluid and cord blood, respectively.
LAM cord blood (µg/ml)
Statistical analysis
1 2
Ratio cord blood
Concomitant medications
prepared by centrifugation of blood samples at 14 171 g for 15 min. Lamotrigine concentrations in maternal serum, amniotic fluid, and umbilical cord blood were determined with an isocratic HPLC system with a UV detector using a reagent kit from Chromsystems Instruments & Chemicals GmbH (Graefelfing/Munich, Germany). The method is linear from the designated limit of quantification of 0.3 µg/ml up to the upper limit of 30 µg/ml for lamotrigine. Intraassay precision and accuracy over a range from 2.7 to 10 µg/ml is less than 2%; interassay precision is less than 6%.
c
Outcome/birth defect
Lamotrigine distribution during pregnancy Paulzen et al. 251
252 International Clinical Psychopharmacology 2015, Vol 30 No 5
blood drug levels were found between 1.4 and 6.2 µg/ml (mean 3.1 µg/ml, SD 2.0 µg/ml). The level-by-dose-ratio was calculated using the following formula: lamotrigine level (µg/ml) × 100/prescribed daily lamotrigine dose (mg) (Clark et al., 2013). In maternal serum, it was 0.90 (SD 0.41, range 0.55–1.55), for amniotic fluid, it was 0.51 (SD 0.23, range 0.18–0.8 µg/ml), and for cord blood, it was 0.71 (SD 0.33, range 0.28–1.20). A significant relation between the daily dosage of lamotrigine and its concentrations in serum, amniotic fluid, and cord blood could not be observed. However, the lamotrigine levels in serum correlated strongly with the lamotrigine levels in amniotic fluid (r = + 0.986, P < 0.001) and cord blood (r = + 0.928, P = 0.008) as shown in Fig. 1a and b. The penetration ratio for lamotrigine into amniotic fluid was in a range between 0.31 and 0.75 (SD 0.17, mean 0.58); the penetration ratio into the fetal circulation, calculated on the basis of umbilical cord blood levels, was found to be in a range between 0.48 and 1.27 (SD 0.28, mean 0.81) (Fig. 1a and b). Lamotrigine levels in amniotic fluid and cord blood were strongly related to each other (r = + 0.882, P = 0.02) (Fig. 2).
Discussion In the 1970s, Wilson (1973) formulated six principles of teratology that have guided research in developmental toxicology to this day. His sixth and final principle ‘Manifestations of deviant development increase in frequency and degree as dosage increases, from no-effect to
the totally lethal level’, among others, describes the range of toxicity from no-effect to completely lethal (Aston, 2014). This means that the outcome depends on the dose, threshold, and duration of xenobiotic influence. With respect to the lack of a correlation between daily doses of lamotrigine and its levels in maternal serum and umbilical cord blood, but the almost perfect correlation of maternal serum concentrations and lamotrigine concentrations in amniotic fluid and umbilical cord blood, one has to consider that the concentration of lamotrigine in blood is a much better indicator for the fetal exposure than the daily dose. Consequently, this study is the first to present data on the distribution pattern of lamotrigine between maternal blood, amniotic fluid, and umbilical cord blood. It is part of an ongoing observational approach to determine the distribution of different psychotropic drugs by comparing maternal blood concentrations, umbilical cord blood concentrations, and amniotic fluid concentrations to characterize placental transfer and accumulation properties in amniotic fluid of each drug using serum concentrations as an indicator for drug concentrations in blood. To ensure patient-matched and safe psychopharmacotherapy, therapeutic drug monitoring has proven a valuable tool and seems to be important to ensure patient-matched psychopharmacotherapy even during pregnancy (Hiemke et al., 2011). Treatment of epilepsy or even mood disorders such as bipolar disorder during pregnancy with lamotrigine seems to be relatively safe in terms of major congenital malformations (Kallen et al., 2013). However, it must be taken into account that lamotrigine in the treatment of bipolar disorders is only
Fig. 1
(b)
(a) 4
7
Cord blood : lamotrigine (μg/ml)
Amniotic fluid : lamotrigine (μg/ml)
6 3
2
1
5 4 3 2 1
0
0 0
1
2 3 4 5 6 Maternal serum : lamotrigine (μg/ml)
7
0
1
2 3 4 5 6 Maternal serum : lamotrigine (μg/ml)
7
(a) Correlation between lamotrigine in maternal serum and amniotic fluid (r = + 0.986, P < 0.001); (b) correlation between lamotrigine in maternal serum and umbilical cord blood (r = + 0.928, P = 0.008).
