In utero exposure to levetiracetam vs valproate Development and language at 3 years of age
R. Shallcross, PhD R.L. Bromley, PhD C.P. Cheyne, PhD M. García-Fiñana, PhD B. Irwin, RGN, RM J. Morrow, MD, PhD G.A. Baker, PhD On behalf of the Liverpool and Manchester Neurodevelopment Group and The UK Epilepsy and Pregnancy Register
Correspondence to Dr. Shallcross: [email protected]
ABSTRACT
Objective: To compare the cognitive and language development of children born to women with epilepsy (WWE) exposed in utero to levetiracetam (LEV) or sodium valproate (VPA) and control children born to women without epilepsy not taking medication during pregnancy.
Methods: The children, aged between 36 and 54 months, were recruited from the United Kingdom and assessed using the Griffiths Mental Development Scales and the Reynell Language Development Scale. Maternal demographic and epilepsy information was also collected for use in statistical regression. This is an observational study with researchers not involved in the clinical management of the mothers enrolled.
Results: After controlling for confounding variables, children exposed to LEV in utero (n 5 53) did not differ from unexposed control children (n 5 131) on any scale administered. Children exposed to VPA (n 5 44) in utero scored, on average, 15.8 points below children exposed to LEV on measures of gross motor skills (95% confidence interval [CI] 224.5 to 27.1, p , 0.001), 6.4 points below on comprehension language abilities (95% CI 211.0 to 21.8, p 5 0.005), and 9.5 points below on expressive language abilities (95% CI 214.7 to 24.4, p , 0.001).
Conclusion: The current study indicates that children exposed to LEV in utero were superior in their language and motor development in comparison to children exposed to VPA. This information should be used collaboratively between health care professionals and WWE when deciding on women’s preferred choice of antiepileptic drug. Neurology® 2014;82:213–221 GLOSSARY AED 5 antiepileptic drug; CI 5 confidence interval; GMDS 5 Griffiths Mental Development Scales; LEV 5 levetiracetam; LMNDG 5 Liverpool and Manchester Neurodevelopment Group; RDLS 5 Reynell Developmental Language Scales; SES 5 socioeconomic status; UKEPR 5 UK Epilepsy and Pregnancy Registry; VPA 5 valproate; WWE 5 women with epilepsy.
Editorial, page 194
The physical and cognitive effects of in utero exposure to sodium valproate (VPA) have been well-documented,1,2 leading practice guidelines to suggest that VPA should be avoided, where possible, for the treatment of women with epilepsy (WWE) of childbearing potential.3 The UK Epilepsy and Pregnancy Registry (UKEPR) reported a low occurrence of malformation rates following levetiracetam (LEV) use in pregnancy,4 consistent with the results of the North American Pregnancy Registry5 and similar to malformation rates found in the nonepilepsy population.4 Animal data report low malformation rates,6 along with minimal impact on animal cognitive development following LEV exposure.7 Unsurprisingly, then, the use of LEV in WWE has increased in recent years, while the use of VPA has declined.8,9 Despite the increase in use of LEV, reliable information on the neurodevelopment and cognitive abilities of children exposed to LEV is limited. Previously, the Liverpool and Manchester Neurodevelopment Group (LMNDG) and the UKEPR reported on the early development of children exposed in utero to LEV at ,24 months of age, with a favorable outcome.10 The current article reports on the developmental functioning and language abilities of children aged 36–54 months exposed in utero to LEV in comparison to children exposed to VPA and a control group of children.
Supplemental data at www.neurology.org From the Departments of Clinical Psychology (R.S.), Molecular and Clinical Pharmacology (R.L.B., G.A.B.), and Biostatistics (C.P.C., M.G.-F.), University of Liverpool; and the Department of Neurology (B.I., J.M.), Royal Group of Hospitals, Belfast, UK. Coinvestigators are listed on the Neurology® Web site at www.neurology.org. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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METHODS Recruitment. WWE were recruited through the UKEPR, a prospective register of WWE designed for the collection of data pertaining to pregnancy and outcome.11 Eligibility criteria for enrollment onto the current study included use of monotherapy LEV throughout pregnancy, with a live birth between December 2003 and September 2007, or monotherapy VPA throughout pregnancy with a live birth between September 2005 and September 2007. Further criteria included maternal IQ .70 and children aged between 36 and 54 months at time of assessment. Eligible women were sent a letter asking if they wanted to take part in a continuation of the UKEPR study. Those who did not respond were sent a follow-up letter and if no further reply was obtained, the mother was recorded as a nonrespondent and no further information was sent. The control group of children born to women without epilepsy, not taking medication during pregnancy, were recruited and assessed by the LMNDG.1 The 36- to 54-month assessment of this cohort has not been previously reported. The utilization of this control group was implemented to ensure that mild to moderate levels of altered development could be detected. The control group was recruited from this source as the UKEPR do not collect information on pregnancies for women without epilepsy. Both the UKEPR and the LMNDG include prospective enrolment (i.e., while mothers are pregnant) and prospective collection of confounding variables and pregnancy data, including maternal IQ, maternal age, gestational age, age of child at assessment, child sex, seizure occurrence during pregnancy, alcohol or nicotine use in pregnancy, and socioeconomic status (SES). The exception to this was the collection of data regarding SES, alcohol, nicotine, seizure exposure, and information regarding epilepsy type, which was collected retrospectively for the mothers from the UKEPR. Epilepsy type was verified following the collection of data regarding seizure type, with a detailed description of seizures being taken from mothers and classified as partial, generalized, or unclassified. In the current study, 5 children (11.4%) exposed to VPA, 17 children (32.1%) exposed to LEV, and 50 control children (38%) were previously reported at 0–24 months.10
Assessment of children. Children were assessed at 36–54 months of age (mean 42 months; range 36–54 months) using standardized neurodevelopment measures: the Griffiths Mental Development Scales (GMDS12) and the Reynell Developmental Language Scales (RDLS13). The GMDS was utilized in the current study to gain a measure of 5 areas of child development: locomotor, personal and social, eye and hand coordination, performance, and practical reasoning abilities. The RDLS was chosen to assess verbal comprehension and expressive language independently of each other.13 Finally, the National Adult Reading Test14 was utilized as a surrogate measure of maternal IQ. Parents received feedback following assessment and, where necessary, a request for a referral (i.e., to a speech and language therapist or pediatrician) was made. Standard protocol approvals, registrations, and patient consents. Ethical approval was obtained from the North West Multi-centre Research Ethics Committee in 2000 (Ref.: MREC 99/8/71). Written consent was obtained from all mothers. This is a cross-sectional observational study with researchers playing no part in the clinical management of the WWE.
