Reproductive Toxicology 20 (2005) 175178

Short communication

Levetiracetam use and pregnancy outcome

Klara ten Berga, , E. Bettina Samrena ,
A. Carla van Oppenb , Martijn Engelsmanc , Dick Lindhouta
a

Department of Medical Genetics, University Medical Centre Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands
b Department of Obstetrics and Perinatology, University Medical Centre Utrecht, The Netherlands
c Department of Neurology and Epileptology, Epilepsy Institute of The Netherlands SEIN, Heemstede, The Netherlands
Received 26 October 2004; received in revised form 23 November 2004; accepted 4 December 2004
Available online 8 January 2005

Abstract
Prenatal exposure to levetiracetam (LEV) has been shown to cause skeletal abnormalities and growth retardation in animal studies, but the
teratogenicity of this new antiepileptic drug in humans is still unknown. We detected no malformations in a series of 11 pregnancies with
LEV exposure, although it was striking that three cases had a low birth weight. There may be an association between maternal LEV use and
reduced birth weight, but too few cases have been monitored so far. We recommend that the outcomes of all pregnancies exposed to LEV
should be carefully registered.
2004 Elsevier Inc. All rights reserved.
Keywords: Levetiracetam; Antiepileptic drugs; Epilepsy; Pregnancy; Malformation; Birth defect; Birth weight; Fetal exposure

1. Introduction
Maternal antiepileptic drug use is associated with an increased frequency of adverse pregnancy outcome including congenital malformations [1]. However, continuation
of medication during pregnancy is often necessary to prevent seizures which would be harmful to mother and fetus.
Recently, some new antiepileptic drugs (AEDs) have been
launched, promising better antiepileptic properties and fewer
side effects; however, the teratogenicity of this new generation of AEDs in humans is still unknown. The same holds
true for levetiracetam (LEV), which has been registered for
treatment of partial epilepsy and seems to be effective in idiopathic generalized epilepsy as well [2]. It is used mostly as
adjunctive therapy in doses of 10003000 mg/day. The drug
is chemically unrelated to existing AEDs and precisely how
it prevents seizures is unknown.
In animal studies, LEV showed developmental toxicity at doses similar to or greater than human therapeutic
doses [35]. In rats and rabbits, treatment with 350 and

Corresponding author. Tel.: +31 30 2503800; fax: +31 30 2503801.

E-mail address: k.tenberg@azu.nl (K. ten Berg).

0890-6238/$ see front matter 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.reprotox.2004.12.001

600 mg/kg/day, respectively, was associated with an increase in embryo-fetal mortality, minor skeletal abnormalities and growth retardation [35]. In a mouse model of
teratogenicity, no gross external malformations were observed in offspring prenatally exposed to LEV and its major
metabolite in humans, 2-pyrrolidinine N-butyric acid (PBA),
at doses up to 2000 mg/kg/day, except for cleft palate in
two fetuses exposed to LEV 1200 mg/kg/day [3]. In both
the LEV and PBA groups, at doses 600 mg/kg/day fetal
weights were reduced and the overall frequency of skeletal abnormalities, specifically of hypoplastic phalanges, was
increased. These skeletal abnormalities were not actual malformations but they are well-recognized indicators of perturbations in fetal growth and development; therefore, they
point towards LEV affecting prenatal growth. Furthermore,
LEV treatment at 600 mg/kg/day caused a 15% reduction
in maternal weight gain associated with the delayed fetal
growth.
Few data are available on the teratogenicity of LEV in
humans. Long [6] reported a normal pregnancy outcome
for three cases treated with monotherapy of 7503000 mg
LEV daily. Birth weights were within the normal range.
During safety trials, 23 women became pregnant while tak-

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K. ten Berg et al. / Reproductive Toxicology 20 (2005) 175178

ing 10004000 mg LEV/day in mono- or poly-therapy [7].

Pregnancy outcomes were: eight healthy children (including
one set of twins), one child with syndactyly between second and third toes, and one child with a tetralogy of fallot
(both exposed to LEV in polytherapy), one prematurely delivered child with abnormal heart rhythm, one ectopic pregnancy, seven spontaneous abortions, three voluntary abortions (no details given about fetal malformations) and two
unknown outcome. No data were published on the birth
weights.
Since there is evidence that LEV has adverse developmental effects in animals, careful monitoring of human pregnancy
outcome with maternal LEV use is of great importance. Here
we present the outcome of 11 well-documented pregnancies
in 10 women on LEV treatment.

