Reproductive Toxicology 46 (2014) 4045

Contents lists available at ScienceDirect

Reproductive Toxicology
journal homepage: www.elsevier.com/locate/reprotox

Review

The fetal safety of Levetiracetam: A systematic review

Shahnaz Akhtar Chaudhry, Geertt Jong, Gideon Koren
The Motherisk Program, Division of Clinical Pharmacology & Toxicology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada

a r t i c l e

i n f o

Article history:
Received 1 May 2013
Received in revised form 13 February 2014
Accepted 22 February 2014
Available online 3 March 2014
Keywords:
Pregnancy
Levetiracetam
Safety
Adverse outcome
Birth defects

a b s t r a c t
Objective: To systematically review the available published evidence on the fetal safety of Levetiracetam
with focus on birth defects.
Results: Eight studies met the inclusion criteria; ve pregnancy registries and one population based cohort
study. A total of 27 major congenital malformations were reported among 1213 Levetiracetam monotherapy exposed pregnant women, yielding an overall major malformation rate of 2.2% (27/1213) [95%
condence interval of 1.533.22]. In contrast, Levetiracetam polytherapy was associated with signicantly higher malformation rate of 6.3% (34/541) [95% CI of 4.538.65] (P < 0.001). Additionally 2 studies
investigating child neurodevelopment in Levetiracetam exposed children revealed that the measured
achievements were well above those children exposed to valproic acid, and similar to unexposed controls.
Conclusions: The current evidence suggests that the overall risk of major malformation after rst trimester
exposure to Levetiracetam is within the population baseline risk of 13%, with no apparent adverse effects
on long term child development.
2014 Published by Elsevier Inc.

Contents
1.
2.

3.
4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Eligibility criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Information sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Data collection process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.
Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Transparency document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Study funding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

Abbreviations: AEDs, antiepileptic drugs; GMDS, Grifths Mental Development

Scale; LEV, Levetiracetam; LTG, lamotrigine; MCM, major congenital malformation;
NAARP, North American Pregnancy Antiepilepsy Registry; TPM, topiramate; VPA,
valproic acid.
Corresponding author at: Hospital for Sick Children, Division of Clinical Pharmacology and Toxicology, 555 University Avenue, Toronto, ON, Canada M5G 1X8.
Tel.: +1 416 813 5781; fax: +1 416 813 7562.
E-mail address: gkoren@sickkids.ca (G. Koren).
http://dx.doi.org/10.1016/j.reprotox.2014.02.004
0890-6238/ 2014 Published by Elsevier Inc.

Epilepsy is one of the most common neurological disorders during pregnancy, often necessitating the use of anti-epileptic drugs
(AEDs). Use of several AEDs during pregnancy has been associated
with increased risk of major congenital malformations (MCM), and
developmental delay [1,2]. There is limited information regarding
the fetal safety of newer AEDs, leading to anxiety among pregnant
patients, often resulting in a lower adherence rate. Decreased
adherence to AEDs in non pregnant adults has been shown to lead
to serious consequences and a threefold increase in mortality [3].

