Epilepsia, **(*):17, 2013

doi: 10.1111/epi.12302

FULL-LENGTH ORIGINAL RESEARCH

Seizure control and treatment changes in pregnancy:

Observations from the EURAP epilepsy pregnancy registry
*Dina Battino, Torbj
orn Tomson, Erminio Bonizzoni, John Craig, #Dick Lindhout, **Anne
Sabers, Emilio Perucca, Frank Vajda, and 1for the EURAP Study Group

*Epilepsy Center, Department of Neurophysiology and Experimental Epileptology, I.R.C.C.S. Neurological Institute Carlo Besta
Foundation, Milan, Italy; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of
Occupational Health Clinica del Lavoro L. Devoto, Section of Medical Statistics and Biometry G.A. Maccacaro, Faculty of
Medicine and Surgery, University of Milan, Milan, Italy; Department of Neurology, Belfast Health and Social Care Trust, Belfast,
Ireland; Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands; #SEIN Epilepsy Institute in the
Netherlands, Heemstede/Zwolle, The Netherlands; **The Epilepsy Clinic, Department of Neurology, Rigshospitalet University State
Hospital, Copenhagen, Denmark; Department of Internal Medicine and Therapeutics, University of Pavia, and Clinical Trial Center,
National Institute of Neurology IRCCS C. Mondino Foundation, Pavia, Italy; and Departments of Medicine and Neurology,
University of Melbourne, Royal Melbourne Hospital, Melbourne, Victoria, Australia

increased dose and/or addition of another AED) than in

SUMMARY
Purpose: To analyze seizure control, dose adjustments,
and other changes of antiepileptic drug (AED) treatment
during pregnancy in a large cohort of women with epi-
lepsy entering pregnancy on monotherapy with carba-
mazepine, lamotrigine, phenobarbital, or valproate.
Methods: Seizure control and AED treatment were
recorded prospectively in 3,806 pregnancies of 3,451
women with epilepsy taking part in European and Interna-
tional Registry of Antiepileptic Drugs and Pregnancy
(EURAP), an international AED and pregnancy registry.
Key Findings: Of all cases, 66.6% remained seizure-free
throughout pregnancy. Generalized tonicclonic seizures
(GTCS) occurred in 15.2% of the pregnancies. Women
with idiopathic generalized epilepsies were more likely to
remain seizure-free (73.6%) than women with localiza-
tion-related epilepsy (59.5%; p < 0.0001). Worsening in
seizure control from the first to second or third trimes-
ters occurred in 15.8% of pregnancies. The AED dose was
increased during pregnancy in 26.0% and a second AED
added to the initial monotherapy in 2.6% of all pregnan-
cies. Seizures were more likely to occur in the first trimes-
ter in pregnancies with an increased drug load (35%;
pregnancies without an increased drug load (15.3%)
(p < 0.0001). Compared with other monotherapies, preg-
nancies exposed to lamotrigine were less likely to be sei-
zure-free, 58.2% (p < 0.0001); had more GTCS, 21.1%
(p < 0.0001); had a greater likelihood of deterioration in
seizure control from first to second or third trimesters,
19.9% (p < 0.01), and were more likely to require an
increase in drug load, 47.7% (p < 0.0001). The mean dose
increases from the first to third trimesters were 26% for
lamotrigine, 5% for carbamazepine, 11% for phenobarbi-
tal, and 6% for valproate. There were 21 cases of status
epilepticus (10 convulsive): none with maternal mortality
and only one with a subsequent stillbirth.
Significance: Although the majority of women remain sei-
zure-free throughout pregnancy, our data suggest that a
more proactive approach to adjusting the dose of all AEDs
in pregnancy should be considered, in particular for those
pregnancies with seizures occurring in the first trimester
and those exposed to lamotrigine, to reduce the risk of
deterioration in seizure control.
KEY WORDS: Epilepsy, Pregnancy, Seizures, Antiepilep-
tic drugs.

