Vývoj terapie těhotných žen s epilepsií v ostravském regionu v letech 1991 až 2006
Práce monitoruje dlouhodobý trend v používání antiepileptik během těhotenství a sleduje jejich koncentrace při porodu. Jako zdroj informací byly použity údaje ze žádanek a koncentrace antiepileptik stanovené v rámci rutinního terapeutického monitorování při porodu v letech 1991–2006. Ve skupině 235 těhotenství jsme během tří pětiletých period sledovali použití mono- versus polyterapie antiepileptiky, četnost výskytu jednotlivých antiepileptik i jejich kombinací a naměřené koncentrace. Monoterapie antiepileptiky byla předepisována v letech 1991–1995 v 61 %, v letech 1996–2000 v 68 % a v letech 2001–2006 u 76 % těhotných. Nejvíce užívanými byly během prvního období fenytoin, karbamazepin a primidon, během druhého období karbamazepin, fenytoin a kyselina valproová a ve třetím období karbamazepin, lamotrigin a kyselina valproová. Většina naměřených koncentrací byla pod terapeutickým rozmezím s výjimkou karbamazepinu ve všech periodách a primidonu v druhém a třetím období. Během 15letého sledování jsme prokázali signifikantní posun v léčbě epilepsie těhotných z poly- na monoterapii a z prvo- a druho-generačních antiepileptik na látky druhé a třetí generace. Ve srovnání s daty švédských autorů došlo u nás k posunu o 10 let později a podíl monoterapie byl stále mírně nižší, avšak naše údaje byly srovnatelné s údaji EURAPu. Výsledky ukazují správný vývoj terapie těhotných epileptiček v ostravském regionu České republiky.
I. Kacířová; M. Grundmann; B. Kořístková; H. Brozmanová
Department of Clinical Pharmacology, Medical Faculty, University Ostrava and University Hospital, Ostrava
Vyšlo v časopise:
Čes. slov. Farm., 2010; 59, 172-178
The paper discusses long-term trends in the utilization of antiepileptic drugs during pregnancy and reports an analysis of their concentrations at delivery. The request forms for routine therapeutic drug monitoring and concentrations of antiepileptic drugs at delivery collected between the years 1991–2006 were used as the data source. Monotherapy versus polytherapy, the utilization of individual antiepileptic drugs and combinations, and concentrations were monitored in a group of 235 pregnancies within three 5-year periods. Monotherapy was used in 61% in the years 1991–1995, in 68% in the years 1996-2000, and in 76% in the years 2001–2006. During the1st period, the most frequently prescribed agents were phenytoin, carbamazepine and primidone, during the 2nd period, carbamazepine, phenytoin, and valproic acid, and during the 3rd period, carbamazepine, lamotrigine, and valproic acid. Concentrations were mostly under the therapeutics range with an exception of carbamazepine and primidone. Our data demonstrate a significant shift from poly- to monotherapy and from the first- and second-generation to the second- and third-generation of antiepileptic drugs in pregnant women suffering from epilepsy. The shift from poly- to monotherapy has taken place 10 years later and, moreover, the rate of monotherapy was lower than in Sweden but the result was in a good agreement with the EURAP report. Our results evidence a good progress in the treatment of pregnant women suffering from epilepsy in the region of Ostrava.
is a neurological disorder with a prevalence of approximately 0.5–1.5% in
general population 1) and women suffering from epilepsy have been
estimated to account for 0.3–0.4% of all pregnancies 2). Until 1993,
six so-called old-generation (or first- and second-generation) antiepileptic
drugs (AEDs) (phenytoin, phenobarbital, primidone, ethosuximide, carbamazepine
and valproate) accounted for the overwhelming majority of prescriptions written
for the treatment of epilepsy. Since 1993, felbamate, gabapentin, lamotrigine,
topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide and pregabalin
(so-called new-generation or third-generation antiepileptic drugs) have been
approved for the treatment of epilepsy 3). In the Czech Republic,
carbamazepine for focal (partial) or secondarily generalised tonic-clonic
seizures, valproate and lamotrigine for all type of seizures when the epileptic
syndrome is not precisely identified, but the type of seizures is known, are
recommended as the first choice of AEDs 4).
decisions for pregnant women suffering from epilepsy are complicated by the
lack of evidence-based data on the comparative teratogenic potential of
different AEDs. However, the most recent consensus guidelines issued by the
American Academy of Neurology, the American College of Obstetricians and
Gynecologists, and the International League against Epilepsy recommend:
optimization treatment prior to conception,
to use monotherapy if possible,
to choose the most effective AED for the seizure type and syndrome,
to use the lowest effective dose,
to supplement treatment with folate,
to treat the child with vitamin K at birth and possibly the mother late in
pregnancy for AEDs that interfere with vitamin K.