S.A. Chaudhry et al. / Reproductive Toxicology 46 (2014) 4045

Women are more comfortable continuing the use of medications

during pregnancy when evidence-based safety data are available
[4].
Levetiracetam (LEV; Keppra ) is a relatively new, 2nd generation antiepileptic drug which was approved by FDA as an
antiepileptic agent in November, 1999 [5] and in Europe in 2000
[6]. LEV demonstrated several advantages over other AEDs such
as twice daily dosage, less requirement for therapeutic drug monitoring, lack of common interactions with other AEDs, and less
adverse effects on users cognitive functioning as compared to
rst generation antiepileptic [7,8]. Pharmacokinetic studies of LEV
have shown complete bioavailability after an oral dose, no binding to plasma proteins, no hepatic metabolism, with one third of
the drug being metabolized by hydrolysis and two thirds excreted
unchanged in the urine [9,10], and a linear dose: concentration
ratio [11]. These properties may make LEV more suitable for use
in child bearing years and during pregnancy. In pregnancy, due
to increased volume of distribution, ltration rate, impaired drug
absorption and poor adherence there is decline in serum concentrations as the pregnancy advances. This decline can be as high
as 50% of the baseline in the third trimester with rapid increase
within the rst week postpartum [12,13]. Hence LEV dose may
need to be increased during the third trimester for adequate seizure
control [14]. Studies conducted in rats, rabbits, and mice have suggested relative fetal safety. Minor skeletal abnormalities were the
only reported defects with delayed ossication of the phalanges
[15,16]. Furthermore, animal studies have also shown decrease in
maternal weight gain that may, per se, lead to delayed fetal growth
[15,16].
To address fetal safety in humans, several registries have been
established to monitor adverse effects of AEDs in pregnancy, with
the primary objective of assessing the risk of major malformations after prenatal exposure to AEDs. These registries differ in
their methods of enrolment, exposure and outcome ascertainment,
exclusion criteria and time window of assessment, leading the
directors and senior staff members of three of the pregnancy registries (EURAPE, UK and Ireland Epilepsy and Pregnancy Register
and North American AED pregnancy Registry) to opine that their
ndings should not be combined [17]. The differences among the
registries are detailed in Section 4.
To allow safe use of LEV in pregnancy, one must establish the
fetal safety of the drug. For that end, we systematically reviewed
the available published evidence on the fetal safety of LEV with
focus on birth defects.
2. Methods
2.1. Eligibility criteria
Types of studies: All human studies published either as peer
review papers or abstracts written in English were included. Case
reports and case series were excluded. Exposure to LEV needed to
occur during at least the rst trimester of pregnancy.
Types of outcome measures: Adverse neonatal outcomes were
dened as any major congenital malformation in the newborn.
Major congenital malformations were dened as structural abnormalities with surgical, medical, or cosmetic importance [18].
2.2. Information sources
Studies were identied by searching electronic databases, scanning reference lists of articles and consultation with experts in the
eld. The databases searched included MEDLINE, EMBASE, Web of
Science with Conference Proceedings and the Cochrane Library. The
dates searched were from inception until January 31, 2013.

41

We used the following search terms to identify all studies:

Levetiracetam, Keppra, major congenital malformations, deformities, pregnancy, adverse effects, adverse outcomes, cohort study,
casecontrol study, and comparative study.
2.3. Data collection process
Eligibility assessment was performed independently by two
reviewers in a standardized manner by reviewing the title and
abstract, and if necessary the full article. Disagreements between
the reviewers were resolved by consensus after further evaluation.
2.4. Statistical analysis
We used Fisher exact test to compare fetal malformation following maternal exposure to LEV monotherapy, polytherapy and
compared to other AEDs.
3. Results
Eight studies met the inclusion criteria; 5 were observational
studies in the form of pregnancy registries and one was a population based study, investigating birth defects. Additional two cohort
studies investigated neurodevelopment of children after in utero
exposure to LEV. The available published data included the results
from The North American AED Pregnancy Registry (NAAPR) revealing 11 major malformations out of 450 pregnancies exposed to LEV
(11/450) [19]; the UK and Ireland Epilepsy and Pregnancy Registers
(2/304) [20], the International Registry of Antiepileptic Drugs and
Pregnancy (EURAP) (2/126) [6], the Australian Pregnancy Register
(0/22) [21], UCB Antiepileptic Drug Pregnancy Registry (12/253),
[22] and a Danish population based cohort (0/58) [23] as shown in
Table 1.
The denitions of major congenital malformations were similar across the studies, but the postpartum time window of the
assessment was different; 3 months for NAAPR and UK & Ireland
registries, and 12 months for the Australian and EURAP registries. In
the EURAP registry more than 30% of malformations were reported
at 12 month after birth, which were not reported initially at 2
months of age [17]. This difference in time window may under
estimate the risk of MCM, especially cardiac defects, hip and renal
malformations which often become apparent at a later time [24].
The UCB AED Pregnancy Registry, phase 4 trial might will resolve
this issue in the future as they plan to follow up the children at 3
years of life after in utero exposure to LEV, as detailed in clinical
trials.gov.
Because most studies did not have their own internal control
unexposed group, a formal meta analysis could not be conducted.
Only NAAPR and the Denmark population based study included an
internal comparison groups (Table 1).
The pooled data from these studies resulted in a total of 1213
pregnant women exposed to LEV monotherapy and 541 exposed to
LEV along with at least one more antiepileptic drug. There were 27
major congenital malformations reported after LEV monotherapy
exposure with an overall rate of 2.2% (27/1213) [95% condence
interval of 1.533.22]. In contrast, results were also available from
three registries for LEV polytherapy with at least one other AED
and risk of major malformation. The UK and Ireland Epilepsy and
Pregnancy Registers (19/367), the Australian Pregnancy Register
(2/69), and the UCB Antiepileptic Drug Pregnancy Registry (13/105)
resulted in a total of 541 LEV polytherapy exposures and with 34
reported major malformations (6.3% with 95% CI of 4.538.65).
(P < 0.001 when compared to LEV monotherapy). The rate of MCM
with polytherapy varied according to the AED combination. The
UK and Ireland Pregnancy Registers reported that MCM were less
common when LEV was combined with lamotrigine (LTG) (1.8%) as

