Epilepsia, 54(3):405414, 2013
doi: 10.1111/epi.12109
CRITICAL REVIEW AND INVITED COMMENTARY
Antiepileptic drug treatment in pregnancy: Changes in drug
disposition and their clinical implications
orn Tomson, Cecilie Johannessen Landmark, and Dina Battino
*Torbj
*Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Pharmacy and Biomedical
Science, Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway; and
Epilepsy Center, Department of Neurophysiology, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy
SUMMARY
Pregnancy is a state where pharmacokinetic changes
are more pronounced and more rapid than during any
other period of life. The consequences of such
changes can be far reaching, not least in the management
of epilepsy where the risks with uncontrolled seizures
during pregnancy need to be balanced against potential
teratogenic effects of antiepileptic drugs (AEDs). This
article aims to review the literature on gestational
effects on the pharmacokinetics of older and newer
generation AEDs and discuss the implications for the
treatment of epilepsy in women during pregnancy.
Pregnancy can affect the pharmacokinetics of AEDs at
any level from absorption, distribution, metabolism, to
elimination. The effect varies depending on the type
of AED. The most pronounced decline in serum
concentrations is seen for AEDs that are eliminated by
glucuronidation (UGT), in particular lamotrigine where
the effect may be profound. Serum concentrations of
AEDs that are cleared mainly through the kidneys, for
example, levetiracetam, can also decline significantly.
The pharmacologic treatment of epilepsy is seldom
more challenging than during pregnancy. Treatment
involves drug exposure to at least two individuals: the
mother with epilepsy and the unborn fetus(es). The mater-
nal and fetal risks imposed by uncontrolled epileptic sei-
zures need to be balanced against the possible adverse
fetal effects of antiepileptic drugs (AEDs). Management
is further complicated by the fact that effects on the fetus
can be difficult to monitor and may be irreversible. Major
convulsive seizures (generalized tonicclonic seizures)
can be harmful to the fetus, in addition to causing medical
risks and psychosocial consequences for the mother with
Accepted December 19, 2012; Early View publication January 29, 2013.
Address correspondence to Torbjorn Tomson, Department of Neuro-
logy, Karolinska University Hospital, SE 171 76 Stockholm, Sweden.
E-mail: torbjorn.tomson@karolinska.se
Wiley Periodicals, Inc.
2013 International League Against Epilepsy
405
Some AEDs, such as carbamazepine seem to be affected
only marginally by pregnancy. Data on pharmacokinetics
during pregnancy are lacking completely for some of the
newer generation AEDs: pregabalin, lacosamide, retiga-
bine, and eslicarbazepine acetate. Where data are avail-
able, the effects of pregnancy on serum concentrations
seem to vary considerably individually and are thus diffi-
cult to predict. Although large-scale systematic studies of
the clinical relevance of the pharmacokinetic alterations
are lacking, prospective and retrospective case series
have reported an association between declining serum
concentrations and deterioration in seizures control. The
usefulness of routine monitoring of AED serum concen-
trations in pregnancy and of dose adjustments based on
falling levels, are discussed in this review. We suggest that
monitoring could be important, in particular when
women have been titrated to the lowest effective AED
dose and serum concentration before pregnancy, and
when that individual optimal concentration can be used as
reference.
KEY WORDS: Epilepsy, Pregnancy, Antiepileptic drugs,
Pharmacokinetics.
epilepsy. Fetal loss has been reported in conjunction with
prolonged seizures, such as status epilepticus (Teramo &
Hiilesmaa, 1982), and frequent tonicclonic seizures dur-
ing pregnancy are associated with poorer cognitive devel-
opment of the child (Meador et al., 2009a). On the other
hand, AEDs can be teratogenic, thereby increasing the
risk of congenital malformations as well as of adverse
cognitive outcomes (Tomson & Battino, 2012). Recent
publications from epilepsy and pregnancy registries have
suggested that AEDs differ in their teratogenic potential,
but also that these adverse effects of AEDs on the fetus
are dose-dependent (Meador et al., 2009a; Tomson et al.,
2011; Hernandez-Diaz et al., 2012; Mawhinney et al.,
2012). Therefore, the usually recommended treatment
strategy is to review and possibly revise treatment well
before conception, selecting the most appropriate AED
for the individual woman, taking efficacy as well as tera-
togenic risks into account, and regardless of which drug is
406
T. Tomson et al.

chosen to titrate to the lowest effective dose before

pregnancy (Harden et al., 2009a; National Institute for
Clinical Excellence, 2012; Tomson & Battino, 2012). The
objectives of the further management during pregnancy
are to maintain control of in particular tonicclonic sei-
zures while at the same time keeping exposure to poten-
tially teratogenic drugs to a minimum. This demanding
task is complicated by the fact that pregnancy can signifi-
cantly affect the pharmacokinetics of AEDs with potential
consequences for seizure control as well as drug exposure
to the fetus. So, although the risk of malformations has
been assessed in relation to AED doses at the time of con-
ception (Tomson et al., 2011), or during the first trimester
(Hernandez-Diaz et al., 2012; Mawhinney et al., 2012),
the level of exposure to the fetus can change during the
course of pregnancy. In this article, we review the litera-
ture on the effects of pregnancy on the pharmacokinetics
of different AEDs and discuss the implications for the
treatment of epilepsy in women during pregnancy.
Search Strategy
References for this review were identified from the
authors files and from a PubMed search (from 1966 to July
2012) using various combinations of the following terms
(by searching as text words) pregnan*, maternal
mother, fetal, fetus with the terms *kinetics, dis- Absorption
position, plasma, utilization and the names of individ-
ual AEDs included in the review or the terms
antiepileptic*, anti-epileptic*, anticonvuls*, anti- can, however, vary with the drug formulation. Gastric pH
convuls*, barbit*.
In addition, the list of references of the retrieved articles
was examined for further studies. Moreover, original
research articles and previously published review articles
were examined.
Only articles published in English were reviewed. The
review was restricted to studies in humans.
Mechanisms of Pregnancy-
Induced Alterations
in Drug Disposition
The physiologic changes that take place during preg-
nancy can affect any level of the disposition of drugs, from
absorption, distribution, metabolism, to excretion (ADME,
Fig. 1). It is important to understand the mechanisms by
which pregnancy alters the pharmacokinetics of AEDs, as
this determines the possible clinical implications as will be
discussed in more detail below. However, every pregnancy
represents a singular occurrence of genetic variables and
environmental factors, and AEDs may interact differently
with any of these in the individual woman and also differ-
ently from pregnancy to pregnancy (Wlodarczyk et al.,
2012).
Figure 1.
Pharmacokinetic changes in drug disposition during pregnancy
and basic pharmacokinetic relationships. CL, total clearance;
AUC, area under the curve of a drug; F, bioavailability; t1/2, half-
life; k, elimination constant and Vd, volume of distribution; Css,
serum concentration at steady state, and , dose frequency).
Epilepsia ILAE
Generally, absorption is extensive and bioavailability
high for most AEDs. The rate and extent of absorption
and rate of emptying, and small intestine motility may all
decrease during pregnancy, leading to a decrease in the
absorption of AEDs (Pennell, 2003), and the pharmacoki-
netic parameters peak concentration (Cmax) and time to
peak concentration (Tmax) (Fig. 1). Malaise and vomiting
in early pregnancy are likely to affect the absorption of
AEDs taken orally. An impaired drug absorption would
result in decreased serum concentrations of AEDs and a
possibly decrease inefficacy. However, to the best of our
knowledge, there is only one published report of break-
through seizures due to poor AED absorption during preg-
nancy. This was a single case of phenytoin malabsorption
leading to status epilepticus during pregnancy (Ramsay
et al., 1978). Hence, it appears that poor drug absorption
is a rare cause of treatment failure during pregnancy.
Distribution
During the course of the pregnancy, the blood volume pro-
gressively increases, with a decrease in the total serum con-
centrations of drugs in parallel. The increase in body water
and in fat stores leads to an alteration of fat/water ratio that
may cause an increase in the volume of distribution (Vd). The
overall effects of gestation-induced alterations in Vd appear
to be variable between individuals, but the net effect on active
AED serum concentrations is generally limited.