2. Materials, methods and results

Our 11 cases form a consecutive series of LEV-exposed
pregnancies registered in the European Registry of
Antiepileptic Drugs and Pregnancy (EURAP) in The Netherlands. Maternal data and pregnancy outcome are listed in
Table 1. Seven women had partial epilepsy of unknown
etiology, two had juvenile myoclonic epilepsy, and one
had idiopathic generalized epilepsy. LEV was prescribed in
monotherapy in two women and in combination with other
AEDs in eight; doses varied from 500 to 3500 mg/day. Nine
pregnancies resulted in the birth of a child, one pregnancy
ended in a spontaneous abortion, and another pregnancy was
voluntarily terminated for other reasons. No fetal malformations were detected.
A striking feature was prenatal growth retardation in three
of these pregnancies: a low birth weight (<10th centile) in
relation to parity, pregnancy duration and sex of the infant in
cases 2 and 10 and a very low birth weight (<2.3rd centile)
in case 8. In eight women LEV treatment was initiated at
least 3 months before pregnancy, case 4 started taking LEV 1
month before becoming pregnant, whereas case 6 started taking LEV only after conception. None of the women reported
substantial changes in body weight during LEV treatment
in the period before pregnancy. No hyperemesis gravidarum
or reduced maternal weight gain during pregnancy were observed. Further details on the three cases with reduced birth
weight are as follows.
Case 2 was a 26-year-old primigravida with partial
epilepsy treated with 2000 mg LEV, 2400 mg oxcarbazepine
and 100 mg lamotrigine daily. Lamotrigine was discontinued after 8 weeks of pregnancy and oxcarbazepine was increased to 2700 mg after 14 weeks. She started taking 0.5 mg
folic acid/day from week 5 onward. During pregnancy she
experienced two or three generalized tonic-clonic seizures
monthly. There was no history of substance abuse or smoking and she was otherwise healthy. Maternal serum alphafetoprotein analysis and ultrasound examination at 18 weeks
showed normal results. Fetal growth retardation was noted

at 33 weeks. Hospital admission because of pre-eclampsia

at 38 weeks was followed by delivery of a boy without congenital malformations. Birth weight was 2390 g (5th centile)
and Apgar scores were 10 and 10, 1 and 5 min postpartum.
Pathohistological examination of the placenta revealed no
abnormalities.
Case 8 was a 23-year-old primigravida with juvenile myoclonic epilepsy and a history of psychogenic pseudoepileptic seizures. She took 1500 mg LEV, 1500 mg oxcarbazepine
and 10 mg clobazam daily. Fluoxetine intake of 20 mg/day
to control mood disturbances was discontinued after 5 weeks
of pregnancy. She started taking folic acid supplements of
5 mg/day before conception. She had tonic-clonic seizures
less than once a month. There was no history of substance
abuse or smoking and she was otherwise healthy. Ultrasound
examination at 20 weeks did not reveal structural abnormalities but growth retardation was noted at 27 weeks. Discovery of abnormal placental blood flow velocity was followed by hospital admission and administration of corticosteroids to improve fetal lung maturation. At 32 weeks,
the infant was delivered prematurely because of concern
about absent end-diastolic flow in the umbilical artery and
fetal heart tracing abnormalities. The boy had no congenital malformations. Birth weight was 930 g (2nd centile)
and Apgar scores were 8 and 9, 1 and 5 min postpartum.
Six weeks postnatally the child was released from hospital in good condition. No structural abnormalities of the
placenta were found. Screening for thrombophilic abnormalities to explain the placental insufficiency was negative.
Case 10 was a 40-year-old multigravida with an obstetric history of a twin pregnancy exposed to 100 mg phenobarbital/day, resulting in the birth of two boys with normal birth weights, one of them having a cleft lip and the
other having hypospadias. She suffered from juvenile myoclonic epilepsy but remained free of seizures throughout
both pregnancies. She was otherwise healthy. Four months
prior to the second pregnancy, she switched from phenobarbital to 1000 mg LEV/day. Five mg/day of folic acid supplement was used only in weeks 715. During both pregnancies she smoked about 10 cigarettes daily. An ultrasound at 22 weeks did not show any structural abnormalities. Blood pressure remained normal throughout pregnancy.
At 40 weeks a girl was delivered by caesarean section, with
a birth weight of 2800 g (5th centile) and Apgar scores of
9 and 10, 1 and 5 min postpartum. No malformations were
detected.

3. Discussion
In a series of 11 pregnancies with LEV exposure, we observed one spontaneous abortion and nine live births, whereas
one pregnancy was terminated because of maternal social
reasons. Among the nine live births no malformations were
found. However, two out of nine live-born children had a

Table 1
Maternal data and pregnancy outcome in 11 pregnancies with LEV treatment
Case no.
1

6
7
8

9-I
9-II
10

Seizure type

Generalized tonic-clonic
seizures

Cigarette smoking
(number/day)

Age (years)

Parity

Pregnancy duration
(weeks)

Sex

Birth weight (g)

(centile)

Abnormal outcome

Levetiracetam
1500a ,
carbamazepine 600,
valproate 2000
Levetiracetam 2000,
oxcarbazepine
2400b , lamotrigine
100c
Levetiracetam 2000,
carbamazepine 2400
Levetiracetam
1000d ,
carbamazepine 400e
Levetiracetam 3500,
carbamazepine 800,
clobazam 20
Levetiracetam 500f ,
valproate 1200g
Levetiracetam 1500
Levetiracetam 1500,
oxcarbazepine 1500,
clobazam 10
Levetiracetam 2000,
carbamazepine 400
Levetiracetam 1500,
carbamazepam 400
Levetiracetam 1000

Partial

22

G1P0

n.a

n.a.