The management of epilepsy in pregnancy is particu-
larly challenging because any riskbenefit assessment
needs to take into account the needs of not only the
woman with epilepsy but also the potential adverse effects
Accepted May 30, 2013.
Address correspondence to Dina Battino, Epilepsy Center, Department
of Neurophysiology and Experimental Epileptology, I.R.C.C.S. Neurologi-
cal Institute Carlo Besta Foundation, Via Celoria 11 20133 Milan, Italy.
E-mail: dbattino@istituto-besta.it
1
The complete list of collaborators is provided in Appendix S1.
Wiley Periodicals, Inc.
2013 International League Against Epilepsy
on the embryo and fetus (Tomson & Battino, 2012). Spe-
cifically, the risks to the offspring from prenatal antiepi-
leptic drug (AED) exposure need to be balanced against
fetal and maternal risks imposed by uncontrolled seizures.
Epilepsy is a serious condition and seizures can have pro-
found effects on maternal health, occasionally including
maternal mortality (Cantwell et al., 2011). Moreover, fre-
quent generalized tonicclonic seizures (GTCS) during
pregnancy have been associated with poorer postnatal
cognitive development of the child (Adab et al., 2004;
Cummings et al., 2011).

1
2
D. Battino et al.
We recently reported rates of major congenital
malformations after monotherapy exposure for the four
most frequently used AEDs based on data from European
and International Registry of Antiepileptic Drugs and
Pregnancy (EURAP), an international prospective epi-
lepsy and pregnancy registry (Tomson et al., 2011). We
found an increase in malformation rates with increasing
doses for all four investigated drugs: carbamazepine
(CBZ), lamotrigine (LTG), phenobarbital (PB), and val-
proate (VPA). Because the general treatment strategy has
been to identify, before pregnancy occurs, the lowest
effective dose of the most appropriate AED for the
womans epilepsy syndrome or seizure type (Harden
et al., 2009), our data provided the prescriber with an esti-
mate of the teratogenic risks associated with use of four
specific treatments, taken in monotherapy, within certain
dose ranges. However, these risk estimates were based on
the dose used at the time of conception, and did not take
subsequent dose adjustments into account.
In the present study we analyzed seizure control, dose
adjustments, and other treatment changes in relation to the
type of AED and dose categories defined at conception,
using the same study cohort as in our previous analysis of
teratogenic risks.
Patients and Methods
Inclusion criteria and study procedures
EURAP is an observational study that was set up in
1999 and that relies on the collaboration of investigators
from 42 countries. Its primary objective is to compare
the prevalence of major congenital malformations in off-
spring exposed to AEDs in utero. Pregnancies are
deemed eligible for prospective assessment when women
who have taken AEDs at the time of conception are
enrolled before gestation week 16 and fetal outcome is
known. Follow-up data are collected by the treating phy-
sician each trimester, at birth, and at 12 months after
birth. Recorded data include demographics, several
potential risk factors for teratogenic outcome, informa-
tion on type of maternal epilepsy, and occurrence of sei-
zures. Seizures are classified by the treating physician as
either GTCS (including primary and secondary general-
ized seizures) or other seizure types. In each trimester
report, seizure types are quantified separately into one of
six predefined categories (no seizures, less than one per
month, monthly, weekly, more than weekly, and daily).
Occurrence of status epilepticus is recorded separately
and classified as convulsive or nonconvulsive. Details on
the study methodology have been published previously
(The EURAP Study, 2006; Tomson et al., 2011), includ-
ing eligibility criteria and the methods used to determine
the doserange categories for comparing the teratogenic
risks of CBZ, LTG, PB, and VPA (Tomson et al., 2011).
Of the 3,909 pregnancies included in that analysis
Epilepsia, **(*):17, 2013
doi: 10.1111/epi.12302
(Tomson et al., 2011), 103 ended prematurely due to