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Lamotrigine distribution during pregnancy Paulzen et al. 253
Fig. 2
(a)
(b) 1.2
4
Amniotic fluid
Amniotic fluid : lamotrigine (μg/ml)
Lamotrigine : mean penetration ratio
Cord blood 1.0
0.8
0.6
0.4
3
2
1
0.2 0 0
Error bars: 95% CI
0
1
2 3 4 5 Cord blood : lamotrigine (μg/ml)
6
7
(a) Mean penetration ratios for lamotrigine were calculated to be 0.58 for amniotic fluid (range 0.31–0.75, SD 0.17) and 0.81 for umbilical cord blood (range 0.48 and 1.27, SD 0.28); (b) lamotrigine levels in amniotic fluid and cord blood were strongly related to each other (r = + 0.882, P = 0.02). CI, confidence interval.
indicated for the prevention of bipolar depressive episodes. Evidence of efficacy in the treatment of acute mania or mixed states in bipolar disorders is lacking, which limits the use during pregnancy. Nonetheless, an increasing metabolism during pregnancy, leading to lower level-to-dose ratios (Clark et al., 2013) with lower serum levels, often requires dose adaptations to prevent seizures in the case of epilepsy or for relapse prevention in the case of bipolar disorder. Irrespective of the contribution of maternal and fetal hepatic elimination of lamotrigine, the data presented here suggest that fetal development occurs in a continuous environment of a pharmacologically active drug when pregnant women are treated with lamotrigine. With respect to the fetal exposure during pregnancy, it is important that the impact of measurable drug levels in amniotic fluid, consistently ingested by swallowing amniotic fluid in late pregnancy or because of respiratory exposure, is investigated systematically (Hostetter et al., 2000; Loughhead et al., 2006). Fetal exposure to psychotropic drugs can be defined more clearly by an improved understanding of the routes of fetal exposure and the factors that influence such pathways. Hence, measurement of drug levels of lamotrigine in amniotic fluid and umbilical cord blood facilitates the understanding of intrauterine drug exposure during pregnancy. A better understanding of the penetration properties of
different drugs into amniotic fluid or fetal circulation and knowledge about the correlation between the concentrations in the different compartments could stimulate the development of novel pharmaceutical agents that less easily enter amniotic fluid or fetal circulation, helping to prevent the unborn child from potentially negative effects. Taken together, measurement of lamotrigine concentrations in maternal blood during pregnancy is a valuable tool for predicting the in-utero exposition of the unborn child. As maternal serum concentrations correlate significantly with concentrations in amniotic fluid and umbilical cord blood with high penetration ratios, it can be stated that lamotrigine can cross the placenta easily without harmful effects. Nonetheless, therapeutic efforts should be guided by an orientation toward the lowest therapeutically effective serum concentrations of lamotrigine in maternal blood for seizure prevention or to prevent relapse in mood disorders to reduce the risk of potentially negative effects on the fetus. The data presented here underscore the need to apply lowest doses for efficacy and to use multiple times of administration (three times daily or four times daily) to avoid an overload of the placental barrier during the course of very high plasma or serum levels of a drug. From a clinical point of view, it might be useful to target effective plasma or serum levels of lamotrigine that had
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254 International Clinical Psychopharmacology 2015, Vol 30 No 5
been measured as part of clinical routine before a pregnancy. As the metabolism of lamotrigine increases during pregnancy, it might be useful during the course of the pregnancy to slightly increase the dose from the effective dose before pregnancy to reduce the risk of negative consequences of sinking drug levels. In both epilepsy and bipolar disorders, preceding (effective) serum levels are a good clinical indicator for dose adaptations during pregnancy. The use of lamotrigine as a mood stabilizer in the treatment of bipolar disorders is limited to the prevention of relapses in bipolar depression. For bipolar disorders during pregnancy, the treatment regimen would be better based on mood stabilizers that are well proven, effective, and thus classified as harmless such as quetiapine with a low placental passage (Newport et al., 2007).