Missed abortion detected by ultrasound

at 14 weeks

Partial

Monthly

26

G1P0

38

2390 (P5)

Low birth weight

Partial

28

G1P0

40

3300 (P50)

Partial

<1/Month

10

22

G2P0

39

3495 (P65)

Partial

Weekly

15

21

G1P0

n.a.

n.a.

Generalized

21

G1P0

39

3500 (P60)

Voluntary abortion
for maternal social
reasons at 8 weeks

Partial
Myoclonic

0
<1/Month

3h
0

33
23

G2P0
G1P0

41
32

F
M

3200 (P25)
930 (P2)

Prematurity and very

low birth weight

Partial

30

G1P0

39

3680 (P80)

Partial

32

G2P1

41

3825 (P60)

Myoclonic

10

40

G2P1

40

2800 (P5)

Low birth weight

K. ten Berg et al. / Reproductive Toxicology 20 (2005) 175178

Medication during
pregnancy (mg/day)

n.a.: information not available.

a Discontinued after 4 weeks.
b Increased to 2700 mg after 14 weeks.
c Discontinued after 8 weeks.
d Discontinued after 9 weeks.
e Started after 7 weeks.
f Started after 4 weeks.
g Discontinued after 7 weeks.
h Discontinued after 4 weeks.

177

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K. ten Berg et al. / Reproductive Toxicology 20 (2005) 175178

low birth weight (<10th centile) and one a very low birth
weight (<2.3rd centile). The daily dose of LEV to which
the pregnancies had been exposed was within the generally
recommended therapeutic dose of 10003000 mg/day with
only two exceptions: 3500 mg/day in case 5 (pregnancy terminated) and 500 mg/day in case 6 (normal outcome). Other
factors than LEV treatment may, however, have been responsible for the reduced birth weights.
In case 2 pre-eclampsia was present, a well-known risk
factor for growth retardation. In case 8 abnormal placental
blood flow was found, suggesting that placental insufficiency
was the major cause of the severe prenatal growth retardation. However, no explanation for this insufficiency could be
found. It is not known whether LEV exposure influences prenatal growth by changing placental blood flow or by inducing
pre-eclampsia.
LEV was prescribed in combination with oxcarbazepine
and lamotrigine in case 2, and with oxcarbazepine and
clobazam in case 8. So far, prenatal exposure to these drugs
has not been associated with reduced birth weight in humans.
Co-medication with oxcarbazepine reduces LEV serum levels compared to LEV monotherapy, whereas lamotrigine has
no significant effect on LEV serum levels [8]. Until now, no
other important pharmacokinetic interactions between LEV
and other AEDs have been observed, so that an effect on birth
weight due to such interactions with co-prescribed drugs is
unlikely whereas pharmacodynamic interactions cannot be
excluded.
The reduced birth weight in case 10 cannot be explained by nicotine exposure [9], since the same mother
gave birth also to healthy twins with normal birth weights
while she smoked the same amount of cigarettes per day. In
that twin pregnancy she had used phenobarbital instead of
LEV.
In animal studies, delayed fetal growth was associated
with reduced maternal weight gain during LEV treatment [3].
In our cases, no abnormal maternal weight changes during
or prior to pregnancy were observed, although weight loss
has been associated with LEV treatment in both adults and
children [1012]. High concentrations of LEV have also been
reported in human breast milk but it is not known whether
this affects postnatal growth [13].
Thus far, experience with LEV treatment in pregnancy
does not point towards a distinct malformation pattern in humans; however, too few cases have been published to draw
conclusions about safety with respect to congenital malformations. Small case series, like this one, may nonetheless be
helpful in signaling adverse effects on continuous pregnancy
outcome parameters like birth weight.
Although animal studies have shown an association between prenatal LEV exposure and growth retardation, no
clear effect on weight in human pregnancies can be established. However, as low birth weight is associated with increased morbidity and mortality [14], our cases suggest we
should be aware of a possible association in humans. Largescale pregnancy registries are needed to find out whether pre-

natal LEV exposure is associated with low birth weight or

congenital malformations.
Acknowledgements
This report is based on data from the European Registry of Antiepileptic Drugs and Pregnancy (EURAP) in The
Netherlands, which is supported by grants from the University Medical Centre Utrecht (Genvlag grant), the Dutch National Epilepsy Fund (project 03-18) and manufacturers of
antiepileptic drugs (Janssen-Cilag, GlaxoSmithKline, Pfizer
and UCB Pharma). The authors are solely responsible for this
report and it does not necessarily represent the official views
of the Dutch National Epilepsy Fund or any pharmaceutical
companies. There are no potential conflicts of interest directly relevant to the contents of this report. We are indebted
to all patients and their physicians for their participation in
the EURAP registry. We thank Jackie Senior for editing the
manuscript.
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