Statistical analysis. Data were collected on confounding variables, identified by previous literature, associated with child outcome. The confounding variables (listed above) were entered into the model and retained if their significance levels were ,0.05. Cohort size was dictated by the principle of 10–15 participants per variable.15 214
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Descriptive statistics and a multivariate linear regression analysis were conducted to compare the effect of drug exposure on child outcome between groups (nonexposed controls, LEV-exposed, and VPA-exposed). The model had nonexposed controls serving as the reference group and comparisons between LEV and VPA groups were also carried out using the same model. Reported results are based on marginal distributions from a multivariate linear regression model. The significance level was set to a 5 0.05/7 z 0.007 (where 7 is the number of outcomes considered) to take into account the multiple comparisons involved. Inverse probability weighting was utilized16 to account for the influence of missing outcomes (84.2% of the total number of children had no missing outcomes) in the multivariate linear regression analysis. Pearson correlation was used to test the relationship between dose and child outcome with a Bonferroni correction applied to account for multiple comparisons. A Fisher exact test revealed that the proportion of patients across epilepsy types differed between the LEV and VPA groups. This suggested an association between the type of epilepsy an individual has and the treatment prescribed in terms of LEV and VPA. However, due to low numbers in some combinations of epilepsy and treatment type, it was not possible to include epilepsy type, treatment type, and their interactions within this study.
A total of 197 children aged between 36 and 54 months were identified from the UKEPR, 65 of whom were exposed to LEV monotherapy and 132 of whom were exposed to VPA monotherapy throughout pregnancy. Figure 1 demonstrates the response rate of those women contacted for each group. Control children (n 5 134) were born to women without epilepsy not exposed to medication in pregnancy. Of the 54 assessments arranged for the LEV group, one assessment could not be completed due to the child’s poor attention span; therefore, 53 children exposed to LEV completed an assessment. Of the 46 mothers of children exposed to VPA who agreed to participate, one child was not assessed as the mother did not take medication throughout pregnancy. Of the 45 appointments arranged, one child was excluded due to the mother stopping medication use upon confirmation of the pregnancy; therefore, 44 children exposed to VPA completed an assessment. Of the 134 control children, one child was excluded as the mother took warfarin during pregnancy, one child was excluded as maternal IQ was ,70, and a final child was excluded due to a suspected genetic condition with unexplained severe global developmental delay (referral to local genetic services was made, but contact with the family was lost); therefore, 131 control children completed an assessment. Consequently, 228 children are included in the analysis: 97 children born to WWE and 131 control children born to women without epilepsy. Table 1 outlines mean child developmental quotient outcomes and descriptive statistics, with significant differences identified. Multiple comparisons of SES revealed no differences between mothers who took LEV and VPA during pregnancy in terms of their SES (p 5 0.4). However, control women
RESULTS
Figure 1
Response rate of mothers
LEV 5 levetiracetam; VPA 5 sodium valproate.
were of lower SES than both women who took LEV (p , 0.001) and women who took VPA during pregnancy (p 5 0.003).
No further significant differences were found between exposure groups on any other subscales.
Regression analysis. Griffiths Mental Development Scales.
variables, maternally reported seizures during pregnancy were predictive of poorer developmental outcome for gross motor skills (coefficient 219.2, 95% CI 228.5 to 29.8, p , 0.001), personal and social skills (coefficient 212.2, 95% CI 220.1 to 24.3, p 5 0.002), hand and eye coordination skills (coefficient 211.4, 95% CI 217.6 to 25.3, p , 0.001), performance skills (coefficient 212.9, 95% CI 220.4 to 25.5, p , 0.001), and comprehensive language abilities (coefficient 27.6, 95% CI 212.5 to 22.8, p 5 0.002; table 2).
Children exposed to VPA demonstrated the lowest adjusted mean scores. After controlling for confounding variables, children exposed to LEV did not differ from control children on any of the GMDS subdomains. Children exposed to VPA, however, scored on average 15.8 points below children exposed to LEV on gross motor skills (95% confidence interval [CI] 224.5 to 27.1, p , 0.001). Children exposed to VPA did not differ from children exposed to LEV in social, hand and eye, or performance (nonverbal tasks) skills (table 2, figure 2). Reynell Developmental Language Scales. After controlling for confounding variables, children exposed to LEV did not differ from controls for either comprehension or expressive language abilities (table 2, figure 3). Children exposed to VPA scored on average 6.4 points below children exposed to LEV on a measure of comprehension language abilities (CI 211.0 to 21.8, p 5 0.005) and 9.5 points below children exposed to LEV for expressive language abilities (CI 214.7 to 24.4, p , 0.001).