induced abortions (n = 41), or stillbirths (n = 62).
Hence, prospective information on medication changes
or seizure control up to the time of delivery was avail-
able for 3,806 pregnancies in 3,451 women.
Statistical analysis
Results were expressed as proportions. Study end points
included occurrence of seizures and GTCS (expressed as
present or absent), changes in number or doses of AEDs,
and changes in seizure frequency (expressed as increase or
decrease, using seizure frequency in the first trimester as
reference). A change in seizure frequency was defined as a
switch from one frequency category to another. In the case
of mixed seizure types, the greater change was recorded
when one seizure type increased and the other decreased.
The relationships of the above end points with three covari-
ates (type of epilepsy, type of AED, and dose groups) were
investigated by means of two chi-square tests using JMP
version 7.0.2 (SAS Institute Inc, Cary, NC, U.S.A.). Results
were considered statistically significant for p-values < 0.05.
Only statistically significant results are reported in the text.
Results
Demographic data
The mean duration of pregnancy at time of enrolment
was 8.9 (standard deviation [SD]  3.3) weeks of gestation.
Age at the last menstrual period ranged from 15.3 to 43.5
(mean 29.5  5.0) years. The epilepsy syndrome was clas-
sified as idiopathic generalized in 1,497 (39.3%), localiza-
tion-related in 1,793 (47.1%), and undetermined in 516
(13.6%) pregnancies.
Overall seizure control
Information on seizure control was available in 3,784 of
the 3,806 pregnancies; 2,521 (66.6%) were free from sei-
zures during the entire pregnancy, with 1,263 (33.4%) hav-
ing seizures, of which 687 (18.2%) were exclusively non-
GTCS and 576 (15.2%) GTCS (with or without other sei-
zure types).
Among the 728 pregnancies exposed to VPA, 75.0%
were completely free from seizures, compared with 67.3%
of those exposed to CBZ (n = 914), 73.4% of those exposed
to PB (n = 157), and 58.2% of those exposed to LTG
(n = 722). The proportion of pregnancies without seizures
was significantly lower for the LTG cohort compared with
the cohorts exposed to each of the other three AEDs
(p < 0.0001). GTCS also occurred more often in LTG-
exposed pregnancies (21.1%) than in pregnancies exposed
to CBZ (12.6%), PB (14.0%), and VPA (11.5%) (p <
0.0001, for each comparison).
Further details on seizure control classified by type of
treatment (AED and dose category at conception) are
given in Table 1. Pregnancies exposed to the highest dose
 Table 1. Seizure control during pregnancy and delivery by type of pharmacologic treatment
No seizures during
Treatment All pregnancy Seizures during pregnancy and delivery (including cases with status epilepticus)
Any seizure type
excluding
Generalized tonicclonic seizures generalized
Type of AED and dose (with or without other seizure) tonicclonic Total
(mg/day) at conception n % n % n % p n % n % p-Value
a, b, c a, d
CBZ < 400 148 3.9 109 73.6 14 9.5 25 16.9 39 26.4
e, a, b, c a, d
CBZ 400 < 1,000 1,015 26.8 722 71.1 117 11.5 176 17.3 293 28.9
f, g, h in
CBZ 1,000 196 5.2 83 42.3 41 20.9 72 36.7 113 57.7
f, k, a o, k, l, h, a
LTG < 300 811 21.4 545 67.2 144 17.8 122 15.0 266 32.8
p, j, g, m i, j, k, m
LTG 300 429 11.3 177 41.3 118 27.5 134 31.2 252 58.7
PB < 150 165 4.4 126 76.4 20 12.1 19 11.5 39 23.6
e e
PB > 150 49 1.3 31 63.3 10 20.4 8 16.3 18 36.7
p
VPA < 700 424 11.2 330 77.8 44 10.4 50 11.8 94 22.2
VPA 700 < 1,500 454 12.0 335 73.8 53 11.7 66 14.5 119 26.2
VPA 1,500 93 2.5 63 67.7 15 16.1 15 16.1 30 32.3
All 3,784 100.0 2,521 66.6 576 15.2 687 18.1 1,263 33.4
a b c d e f
p < 0.0001 versus LTG 300; p < 0.01 versus LTG < 300; p < 0.001 versus CBZ 1,000; p < 0.0001 versus CBZ 1,000; p < 0.05 versus VPA < 700; p < 0.01 versus VPA 1,500; gp < 0.001 versus
VPA < 700; hp < 0.05 versus PB 150; ip < 0.0001 versus VPA 1,500; jp < 0.0001 versus VPA 700 < 1,500; kp < 0.0001 versus VPA < 700; lp < 0.001 versus PB 150; mp < 0.001 versus PB < 150; np < 0.0001
versus LTG < 300; op < 0.05 versus VPA 700 < 1,500; pp < 0.05 versus VPA 1,500.
Seizure Control and Treatment in Pregnancy