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S.A. Chaudhry et al. / Reproductive Toxicology 46 (2014) 4045

Table 1
Adjusted rate of major congenital malformations after exposure to Levetiracetam as monotherapy after correction for UCB Registry for positional anomalies and birth marks.
Study

Period of study

North American AED Pregnancy

Registry (NAAPR) [19]
UK and Ireland Epilepsy and
Pregnancy
Registers [20]
Population-based cohort study
(Denmark) [23]
Australian Pregnancy Register [21]
European & International Registry
of Antiepileptic drugs in
Pregnancy (EURAP) [6]
UCB Pregnancy Registry [22]
Total

19972011

Mono-therapy N
450

Major malformation N (%)

11 (2.4)

19962011

304

2 (0.7)

19962008

58

19992010
19992011

22
126

Up to 2010

253
1213

Internal comparison group MCM/N (%)

5/442 (1.1)

19911/836263 (2.4)

0
2 (1.6)

6 (2.4) after Correction

21 (1.7) 95%CI 1.142.63

After excluding positional anomalies and birth marks from the UCB registry there were 6 major malformations (MCM) among 253 (2.4%) exposed pregnancies to montherapy.
After using the adjusted rate for UCB registry, pooling of the data from all registries there were, a total of 1213 pregnancies with Levetiracetam monotherapy resulting in
reported 21 MMF (1.7%) with 95% CI 1.142.63.
Internal comparison group was available in only two registries, which are presented in the last column.
The six minor and positional malformations which were excluded are; bilateral club feet (positional), positional plagiocephaly/intermittent esophoria/at feet, congenital
torticollis/hydrocele, polydactyly/hemangioma, congenital nystagmus/scalp hemangioma, and congenital nevus/achrochordon/nevus simplex.

compared to valproic acid (VPA) (6.9%) or carbamazepine (9.4%). In

the UCB registry MCM were reported in 12.4% after LEV polytherapy
exposure, and all combinations were without VPA.
The registries vary in dening the exclusion criteria for major
malformations. The NAAPR registry excluded minor anomalies,
birth marks, positional deformations, and genetic disorders such
as chromosomal abnormalities [19]. The UK registry analyzed the
minor and major abnormalities separately [20]. Chromosomal and
genetic abnormalities were excluded or analyzed separately by
all registries. UCB Antiepileptic Drug Pregnancy Registry did not
dene clear cut exclusion criteria and included birth marks and
positional deformation under a single heading of malformations,
resulting in higher rate (4.6%) of malformations as compare to other
registries [22]. As we set the criteria for major malformation for
our review, we readjusted the rate of major malformation for UCB
epilepsy pregnancy registry after exclusion of birth marks, positional deformations, and minor anomalies to 2.4% (6/253). When
this adjusted outcome of UCB registry was used for pooling of data
with other registries, there were total of 21 malformtions after
exposure of 1213 pregnancies to LEV monotherapy resulting in
adjusted rate of 1.7% with 95% condence interval of 1.142.63
as shown in Table 1. Similarly when we excluded from the cases
of polytherapy 4 minor malformations (capillary hemangioma, 4th
toe crosses under 3rd toe/hemangioma lower back, hypopigmentation ngers (all with lamotrigine), hemangiomas (valproate), the
rate of MMF was reduced to 9/105 from 13/105. Hence, combining this rate with the poly therapy data from the UK and Ireland
Pregnancy Registers (19/367) and the Australian Pregnancy Register (2/69) resulted in 30 malformations among 541 LEV polytherapy
exposures (5.5% with 95% CI of 4.18.5) (P < 0.001 when compared
to LEV monotherapy.
We also compared the outcome of LEV-exposed pregnancies to
those exposed to lamotrigine (LTG) and VPA where data were available (Table 2). The difference in rates of MCM was not statistically
signicant between LEV exposed and LTG exposed (2.0% and 2.9%
respectively (P = 0.2)) but was statistically signicant when LEV
was compared to VPA-exposed pregnancies (10.5% (P < .001). There
was no consistency or a pattern of malformations after pooling all
results (Table 3).
The UK and Ireland Epilepsy and Pregnancy Registers did not
nd an association between the dose of LEV and MCM although
there was a trend; the mean dose associated with MCM was nearly
double (3000 mg) as compared to 1680 mg for normal pregnancy
outcome (P = 0.09). The North American AEDs Pregnancy Registry
also failed to nd apparent dose dependence for LEV-exposed