Seizures during pregnancy. After control of confounding
Dose effect. The mean dose of LEV was 2,070 mg
(range 500–5,000 mg) and the mean dose of VPA was 980 mg (range 400–3,500 mg). No dose effect was detected for either LEV or VPA exposure on any outcome measure. DISCUSSION The results suggest that children exposed in utero to LEV do not differ significantly from control children for developmental or language abilities. Furthermore, children exposed to LEV score significantly higher than children exposed to VPA on Neurology 82
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Table 1
Child developmental quotient outcomes and demographic variables
Continuous variable
Controls, mean (SD)
LEV, mean (SD)
p Value vs controls
VPA, mean (SD)
p Value vs controls
p Value vs Total, LEV mean (SD)
Maternal IQ
105.0 (11.0)
104.1 (11.3)
0.6a
101.6 (13.5)
0.1a
0.3a
a
a
a
104.1 (11.6)
Maternal age, y
30.3 (5.2)
30.2 (5.3)
0.9
30.3 (5.1)
0.9
0.9
30.3 (5.2)
Gestational age, wk
39.3 (2.2)
39.1 (1.8)
0.2b
39.9 (2.2)
0.07b
0.01b
39.4 (2.1)
41.1 (5.0)
b
Age at assessment, mo c
41.6 (4.8)
43.1 (6.0)
0.4
a
96.8 (22.1)
b
b
0.2
0.1 b,g
41.8 (5.1) b,g
Griffiths motor score
110.9 (20.1)
110.4 (17.2)
0.9
0.001
0.002
108.0 (20.6)
Griffiths personal scorec
119.9 (16.3)
116.5 (19.1)
0.1b
108.4 (21.4)
0.002b,g
0.2b
116.9 (18.5)
Griffiths hand and eye scorec
103.3 (15.6)
104.8 (13.9)
0.8b
102.1 (17.7)
0.9b
0.8b
103.4 (15.6)
Griffiths performance scorec
110.5 (16.3)
109.9 (15.4)
0.6b
111.4 (23.1)
0.7b
0.6b
110.5 (17.5)
Griffiths practical scorec
113.9 (17.0)
113.4 (16.6)
0.5b
108.9 (18.8)
0.06b
0.2b
112.9 (17.3)
Reynell comprehension scorec
52.2 (9.6)
49.6 (10.3)
0.2b
44.0 (16.1)
0.003b,g
0.2b
50.0 (11.7)
Reynell expressive scorec
46.6 (10.2)
52.0 (13.4)
0.01a
43.1 (15.9)
0.9b
0.005b,g
47.1 (12.5)
Binary/categorical variable
Controls, n (%)
LEV, n (%)
VPA, n (%)
p Value
Total, n (%)
0.8d
111 (48.7)
Sex Male
63 (48.1)
28 (52.8)
20 (45.5)
Female
68 (51.9)
25 (47.2)
24 (54.5)
117 (51.3)
Seizures Yes
0 (0)
20 (42.6)
12 (27.9)
No
131 (100)
27 (57.4)
31 (72.1)
Yes
39 (33.3)
13 (27.7)
11 (25.6)
No
78 (66.7)
34 (72.3)
32 (74.4)
16 (13.7)
6 (12.8)
13 (30.2)
101 (86.3)
41 (87.2)
30 (69.8)
Professional
27 (23.3)
22 (45.8)
15 (34.9)
Skilled
11 (9.5)
13 (27.1)
11 (25.6)
0.2e
32 (14.5) 189 (85.5)
Alcohol 0.6d
63 (30.4) 144 (69.6)
Smoking Yes No
0.03d
35 (16.9) 172 (83.1)
SES
Manual/unemployed Nf
78 (67.2) 131
13 (27.1)
17 (39.5)
53
44
,0.001d,g
64 (30.9) 35 (16.9) 108 (52.2)
—
228
Abbreviations: LEV 5 levetiracetam; SES 5 socioeconomic status; VPA 5 sodium valproate. a p Values are from a t test. b p Values are from a Mann-Whitney U test. c Number of missing data for each outcome variable: motor, n 5 25 (11.0%); personal, n 5 18 (7.9%); hand and eye, n 5 10 (4.4%); performance, n 5 6 (2.6%); practical, n 5 12 (5.3%); comprehension, n 5 8 (3.5%); expressive, n 5 11 (4.8%); total, 36 (15.8%). d p Values are from a x2 test testing for differences in the variable groups across the drug groups. e p Values are from a x2 test testing for differences in the variable groups across the LEV and VPA groups only. f Group totals include individuals with missing values for some of the binary/categorical variables listed. g Significant.