Epilepsia, 54(3):405414, 2013

doi: 10.1111/epi.12109

Serum albumin and a1-acid glycoprotein levels decline
as pregnancy progresses, and these are essential transporters
for AEDs in the bloodstream. A decrease in serum albumin
and protein binding capacity, and displacement of AEDs by
endogenous compounds, may result in an alteration in the
ratio between the total and the unbound concentration of
highly protein-bound drugs, for example, phenytoin, stirip-
entol, tiagabine, and valproate, AEDs with a protein binding
ranging from 90% to 99% (for review, see (Johannessen
Landmark et al., 2012)). The total serum concentrations of
valproate and phenytoin have been shown to decline in par-
allel with the falling albumin levels (Yerby et al., 1990,
1992). The net effect of a decrease in protein binding is a fall
in the total (bound plus unbound) serum concentration of
the drug, whereas the unbound drug concentration may be
essentially unchanged. The unbound concentration is the
pharmacologically active, and also presumably the concen-
tration determining drug exposure to the fetus. A decrease
in protein binding would thus not alter the effect of treat-
ment, but total serum concentrations as routinely measured
would be misleading and underestimating the effective
concentration and the fetal exposure. Monitoring of
free concentrations may be preferable in such situations
(Johannessen & Tomson, 2006; Patsalos et al., 2008).
Metabolism
The total clearance of AEDs that are metabolized by the
liver depends on the hepatic clearance. The main route is
phase I oxidative metabolism through the cytochrome P450
system (CYP). There are different CYP isoenzymes, each of
which is a specific gene product with characteristic sub-
strate specificity, where CYP3A4, CYP2C9, CYP2C19 are
among the most important for the metabolism of AEDs
(Johannessen & Landmark, 2010; Johannessen Landmark
& Patsalos, 2010, 2012).
Phase I CYP enzymes as well as phase II enzymes (uri-
dine glucuronyl transferases, UGTs) can be induced during
pregnancy. Such enzyme induction is the clinically most
important mechanism for declining serum concentrations of
AEDs during pregnancy, as it will result in a fall in unbound
as well as total serum concentrations. Enzyme induction
appears to be most pronounced for AEDs that are metabo-
lized through glucuronidation such as lamotrigine,
oxcarbazepine (or rather its active MHD-derivative), and
valproate. The extent to which pregnancy affects AED
metabolism varies considerably between patients and is
therefore difficult to predict (Tomson & Battino, 2007;
Patsalos et al., 2008; Johannessen Landmark et al., 2012).
Excretion
During pregnancy, there is a significant increase in renal
blood flow and glomerular filtration rate, up to 5080% of the
prepregnancy rate (Sturgiss et al., 1994; Pennell, 2003). This
process starts shortly after conception and continues throughout
the second trimester and then declines in the last part of the
407
Pharmacokinetics in Pregnancy
pregnancy (Sturgiss et al., 1994). Increased renal clearance can
affect serum concentrations of AED that are mainly excreted
renally, such as gabapentin, levetiracetam, pregabalin, and
vigabatrin. It has also been suggested as an important contrib-
uting cause for the pronounced increase in clearance of lamo-
trigine and its N2-glucuronide metabolite in early pregnancy
(Reimers et al., 2011; Reimers & Brodtkorb, 2012).
Most documented changes can thus be considered the
consequence of enzyme induction and to some extent
increased renal clearance. Still, several issues are poorly
investigated, for example, some isoenzymes have been
investigated for only one drug, the effect of transport pro-
teins during pregnancy remains to be clarified, as well as
effects of pregnancy on drugs that are eliminated through
non-CYP/UGT or multiple pathways (Anderson, 2005).
Gestation-Induced Alterations
in Kinetics of Individual AEDs
Published data on some basic pharmacokinetic properties
and on alterations in pharmacokinetics of different AEDs dur-
ing pregnancy are summarized in Table 1. Because lamotri-
gine is the most extensively studied AED in this regard, data
on its kinetics during pregnancy are reported separately and
in more detail in Table 2. A brief account of data on individ-
ual AEDs (in alphabetical order) is provided in the following.
Carbamazepine
Carbamazepine is approximately 75% protein bound and
is eliminated by hepatic metabolism through CYP1A2,
CYP2C8, and CYP3A4 (Johannessen Landmark et al.,
2012). Several studies have analyzed the effect of preg-
nancy on carbamazepine serum concentrations (Lander
et al., 1981; Battino et al., 1985; Yerby et al., 1985;
Tomson et al., 1994a,b; Bernus et al., 1995), and the results
are slightly conflicting. Reported declines in total concen-
trations from prepregnancy to late pregnancy have ranged
from 0% to 42%. The fall in unbound concentrations has
been more limited: 028% (Lander et al., 1981; Battino
et al., 1985; Yerby et al., 1985; Tomson et al., 1994a,b;
Bernus et al., 1995). In fact, the largest study of women on
monotherapy reported a very limited decline in total con-
centrations during the second and third trimesters (912%),
whereas unbound concentrations remained essentially
unchanged (Tomson et al., 1994b).
Gabapentin
Gabapentin is absorbed form the gastrointestinal tract
through saturable active transportation (Gidal et al., 2000),
but there are no data on the effects of pregnancy on its
absorption. Gabapentin is not bound to serum proteins; it is
not metabolized but eliminated by renal excretion (Johann-
essen Landmark et al., 2012). No studies have followed the
course of gabapentin serum concentrations throughout
Epilepsia, 54(3):405414, 2013
doi: 10.1111/epi.12109
408
T. Tomson et al.