Nevertheless, no recommendations related to different
AEDs teratogenetic risk are offered 5). Pregnancy can affect the
pharmacokinetics of AEDs at all levels, absorption, distribution, metabolism and
elimination, resulting in declining plasma concentrations of AEDs as the
pregnancy progresses. The alterations can be expected but their magnitude is
difficult to predict. Therefore regular therapeutic drug monitoring (TDM) of
AEDs during pregnancy and postpartum is recommend 6). There are only
a few papers following-up the development of AEDs therapy during pregnancy.
Wide et al. 7) analyzed AEDs therapy in a Swedish population over a
period of 25 years. From 1999 some collected data of 42 countries are available
in International Antiepileptic Drugs and Pregnancy Registry (EURAP) 8).
trends in the utilization of antiepileptic drugs during pregnancy in the region
of Ostrava in the Czech Republic was the primary aim of our study, an analysis
of maternal concentrations of AEDs at delivery being the secondary aim.
request forms for routine therapeutic drug monitoring and maternal AEDs plasma
levels measured at delivery were used as the data source. The study involved
all samples from pregnant women treated with AEDs and collected in our
department between the years 1991–2006. During three study periods (1991–1995,
1996–2000, 2001–2006), AEDs monotherapy versus polytherapy, the utilization of
individual AEDs and the utilization of combinations of AEDs, and plasma levels
were analyzed. Plasma concentrations of AEDs were measured by gas
chromatography and liquid chromatography 9–12). Collected data were
statistically analyzed by χ2 test.
study group consisted of 235 women. Maternal age and weight are presented in
Table 1. A total daily dose of AEDs and a daily dose related to the body weight
are stated in Table 2 and Table 3.
Monotherapy was used during the first period in 61% of
women, during the second period in 68% of women, and in the third period in 76%
of women. Utilization of monotherapy in the third period was significantly
higher than in the first period (p < 0.05) (Fig. 1). The most frequently
prescribed AEDs independently of mono- and polytherapy during the first study
period were phenytoin (PHT) (45.3%), carbamazepine (CBZ) (24.0%) and primidone
(PRM) (9.3%), during the second period CBZ (50.5%), PHT (21.0%) and valproic acid
(VPA) (11.4%), and during the third period CBZ (34.6%), lamotrigine (LTG)
(24.4%) and VPA (21.3%), respectively. The most widely administered AEDs and
combinations in relation to mono- and polytherapy were found during the firststudy period PHT (33.3%), CBZ (13.7%) and CBZ+PHT (13.7%), during the
second period CBZ (44.4%), PHT (13.6%) and CBZ+VPA (8.6%), and during the third
period CBZ (31.0%), LTG (22.3%) and VPA (12.6%), respectively (Table 4).
In all three study periods plasma levels of individual
AEDs were mostly under the therapeutic range (estimated for non-pregnant women)
with an exception of CBZ (during the first period 50% of women were in the
therapeutics range, during the second period 40% of women were in the
therapeutics range, and during the third period 45% of women were in the
therapeutics range) and PRM (during the second period 44% of women were in the
therapeutics range and 11% of women were above the therapeutic range, and
during the third period 50% of women were in the therapeutics range) (Tables 5
and 6). Non-detectable concentrations have been found in 6.0% of patients, most
frequently for lamotrigine followed by phenytoin, carbamazepine and primidone,
indicating possible non-compliance.
data showed a significant shift over the years from AEDs polytherapy to
monotherapy, which is in good agreement with the recommendations of the
American Academy of Neurology, the American College of Obstetricians and
Gynecologists, and the International League against Epilepsy 5) for
the treatment of pregnant women suffering from epilepsy as well as for the
treatment of epilepsy in general population 14). The result of our
third study period was comparable with the EURAP group 8) but
the rate of monotherapy we found lower than in the latest data set of Wide et
al. 7) in the years 1995–1997 (Table 7). Earlier results of Wide et
al. 7) showed monotherapy of AEDs in the first data set
(1973–1981) only in 47% of the mothers (polytherapy in 53%) and in the second
data set (1984–1994) monotherapy was used in 82% of the mothers (polytherapy in
Carbamazepine was the most often used antiepileptic drug
in all three compared studies, followed by lamotrigine and valproic acid in the
EURAP 8) and in our study group (Table 8). In the study of Wide et
al. 7), carbamazepine was followed by valproic acid and phenytoin
due to earlier time of analysis.