measures of gross locomotor, comprehension, and expressive language skills, suggesting that LEV exposure may be a preferential antiepileptic drug (AED) during pregnancy if seizures can be controlled. 216
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While research into the effects of LEV in utero upon child development remains extremely limited, the results reported in the current study are supported by previous human10 and animal research.7 The current
Table 2
Results of the multivariate analysis Gross motor
Personal and social
Explanatory variable/group
Coefficient (SE)
Control
Reference group
pa
95% CI
Coefficient (SE)
Hand-eye coordination pa
95% CI
Performance
Coefficient (SE)
95% CI
pa
Coefficient (SE)
95% CI
pa
Treatment LEV
4.1 (4.0)
23.8, 11.9
0.3
1.2 (3.3)
25.4, 7.8
0.7
0.8 (2.8)
24.8, 6.4
0.7
2.7 (3.2)
23.6, 9.0
0.4
VPA
211.7 (3.9)b
219.4 to 24.1b
0.003b
26.5 (3.2)
212.8 to 20.2
0.04
21.2 (2.7)
26.6, 4.2
0.7
3.6 (3.1)
22.5, 9.7
0.3
Treatment LEV
Reference group
VPA
215.8 (4.4)b
224.5 to 27.1b
,0.001b
27.7 (3.8)
215.2 to 20.2
0.04
22.0 (2.9)
27.8, 3.8
0.5
0.9 (3.5)
26.1, 7.9
0.8
Seizures
219.2 (4.8)b
228.5 to 29.8b
,0.001b
212.2 (4.0)b
220.1 to 24.3b
0.002b
211.4 (3.1)b
217.6 to 25.3b
,0.001b
212.9 (3.8)b
220.4 to 25.5b
,0.001b
Gestational age
1.7 (0.7)
0.4, 3.0
0.01
—
—
—
1.2 (0.5)
0.3, 2.0
0.01
1.8 (0.6)b
0.7, 2.8b
0.001b
—
—
—
Covariates
Age at assessment Sex
—
—
—
—
—
—
b
b
21.1 (0.2) 7.8 (2.3)
21.6 to 20.6
b
3.2, 12.4
b
,0.001
b
,0.001
b
—
—
5.5 (1.9)
b
—
1.7, 9.3
b
b
0.005
—
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0.005b
0.6 (0.3)
0.1, 1.1
0.01
0.4
—
—
—
0.01
—
—
—
Coefficient (SE)
95% CI
pa
5.5 (2.6)
0.4, 10.5
0.03
24.1 (2.4)
28.7, 0.6
0.09
—
—
—
—
—
—
0.2 (0.09)
0.02, 0.4
0.03
0.3 (0.1)
Maternal age
—
—
—
—
—
—
—
—
—
SES 1 (professional)
Reference status
SES 2 (skilled employment)
—
—
—
—
—
—
2.3 (3.0)
23.6, 8.1
SES 3 (manual/unemployed)
—
—
—
—
—
—
26.0 (2.5)
210.9 to 21.2
Explanatory variable/group
Comprehension of language
—
0.09, 0.5
Maternal IQ
Practical reasoning
— b
b
Expressive language
Coefficient (SE)
95% CI
pa
Coefficient (SE)
95% CI
22.5 (2.9)
28.3, 3.2
0.4
22.3 (2.3)
26.8, 2.2
pa
Control Treatment LEV VPA
b
0.3 b
,0.001
b
25.6 (3.0)
211.6, 0.3
0.06
28.7 (2.1)
212.9, 4.5
23.1 (3.5)
210.0, 3.8
0.4
26.4 (2.3)b
211.0 to 21.8b
0.005b
29.5 (2.6)b
214.7 to 24.4b
,0.001b
—
—
—
27.6 (0.002)b
212.5 to 22.8b
0.002b
26.1 (2.8)
211.5 to 20.7
0.02
1.0 (0.4)
0.3, 1.8
0.008
Treatment LEV VPA Covariates Seizures Gestational age
b
1.7 (0.5)
b
0.7, 2.7
b
,0.001
1.1 (0.4)
b
0.4, 1.8
b
0.002
b
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Continued
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0.01 212.5 to 21.4 26.9 (2.8) SES 3 (manual/unemployed)
0.4 29.5, 4.0 22.8 (3.5)
— SES 1 (professional)
SES 2 (skilled employment)
— — Maternal age
0.2, 0.6
b
January 21, 2014
Abbreviations: LEV 5 levetiracetam; SES 5 socioeconomic status; VPA 5 sodium valproate. a Only p values equal to 0.007 or less were considered to be statistically significant after using the Bonferroni correction when considering multiple comparisons (p 5 0.05/7 5 0.007). b Significant.
0.02 29.4 to 20.8 25.1 (2.2) 0.02 28.5 to 20.8
1.1 (2.6) 0.5 23.2, 6.0 1.4 (2.3)
24.6 (2.0)
0.7 24.1, 6.2
— — — — — —
0.05 0.001, 0.3 0.2 (0.08) 0.04 0.003, 0.3 ,0.001 0.4 (0.1)
b
Maternal IQ
0.01
— — Sex
—
21.0 to 20.1 20.6 (0.2) Age at assessment
Explanatory variable/group
Coefficient (SE)
95% CI
pa
b
0.1 (0.07)
—
— —
— —
— —
— —
— —
Coefficient (SE)
—
pa 95% CI 95% CI
pa
Coefficient (SE)
Expressive language Comprehension of language Practical reasoning
Continued Table 2 218
research is supported by many previous studies documenting the poor developmental outcome, including motor and language development, in children exposed in utero to VPA.1,17,18 Research surrounding apoptosis in the rodent brain may go some way to explaining the developmental differences found between LEV- and VPA-exposed children.19,20,21 Replication of a failure to associate LEV with altered infant neurodevelopment is required. A number of demographic variables were associated with infant neurodevelopment scores, with maternally reported seizures during pregnancy found to be predictive of poorer developmental outcome on several measures. This is consistent with previous research22 and inconsistent with other research.1,17,18,23,24 Therefore, the findings of the current research should be interpreted with some caution, especially as the impact of occurring generalized tonic-clonic seizures upon child development is not well-established. The methodology for the collection of seizure information in the current cohort is a limitation of the study. Due to the methodology of the UKEPR,11 seizure information was collected retrospectively on a “yes/no” basis. No more detail was provided about seizures during pregnancy (frequency, duration, type, severity). Therefore, conclusions cannot accurately be drawn in regards to the effect of seizures during pregnancy upon the developing child. There were no significant differences between LEV- and VPA-exposed children in the number of children exposed to seizures during pregnancy, suggesting that differences between the groups in terms of seizures cannot account for differences in developmental outcome between LEV- and VPA-exposed children. Interestingly, previous research with retrospective collection of seizure information22 also found an association with developmental outcome, while cohorts whereby data were collected prospectively1,18,24 failed to find an association. A larger cohort, with a prospective record of seizures during pregnancy, is needed to extrapolate the relationship between drug type, seizures during pregnancy, and child developmental outcome, which was beyond the scope of the current study. In regards to epilepsy type, Fisher exact test revealed that there are statistically significant differences between the LEV- and VPA-exposed groups in terms of the distribution of different epilepsy types. For example, of mothers prescribed LEV during pregnancy, 46.9% were classified as focal epilepsy, 44.9% generalized epilepsy, and 8.2% unclassified. Of mothers prescribed VPA during pregnancy, 7.0% were classified as focal epilepsy, 79.0% generalized epilepsy, and 14.0% unclassified. Therefore, one cannot rule out from these data that differences observed between drug groups could be fully (or partially)
Figure 2
Treatment group 95% confidence intervals of the adjusted means for developmental outcome
LEV 5 levetiracetam; VPA 5 sodium valproate.