Table 1. Pharmacokinetic data and effects of pregnancy on serum concentrations of antiepileptic drugs
Pregnancies
with published
pharmacokinetic Protein Effect of pregnancy
References Antiepileptic drug data (n) Elimination binding on serum concentrations
Bardy et al. (1982); Battino et al. Carbamazepine 157 Almost completely metabolized, About 75% Decrease by 042%
(1985); Bernus et al. (1995); the most important pathway
Lander and Eadie (1991); being the formation of
Tomson et al. (1994a); and carbamazepine epoxide
Yerby et al. (1992, 1985)

Ohman et al. (2005) Gabapentin 3 Unchanged via kidney Not bound No decline
Johannessen et al. (2005); Levetiracetam 45 Two thirds unchanged in Not bound Decrease by 4060%
Pennell et al. (2005); urine, one-third
Tomson et al. (2007); and metabolized by peripheral
Westin et al. (2008) hydrolysis
Christensen et al. (2006); Oxcarbazepine 27 Pre-systemic 10-keto reduction About 40% Decrease by 3038%
Mazzucchelli et al. (2006); to the two enantiomers of
and Petrenaite et al. (2009) MHD than glucuronidation
of the active metabolite
MHD via UGT
Bardy et al. (1987); Battino Phenytoin 307 Mainly via hepatic microsomal- 8590% Decrease by 5661%
et al. (1982); Dansky et al. mixed function oxidase
(1982); Lander and Eadie (1991); reaction, with subsequent
and Tomson et al. (1994a) glucuronidation and
excretion of hydroxylated
derivative
Bardy et al. (1982); Battino et al. Phenobarbital 56 Hepatic oxidation, 5060% Decrease by 5055%
(1984a); Lander and Eadie (1991); glucosidation, hydroxylation
and Yerby et al. (1992) and subsequent conjugation
Battino et al. (1984a); and Rating Primidone-derived 23 Decreased by 70%
et al. (1982) phenobarbital

Ohman et al. (2009, 2002); and Topiramate 34 Mainly unchanged in urine, About 15% Decrease by 1340%
Westin et al. (2009) 2030% hepatic
biotransformation
Battino et al. (1982); Lander and Valproate 68 Hepatic metabolism, 8595% Decrease by 028%
Eadie (1991); Omtzigt et al. mainly by glucuronidation
(1992); Philbert et al. (1985);
and Yerby et al. (1992)
Kawada et al. (2002); and Zonisamide 2 Mainly hepatic 4060% Decreased by 4050%
Oles and Bell (2008); biotransformation,
1530% unchanged in urine

pregnancy. Available data are limited to maternal plasma
concentrations at delivery and 3 weeks after delivery in
three women who were taking gabapentin in combination
with other AEDs (Ohman et al., 2005). These limited data
do not suggest lower gabapentin levels in late pregnancy
compared to 2 to 3 weeks after. The only potential antici-
pated effects of pregnancy on its kinetics are those related to
changes in glomerular filtration. The reported few cases,
however, do not suggest any major effects on the plasma
concentration (Ohman et al., 2005) (Table 1).
Lamotrigine
The serum protein binding of lamotrigine is approxi-
mately 55% (Fitton & Goa, 1995). The drug is metabolized
mainly by glucuronidation catalyzed by UDP-glucuronosyl-
transferase (UGT), UGT1A4 and 2B7 (Hussein & Posner,
1997).
Lamotrigine is by far the most extensively studied newer-
generation AED in conjunction with pregnancy, and the
results are summarized in Table 2. In patients taking lamo-
trigine, monotherapy serum concentrations usually decline
markedly as pregnancy progresses. A decrease in serum
concentration can be seen already in the first trimester but is
most marked in the midthird trimester (Ohman et al.,
2000; Tran et al., 2002; de Haan et al., 2004; Pennell et al.,
2004; Petrenaite et al., 2005; Reimers et al., 2011). On
average, lamotrigine serum concentrations decrease by 50
60%, but an even more pronounced decline has been
reported in individual patients (Tomson et al., 1997). The
effects of pregnancy on lamotrigine disposition, however,
vary considerably between individuals and are thus difficult
to predict (Petrenaite et al., 2005; Franco et al., 2008; Pen-
nell et al., 2008). The effects are much less pronounced in
women taking lamotrigine in combination with valproate

Epilepsia, 54(3):405414, 2013

doi: 10.1111/epi.12109
 Table 2. Effects of pregnancy on the disposition of lamotrigine
No. of
pregnancies on LTG Time of
monotherapy/total sampling after
Authors pregnancies Data presented as Preconception Trimester 1 Trimester 2 Trimester 3 delivery Postpartum
Tran 2/14 Mean apparent clearance 1.2 0.37 1.97 0.53 2.31 0.91 2.26 0.94 236 weeks 1.22 0.54
et al. (2002) (L/[kg/day])SD
% change apparent >65% p < 0.05 >65% p < 0.05 vs.
clearance vs. PC and PP PC and vs. PP
Fotopoulou 9/9 Median dose/serum 39 (3941) 77 (68154) 92 (76167) 97 (74110) On average 3 weeks 35 (3536)
et al. (2009) concentration
(2575% percentile)
197% NS 236% p < 0.05 248% p < 0.05
Pennell 14/14 Apparent 52.9 20.8 89 41 133 71 171 100 212 weeks 66 29
et al. (2004)a clearance mg/(mg/L) (from figure)
% change apparent 191 107 249 142 361 194 150 69
clearance
Reimers 17/21 Mean doses 244 144 342 180 At least 4 weeks
et al. (2011) (mg/day)  SD
% change mean >34% vs. PC
doses
Petrenaite 11/11 Mean ratio LTG 63.5 30.8 46.7 18.3 22.1 5.4 21.7 7.1 6 weeks (from 70 10
et al. (2005) plasma level-to-dose
(lmol/l/mg)  SD figure)
27% NS 65% p < 0.01 66% p < 0.01
b
Ohman 8/8 Mean 2-N-GLUC/LTG 1.02 0.27 Up to 3 months 0.4 0.06
et al. (2008b) ratio
% change 2-N-GLUC/LTG 154% >PP p < 0.01
ratio

Ohman 17/17b Mean dose/plasma 227.1 74 At least 1 month 66.5 17.9
et al. (2008a) concentrations
% change mean 250% >PP
dose/plasma
concentration
LTG 2-N-glucuronide/LTG 0.349 0.141
concentrations lmol/L
147% >PP
de Haan 12/12 Weeks 110 Weeks 1120 Weeks 2130 Weeks 3140 PP
et al. (2004) Mean level-to-dose 82% 14% 51% 14% 40% 8% 97% 15% 48% 10%
ratios (presented as
percentage of
baseline  SD) for
consecutive
10-week periods
LTG, lamotrigine; PC, preconception; PP, postpartum; 2-N-GLUC, lamotrigine-2-Nglucuronide.
a
Post hoc analyses of % change of apparent clearance: first trimester versus second trimester: p < 0.0001; first trimester versus third trimester: p < 0.0001; first trimester versus postpartum: p < 0.03; second tri-
mester versus third trimester: p < 0.04; second trimester versus postpartum: p < 0.0001; third trimester versus postpartum: p < 0.0001.
b
Pregnancies on LTG monotherapy (or without concomitant use of other drugs known to interact with lamotrigine).
Pharmacokinetics in Pregnancy