Acknowledgements The authors wish to thank Mr Geer Janssen, Dr Roland Hansen, and Dr Bernhard Wolf from the Medical Care Center; Dr Stein and colleagues, Moenchengladbach, Germany, for determination of lamotrigine for this investigation and for the fruitful collaboration. Authorship contributions: M.P., G.G., C.H.: participated in research design; M.P., T.W.G., T.V.: conducted experiments; M.P., S.E.L.: performed data analysis; and M.P., S.E.L., T.W.G., T.V., C.H., G.G.: wrote or contributed to the writing of the manuscript. Conflicts of interest
Dr Gründer has served as a consultant for Bristol-Myers Squibb (New York, NY), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, IN, USA), Forest Laboratories (New York, NY, USA), Lundbeck (Copenhagen, Denmark), Otsuka (Rockville, MD, USA), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Bristol-Myers Squibb, Eli Lilly, Gedeon Richter (Budapest, Hungary), Otsuka, Roche, and Servier. He has received grant support from Alkermes, Eli Lilly, and Roche. He is cofounder of Pharma-Image – Molecular Imaging Technologies GmbH, Düsseldorf, and Brainfoods UG, Düsseldorf. Dr Hiemke has served as a consultant for Servier (Paris, France) and JanssenCilag (Beerse, Belgium). He has served on the speakers’ bureau of Bristol-Myers Squibb, Eli Lilly, Pfizer, and Servier. He is managing director of the Psiac GmbH, Mainz, which provides an internet-based drug interaction program for psychoactive drugs. For the remaining authors there are no conflicts of interest.
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Lamotrigine in pregnancy – therapeutic drug monitoring in maternal blood, amniotic fluid, and cord blood Michael Paulzena, Sarah E. Lammertza, Tanja Veselinovica, Tamme W. Goeckeb, Christoph Hiemkec and Gerhard Gründera This study is the first to measure and correlate lamotrigine concentrations in maternal blood, amniotic fluid, and umbilical cord blood and account for distribution of the drug between these three compartments. Concentrations of lamotrigine were measured in six mother–infant pairs at the time of delivery. Daily doses of lamotrigine ranged between 200 and 650 mg. Daily doses were correlated with maternal serum and umbilical cord blood concentrations, and serum levels were correlated with levels in amniotic fluid. Lamotrigine levels in serum correlated strongly with the lamotrigine levels in amniotic fluid (r = + 0.986, P < 0.001) and cord blood (r = + 0.928, P = 0.008). The penetration ratio into amniotic fluid was in a range between 0.31 and 0.75 (mean 0.58, SD 0.17); the penetration ratio into the fetal circulation, calculated on the basis of umbilical cord blood levels, was found to be in a range between 0.48 and 1.27 (mean 0.81, SD 0.28). Lamotrigine concentrations in amniotic fluid provided evidence that maternally administered lamotrigine is accessible to the fetus in a manner not previously
Introduction The use of psychotropic drugs during pregnancy is increasing (Thomas and Yates, 2012; Kallen et al., 2013), but pregnant women and prescribers are rightly concerned about potential adverse effects on the fetus. This is because of the fact that for the majority of psychotropic drugs, clinical experience is still insufficient with respect to their safety in pregnancy (Schaefer, 2011). Accordingly, the treatment of psychiatric and/or neurologic diseases during pregnancy using psychotropic drugs is always complicated by the concern for the safety of the mother and the unborn child. By balancing the risks, one has to take into account that every pregnancy outcome is influenced by the natural course of the untreated disease such as epilepsy, depression, or psychosis on the one hand or by potential negative effects of drug intake on the other. Leaving epilepsy untreated during pregnancy appears to be disadvantageous from the standpoint of seizure control, but does not seem to reduce the risk of fetal malformation unless one avoids valproate (Vajda et al., 2014). Children of mothers with untreated or inadequately treated psychiatric diseases such as depression or psychosis might be at risk of future psychopathology (Nulman et al., 2012), intrauterine growth retardation (Grote et al., 2010; Uguz et al., 2011), or even at risk for maternal suicidal behavior because of uncontrolled symptomatology (Klys et al., 2007). When the thalidomide scandal occurred in the early 1960s, it became obvious that the placenta is not able to 0268-1315 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