Epilepsia, **(*):17, 2013

doi: 10.1111/epi.12302
3
4
D. Battino et al.

categories of CBZ and LTG were the least likely to be free

p-Values

p < 0.0001 versus LTG < 300; bp < 0.0001 versus LTG 300; cp < 0.05 versus PB < 150; dp < 0.0001 versus PB < 150; ep < 0.05 versus VPA < 700; fp < 0.001 versus VPA 700 < 1,500; gp < 0.001 versus
Pregnancies with higher doses in third trimester compared to

a, b, h, e, i
a, b, df
from seizures (41.9% and 41.2%, respectively). Of 1,491

a, b, h
a, b

g, b
g, b
ac

a-c
pregnancies occurring in 1,356 women with idiopathic

b
generalized epilepsies and for which there was information

20.9
15.9
17.7
42.7
57.3
31.9
20.4
21.2
21.7
11.8
28.6
on seizure control, 1,096 (73.6%) were seizure-free. This

%
and/or dose
AED added

increased
compared with seizure freedom in 1,063 (59.5%) of 1,786
pregnancies occurring in 1,607 women with localization-

162

349
248

1,088
31

35

53
10
90
99
11
related epilepsies (p < 0.0001).

n
first
Changes in seizure frequency

increased
Seizure control during the second and third trimesters

Dose

151

323
216

990
30

24

49

86
94
9

8
n
was compared with that during the first trimester. Informa-

Table 2. Increase in AED dose or addition of another AED, by treatment and dose categories
tion on changes in seizure frequency was available for 3,735
pregnancies. Seizure frequency was unchanged in 2,634

AED added
cases (70.5%), of whom 2,521 (95.7%) were seizure-free

Other

11
11
26
32

98
1

4
1
4
5
3
n
during the entire pregnancy. Of the remaining 1,037 preg-
nancies, 448 (12.0%) had a reduction in seizure frequency
in the second or third trimester (or both), and 589 (15.8%)
deteriorated. Of those who deteriorated, 189 (32%) had an

13.5
12.0
11.6
34.6
47.3
24.7
18.4
16.3
14.2
10.8
22.3
and/or dose
AED added

%
increased
Pregnancies with increase in AED dose or
increase in seizures during the second trimester, 229 (39%)
in the third, and 171 (29%) in the second as well as the third
AED added in third trimester

122

283
205

847
20

23

41

69
65
10
9
compared to the first trimester. In 64 pregnancies (1.7%),

n
seizure frequency category changed in opposite directions
(increase or decrease, or vice versa) in the second and the
increased
Dose

117

269
189

801
19

18

40

67
65
9

8
third trimesters compared with the first trimester.
n
Worsening seizure control in the second and the third tri-
mesters compared with the first trimester was more com-
mon in pregnancies exposed to LTG (19.9%) than in those
AED added

exposed to CBZ (14.6%, p < 0.001), PB (11.7%, p < 0.01),

Other

14
16

46
1
5
5

1
0
2
0
2
n

or VPA (13.2%, p < 0.0001).

Seizures occurred during delivery in 2.6% of pregnancies
exposed to CBZ and to LTG, in 1.9% of those exposed to
10.1

11.6
20.7
30.0
10.2
10.2

10.7

13.6
6.4

8.3

8.6
and/or dose

PB, and in 1.4% of those exposed to VPA.