Epilepsia, 54(3):405414, 2013

409

doi: 10.1111/epi.12109
410
T. Tomson et al.
(Tomson et al., 2006). Although the dose-to-plasma con-
centration ratio of lamotrigine increased from baseline to
midgestation by 295% in women on lamotrigine monothera-
py; the increase was only 60% among women on lamotri-
gine in combination with valproate.
The decline in lamotrigine levels is probably mainly due
to enhanced metabolic elimination by induction of the
UGT. This hypothesis is supported by observations of
increased ratios in late pregnancy between the lamotrigine-
2-Nglucuronide metabolite and lamotrigine in plasma and
in urine (Ohman et al., 2008a,b). However, a more detailed
analysis of the ratio lamotrigine-2-Nglucuronide/lamotri-
gine throughout pregnancy suggests that an enhanced renal
excretion may contribute in particular to the fall in lamotri-
gine concentrations in early pregnancy (Reimers et al.,
2011). Regardless of whether the mechanism is by increased
hepatic or renal clearance, the net effect is a decline on total
as well as unbound lamotrigine concentrations.
Serum lamotrigine concentrations return rapidly to prep-
regnancy values after pregnancy. The process starts within
days after delivery and is complete 2 to 3 weeks postpartum
(Ohman et al., 2000; Tran et al., 2002; de Haan et al.,
2004).
Levetiracetam
Levetiracetam is not bound to serum proteins and its
elimination is primarily renal, although nonoxidative
metabolism by hydrolysis accounts for approximately 30%
of its elimination. (Patsalos, 2000; Radtke, 2001).
Two reports based on 15 (Tomson et al., 2007) and 21
(Westin et al., 2008) pregnancies observed a significant
decline in plasma concentrations during pregnancy by 40%
to 60% at the end of pregnancy compared to baseline levels
before or after pregnancy. A decrease in serum concentra-
tions, or increase in apparent clearance, is observed already
in the first trimester (Pennell et al., 2005). As with lamotri-
gine, the effects of pregnancy on levetiracetam disposition
vary considerably between individuals (Westin et al.,
2008). Serum concentrations have been found to increase
rapidly after delivery to reach prepregnancy levels within
the first week (Westin et al., 2008). Although the mecha-
nisms have not been studied in detail, it is likely that the
decline in levetiracetam levels is caused by a combination
of an increased renal elimination and enhanced enzymatic
hydrolysis.
Oxcarbazepine
Oxcarbazepine is a prodrug, which is almost completely
metabolized to mono-hydroxycarbazepine (MHD). MHD is
responsible for the effects of oxcarbazepine. The protein
binding of MHD is about 40%, and it is cleared from the
human body mainly by glucuronidation (May et al., 2003).
Because its elimination is by the same metabolic route as
for lamotrigine, significant effects of pregnancy can be
expected. Three studies, comprising altogether 27 pregnan-
Epilepsia, 54(3):405414, 2013
doi: 10.1111/epi.12109
cies, confirm that serum concentrations of MHD decline by
on average 3040%, hence slightly less than what is seen for
lamotrigine (Christensen et al., 2006; Mazzucchelli et al.,
2006; Petrenaite et al., 2009). An increase in MHD serum
concentrations was observed within 78 days after delivery
(Mazzucchelli et al., 2006).
Phenytoin
Phenytoin is approximately 90% bound to serum pro-
teins. It is eliminated by oxidative metabolism through
CYP2C9 and CYPC19 (Johannessen Landmark et al.,
2012). Pregnancy can thus affect the disposition of phenyt-
oin by decrease in protein binding as well as by induced
metabolism. The decrease of phenytoin serum concentra-
tions generally starts during the first trimester and becomes
more evident in the third when total concentrations are
decreased by 5561%, on average. However, the unbound
and pharmacologically active concentrations decline to a
lesser extent, by 1631% (Battino et al., 1982; Dansky
et al., 1982; Bardy et al., 1987; Yerby et al., 1992; Tom-
son et al., 1994a).
Phenobarbital
Phenobarbital is approximately 50% bound to serum pro-
teins, and is eliminated through metabolism by CYP2C19
and 2E1. Phenobarbital levels have been reported to decline
by 5055% during pregnancy (Battino et al., 1984b; Yerby
et al., 1990), whereas the decline has been suggested to be
more pronounced, up to 70%, for primidone-derived pheno-
barbital (Rating et al., 1982; Battino et al., 1984b).
Topiramate
Topiramate is only 15% bound to serum proteins and
eliminated mainly unchanged via the kidneys, but a small
fraction undergoes hepatic CYP-dependent metabolism
(Langtry et al., 1997).
Two studies have assessed the effects of pregnancy on to-
piramate serum concentrations (Ohman et al., 2009; Westin
et al., 2009). These reports suggest an average decline in to-
piramate levels of 30% to 40% during the third trimester
compared with before or after pregnancy, but with a consid-
erable interindividual variation (Table 1). These effects are
most likely explained by increased renal excretion.
Valproate
Valproate is highly protein bound, approximately 90%,
and is cleared through hepatic metabolism, mainly by
glucuronidation through UGT1A3 and 2B7 in addition to
several CYPs. Data on the effects of pregnancy on the
disposition of valproate are limited. Total concentrations
have been reported to fall in late pregnancy by up to 40%
compared with before pregnancy, but this appears to be due
mainly to decreased protein binding, since unbound valpro-
ate concentrations remain essentially unchanged (Philbert
et al., 1985; Omtzigt et al., 1992; Yerby et al., 1992).