appreciated. Furthermore, the penetration ratio into umbilical cord blood calculated here is in line with the largest study carried out so far to explore transplacental transfer. Int Clin Psychopharmacol 30:249–254 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. International Clinical Psychopharmacology 2015, 30:249–254 Keywords: amniotic fluid, cord blood, epilepsy, lamotrigine, mood stabilizer, pharmacokinetics, placental transfer, pregnancy, therapeutic drug monitoring a Department of Psychiatry, Psychotherapy and Psychosomatics and JARA – Translational Brain Medicine, bDepartment of Gynaecology and Obstetrics, RWTH Aachen University, Aachen and cDepartment of Psychiatry and Psychotherapy, Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany
Correspondence to Michael Paulzen, MD, Department of Psychiatry, Psychotherapy and Psychosomatics and JARA – Translational Brain Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany Tel: + 49 241 80 89508; fax: + 49 241 80 82401; e-mail: [email protected] Received 25 March 2015 Accepted 19 May 2015
provide a fully protected environment for the fetus (Eshkoli et al., 2011). However, the placenta constitutes the sole structural barrier at the maternal–fetal interface (Ganapathy et al., 2000) and separates the maternal and fetal circulations. It performs many functions that support the maintenance of pregnancy and the normal development of the fetus, but various factors can influence placental transfer, including the physicochemical properties of a drug (Hutson et al., 2011). Passive diffusion of drugs across the human placental barrier mainly depends on properties related to the chemical structure of the drugs and compartmental pH, being also influenced by pharmacokinetic parameters and physiological conditions such as protein binding, volume of distribution, renal plasma flow, and glomerular filtration rate. Moreover, the placenta expresses a multitude of transporters such as p-glycoprotein, multidrug-resistance proteins, and others facilitating or preventing the passage of xenobiotics (Giaginis et al., 2012). Through enzyme activity such as cytochromes or uridine 5′-diphosphoglucuronosyltransferase (UGT), the human placenta can metabolize a large diversity of pharmacologically active molecules eliciting or inhibiting fetotoxic effects (Reimers et al., 2011; Giaginis et al., 2012). Quantification of the extent of placental passage or knowledge of the accumulation of a drug in amniotic fluid as another route of fetal exposure (Loughhead et al., 2006) can facilitate medication selection on the basis of DOI: 10.1097/YIC.0000000000000088
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250 International Clinical Psychopharmacology 2015, Vol 30 No 5
the extent of fetal drug exposure and ultimately provide insight into whether or not neonatal complications are directly related to medication exposure with measurable drug levels in amniotic fluid or fetal circulation. Accumulating evidence suggests an association between prenatal exposure to antiepileptic drugs and increased risk of both physical anomalies and neurodevelopmental impairment (Bromley et al., 2014). Hence, any decision for or against a psychopharmacological treatment with antiepileptic drugs detached from the indication of treating epilepsy or for the treatment of bipolar disorder or depression requires a careful balance between the risks for the mother and the unborn child. The difficulty of a drug therapy using antiepileptic drugs during pregnancy is to find a balance between minimal fetal drug exposure and maximum maternal relapse prevention or seizure control in the case of epilepsy. Lamotrigine, an antiepileptic drug of the phenyltriazine class, is chemically unrelated to other existing antiepileptic drugs (Glaxosmithkline, 2014). It is used for the adjunctive treatment of partial seizures in epilepsy and generalized seizures of Lennox–Gastaut syndrome. In psychiatry, lamotrigine is recommended in bipolar disorder maintenance when depression is prominent (Reid et al., 2013). It is believed to exert its anticonvulsant effect by stabilizing presynaptic neuronal membranes; however, the mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder or depression have not been established. Lamotrigine inhibits sodium currents by selectively binding to the inactivated state of the sodium channel and subsequently suppresses the release of the