AED added

%
Pregnancies with increase in AED dose or

increased
AED added in second trimester

Change in treatment

LTG < 300; hp < 0.001 versus PB < 150; ip < 0.05 and versus VPA 700 < 15.
169
130

516
15
65
23

17

35
49
5

8
n

The AED dose was increased from the first to the third tri-
mester in 26.0% of pregnancies (990/3,806). Another AED
ncreased

was added in 98 pregnancies (including 41 in which the dose

Dose

157
114

464
15
59
17

14

33
44
4

7
n

was not increased). An increase in dose and/or addition of

another AED between the first and the third trimesters
occurred in 16.7% of pregnancies exposed initially to CBZ
Other AED

monotherapy, compared to 47.7% of those exposed to LTG,

added

12
16

52
0
6
6

3
1
2
5
1

29.3% of those exposed to PB, and 20.5% of those exposed

n

to VPA (p < 0.0001). Treatment changes by trimester for

different AEDs and dose categories are summarized in
Table 2. The mean dose increase from the first to the third
148
1,020
198
818
433
166

424
457

3,806
49

93
Total

trimester was 5% for CBZ, 26% for LTG, 11% for PB, and
6% for VPA. Adding a second AED was more common
among LTG pregnancies (58/1,251 4.6%, p < 0.0001).
(mg/day) at conception
Type of AED and dose

AEDs most frequently added were VPA (n = 22), clobazam

CBZ 400 < 1,000

VPA 700 < 1,500

(n = 10), levetiracetam (n = 9), and clonazepam (n = 8).

CBZ 1,000

VPA 1,500

An increase in drug dose or addition of another drug was

CBZ < 400

LTG < 300

LTG 300

VPA < 700

Treatment

PB < 150
PB 150

significantly more common in pregnancies with seizures

Total

during the first trimester. GTCS were reported in 14.8% of

a

pregnancies in which the dose was increased or another

Epilepsia, **(*):17, 2013
doi: 10.1111/epi.12302
 5
Seizure Control and Treatment in Pregnancy

AED was added, compared with 4.6% of pregnancies not

p-Values
associated with such treatment changes. The corresponding

Pregnancies with higher doses in third trimester

a, b
ac
values for all seizure types combined (first trimester) were
35.4% and 15.3%, respectively (p < 0.0001). However,

8.8
35.0
27.4
14.6
19.1
and/or dose
AED added

%
increased
increased AED load was also common in pregnancies with-
out seizures if women entered pregnancy on monotherapy

compared to first

80
253

106
482
43
with lamotrigine (35% having higher dose in third vs. first

n
trimester) or phenobarbital (27.4%) (Table 3).

increased
Dose

76
244

103
466
43
Status epilepticus

n
There were 21 cases of status epilepticus, of which 10
were convulsive. These cases were evenly distributed over

Other AED
the three trimesters. One case of convulsive status epilepti-

added

16
9
0
3
cus in the third trimester ended in perinatal death, although

n
Table 3. Increase in AED dose or addition of another AED by type of treatment
it was not in proximity to the episode of status epilepticus.
Three offspring born to three women who developed status

6.8
26.3
24.2
10.6
13.8
and/or dose
epilepticus during pregnancy were diagnosed with major

AED added
Pregnancies with increase in AED load in

%
increased
third trimester compared to second
congenital malformations: one had high grade stenosis of
the duodenum (mother on CBZ, convulsive status in third

62
190

367
38
77
n
trimester); one had spina bifida (mother on PB, nonconvul-
sive status in the third trimester); and one had a cardiac mal-

trimester

increased
Dose
formation (mother on CBZ, convulsive status in the first

59
183

356
38
76
n
trimester). There were no maternal fatalities.

AED added
Discussion
Other

11
7
0
1
n
Preliminary information on seizure control and treatment
changes in 1,956 women followed prospectively in the EU-
RAP registry who were exposed to any type of treatment
2.8
16.2
7.0
6.7
8.1
and/or dose
AED added
Pregnancies with increase in AED load in

%
increased

was reported in 2006 (The EURAP Study, 2006). That

second trimester compared to first

report included 1,026 of the 3,806 pregnancies analyzed in

26
117

203
11
49
n

the present study, which is based on a more homogenous

cohort of pregnancies exposed to the four most frequently
trimester

increased

used monotherapies, organized by dose taken at the time of

Dose

25
115

198
11
47
n

enrollment. Hence, 930 pregnancies from the 2006 report

did not meet the inclusion criteria for the present analysis.
p < 0.0001 versus LTG; bp < 0.0001 versus PB; cp < 0.001 versus VPA.