Zonisamide
The serum protein binding of zonisamide is approxi-
mately 60%. Zonisamide is extensively metabolized by
acetylation, glucuronide conjugation, and oxidation, and is
eliminated also partly by renal excretion (Seino et al., 1995;
Perucca & Bialer, 1996).
There are no systematic studies of the kinetics of zonisa-
mide in pregnancy. In a single reported case, zonisamide
levels were followed regularly from the fifth gestational
week to the end of pregnancy. The patient received 200 mg/
day of zonisamide as monotherapy until week 29, when the
dose was increased to 300 mg/day, since plasma concentra-
tions decreased from values ranging between 7.5 and 10.1
(from week 5 to week 22) to 4.4 lg/ml in week 27 (Oles &
Bell, 2008).
Hence, no firm conclusions can be drawn concerning ges-
tation-related alterations in zonisamide kinetics, but induc-
tion of its metabolism might occur.
Other newer AEDs
To the best of our knowledge no published data exist on
the pharmacokinetics of felbamate, pregabalin, tiagabine,
vigabatrin, lacosamide, retigabine, perampanel, or
eslicarbazepine acetate during pregnancy.
Clinical Implications and
Conclusions
It is thus undisputable that pregnancy can affect the phar-
macokinetics of AEDs and that this effect varies depending
on the type of AED. For some, for example, lamotrigine, the
effect is profound, whereas other AEDs, for example, carba-
mazepine, seem to be affected only marginally. For some of
the newer generation AEDs, data are scarce or even lacking
completely. However, some general assumptions can be
made based on available data. A pronounced decline in
serum concentrations can be expected for AEDs that are
eliminated by glucuronidation (UGT). This might be
relevant for eslicarbazepine acetate and possibly also for
retigabine (ezogabine) (Bialer et al., 2009). Plasma concen-
trations of AEDs that are cleared mainly through the
kidneys, for example, gabapentin, pregabalin, and lacosa-
mide, can also be expected to decline significantly.
Perampanel is protein bound to a high degree, 96%, and
metabolized through CYP3A4 (Bialer et al., 2009). A
displacement can thus be expected during pregnancy, lead-
ing to declining total concentrations, whereas the active
unbound concentrations could remain fairly stable. For
AEDs whose pharmacokinetic properties are affected, the
extent varies between individuals and is therefore difficult
to predict. Polytherapy makes it even more difficult to
predict the course of AED concentrations during pregnancy.
The key issue is if these alterations in serum concentra-
tions are of clinical relevance. It appears obvious that a fall
411
Pharmacokinetics in Pregnancy
in serum AED concentrations in an individual patient is
accompanied by a change in efficacy, and in general an
increased risk of seizures. The usefulness of serum level
monitoring and the need to adjust the dose to maintain sta-
ble serum concentrations is nevertheless often questioned
(Scottish Intercollegiate Guidelines Network, 2003). Such
a position would assume either that pregnancy as such
makes patients less likely to have seizures or more respon-
sive to the drug treatment, or that the woman enters preg-
nancy with a higher AED dose than necessary. There is no
evidence whatsoever for the former, and the latter is also
unlikely if the general management policy to titrate to the
lowest effective AED dose before pregnancy has been fol-
lowed.
Clinical observations of lamotrigine and oxcarbazepine
pregnancies also seem to support that the decline in serum
concentrations is associated with an increased risk of sei-
zures. Increase in lamotrigine dose was considered to be
needed in 11 of 12 pregnancies in one series (Tran et al.,
2002), and dose adjustment in all 14 lamotrigine monothera-
py pregnancies in another (Pennell et al., 2004). Seizure
aggravation was observed in 9 of 12 cases of pregnancies
from a Dutch series (de Haan et al., 2004) and in 5 of 11
pregnancies from Denmark, all of whom were taking lamo-
trigine monotherapy (Petrenaite et al., 2005). Low concen-
trations of the active oxcarbazepine metabolite were
associated with emergence of seizures in two of four in an
Italian series (Mazzucchelli et al., 2006). Another Danish
case series found that changes in oxcarbazepine disposition
were often associated with worsening in seizure frequency
in a study of 13 pregnancies, 10 of which were on monother-
apy (Petrenaite et al., 2009), although others have failed to
find an association between changes in serum concentra-
tions of the active metabolite of oxcarbazepine and seizure
control (Christensen et al., 2006). In the prospective obser-
vational EURAP study, the dosage was increased more
often in pregnancies with monotherapy with lamotrigine or
oxcarbazepine compared with other treatments (The
EURAP study group, 2006). The best evidence for an
association between declining serum concentrations and
deterioration in seizure control comes from a prospective
study of 36 pregnancies with lamotrigine monotherapy, of
which 39% experienced an increase in seizure frequency
during pregnancy (Pennell et al., 2008). The risk was
significantly increased when the lamotrigine serum concen-
trations dropped by >35% from the individual optimal
serum concentration before pregnancy.
Although there seems to be an association between
declining serum concentrations of AEDs and deterioration
in seizure control, many women remain seizure free despite
lower drug concentrations. Some therefore advise against
drug level monitoring and also against increasing the dose
unless the patient has had deterioration in seizure control
(Scottish Intercollegiate Guidelines Network, 2003). This
position rests on the assumption that risks associated with
Epilepsia, 54(3):405414, 2013
doi: 10.1111/epi.12109
412
T. Tomson et al.
an increase of the AED dose outweigh seizure-related
maternal and fetal risks. We question this assumption. A
dose increase should aim primarily at maintaining the
womans individual optimal serum concentration, not
increase it. In general, organogenesis is already completed
at the stage of pregnancy when such dose adjustments are
considered, and a dose adjustment would not increase the
risk of birth defects. It can be argued that drug exposure later
in pregnancy can be of relevance for cognitive development.
However, adverse effects of AEDs on cognitive outcomes
have been shown convincingly only for valproate (Meador
et al., 2009a), and this is an AED where serum concentra-
tions of the active unbound drug is normally unchanged.
Seizures probably do not induce birth defects, and a single
seizure is unlikely to cause significant harm to the fetus.
However, five or more tonicclonic seizures during preg-
nancy have been associated with poorer cognitive develop-
ment of the child (Adab et al., 2004; Meador et al., 2009b),
and a single seizure in a previously seizure free woman can
have a major impact on that womans everyday life. In
addition, although rarely, a single tonicclonic seizure can
even be fatal. The Confidential Enquiries into Maternal
Deaths in the United Kingdom noted that of 261
maternal deaths, 14 women died of epilepsy, 5.4% of all
maternal deaths (Cantwell et al., 2011). The potential
consequences of unnecessary seizures are thus significant.
Admittedly, the evidence for an association between
pharmacokinetic alterations and deterioration in seizure
control during pregnancy is circumstantial. Class I evidence
would require a randomized controlled trial. However,
based on the available data and on common sense, it is the
opinion of the present authors that it would be unethical to
randomize pregnant women to having their AED dose
guided by clinical judgment only or by clinical judgement
supported by serum concentration data in settings where
drug level monitoring is available. We find it difficult to see
the true equipoise in the two management alternatives.
The evidence-based practice parameter update of the
American Academy of Neurology and American Epilepsy
Society concluded that monitoring of lamotrigine, carba-
mazepine, and phenytoin levels during pregnancy should be
considered; monitoring of levetiracetam and oxcarbazepine
(as MHD) levels may be considered, and although there is
insufficient evidence to support or refute changes in
phenobarbital, valproate, primidone, or ethosuximide lev-
els, this lack of evidence should not discourage monitoring
during pregnancy (Harden et al., 2009b).
We agree that the usefulness of drug level monitoring in
pregnancy depends on the AED, but also on the individual
characteristics of the patient and her epilepsy. Therefore,
monitoring appears less important for drugs such as carba-
mazepine and valproate, where alterations in active drug
levels are usually minor. On the other hand, monitoring is
more important for drugs with marked but unpredictable
alterations such as lamotrigine, levetiracetam, oxcarbaze-
Epilepsia, 54(3):405414, 2013
doi: 10.1111/epi.12109
pine, and possibly topiramate. The value of monitoring
during pregnancy largely depends on whether the patients
optimal serum concentration has been determined before
pregnancy. The sampling frequency during pregnancy
depends on the AED as well as on knowledge of the individ-
ual womans prior sensitivity to dose changes. Sampling
monthly could be justified for a woman on lamotrigine, who
has been carefully titrated to the lowest effective dose (and
serum concentration) prior to pregnancy, and where a lower
dose in the past has been associated with major seizures. For
such women, we would also propose a proactive approach
with dose adjustments before breakthrough seizures, aiming
at maintaining the optimal prepregnancy levels. Less fre-
quent sampling could on the other hand be considered in a
woman who is on a drug with less pronounced gestational
changes in kinetics, who has been seizure free for a long per-
iod prior to pregnancy, and for whom it is possible that the
used dose could be higher than necessary for seizure control.
In such one would also be less inclined to increase the dose
based only on a fall in serum concentration. If the AED dose
has been increased during pregnancy, one needs to be aware
of the rapid reversal of the kinetics after delivery: dose
reductions may be necessary during the first few days after
delivery to avoid toxicity.
In conclusion, pregnancy can have profound effects on
AED pharmacokinetics. Declining serum concentrations is
likely to have an impact on the efficacy of the treatment,
although for obvious reasons, class I evidence is lacking.
Drug level monitoring should nevertheless be considered
and decisions on dose adjustments made on an individual
basis. If monitoring is considered for highly protein-bound
AEDs, such as phenytoin and valproate, free concentrations
are preferred. The value of monitoring relies on comparison
with the individual optimal serum concentration established
before pregnancy rather than with general so-called refer-
ence ranges.
Disclosure
TT has received speakers honoraria or research funding from Bial,
Eisai, GSK, UCB, Sanofi-Aventis, and Novartis. CJL declares no conflicts
of interest. DB has received speakers honoraria from Eisai and UCB
Pharma. We confirm that we have read the Journals position on issues
involved in ethical publication and affirm that this report is consistent with
those guidelines.
References
Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J, Coyle H,
Fryer A, Gorry J, Gregg J, Mawer G, Nicolaides P, Pickering L,
Tunnicliffe L, Chadwick DW. (2004) The longer term outcome of
children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry
75:15751583.
Anderson GD. (2005) Pregnancy-induced changes in pharmacokinetics: a
mechanistic-based approach. Clin Pharmacokinet 44:9891008.
Bardy A, Teramo K, Hiilesmaa V. (1982) Apparent plasma clearances of
phenytoin, phenobarbitone, primidone, and carbamazepine during
pregnancy: result of the prospective Helsinki study. In Janz D, Dam M,