excitatory amino acid glutamate. Lamotrigine is metabolized primarily through the liver by glucuronidation (Cohen et al., 1987; Green et al., 1995). UGT1A4 catalyzes 90% of lamotrigine conjugation and the major metabolite, lamotrigine-2-N-glucuronide, is excreted through the kidneys (Green et al., 1995). Estradiol upregulates the expression of UGT1A4, which increases lamotrigine clearance associated with increasing estrogen levels during pregnancy (Chen et al., 2009). Furthermore, decreasing levels of lamotrigine during pregnancy might be a result of placental expression of UGT1A isozymes facilitating the lamotrigine metabolism (Reimers et al., 2011). In terms of increasing the risk for major congenital malformations, lamotrigine seems to be unsuspicious (Kallen et al., 2013) and only one study found a dosedependent increase in the malformation rate (2% at < 300 mg/day and 4.5% at ≥ 300 mg/day) (Tomson et al., 2011). However, correlations between drug levels in maternal serum, amniotic fluid, or umbilical cord blood and malformation rates have never been investigated. The ‘International Lamotrigine Pregnancy Registry’ did not detect an appreciable increase in major congenital malformations frequency following first-trimester lamotrigine monotherapy exposure (Cunnington et al., 2011)
and fetal exposure was not associated with neurocognitive deficits in early childhood (Meador et al., 2012). The aim of our study was to analyze the distribution pattern of lamotrigine in maternal serum, amniotic fluid, and umbilical cord blood, to account for the relation between the applied daily doses of lamotrigine and the serum as well as the umbilical cord blood concentrations and concentrations in amniotic fluid at the time of delivery in patients with epilepsy under naturalistic/ clinical conditions. To account for the placental penetration, the correlation between maternal serum concentrations of lamotrigine and the cord blood concentration was calculated. Furthermore, the correlation between maternal serum and amniotic fluid was computed to account for the impact of drug accumulation in amniotic fluid as one way of fetal exposure.
Materials and methods Patients
This investigation is part of an observational study examining the distribution pattern of different psychotropic drugs in maternal blood, amniotic fluid, and umbilical cord blood in pregnant women at the time of delivery. It has been carried out as a collaboration between the Department of Psychiatry, Psychotherapy, and Psychosomatics, and the Department of Gynaecology and Obstetrics – Perinatalcenter Level I, at the University Hospital of RWTH Aachen University, Germany, since November 2012. The study protocol was approved by the local Ethics Committee. Data of six pregnant women, ranging in age from 19 to 35 years (mean age = 28.8 ± 6; median = 29.5), and six newborns are presented. Women were treated throughout their pregnancies with lamotrigine in fixed daily doses between 200 and 650 mg. The last dose adaptations were performed more than 2 weeks before delivery. Two patients were comedicated with 25 mg clobazam per day at the time of delivery for seizure control (started some days before delivery) and one patient received 3000 mg levetiracetam additionally throughout the entire pregnancy. All patients were diagnosed with localizationrelated idiopathic epilepsy and epileptic syndromes with seizures of localized onset according to ICD-10, G44.0. All six mother–infant pairs provided maternal serum levels, amniotic fluid levels, and umbilical cord levels at delivery. Methods
The present study is a naturalistic prospective investigation of lamotrigine concentrations in maternal serum and amniotic fluid in six women and umbilical cord blood of their six newborns. Blood was taken at the same time as delivery under steady-state conditions with respect to the ingested drug, but because of clinical circumstances not as trough levels. As an indicator for drug levels in blood, we used serum concentrations. Serum was
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– 0.59 2.4 0.68 2.8 1.17 4.1
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LAM, lamotrigine; LDR, level-to-dose ratio. a All patients had epilepsy and lamotrigine was used in this particular indication. b LDR is calculated by the formula: lamotrigine level (µg/ml) × 100/prescribed daily lamotrigine dose (mg). c Patient 1 delivered two infants with two pregnancies within 16 months.