An added value of the present study is that the analyzed sei-

Other AED
added

zure outcomes and treatment changes refer to pregnancies

1
n

2
0
2
5

for which the teratogenic outcome has been reported (Tom-

son et al., 2011). The majority (66.5%) of these pregnancies
remained completely free from seizures, a proportion
pregnancies assessed

slightly higher than that (58.3%) found in the 2006 study

Total number of

(seizure-free)

(The EURAP Study, 2006). The difference between the cur-

914
722
157
728
2,521

rent and the earlier finding could be because the latest analy-
n

sis excluded women on polytherapy, who are known to be

less likely to exhibit complete seizure control (The EURAP
Study, 2006). The seizure freedom rate was also higher in
women with idiopathic generalized epilepsies (73.6%) than
Type of AED at conception

in those with localization-related epilepsy (59.5%), in

agreement with previous findings (Thomas et al., 2012).
Treatment

Fewer pregnancies exposed to the highest dose category of

Carbamazepine

Phenobarbital
Valproic acid

CBZ (41.9%) or LTG (41.2%) were free from seizures, an

Lamotrigine

observation that probably reflects a greater severity of epi-

Total

lepsy in women who received higher AED doses at concep-

a

tion (Table 1). In almost one third of the pregnancies, drug

Epilepsia, **(*):17, 2013
doi: 10.1111/epi.12302
6
D. Battino et al.
dose was increased or a second AED was added to the initial
monotherapy. These changes in treatment schedule
were more common in pregnancies associated with seizures,
suggesting that they could have been prompted by poor sei-
zure control. However, the AED load was also increased in
19.1% of pregnancies without seizures, significantly more
often with LTG and PB than with CBZ or VPA (Table 3).
This suggests that some treating physicians were aware of
the effects of pregnancy on serum concentrations of these
AEDs and increased the dose to prevent breakthrough
seizures.
Compared with pregnancies exposed to other monothera-
pies, fewer pregnancies exposed to LTG were free from
GTCS, or from seizures in general. Worsening in seizure
control after the first trimester was also more common
among LTG pregnancies, and could explain the higher pro-
portion of pregnancies with dose increments or addition of
another AED among LTG-treated women (Table 2). This
finding, which is in line with earlier observations from our
group (The EURAP Study, 2006) and from other investiga-
tors (Vajda et al., 2006; Pennell et al., 2008) could be
explained at least in part by the marked fall in serum LTG
concentration that is often observed during pregnancy
(Ohman et al., 2008; Pennell et al., 2008). The fact that
increases in doses and/or number of AEDs were more com-
mon in pregnancies with seizures may suggest that treat-
ment changes in many cases were reactive to seizures,
rather than being made proactively to prevent seizure deteri-
oration. In this respect, it is of interest that increases in dose
or number of AEDs were recorded in no >50% of LTG-
exposed pregnancies, and that the mean LTG dose was only
26% higher in the third trimester compared with the first
trimester. This dose increment is less than what would be
expected to be necessary to maintain stable serum LTG
concentrations, considering that LTG clearance increases
by 200300% in late pregnancy compared with the
pre-pregnant state (Ohman et al., 2008; Pennell et al., 2008;
Tomson et al., 2013). The EURAP protocol does not
include provisions for collection of information on serum
AED concentrations, or the physicians reasons for making
treatment changes. Nevertheless, our data suggest that there
might be scope for a more proactive approach in adjusting
LTG dose, a strategy that has been claimed to reduce the risk
of deterioration in seizure control (Sabers & Petrenaite,
2009).
Status epilepticus was reported in 0.6% of all pregnan-
cies, and convulsive status in 0.3%. None of the episodes of
status epilepticus were associated with maternal mortality,
and the only fetal mortality occurred perinatally and was not
temporally related to the status. These data confirm our pre-
vious observations (The EURAP Study, 2006) and are in
contrast with earlier estimates, which were probably
affected by reporting bias, suggesting high rates of maternal
and fetal mortality in status epilepticus during pregnancy
(Teramo & Hiilesmaa, 1982).
Epilepsia, **(*):17, 2013
doi: 10.1111/epi.12302
Strengths of the EURAP registry include its prospective
design, strict inclusion and exclusion criteria, close and reg-
ular follow-ups, and relatively large size of the investigated
cohort. However, there are also important limitations. First,
EURAP is not a population-based study, and it is unclear to
what extent findings can be generalized. However, although
the possibility of selection bias is acknowledged, all data
reported in this article refer to women on monotherapy,
which is the prevailing treatment strategy in epilepsy (Mor-
row et al., 2006; Harden et al., 2009; Veiby et al., 2009;
Hernandez-Diaz et al., 2012), and to different dose levels,
presumably representing different levels of severity of the
seizure disorder. Second, the primary objective of EURAP
is to compare teratogenic outcomes, not to assess seizure
control or treatment changes. Hence, the registry does not
collect data on seizure control prior to pregnancy for com-
parison, and seizures are grouped into broad categories,
GTCS and others, rather than being classified according to
International League Against Epilepsy (ILAE) criteria.
Nevertheless, most of the reporting physicians participating
in EURAP are experienced neurologists or epileptologists,
which presumably adds to the quality of seizure counts and
seizure and epilepsy classification. Another limitation is
inherent to the observational study design. Because women
were not randomized to the different AEDs or AED doses,
treatment choices were presumably dictated by individual
characteristics and needs. This assumption is supported by
the observation that seizure control tended to be worse at
higher doses rather than the opposite. Finally, as mentioned
above, no information is available on serum drug levels or
the reasons for making treatment changes, which remain
open to speculation.
Despite the above limitations, the present findings on sei-
zure control and treatment changes, combined with those
previously reported for malformation risks (Tomson et al.,
2011), provide useful information for physicians who are
managing women with epilepsy who are of childbearing
potential. We have shown that the risk of malformations
increases with AED dose at the time of conception (Tomson
et al., 2011); that many women enter pregnancy at low
doses; that many can maintain seizure control throughout
pregnancy, although frequent dose adjustments may be
required, depending on the AED used; that the risk of status
epilepticus is low and in most cases apparently without seri-
ous consequences for the pregnant woman and the fetus;
that monotherapy can be maintained throughout pregnancy
in most and that addition of a second AED was deemed nec-
essary in only 2.6% of pregnancies. A recent report from the
North American AED Pregnancy Registry suggested that
AEDs associated with a higher frequency of seizures during
pregnancy tend to be associated with a lower risk of fetal
malformations (Hernandez-Diaz et al., 2012). This is con-
sistent with our findings concerning seizure control with
LTG and VPA, and illustrates the challenge in balancing
efficacy against teratogenic risks. Although it is important