explained by epilepsy type. However, in a literature review, fetal exposure to VPA in rodents (whereby maternal epilepsy is not a factor) was found to be associated with microcephaly, cerebellar abnormalities, and detrimental impact upon cognitive functions.25 The authors warn that while animal models allow for careful and controlled assessment of AEDs, care must be taken in generalizing to humans. However, the human data available in larger studies with a more equal distribution of epilepsy type across medications support animal data and fail to find an association between maternal epilepsy type and child developmental outcome.18 Limitations of the current study include the retrospective invitation to participate in neurodevelopmental follow-up. However, both the VPA and the LEV group were approached in the same way and
Figure 3
therefore it is not thought that this alone can account for the rise of neurodevelopmental difficulty in the VPA group in isolation. A much poorer level of response was obtained for the VPA group, the reasons for which are unclear. Children exposed to LEV were more likely to have been seen at 1 year of age (32.1%) than children exposed to VPA (11.4%) due to delays in recruiting VPA-exposed children aged 0–24 months. Contact with the family at 1 year of age may have increased participation rates in the current study due to improved relationship with the researcher and higher likelihood of holding a correct address on file. This is one possible explanation; however, this is a potential source of bias and therefore consideration should be given to the generalizability of these findings and replication is required. Details regarding nicotine and
Treatment group 95% confidence intervals of the adjusted means for language
LEV 5 levetiracetam; VPA 5 sodium valproate. Neurology 82
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alcohol use, along with seizure frequency, were all collected retrospectively and may be subject to recall bias. Further bias may appear through the ascertainment of a control group from an alternative source due to resource restrictions and the inability to recruit women without epilepsy from the UKEPR. Several previous studies have not included a control group,18,24 limiting conclusions about less teratogenic AEDs. It was important to have a control group born to women without epilepsy, even if recruited from a different source, to ensure that risk estimates could be calculated for LEV. This follows a similar methodology employed by previous research.26 Despite the limitations of the control group, this cannot account for the significant difference between VPA and LEV. The assessor was unblinded to exposure type and therefore bias is possible. It is of note that analysis of children exposed at 6 years of age is currently being undertaken by the LMNDG, where assessors are blinded to the exposure of the children at assessment. Moreover, the results here pertaining to VPA exposure are consistent with previous research that utilized blinded assessment.1,18,24 The GMDS has been widely used in child development research,27 although consideration is required about the age of its normative sample, which likely accounts for the inflated mean group scores, possibly representing a Flynn effect.28 However, all groups were assessed with the measure and therefore this cannot account for the reported between-group differences. The age of the child at assessment should be considered, as assessment at school age, when cognitive abilities are more complex, may reveal different results. We are unable to report the Griffiths General Quotient as the language subscale was not administered due to administration of the RDLS in its place. It is believed that obtaining a measure of expressive and comprehension of language abilities outweighs obtaining an overall quotient of development, which would fail to highlight specific areas of difficulty. No information was collected on use of folic acid prior to or during pregnancy. Despite limitations, the current research has several strengths. This study provides valuable information in regards to the neurodevelopmental outcome of older infants exposed to LEV in utero. Currently, the use of LEV is increasing, creating an urgent need for reliable risk information on which to base preconception counseling. The enrollment of women during pregnancy into the UKEPR or LMNDG prior to pregnancy outcome limits recall bias surrounding medication type and doses. This research has adequate numbers in both experimental groups, allowing reliable conclusions regarding medium to large effect sizes. Utilization of regression analysis to adjust for a number of influential variables is essential in child research. The generalizability of our cohort is supported by the finding that previously documented 220
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variables found to be predictive of outcome (i.e., maternal IQ and gestational age) are also predictive of some outcomes in the current research.29 Importantly, the study utilized a control group and assessed children using a comprehensive, appropriate, and widely used battery of neurodevelopmental assessments across the groups to ensure that the abilities of children exposed to LEV were appropriately investigated. The aim of this research is not to imply that VPA should not be used under any circumstances in WWE of childbearing age. This is an important point, as often research of this nature may be misinterpreted. The purpose of the current research is to add to our understanding of the risks associated with both established and newer treatment options for WWE. The current research suggests LEV may be a viable alternative for many WWE, in terms of the later development of the child. WWE should be fully informed of the potential risks associated with VPA should a pregnancy occur, so that they can make evidence-based, informed decisions about the risks and benefits of their treatment. AUTHOR CONTRIBUTIONS Dr. Shallcross: drafting/revising the manuscript for content, study design, interpretation of data, acquisition of data, study coordination. Dr. Bromley: revising the manuscript for content, study design, interpretation of data, study supervision, acquisition of data. Dr. Cheyne: revising the manuscript for content, analysis and interpretation of data, statistical analysis. Dr. García-Fiñana: revising the manuscript for content, study supervision of statistical analysis, interpretation of data. B. Irwin: revising the manuscript for content, acquisition of data. Dr. Morrow: revising the manuscript for content, study design, obtaining funding for the UKEPR. Dr. Baker: revising the manuscript for content, study design, study supervision, obtaining funding.