350 10/10/10 Female 62th 3395 Section 34 6
38 + 4
Clobazam 0.77 4.8 0.45 2.8 1.55 6.20 400 10/10/10 Male 59th 2600 Section 19 5
33 + 4
– 0.48 1.4 0.31 0.9 0.58 2.9 500 9/10/10 Male 44th 3270 Section 27 4
38 + 1
31 3
34 + 1
Section
2440
56th
Male
7/9/9
200
1.1
0.55
0.75
0.68
1.4
1.27
–
Normal Hyponatriaemia, hyperbilirubinemia Respiratory distress syndrome, hyperbilirubinemia DiGeorge syndrome, interrupted aortic arc type B, ventricle septal defect Slow feeding of newborn Normal Clobazam Levetiracetam 0.95 0.80 6.2 2.65 0.58 0.75 3.8 2.47 1.00 0.55 6.53 3.31 650 600
LDR
b
APGAR
9/10/10 9/9/9 Male Female 10th 78th 2900 3170 Section Spontanous 38 + 6 35 + 6 35 26
Ratio amniotic fluid LAM amniotic fluid (µg/ml) LAM maternal serum (µg/ml) Daily dose of LAM (mg) Patient numbera
Obstetrical outcome data, and data on daily doses, serum, amniotic fluid, and cord blood concentrations of lamotrigine are shown in Table 1. Obstetrical outcome data are available for all six infants. Obstetrical complications included two of six preterm deliveries (i.e. < 37 weeks’ gestational age). One infant had a prenatally diagnosed DiGeorge syndrome with an interrupted aortic arc type B and a ventricle septal defect, one infant showed signs of a respiratory distress syndrome, and one infant showed a slow feeding syndrome. These three infants were temporarily admitted to the ICU. With respect to the weight, only one infant had a low birth weight (i.e. < 2.5 kg); all six were within a range between the 10th and the 78th percentile. The average daily dose of lamotrigine was 458.3 mg (SD 162.5, range 200–650 mg), applied twice daily. Maternal serum levels of lamotrigine were in a range between 1.1 and 6.5 µg/ml (mean 4.0 µg/ml, SD 2.1 µg/ml, recommended therapeutic drug concentration range 3–14 µg/ml) (Hiemke et al., 2011). In amniotic fluid, lamotrigine levels ranged between 0.8 and 3.8 µg/ml (mean 2.3 µg/ml, SD 1.2 µg/ml) and in the cord
Gestational age at delivery Maternal age (weeks) Mode of delivery Weight (g) Percentile Infant sex
Results
Patients’ characteristics and clinical characteristics of six mothers taking lamotrigine during pregnancy and their infants
Correlations were computed to assess the relation between the level of drug concentrations in maternal serum, amniotic fluid, and cord blood, as well as the relation of these concentrations with the daily dose of lamotrigine. Because of the small sample size, nonparametric tests were used to analyze data. Statistical analyses were carried out using SPSS (version 21; IBM Corp., Armonk, New York, USA).
Table 1
To account for the range of doses of lamotrigine received by the patients, we divided the serum, amniotic fluid, and cord blood levels of lamotrigine by the applied dose of lamotrigine (applied twice daily), resulting in a levelby-dose-ratio of lamotrigine for serum, amniotic fluid, and cord blood, respectively. In addition, the penetration ratio into the amniotic fluid and cord blood of lamotrigine was calculated. For this purpose, the levels of lamotrigine in amniotic fluid as well as cord blood were divided by their counterpart levels in the maternal serum, reflecting the penetration ratio into amniotic fluid and cord blood, respectively.
LAM cord blood (µg/ml)
Statistical analysis
1 2
Ratio cord blood
Concomitant medications
prepared by centrifugation of blood samples at 14 171 g for 15 min. Lamotrigine concentrations in maternal serum, amniotic fluid, and umbilical cord blood were determined with an isocratic HPLC system with a UV detector using a reagent kit from Chromsystems Instruments & Chemicals GmbH (Graefelfing/Munich, Germany). The method is linear from the designated limit of quantification of 0.3 µg/ml up to the upper limit of 30 µg/ml for lamotrigine. Intraassay precision and accuracy over a range from 2.7 to 10 µg/ml is less than 2%; interassay precision is less than 6%.
c
Outcome/birth defect
Lamotrigine distribution during pregnancy Paulzen et al. 251
252 International Clinical Psychopharmacology 2015, Vol 30 No 5
blood drug levels were found between 1.4 and 6.2 µg/ml (mean 3.1 µg/ml, SD 2.0 µg/ml). The level-by-dose-ratio was calculated using the following formula: lamotrigine level (µg/ml) × 100/prescribed daily lamotrigine dose (mg) (Clark et al., 2013). In maternal serum, it was 0.90 (SD 0.41, range 0.55–1.55), for amniotic fluid, it was 0.51 (SD 0.23, range 0.18–0.8 µg/ml), and for cord blood, it was 0.71 (SD 0.33, range 0.28–1.20). A significant relation between the daily dosage of lamotrigine and its concentrations in serum, amniotic fluid, and cord blood could not be observed. However, the lamotrigine levels in serum correlated strongly with the lamotrigine levels in amniotic fluid (r = + 0.986, P < 0.001) and cord blood (r = + 0.928, P = 0.008) as shown in Fig. 1a and b. The penetration ratio for lamotrigine into amniotic fluid was in a range between 0.31 and 0.75 (SD 0.17, mean 0.58); the penetration ratio into the fetal circulation, calculated on the basis of umbilical cord blood levels, was found to be in a range between 0.48 and 1.27 (SD 0.28, mean 0.81) (Fig. 1a and b). Lamotrigine levels in amniotic fluid and cord blood were strongly related to each other (r = + 0.882, P = 0.02) (Fig. 2).