to aim for the lowest effective AED dose at conception and
during early pregnancy, our data suggest that more consid-
eration should be given to dose adjustments as pregnancy
progresses in order to optimize the outcome.
Acknowledgments
EURAP has received financial support from the following pharmaceuti-
cal companies: Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis,
Pfizer, Sanofi-Aventis, and UCB.
Disclosures
Dina Battino received honoraria for giving a lecture from UCB Pharma.
John Craig received grants to undertake research and honoraria for giving
lectures and funding to attend scientific meetings from UCB Pharma, Sano-
fi-Synthelabo, GlaxoSmithKline (GSK), Janssen-Cilag, Pfizer, and Eisai.
Emilio Perucca received speakers or consultancy fees and/or research
grants from Eisai, GSK, Lundbeck, Medichem, Sun Pharma, Supernus, and
UCB Pharma. Anne Sabers served as a paid consultant for Eisai Denmark,
UCB Nordic, and GSK and has received travel support from Eisai Denmark
and UCB Nordic. Torbjorn Tomson received research grants from GSK
and UCB and has received speakers or consultancy fees from GSK, UCB,
Eisai, Sun Pharma, and Bial. Erminio Bonizzoni, Dick Lindhout, and Frank
Vajda have no relevant conflicts of interest to report. 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.
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Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Appendix S1. EURAP Study group.
Epilepsia, **(*):17, 2013
doi: 10.1111/epi.12302