Reproductive Toxicology 46 (2014) 40–45

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

Review

The fetal safety of Levetiracetam: A systematic review Shahnaz Akhtar Chaudhry, Geert’t 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 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; five 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% confidence interval of 1.53–3.22]. In contrast, Levetiracetam polytherapy was associated with significantly higher malformation rate of 6.3% (34/541) [95% CI of 4.53–8.65] (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 first trimester exposure to Levetiracetam is within the population baseline risk of 1–3%, 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transparency document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Study funding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40 41 41 41 41 41 41 42 44 44 44 44 45

1. Introduction

Abbreviations: AEDs, antiepileptic drugs; GMDS, Griffiths 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: [email protected] (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) 40–45

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 first 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, filtration 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 first 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 ossification 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 findings 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 first trimester of pregnancy. Types of outcome measures: Adverse neonatal outcomes were defined as any major congenital malformation in the newborn. Major congenital malformations were defined as structural abnormalities with surgical, medical, or cosmetic importance [18]. 2.2. Information sources Studies were identified by searching electronic databases, scanning reference lists of articles and consultation with experts in the field. 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, case–control 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 definitions 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% confidence interval of 1.53–3.22]. 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 4.53–8.65). (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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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

1997–2011

Mono-therapy N 450

Major malformation N (%) 11 (2.4)

1996–2011

304

2 (0.7)

1996–2008

58

1999–2010 1999–2011

22 126

Up to 2010

253 1213

0

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 1.14–2.63

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 1.14–2.63. 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/flat 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 defining 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 define 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% confidence interval of 1.14–2.63 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 fingers (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 4.1–8.5) (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 significant between LEV exposed and LTG exposed (2.0% and 2.9% respectively (P = 0.2)) but was statistically significant 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 find 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 find 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 Griffiths 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 3–4 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 significantly 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 findings suggest that in utero exposure to LEV does not have adverse effects on neurodevelopment and language skills of children at 3–4 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 [28–30]. The risk of MCM as a result of first trimester exposure to AEDs varies among the AED used. In this review, first trimester exposure to LEV monotherapy was not associated with an increased risk for

S.A. Chaudhry et al. / Reproductive Toxicology 46 (2014) 40–45

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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 significant 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 significant 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 first trimester exposure to LEV2.2% and the adjusted rate 1.7% are well within the normal population rates of 1–3%. 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 first 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 findings. 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 first 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

1

1

0

0

Details not available

2

0

0

0

0

Inguinal hernia and reflux requiring surgery

0

0

0

0

0

0

0

0

0

0

0

0

2









Details not available

12

0

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

1

Pyloric stenosis, macrocephaly,

Showing the malformations as mentioned in different registries. The first column presents the total number of malformations. The next 4 columns show the prevalence of most common specific 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 specific pattern of malformations. From the UCB registry 6 malformations were excluded as they were positional malformations, genetics, or birthmarks and did not meet the definition of MMF (bilateral club feet, positional plagiocephaly/intermittent esophoria/flat feet, congenital torticollis/hydrocele, polydactyly/hemangioma, congenital nystagmus/scalp hemangioma, and congenital nevus/achrochordon/nevus simplex).

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Table 4 Neurodevelopment assessment at under 24 months and at age 3–4 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 3–4 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

The fetal safety of Levetiracetam: a systematic review.

To systematically review the available published evidence on the fetal safety of Levetiracetam with focus on birth defects...
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