Bossi L, Helge H, Richens A, Schmidt D (Eds) Epilepsy, pregnancy,
and the child. Raven Press, New York, pp. 141145.
Bardy AH, Hiilesmaa VK, Teramo KA. (1987) Serum phenytoin during
pregnancy, labor and puerperium. Acta Neurol Scand 75:374375.
Battino D, Avanzini G, Bossi L, Canger R, Como ML, Croci D, Spina S.
(1982) Monitoring of antiepileptic drugs plasma levels during
pregnancy and puerperium. In Janz D, Dam M, Bossi L, Helge H,
Richens A, Schmidt D (Eds) Epilepsy, pregnancy and the child. Raven
Press, New York, pp. 147154.
Battino D, Binelli S, Bossi L, Canger R, Como ML, Croci D, Cusi C,
De Giambattista M, Pardi GGA. (1984a) Monitoring of antiepileptic
drugs and hormones in pregnant epileptic women. In Porter RJ, Mattson
RH, Ward AA, Dam M (Eds) Advances in epileptology: the XVth
Epilepsy International Symposium. Raven Press, New York, pp. 227
232.
Battino D, Binelli S, Bossi L, Como ML, Croci D, Cusi C, Avanzini G.
(1984b) Changes in primidone/phenobarbitone ratio during pregnancy
and the puerperium. Clin Pharmacokinet 9:252260.
Battino D, Binelli S, Bossi L, Canger R, Croci D, Cusi C, De Giambattista
M, Avanzini G. (1985) Plasma concentrations of carbamazepine and
carbamazepine 10,11-epoxide during pregnancy and after delivery.
Clin Pharmacokinet 10:279284.
Bernus I, Hooper WD, Dickinson RG, Eadie MJ. (1995) Metabolism of
carbamazepine and co-administered anticonvulsants during pregnancy.
Epilepsy Res 21:6575.
Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS.
(2009) Progress report on new antiepileptic drugs: a summary of the
Ninth Eilat Conference (EILAT IX). Epilepsy Res 83:143.
Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, Garrod D,
Harper A, Hulbert D, Lucas S, McClure J, Millward-Sadler H, Neilson
J, Nelson-Piercy C, Norman J, OHerlihy C, Oates M, Shakespeare J,
de Swiet M, Williamson C, Beale V, Knight M, Lennox C, Miller A,
Parmar D, Rogers J, Springett A. (2011) Saving Mothers Lives:
reviewing maternal deaths to make motherhood safer: 20062008. The
Eighth Report of the Confidential Enquiries into Maternal Deaths in the
United Kingdom. BJOG 118(Suppl. 1):1203.
Christensen J, Sabers A, Sidenius P. (2006) Oxcarbazepine concentrations
during pregnancy: a retrospective study in patients with epilepsy.
Neurology 67:14971499.
Dansky L, Andermann E, Shervin A, Andermann F. (1982) Plasma levels
of pheytoin during pregnancy ant the puerperium. In Janz D, Dam M,
Bossi L, Helge H, Richens A, Schmidt D (Eds) Epilepsy, pregnancy,
and the child. Raven Press, New York, pp. 155162.
de Haan GJ, Edelbroek P, Segers J, Engelsman M, Lindhout D, Devile-
Notschaele M, Augustijn P. (2004) Gestation-induced changes in
lamotrigine pharmacokinetics: a monotherapy study. Neurology 63:
571573.
Fitton A, Goa KL. (1995) Lamotrigine. An update of its pharmacology and
therapeutic use in epilepsy. Drugs 50:691713.
Fotopoulou C, Kretz R, Bauer S, Schefold JC, Schmitz B, Dudenhausen
JW, Henrich W. (2009) Prospectively assessed changes in lamotrigine-
concentration in women with epilepsy during pregnancy, lactation and
the neonatal period. Epilepsy Res 85:6064.
Franco V, Mazzucchelli I, Gatti G, Specchio LM, La Neve A, Papantonio
A, Ozkaynakci AE, Perucca E. (2008) Changes in lamotrigine
pharmacokinetics during pregnancy and the puerperium. Ther Drug
Monit 30:544547.
Gidal BE, Radulovic LL, Kruger S, Rutecki P, Pitterle M, Bockbrader HN.
(2000) Inter- and intra-subject variability in gabapentin absorption and
absolute bioavailability. Epilepsy Res 40:123127.
Harden CL, Meador KJ, Pennell PB, Hauser WA, Gronseth GS, French JA,
Wiebe S, Thurman D, Koppel BS, Kaplan PW, Robinson JN, Hopp J,
Ting TY, Gidal B, Hovinga CA, Wilner AN, Vazquez B, Holmes L,
Krumholz A, Finnell R, Hirtz D, Le Guen C. (2009a) Practice
Parameter update: management issues for women with epilepsyfocus
on pregnancy (an evidence-based review): Teratogenesis and perinatal
outcomes. Report of the Quality Standards Subcommittee and
Therapeutics and Technology Subcommittee of the American
Academy of Neurology and American Epilepsy Society. Neurology
50:12371246.
Harden CL, Pennell PB, Koppel BS, Hovinga CA, Gidal B, Meador KJ,
Hopp J, Ting TY, Hauser WA, Thurman D, Kaplan PW, Robinson JN,
French JA, Wiebe S, Wilner AN, Vazquez B, Holmes L, Krumholz A,
413
Pharmacokinetics in Pregnancy
Finnell R, Shafer PO, Le Guen C. (2009b) Practice Parameter update:
management issues for women with epilepsyfocus on pregnancy (an
evidence-based review): vitamin K, folic acid, blood levels, and
breastfeeding. Report of the Quality Standards Subcommittee and
Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology and American Epilepsy Society.
Neurology 3:142149.
Hernandez-Diaz S, Smith CR, Shen A, Mittendorf R, Hauser WA, Yerby
M, Holmes LB. (2012) Comparative safety of antiepileptic drugs
during pregnancy. Neurology 78:16921699.
Hussein Z, Posner J. (1997) Population pharmacokinetics of lamotrigine
monotherapy in patients with epilepsy: retrospective analysis of routine
monitoring data. Br J Clin Pharmacol 43:457465.
Johannessen SI, Landmark CJ. (2010) Antiepileptic drug interactions -