Plasma levels of AEDs during pregnancy were recorded
only by Wide et al. 13) between the years 1985 and 1995. During the
third trimester, plasma concentrations of CBZ (N = 39) ranged from 11 to 32 μmol/L (2.6–7.6 mg/L)
with a mean of 20 μmol/L (4.7 mg/L) and plasma concentrations of PHT (N =
22) ranging from 5 to 78 μmol/L (1.3–19.7 mg/L) with a mean 20 μmol/L (5.1 mg/L). The
mean of CBZ and PHT plasma levels measured during our first study period was
similar as that recorded by Wide et al. 13). The results of our
study concerning to the plasma levels are more complex and include TDM of
primidone, phenobarbital, phenobarbital as a metabolite of primidone,
ethosuximide, phenytoin, valproic acid, carbamazepine, epoxy-metabolite of
carbamazepine, clonazepam, diazepam and its metabolite nordiazepam, lamotrigine
and topiramate. The most of the measured values were under the usual
therapeutic range for non-pregnant patients, which was caused either by
gestational alterations in the pharmacokinetics of AEDs at all levels
(absorption, distribution, metabolism and elimination) 6) or by
non-compliance of pregnant women. These changes could be a reason for the
failure to attain the expected effect of AEDs treatment 14).
In conclusion, our data demonstrate a significant shift
from AEDs poly- to monotherapy and from the first- and second- generation AEDs
(PHT, CBZ and PRM) to the second- and third-generation AEDs (CBZ, LTG and VPA)
in the treatment of pregnanty women suffering from epilepsy between the years
1991 and 2006 in our study group. The result is in good agreement with the
EURAP report 8). The shift from AEDs poly- to monotherapy has taken
place ten years later than in the period described by Wide et al. 7)
and, moreover, the rate of monotherapy in the third period of our study was
lower than in the latest data set of Wide et al. 7) of Sweden who
had excellent access to prenatal care 15). One of the reasons of
discrepancy between the Swedish and our results could be gestational
alterations in the pharmacokinetics of AEDs resulting in declining plasma
concentrations of AEDs as pregnancy progresses 6), which correlate
with the plasma levels under the usual therapeutic range for the most of AEDs
in our study group. This changes may result in a failure of AED monotherapy 14)
followed by an addition of another antiepileptic drug (polytherapy) instead of
dose adjustment. For example, in the case of lamotrigine, an increased seizure
frequency in the second trimester was associated with a lower ratio of current
LTG concentration to the baseline target concentration, and a ratio < 0.65
was a significant predictor of seizure worsening 16). Nevertheless,
our results in the third study period evidence a good progress in the treatment
of pregnant women suffering from epilepsy in the region of Ostrava in the Czech
Republic. Therapeutic drug monitoring of AEDs during pregnancy and after
delivery can be helpful to optimize the treatment in women suffering from
epilepsy in this period of unstable kinetics.
phenytoin: 10–20 mg/L primidone: 5–15 mg/L phenobarbital: 15–35
mg/L ethosuximide: 40–100
mg/L carbamazepine: 4–12
mg/L (in years 1991–2001) 4–9 mg/L (in years
2002–2006) valproic acid: 40–100
mg/L (in years 1991–2000) 50–100 mg/L (in years
2001–2006) clonazepam: 20–80 μg/L lamotrigine: 3–14 mg/L topiramate: 5–20 mg/L
International Antiepileptic Drugs and Pregnancy Registry
phenobarbital as a metabolite of primidone
therapeutic drug monitoring
Address for correspondence:
MUDr. Ivana Kacířová Ústav klinické
farmakologie FN 17. listopadu 1790, 708
52 Ostrava e-mail:
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