pregnancies and the risk for MCM. The UK and Ireland Epilepsy
and Pregnancy Registers reported no association between the LEV
exposed pregnancies and low birth weight of exposed infants which
was suspected in some of their earlier studies [25].
There were 2 studies investigating the neurodevelopment
effects of the LEV after in utero exposure. In one study the authors
used the Grifths Mental Development Scale (GMDS) and measured
developmental scores for locomotor, personal and social, hearing
and language, hand and eye coordination, and performance area.
The mean age of the children was 14 months ranging from 3 to
24 months and the study period ranged from 2003 to 2010. 51
LEV-exposed children were assessed for early cognitive development at less than 24 months of age and were compared to 44
VPA exposed children and 97 control children born to healthy
women. Children exposed to LEV exhibited higher developmental
scores than children exposed to VPA (P < 0.001) and did not differ
from control children on overall development (P = 0.62) (Table 4)
[26]. In summary, children exposed to LEV during intrauterine life
did not exhibit delay in cognitive development at 24 months of
age.
Another recent study was presented in an abstract form investigating neurodevelopment and language abilities of children
34 years of age after in utero exposure to AED. The study
recruited 40 children exposed to LEV and compared them to 32
children exposed to VPA, and to 125 born to healthy women
[27]. The authors used the GMDS and Reynell Language Scales.
LEV-exposed children obtained signicantly higher sores when
compared to VPA-exposed children for their locomotors skills
(P = 0.001), personal and social skills (P = 0.018), and their hand and
eye coordination skills (P = 0.019). Similarly children exposed to
LEV scored high in expressive language as compare to VPA exposed
children (P = 0.01) (Table 4). Similar to the two previous studies,
these ndings suggest that in utero exposure to LEV does not have
adverse effects on neurodevelopment and language skills of children at 34 years of age.
4. Discussion
Adequate seizure control during pregnancy is of paramount
importance, as gestational seizures may be associated with risks for
fetal hypoxia, intracranial hemorrhage, premature delivery, fetal
demise, and cognitive dysfunctions with repeated seizures [2830].
The risk of MCM as a result of rst trimester exposure to AEDs
varies among the AED used. In this review, rst trimester exposure
to LEV monotherapy was not associated with an increased risk for

S.A. Chaudhry et al. / Reproductive Toxicology 46 (2014) 4045

43

Table 2
Rates of malformations after exposure to Levetiracetam as compare to Lamotrigine and Valproic acid exposure.
Study

LEV MCM/N (total #) (%)

North American AED Pregnancy Registry

Population based Cohort Study (Denmark)
Australian Pregnancy Register
European & International Registry of
Antiepileptic drugs in Pregnancy
(EURAP)
Total

11/450 (2.4%)
0/58
0/22
2/126 (1.6%)

13/656 (2%)

LTG MCM/N (total #) (%)

P-value

31/1562 (2.0%)
38/1019 (3.7%)
12/231 (5.2%)
37/1280 (2.9%)

0.68

118/4092 (2.9%)

VPA MCM/N (total #) (%)

P-value
0.0001

0.57

30/323 (9.3%)

35/215 (16.3%)
98/1010 (9.7%)

0.20

163/1548 (10.5%)

0.0001

0.052
0.0007

When LEV exposed pregnancies were compared to LTG exposed pregnancies, there was no statistically signicant difference in MCM (P = 0.2) although the rates of
malformation were low (2% in case of LEV exposure and 2.9% in case of LTG exposure). There was statistically signicant difference when LEV was compared to those exposed
to VPA (P = 0.0001).
LEV, Levetiracetam; LTG, lamotrigine; VPA, valproic acid; MCM, major congenital malformation; AED, antiepileptic drugs.