principles and clinical implications. Curr Neuropharmacol 8:254267.
Johannessen SI, Tomson T. (2006) Pharmacokinetic variability of newer
antiepileptic drugs: when is monitoring needed? Clin Pharmacokinet
45:10611075.
Johannessen SI, Helde G, Brodtkorb E. (2005) Levetiracetam
concentrations in serum and in breast milk at birth and during lactation.
Epilepsia 46:775777.
Johannessen Landmark C, Patsalos PN. (2010) Drug interactions involving
the new second and third generation antiepileptic drugs. Expert Rev
Neurother 10:119140.
Johannessen Landmark C, Patsalos PN. (2012) Methodologies used to
identify and characterize interactions among antiepileptic drugs. Expert
Rev Clin Pharmacol 5:281292.
Johannessen Landmark C, Johannessen SI, Tomson T. (2012) Host factors
affecting antiepileptic drug delivery-pharmacokinetic variability. Adv
Drug Deliv Rev 64:896910.
Kawada K, Itoh S, Kusaka T, Isobe K, Ishii M. (2002) Pharmacokinetics of
zonisamide in perinatal period. Brain Dev 24:9597.
Lander CM, Eadie MJ. (1991) Plasma antiepileptic drug concentrations
during pregnancy. Epilepsia 32:257266.
Lander CM, Livingstone I, Tyrer JH, Eadie MJ. (1981) The clearance of
anticonvulsant drugs in pregnancy. Clin Exp Neurol 17:7178.
Langtry HD, Gillis JC, Davis R. (1997) Topiramate. A review of its
pharmacodynamic and pharmacokinetic properties and clinical efficacy
in the management of epilepsy. Drugs 54:752773.
Mawhinney E, Campbell J, Craig J, Russell A, Smithson W, Parsons L,
Robertson I, Irwin B, Morrison P, Liggan B, Delanty N, Hunt S,
Morrow J. (2012) Valproate and the risk for congenital malformations:
is formulation and dosage regime important? Seizure 21:215218.
May TW, Korn-Merker E, Rambeck B. (2003) Clinical pharmacokinetics
of oxcarbazepine. Clin Pharmacokinet 42:10231042.
Mazzucchelli I, Onat FY, Ozkara C, Atakli D, Specchio LM, Neve AL,
Gatti G, Perucca E. (2006) Changes in the disposition of oxcarbazepine
and its metabolites during pregnancy and the puerperium. Epilepsia
47:504509.
Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT,
Cohen M, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera
M, Loring DW. (2009a) Cognitive function at 3 years of age after fetal
exposure to antiepileptic drugs. N Engl J Med 360:15971605.
Meador KJ, Penovich P, Baker GA, Pennell PB, Bromfield E, Pack A,
Liporace JD, Sam M, Kalayjian LA, Thurman DJ, Moore E, Loring
DW. (2009b) Antiepileptic drug use in women of childbearing age.
Epilepsy Behav 16:609616.
National Institute for Clinical Excellence. (2012) The epilepsies: the
diagnosis and management of the epilepsies in adults and children in
primary and secondary care. NICE Clinical guideline 137. Available at
http://www.nice.org.uk/nicemedia/live/13635/57779/57779.pdf.
Ohman I, Vitols S, Tomson T. (2000) Lamotrigine in pregnancy:
pharmacokinetics during delivery, in the neonate, and during lactation.
Epilepsia 41:709713.
Ohman I, Vitols S, Luef G, Soderfeldt B, Tomson T. (2002) Topiramate
kinetics during delivery, lactation, and in the neonate: preliminary
observations. Epilepsia 43:11571160.
Ohman I, Vitols S, Tomson T. (2005) Pharmacokinetics of gabapentin
during delivery, in the neonatal period, and lactation: does a fetal
accumulation occur during pregnancy? Epilepsia 46:16211624.
Ohman I, Beck O, Vitols S, Tomson T. (2008a) Plasma concentrations of
lamotrigine and its 2-N-glucuronide metabolite during pregnancy in
women with epilepsy. Epilepsia 49:10751080.
Epilepsia, 54(3):405414, 2013
doi: 10.1111/epi.12109
414
T. Tomson et al.
Ohman I, Luef G, Tomson T. (2008b) Effects of pregnancy and
contraception on lamotrigine disposition: new insights through analysis
of lamotrigine metabolites. Seizure 17:199202.
Ohman I, Sabers A, de Flon P, Luef G, Tomson T. (2009) Pharmacokinetics
of topiramate during pregnancy. Epilepsy Res 87:124129.
Oles KS, Bell WL. (2008) Zonisamide concentrations during pregnancy.
Ann Pharmacother 42:11391141.
Omtzigt JG, Nau H, Los FJ, Pijpers L, Lindhout D. (1992) The disposition
of valproate and its metabolites in the late first trimester and early
second trimester of pregnancy in maternal serum, urine, and amniotic
fluid: effect of dose, co-medication, and the presence of spina bifida.
Eur J Clin Pharmacol 43:381388.
Patsalos PN. (2000) Pharmacokinetic profile of levetiracetam: toward ideal
characteristics. Pharmacol Ther 85:7785.
Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen
SI, Leppik IE, Tomson T, Perucca E. (2008) Antiepileptic drugsbest
practice guidelines for therapeutic drug monitoring: a position paper by
the subcommission on therapeutic drug monitoring, ILAE Commission
on Therapeutic Strategies. Epilepsia 49:12391276.
Pennell PB. (2003) Antiepileptic drug pharmacokinetics during pregnancy
and lactation. Neurology 61:S35S42.
Pennell PB, Newport DJ, Stowe ZN, Helmers SL, Montgomery JQ, Henry
TR. (2004) The impact of pregnancy and childbirth on the metabolism
of lamotrigine. Neurology 62:292295.
Pennell PB, Koganti A, Helmers S, Beach A, Newman M, Newport DJ,
Stowe ZN. (2005) The impact of pregnancy and childbirth on the
elimination of levetiracetam [abstract]. Epilepsia 46:89.