ACKNOWLEDGMENT The authors thank Arif Shukralla, MRCP, Division of Neuroscience, The University of Liverpool, UK, for classification of seizure types.
STUDY FUNDING An educational grant was provided by UCB Pharma Ltd. Work carried out by the UK Pregnancy and Epilepsy Register is supported by a research grant from the Epilepsy Research Foundation and a number of unrestricted educational grants from pharmaceutical companies (Glaxo-Smith-Kline, Sanofi-Aventis, UCB Pharma Ltd., Janssen-Cilag, Novartis, Pfizer, Eisai). An Internet-based site detailing the aims of the UK Epilepsy and Pregnancy Register was made possible by a grant from Glaxo-Smith-Kline and UCB Pharma Ltd. The Liverpool and Manchester Neurodevelopment Group have received an educational grant from Sanofi-Aventis and grants from Epilepsy Research UK RB219738 (National Lottery Charities Board).
DISCLOSURE R. Shallcross has attended conferences with the support of UCB Pharma Ltd. and has received honorarium for lectures at the bequest of UCB Pharma Ltd. R. Bromley has given expert testimony on fetal anticonvulsant syndrome and honorarium for advisory board presentation for Sanofi-Aventis. C. Cheyne and M. García-Fiñana report no disclosures. B. Irwin has received honorarium for an advisory board with SanofiAventis and has attended meetings with the support of various pharmaceutical companies. J. Morrow has attended meetings with the support of various pharmaceutical companies and has given lectures at the bequest of pharmaceutical companies, for which he has received honoraria. He has given expert testimony on anticonvulsant teratogenicity and has received
a grant from UCB Pharma Ltd. to support this research. G. Baker has given expert testimony on fetal anticonvulsant syndrome, has attended meetings with the support of various pharmaceutical companies, and has received a grant from UCB Pharma Ltd. to support this research. Go to Neurology.org for full disclosures.
14.
Received April 11, 2013. Accepted in final form September 3, 2013.
17.
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In utero exposure to levetiracetam vs valproate: Development and language at 3 years of age R. Shallcross, R.L. Bromley, C.P. Cheyne, et al. Neurology 2014;82;213-221 Published Online before print January 8, 2014 DOI 10.1212/WNL.0000000000000030 This information is current as of January 8, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/3/213.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/01/08/WNL.000000000 0000030.DC1.html http://www.neurology.org/content/suppl/2014/01/08/WNL.000000000 0000030.DC2.html
References
This article cites 25 articles, 9 of which you can access for free at: http://www.neurology.org/content/82/3/213.full.html##ref-list-1
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
R. Shallcross, PhD R.L. Bromley, PhD C.P. Cheyne, PhD M. García-Fiñana, PhD B. Irwin, RGN, RM J. Morrow, MD, PhD G.A. Baker, PhD On behalf of the Liverpool and Manchester Neurodevelopment Group and The UK Epilepsy and Pregnancy Register
Correspondence to Dr. Shallcross: [email protected]
ABSTRACT
Objective: To compare the cognitive and language development of children born to women with epilepsy (WWE) exposed in utero to levetiracetam (LEV) or sodium valproate (VPA) and control children born to women without epilepsy not taking medication during pregnancy.
Methods: The children, aged between 36 and 54 months, were recruited from the United Kingdom and assessed using the Griffiths Mental Development Scales and the Reynell Language Development Scale. Maternal demographic and epilepsy information was also collected for use in statistical regression. This is an observational study with researchers not involved in the clinical management of the mothers enrolled.
Results: After controlling for confounding variables, children exposed to LEV in utero (n 5 53) did not differ from unexposed control children (n 5 131) on any scale administered. Children exposed to VPA (n 5 44) in utero scored, on average, 15.8 points below children exposed to LEV on measures of gross motor skills (95% confidence interval [CI] 224.5 to 27.1, p , 0.001), 6.4 points below on comprehension language abilities (95% CI 211.0 to 21.8, p 5 0.005), and 9.5 points below on expressive language abilities (95% CI 214.7 to 24.4, p , 0.001).
Conclusion: The current study indicates that children exposed to LEV in utero were superior in their language and motor development in comparison to children exposed to VPA. This information should be used collaboratively between health care professionals and WWE when deciding on women’s preferred choice of antiepileptic drug. Neurology® 2014;82:213–221 GLOSSARY AED 5 antiepileptic drug; CI 5 confidence interval; GMDS 5 Griffiths Mental Development Scales; LEV 5 levetiracetam; LMNDG 5 Liverpool and Manchester Neurodevelopment Group; RDLS 5 Reynell Developmental Language Scales; SES 5 socioeconomic status; UKEPR 5 UK Epilepsy and Pregnancy Registry; VPA 5 valproate; WWE 5 women with epilepsy.
Editorial, page 194
The physical and cognitive effects of in utero exposure to sodium valproate (VPA) have been well-documented,1,2 leading practice guidelines to suggest that VPA should be avoided, where possible, for the treatment of women with epilepsy (WWE) of childbearing potential.3 The UK Epilepsy and Pregnancy Registry (UKEPR) reported a low occurrence of malformation rates following levetiracetam (LEV) use in pregnancy,4 consistent with the results of the North American Pregnancy Registry5 and similar to malformation rates found in the nonepilepsy population.4 Animal data report low malformation rates,6 along with minimal impact on animal cognitive development following LEV exposure.7 Unsurprisingly, then, the use of LEV in WWE has increased in recent years, while the use of VPA has declined.8,9 Despite the increase in use of LEV, reliable information on the neurodevelopment and cognitive abilities of children exposed to LEV is limited. Previously, the Liverpool and Manchester Neurodevelopment Group (LMNDG) and the UKEPR reported on the early development of children exposed in utero to LEV at ,24 months of age, with a favorable outcome.10 The current article reports on the developmental functioning and language abilities of children aged 36–54 months exposed in utero to LEV in comparison to children exposed to VPA and a control group of children.