Discussion In the 1970s, Wilson (1973) formulated six principles of teratology that have guided research in developmental toxicology to this day. His sixth and final principle ‘Manifestations of deviant development increase in frequency and degree as dosage increases, from no-effect to
the totally lethal level’, among others, describes the range of toxicity from no-effect to completely lethal (Aston, 2014). This means that the outcome depends on the dose, threshold, and duration of xenobiotic influence. With respect to the lack of a correlation between daily doses of lamotrigine and its levels in maternal serum and umbilical cord blood, but the almost perfect correlation of maternal serum concentrations and lamotrigine concentrations in amniotic fluid and umbilical cord blood, one has to consider that the concentration of lamotrigine in blood is a much better indicator for the fetal exposure than the daily dose. Consequently, this study is the first to present data on the distribution pattern of lamotrigine between maternal blood, amniotic fluid, and umbilical cord blood. It is part of an ongoing observational approach to determine the distribution of different psychotropic drugs by comparing maternal blood concentrations, umbilical cord blood concentrations, and amniotic fluid concentrations to characterize placental transfer and accumulation properties in amniotic fluid of each drug using serum concentrations as an indicator for drug concentrations in blood. To ensure patient-matched and safe psychopharmacotherapy, therapeutic drug monitoring has proven a valuable tool and seems to be important to ensure patient-matched psychopharmacotherapy even during pregnancy (Hiemke et al., 2011). Treatment of epilepsy or even mood disorders such as bipolar disorder during pregnancy with lamotrigine seems to be relatively safe in terms of major congenital malformations (Kallen et al., 2013). However, it must be taken into account that lamotrigine in the treatment of bipolar disorders is only
Fig. 1
(b)
(a) 4
7
Cord blood : lamotrigine (μg/ml)
Amniotic fluid : lamotrigine (μg/ml)
6 3
2
1
5 4 3 2 1
0
0 0
1
2 3 4 5 6 Maternal serum : lamotrigine (μg/ml)
7
0
1
2 3 4 5 6 Maternal serum : lamotrigine (μg/ml)
7
(a) Correlation between lamotrigine in maternal serum and amniotic fluid (r = + 0.986, P < 0.001); (b) correlation between lamotrigine in maternal serum and umbilical cord blood (r = + 0.928, P = 0.008).
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Lamotrigine distribution during pregnancy Paulzen et al. 253
Fig. 2
(a)
(b) 1.2
4
Amniotic fluid
Amniotic fluid : lamotrigine (μg/ml)
Lamotrigine : mean penetration ratio
Cord blood 1.0
0.8
0.6
0.4
3
2
1
0.2 0 0
Error bars: 95% CI
0
1
2 3 4 5 Cord blood : lamotrigine (μg/ml)
6
7
(a) Mean penetration ratios for lamotrigine were calculated to be 0.58 for amniotic fluid (range 0.31–0.75, SD 0.17) and 0.81 for umbilical cord blood (range 0.48 and 1.27, SD 0.28); (b) lamotrigine levels in amniotic fluid and cord blood were strongly related to each other (r = + 0.882, P = 0.02). CI, confidence interval.