MCM as compared to other AEDSs in different cohorts. The overall

reported rate of MCM after rst trimester exposure to LEV2.2% and
the adjusted rate 1.7% are well within the normal population rates
of 13%.
The strength of the included studies is that all the participants
were prospectively collected. The low rate of MCM after use of LEV
monotherapy, along with favorable pharmacokinetic properties of
LEV in pregnancy, especially less interactions with other drugs such
as oral contraceptives [31], makes LEV a promising choice in women
of child bearing age.
However, there are several challenges in this review that need
to be addressed. Pooling of data from different registries was challenging as they differ in a variety of methodological aspects, and
for this reason no formal meta analysis was performed. Yet, they
are all prospective cohorts with a primary objective of assessing
the incidence of major malformations after rst trimester exposure
to AEDs [17]. These registries are the most effective and essential
source of prospective data after exposure to AEDs and assessment of

teratogenic potential of individual AED. As examples, collection of

cases in the NAAPR and the Australian registry were by self enrollment of pregnant women taking AEDs, while the EURAP registry
is dependent on physicians referral, and the UK and Ireland Registers use both self-as well as physician referral. Physicians referral
may lead to gathering of more accurate data but at the same time
more severely affected women are likely to be enrolled [17]. In
cases of self-enrollment the comprehensiveness of enrollment may
be limited, as there are regional differences in ascertainment rates,
raising questions about the generalizability of the ndings. There is
some potential for overlap of subjects in EURAP, UK, and Australian
registries. NAAPR and EURAP enrolled women taking AED for any
reason during pregnancy, while the UK registry recruited women
with epilepsy with or without AEDs in rst trimester. Although
the proportion of women taking AEDs for indications other than
epilepsy in NAAPR and EURAP registry is low, 10% and 2% respectively, an effect of the epilepsy itself on malformation rate has been
largely rejected [17].

Table 3
Major congenital malformations after exposure to Levetiracetam.
Registry/study

Total
malformations

Neural tube
defects

Cardiovascular anomalies

Hypospadias

Oral clefts

Other
malformations

North American AED

Pregnancy Registry
(NAAPR) (11/450)
UK and Ireland
Epilepsy and
Pregnancy Registers
[20] (2/304)
Population-based
cohort study
(Denmark)[23]
(0/58)
Australian Pregnancy
Register [21]
(0/22)
European &
International
Registry of
Antiepileptic drugs
in Pregnancy
(EURAP) [6] (2/126)
UCB Pregnancy
Registry [22]
(12/253)

11

Details not
available

Inguinal hernia and

reux requiring
surgery

Details not
available

12

3 (1.Pulmonary artery
stenosis/patent foramen
ovale
Subaortic ventricular
septal defect
3Pulmonary
stenosis/dysplastic
pulmonary valve)

Pyloric stenosis,
macrocephaly,

Showing the malformations as mentioned in different registries. The rst column presents the total number of malformations. The next 4 columns show the prevalence
of most common specic malformation, neural tube defects, cardiovascular anomalies, hypospadias and oral clefts. The last column presents the rest of the malformations
in the respective registries. This table does not suggest a specic pattern of malformations. From the UCB registry 6 malformations were excluded as they were positional
malformations, genetics, or birthmarks and did not meet the denition of MMF (bilateral club feet, positional plagiocephaly/intermittent esophoria/at feet, congenital
torticollis/hydrocele, polydactyly/hemangioma, congenital nystagmus/scalp hemangioma, and congenital nevus/achrochordon/nevus simplex).

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S.A. Chaudhry et al. / Reproductive Toxicology 46 (2014) 4045

Table 4
Neurodevelopment assessment at under 24 months and at age 34 years after in utero exposure to Levetiracetam as compare to in utero exposure to valproic acid and control
group.
Study

Parameters

Shallcross 2011
Under 24 Months

GMDS Scale

Shallcross
2010
Age 34 years
GMDS Scale
Reynell
Development
Language
Scale 3.