Supplemental data at www.neurology.org From the Departments of Clinical Psychology (R.S.), Molecular and Clinical Pharmacology (R.L.B., G.A.B.), and Biostatistics (C.P.C., M.G.-F.), University of Liverpool; and the Department of Neurology (B.I., J.M.), Royal Group of Hospitals, Belfast, UK. Coinvestigators are listed on the Neurology® Web site at www.neurology.org. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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METHODS Recruitment. WWE were recruited through the UKEPR, a prospective register of WWE designed for the collection of data pertaining to pregnancy and outcome.11 Eligibility criteria for enrollment onto the current study included use of monotherapy LEV throughout pregnancy, with a live birth between December 2003 and September 2007, or monotherapy VPA throughout pregnancy with a live birth between September 2005 and September 2007. Further criteria included maternal IQ .70 and children aged between 36 and 54 months at time of assessment. Eligible women were sent a letter asking if they wanted to take part in a continuation of the UKEPR study. Those who did not respond were sent a follow-up letter and if no further reply was obtained, the mother was recorded as a nonrespondent and no further information was sent. The control group of children born to women without epilepsy, not taking medication during pregnancy, were recruited and assessed by the LMNDG.1 The 36- to 54-month assessment of this cohort has not been previously reported. The utilization of this control group was implemented to ensure that mild to moderate levels of altered development could be detected. The control group was recruited from this source as the UKEPR do not collect information on pregnancies for women without epilepsy. Both the UKEPR and the LMNDG include prospective enrolment (i.e., while mothers are pregnant) and prospective collection of confounding variables and pregnancy data, including maternal IQ, maternal age, gestational age, age of child at assessment, child sex, seizure occurrence during pregnancy, alcohol or nicotine use in pregnancy, and socioeconomic status (SES). The exception to this was the collection of data regarding SES, alcohol, nicotine, seizure exposure, and information regarding epilepsy type, which was collected retrospectively for the mothers from the UKEPR. Epilepsy type was verified following the collection of data regarding seizure type, with a detailed description of seizures being taken from mothers and classified as partial, generalized, or unclassified. In the current study, 5 children (11.4%) exposed to VPA, 17 children (32.1%) exposed to LEV, and 50 control children (38%) were previously reported at 0–24 months.10
Assessment of children. Children were assessed at 36–54 months of age (mean 42 months; range 36–54 months) using standardized neurodevelopment measures: the Griffiths Mental Development Scales (GMDS12) and the Reynell Developmental Language Scales (RDLS13). The GMDS was utilized in the current study to gain a measure of 5 areas of child development: locomotor, personal and social, eye and hand coordination, performance, and practical reasoning abilities. The RDLS was chosen to assess verbal comprehension and expressive language independently of each other.13 Finally, the National Adult Reading Test14 was utilized as a surrogate measure of maternal IQ. Parents received feedback following assessment and, where necessary, a request for a referral (i.e., to a speech and language therapist or pediatrician) was made. Standard protocol approvals, registrations, and patient consents. Ethical approval was obtained from the North West Multi-centre Research Ethics Committee in 2000 (Ref.: MREC 99/8/71). Written consent was obtained from all mothers. This is a cross-sectional observational study with researchers playing no part in the clinical management of the WWE.
Statistical analysis. Data were collected on confounding variables, identified by previous literature, associated with child outcome. The confounding variables (listed above) were entered into the model and retained if their significance levels were ,0.05. Cohort size was dictated by the principle of 10–15 participants per variable.15 214
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Descriptive statistics and a multivariate linear regression analysis were conducted to compare the effect of drug exposure on child outcome between groups (nonexposed controls, LEV-exposed, and VPA-exposed). The model had nonexposed controls serving as the reference group and comparisons between LEV and VPA groups were also carried out using the same model. Reported results are based on marginal distributions from a multivariate linear regression model. The significance level was set to a 5 0.05/7 z 0.007 (where 7 is the number of outcomes considered) to take into account the multiple comparisons involved. Inverse probability weighting was utilized16 to account for the influence of missing outcomes (84.2% of the total number of children had no missing outcomes) in the multivariate linear regression analysis. Pearson correlation was used to test the relationship between dose and child outcome with a Bonferroni correction applied to account for multiple comparisons. A Fisher exact test revealed that the proportion of patients across epilepsy types differed between the LEV and VPA groups. This suggested an association between the type of epilepsy an individual has and the treatment prescribed in terms of LEV and VPA. However, due to low numbers in some combinations of epilepsy and treatment type, it was not possible to include epilepsy type, treatment type, and their interactions within this study.