indicated for the prevention of bipolar depressive episodes. Evidence of efficacy in the treatment of acute mania or mixed states in bipolar disorders is lacking, which limits the use during pregnancy. Nonetheless, an increasing metabolism during pregnancy, leading to lower level-to-dose ratios (Clark et al., 2013) with lower serum levels, often requires dose adaptations to prevent seizures in the case of epilepsy or for relapse prevention in the case of bipolar disorder. Irrespective of the contribution of maternal and fetal hepatic elimination of lamotrigine, the data presented here suggest that fetal development occurs in a continuous environment of a pharmacologically active drug when pregnant women are treated with lamotrigine. With respect to the fetal exposure during pregnancy, it is important that the impact of measurable drug levels in amniotic fluid, consistently ingested by swallowing amniotic fluid in late pregnancy or because of respiratory exposure, is investigated systematically (Hostetter et al., 2000; Loughhead et al., 2006). Fetal exposure to psychotropic drugs can be defined more clearly by an improved understanding of the routes of fetal exposure and the factors that influence such pathways. Hence, measurement of drug levels of lamotrigine in amniotic fluid and umbilical cord blood facilitates the understanding of intrauterine drug exposure during pregnancy. A better understanding of the penetration properties of
different drugs into amniotic fluid or fetal circulation and knowledge about the correlation between the concentrations in the different compartments could stimulate the development of novel pharmaceutical agents that less easily enter amniotic fluid or fetal circulation, helping to prevent the unborn child from potentially negative effects. Taken together, measurement of lamotrigine concentrations in maternal blood during pregnancy is a valuable tool for predicting the in-utero exposition of the unborn child. As maternal serum concentrations correlate significantly with concentrations in amniotic fluid and umbilical cord blood with high penetration ratios, it can be stated that lamotrigine can cross the placenta easily without harmful effects. Nonetheless, therapeutic efforts should be guided by an orientation toward the lowest therapeutically effective serum concentrations of lamotrigine in maternal blood for seizure prevention or to prevent relapse in mood disorders to reduce the risk of potentially negative effects on the fetus. The data presented here underscore the need to apply lowest doses for efficacy and to use multiple times of administration (three times daily or four times daily) to avoid an overload of the placental barrier during the course of very high plasma or serum levels of a drug. From a clinical point of view, it might be useful to target effective plasma or serum levels of lamotrigine that had
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254 International Clinical Psychopharmacology 2015, Vol 30 No 5
been measured as part of clinical routine before a pregnancy. As the metabolism of lamotrigine increases during pregnancy, it might be useful during the course of the pregnancy to slightly increase the dose from the effective dose before pregnancy to reduce the risk of negative consequences of sinking drug levels. In both epilepsy and bipolar disorders, preceding (effective) serum levels are a good clinical indicator for dose adaptations during pregnancy. The use of lamotrigine as a mood stabilizer in the treatment of bipolar disorders is limited to the prevention of relapses in bipolar depression. For bipolar disorders during pregnancy, the treatment regimen would be better based on mood stabilizers that are well proven, effective, and thus classified as harmless such as quetiapine with a low placental passage (Newport et al., 2007).
Acknowledgements The authors wish to thank Mr Geer Janssen, Dr Roland Hansen, and Dr Bernhard Wolf from the Medical Care Center; Dr Stein and colleagues, Moenchengladbach, Germany, for determination of lamotrigine for this investigation and for the fruitful collaboration. Authorship contributions: M.P., G.G., C.H.: participated in research design; M.P., T.W.G., T.V.: conducted experiments; M.P., S.E.L.: performed data analysis; and M.P., S.E.L., T.W.G., T.V., C.H., G.G.: wrote or contributed to the writing of the manuscript. Conflicts of interest
Dr Gründer has served as a consultant for Bristol-Myers Squibb (New York, NY), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, IN, USA), Forest Laboratories (New York, NY, USA), Lundbeck (Copenhagen, Denmark), Otsuka (Rockville, MD, USA), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Bristol-Myers Squibb, Eli Lilly, Gedeon Richter (Budapest, Hungary), Otsuka, Roche, and Servier. He has received grant support from Alkermes, Eli Lilly, and Roche. He is cofounder of Pharma-Image – Molecular Imaging Technologies GmbH, Düsseldorf, and Brainfoods UG, Düsseldorf. Dr Hiemke has served as a consultant for Servier (Paris, France) and JanssenCilag (Beerse, Belgium). He has served on the speakers’ bureau of Bristol-Myers Squibb, Eli Lilly, Pfizer, and Servier. He is managing director of the Psiac GmbH, Mainz, which provides an internet-based drug interaction program for psychoactive drugs. For the remaining authors there are no conflicts of interest.
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