Pennell PB, Peng L, Newport DJ, Ritchie JC, Koganti A, Holley DK, Newman
M, Stowe ZN. (2008) Lamotrigine in pregnancy: clearance, therapeutic
drug monitoring, and seizure frequency. Neurology 70:21302136.
Perucca E, Bialer M. (1996) The clinical pharmacokinetics of the newer
antiepileptic drugs. Focus on topiramate, zonisamide and tiagabine.
Clin Pharmacokinet 31:2946.
Petrenaite V, Sabers A, Hansen-Schwartz J. (2005) Individual changes in
lamotrigine plasma concentrations during pregnancy. Epilepsy Res
65:185188.
Petrenaite V, Sabers A, Hansen-Schwartz J. (2009) Seizure deterioration in
women treated with oxcarbazepine during pregnancy. Epilepsy Res
84:245249.
Philbert A, Pedersen B, Dam M. (1985) Concentration of valproate during
pregnancy, in the newborn and in breast milk. Acta Neurol Scand
72:460463.
Radtke RA. (2001) Pharmacokinetics of levetiracetam. Epilepsia 42(Suppl.
4):2427.
Ramsay RE, Strauss RG, Wilder BJ, Willmore LJ. (1978) Status epilepticus
in pregnancy: effect of phenytoin malabsorption on seizure control.
Neurology 28:8589.
Rating D, Nau H, Jager-Roman E, Gopfert-Geyer I, Koch S, Beck-
Mannagetta G, Schmidt D, Helge H. (1982) Teratogenic and
pharmacokinetic studies of primidone during pregnancy and in the
offspring of epileptic women. Acta Paediatr Scand 71:301311.
Reimers A, Brodtkorb E. (2012) Second-generation antiepileptic drugs and
pregnancy: a guide for clinicians. Expert Rev Neurother 12:707717.
Reimers A, Helde G, Brathen G, Brodtkorb E. (2011) Lamotrigine and its
N2-glucuronide during pregnancy: the significance of renal clearance
and estradiol. Epilepsy Res 94:198205.
Scottish Intercollegiate Guidelines Network. (2003) Guideline No. 70.
Diagnosis and management of epilepsy in adults: a national clinical
Epilepsia, 54(3):405414, 2013
doi: 10.1111/epi.12109
guideline recommended for use in Scotland. Available at http://www.
sign.ac.uk/guidelines/fulltext/70/index.html.
Seino M, Naruto S, Ito T, Miyazaki H. (1995) Zonisamide. In Levy RH,
Mattson RH, Meldrum BS (Eds) Antiepileptic drugs. 4th ed. Raven
Press, New York, pp. 10011024.
Sturgiss SN, Dunlop W, Davison JM. (1994) Renal haemodynamics and
tubular function in human pregnancy. Baillieres Clin Obstet Gynaecol
8:209234.
Teramo K, Hiilesmaa V. (1982) Pregnancy and fetal complications in
epileptic pregnancies. In Janz D, Dam M, Bossi L, Helge H, Richens A,
Schmidt D (Eds) Epilepsy, pregnancy, and the child. Raven Press, New
York, pp. 5359.
The EURAP study. (2006) Seizure control and treatment in pregnancy:
observations from the EURAP epilepsy pregnancy registry. Neurology
66:354360.
Tomson T, Battino D. (2007) Pharmacokinetics and therapeutic drug
monitoring of newer antiepileptic drugs during pregnancy and the
puerperium. Clin Pharmacokinet 46:209219.
Tomson T, Battino D. (2012) Teratogenic effects of antiepileptic drugs.
Lancet Neurol 11:803813.
Tomson T, Lindbom U, Ekqvist B, Sundqvist A. (1994a) Disposition
of carbamazepine and phenytoin in pregnancy. Epilepsia 35:131
135.
Tomson T, Lindbom U, Ekqvist B, Sundqvist A. (1994b) Epilepsy and
pregnancy: a prospective study of seizure control in relation to free and
total plasma concentrations of carbamazepine and phenytoin. Epilepsia
35:122130.
Tomson T, Ohman I, Vitols S. (1997) Lamotrigine in pregnancy and
lactation: a case report. Epilepsia 38:10391041.
Tomson T, Luef G, Sabers A, Pittschieler S, Ohman I. (2006) Valproate
effects on kinetics of lamotrigine in pregnancy and treatment with oral
contraceptives. Neurology 67:12971299.
Tomson T, Palm R, Kallen K, Ben-Menachem E, Soderfeldt B, Danielsson
B, Johansson R, Luef G, Ohman I. (2007) Pharmacokinetics of
levetiracetam during pregnancy, delivery, in the neonatal period, and
lactation. Epilepsia 48:11111116.
Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, Perucca
E, Vajda F. (2011) Dose-dependent risk of malformations with
antiepileptic drugs: an analysis of data from the EURAP epilepsy and
pregnancy registry. Lancet Neurol 10:609617.
Tran TA, Leppik IE, Blesi K, Sathanandan ST, Remmel R. (2002)
Lamotrigine clearance during pregnancy. Neurology 59:251255.
Westin AA, Reimers A, Helde G, Nakken KO, Brodtkorb E. (2008) Serum
concentration/dose ratio of levetiracetam before, during and after
pregnancy. Seizure 17:192198.
Westin AA, Nakken KO, Johannessen SI, Reimers A, Lillestolen KM,
Brodtkorb E. (2009) Serum concentration/dose ratio of topiramate
during pregnancy. Epilepsia 50:480485.
Wlodarczyk BJ, Palacios AM, George TM, Finnell RH. (2012)
Antiepileptic drugs and pregnancy outcomes. Am J Med Genet A
158A:20712090.
Yerby MS, Friel PN, Miller DQ. (1985) Carbamazepine protein binding
and disposition in pregnancy. Ther Drug Monit 7:269273.
Yerby MS, Friel PN, McCormick K, Koerner M, Van Allen M, Leavitt AM,
Sells CJ, Yerby JA. (1990) Pharmacokinetics of anticonvulsants in
pregnancy: alterations in plasma protein binding. Epilepsy Res 5:223228.
Yerby MS, Friel PN, McCormick K. (1992) Antiepileptic drug disposition
during pregnancy. Neurology 42:1216.
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy.
Users should refer to the original published version of the material.