1. Locomotor Skills
2. Personal & Social Skills
3. Hearing and Language
4. Hand & Eye Coordination
5. Performance
6. Overall Development Quotient

1. Locomotor Skills
2. Personal & Social Skills
3. Hand & Eye Coordination Skills
4. Expressive Language
5. Comprehensive Language

LEV

VPA

Control

51 (Mean)

44 (Mean)

97 (Mean)

97.35
98
100.5
101.88
101.75
99.96

84.66
89.82
90.48
88.21
88.88
87.93

95.24
97.95
101.27
97.43
101.48
98.87

40

32

125

112
116
106
52
49

93
103
95
40.7
43

NA
NA
NA
46
52

P value LEV vs VPA

0.001
0.03
0.01
<0.001
<0.001
<0.001

0.001
0.018
0.019
0.01
0.14

Children exposed to LEV in utero did not differ signicantly from control children on scores for GMDS or the Reynell Language Scales with the exception of expressive
language ability where LEV exposed children scored signicantly higher scores.
LEV, Levetiracetam; VPA, valproic acid, GMDS, Grifths mental development scales.
NA results not available in the published paper.

Another difference among the registries is in how they dene

prospective enrollment. For example, the UK registry considered
subjects as prospective; if they were enrolled before the outcome
of the pregnancy was known and excluded cases if prenatal tests
have shown an abnormality [20]. These exclusion may lead to lower
reporting rates of cases. On other hand the NAAPR classied the
cohort as purely prospective if at the time of enrollment women
are unaware of fetal malformation and traditional prospective
if the subjects had some knowledge of fetal status, but were still
pregnant at the time of enrollment [19]. While EURAP applied
strictest criteria for prospective enrollment and included only subjects before the outcome of pregnancy was known and enrolled no
later than 16 weeks of gestation [17]. Although these differences
can lead to different rates of reported malformations, all registries
made an effort not to include cases where malformations were
known prior to enrollments. The data regarding AED used, indications, and dosing information was collected by physicians in the
UK, Australian, and EURAP registries, while in the NAAPR registry
data were collected by the subjects reporting, but was corroborated
with medical records in 60% of the cases [17,19]. It is reasonable
to assume that pregnant women with a chronic condition contacting a registry have accurate information about dose schedule of
their antiepileptic drugs. While adherence with therapy may be
questioned, none of the studies recorded either LEV serum levels
or changes in dosing throughout the pregnancy.
NAAPR, UK, Australian, and EURAP registries clearly
dened major malformations and either excluded the genetic/
chromosomal, minor and positional deformities or analyzed them
separately. Indeed, the UCB registry, which did not standardize the
denition of major malformations and included genetic and minor
anomalies as well as positional deformities, reported higher rates
of malformations after exposure to LEV during pregnancy as compare to the other registries. We addressed this issue by reanalyzing
UCB registry data after excluding the genetic and minor anomalies,
as well as positional deformities, showing overall similar results
as compared to the other registries. Importantly, the overall low
and similar rates of major malformations in the different registries
suggest that the methodological differences detailed above did not
result in signicant bias among these prospective cohorts.
Another limitation of this review is that the existing registries
reported only on the rates of major malformation in general, but
did not detail specic malformations; hence one cannot consider

clustering or specic patterns. It is hoped that such data will

become available in the future, to facilitate improved synthesis of
existing data.
Although this review suggests no adverse effects of LEV on neurocognitive function of the offspring, these studies have a relatively
small sample size and relatively young ages of the tested children.
The two available studies would allow detection of 8 point IQ difference between LEV and healthy controls with a power of 80% and
alpha of 0.05.
Our data synthesis suggests a better fetal safety prole after
exposure to LEV monotherapy as far as malformations are concerned, despite of differences in methodologies. This fact further
corroborates the validity of combining the results of the different
existing cohorts. As randomized control trials are not ethically feasible during pregnancy, these observational cohorts are the best
available source of data to investigate fetal safety after LEV exposure.
In conclusion, this systematic review suggests a favorable fetal
safety prole of LEV, both as monotherapy and in combination with
other AEDs. As the existing body of evidence is relatively small more
data are needed to draw denitive conclusions.
Conict of interest
The authors declare that there are no conicts of interest.
Transparency document
The Transparency document associated with this article can be
found in the online version.
Study funding
No study funding reported.
Acknowledgements
Dr. Chaudhry and Dr. Jong are members of Motherisk program at division of Clinical Pharmacology and Toxicology at
hospital for Sick Children. Dr. Koren, the Director of Motherisk
Program, is supported by the Ivey Chair in Molecular Toxicology,

S.A. Chaudhry et al. / Reproductive Toxicology 46 (2014) 4045

at Western University and the Research Leadership for Better

Pharmacotherapy during Pregnancy and Lactation, at Sick kids
Hospital.
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