A total of 197 children aged between 36 and 54 months were identified from the UKEPR, 65 of whom were exposed to LEV monotherapy and 132 of whom were exposed to VPA monotherapy throughout pregnancy. Figure 1 demonstrates the response rate of those women contacted for each group. Control children (n 5 134) were born to women without epilepsy not exposed to medication in pregnancy. Of the 54 assessments arranged for the LEV group, one assessment could not be completed due to the child’s poor attention span; therefore, 53 children exposed to LEV completed an assessment. Of the 46 mothers of children exposed to VPA who agreed to participate, one child was not assessed as the mother did not take medication throughout pregnancy. Of the 45 appointments arranged, one child was excluded due to the mother stopping medication use upon confirmation of the pregnancy; therefore, 44 children exposed to VPA completed an assessment. Of the 134 control children, one child was excluded as the mother took warfarin during pregnancy, one child was excluded as maternal IQ was ,70, and a final child was excluded due to a suspected genetic condition with unexplained severe global developmental delay (referral to local genetic services was made, but contact with the family was lost); therefore, 131 control children completed an assessment. Consequently, 228 children are included in the analysis: 97 children born to WWE and 131 control children born to women without epilepsy. Table 1 outlines mean child developmental quotient outcomes and descriptive statistics, with significant differences identified. Multiple comparisons of SES revealed no differences between mothers who took LEV and VPA during pregnancy in terms of their SES (p 5 0.4). However, control women
RESULTS
Figure 1
Response rate of mothers
LEV 5 levetiracetam; VPA 5 sodium valproate.
were of lower SES than both women who took LEV (p , 0.001) and women who took VPA during pregnancy (p 5 0.003).
No further significant differences were found between exposure groups on any other subscales.
Regression analysis. Griffiths Mental Development Scales.
variables, maternally reported seizures during pregnancy were predictive of poorer developmental outcome for gross motor skills (coefficient 219.2, 95% CI 228.5 to 29.8, p , 0.001), personal and social skills (coefficient 212.2, 95% CI 220.1 to 24.3, p 5 0.002), hand and eye coordination skills (coefficient 211.4, 95% CI 217.6 to 25.3, p , 0.001), performance skills (coefficient 212.9, 95% CI 220.4 to 25.5, p , 0.001), and comprehensive language abilities (coefficient 27.6, 95% CI 212.5 to 22.8, p 5 0.002; table 2).
Children exposed to VPA demonstrated the lowest adjusted mean scores. After controlling for confounding variables, children exposed to LEV did not differ from control children on any of the GMDS subdomains. Children exposed to VPA, however, scored on average 15.8 points below children exposed to LEV on gross motor skills (95% confidence interval [CI] 224.5 to 27.1, p , 0.001). Children exposed to VPA did not differ from children exposed to LEV in social, hand and eye, or performance (nonverbal tasks) skills (table 2, figure 2). Reynell Developmental Language Scales. After controlling for confounding variables, children exposed to LEV did not differ from controls for either comprehension or expressive language abilities (table 2, figure 3). Children exposed to VPA scored on average 6.4 points below children exposed to LEV on a measure of comprehension language abilities (CI 211.0 to 21.8, p 5 0.005) and 9.5 points below children exposed to LEV for expressive language abilities (CI 214.7 to 24.4, p , 0.001).
Seizures during pregnancy. After control of confounding
Dose effect. The mean dose of LEV was 2,070 mg
(range 500–5,000 mg) and the mean dose of VPA was 980 mg (range 400–3,500 mg). No dose effect was detected for either LEV or VPA exposure on any outcome measure. DISCUSSION The results suggest that children exposed in utero to LEV do not differ significantly from control children for developmental or language abilities. Furthermore, children exposed to LEV score significantly higher than children exposed to VPA on Neurology 82
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Table 1
Child developmental quotient outcomes and demographic variables
Continuous variable
Controls, mean (SD)
LEV, mean (SD)
p Value vs controls
VPA, mean (SD)
p Value vs controls
p Value vs Total, LEV mean (SD)
Maternal IQ
105.0 (11.0)
104.1 (11.3)
0.6a
101.6 (13.5)
0.1a
0.3a
a
a
a
104.1 (11.6)
Maternal age, y
30.3 (5.2)
30.2 (5.3)
0.9
30.3 (5.1)
0.9
0.9
30.3 (5.2)
Gestational age, wk
39.3 (2.2)
39.1 (1.8)
0.2b
39.9 (2.2)
0.07b
0.01b
39.4 (2.1)
41.1 (5.0)
b
Age at assessment, mo c
41.6 (4.8)
43.1 (6.0)
0.4
a
96.8 (22.1)
b
b
0.2
0.1 b,g
41.8 (5.1) b,g
Griffiths motor score
110.9 (20.1)
110.4 (17.2)
0.9
0.001
0.002
108.0 (20.6)
Griffiths personal scorec
119.9 (16.3)
116.5 (19.1)
0.1b
108.4 (21.4)
0.002b,g
0.2b
116.9 (18.5)
Griffiths hand and eye scorec
103.3 (15.6)
104.8 (13.9)
0.8b
102.1 (17.7)
0.9b
0.8b
103.4 (15.6)
Griffiths performance scorec
110.5 (16.3)
109.9 (15.4)
0.6b
111.4 (23.1)
0.7b
0.6b
110.5 (17.5)
Griffiths practical scorec
113.9 (17.0)
113.4 (16.6)
0.5b
108.9 (18.8)
0.06b
0.2b
112.9 (17.3)
Reynell comprehension scorec
52.2 (9.6)
49.6 (10.3)
0.2b
44.0 (16.1)
0.003b,g
0.2b
50.0 (11.7)
Reynell expressive scorec
46.6 (10.2)
52.0 (13.4)
0.01a
43.1 (15.9)
0.9b
0.005b,g
47.1 (12.5)
Binary/categorical variable
Controls, n (%)
LEV, n (%)
VPA, n (%)
p Value
Total, n (%)
0.8d
111 (48.7)
Sex Male
63 (48.1)
28 (52.8)
20 (45.5)
Female
68 (51.9)
25 (47.2)
24 (54.5)
117 (51.3)
Seizures Yes
0 (0)
20 (42.6)
12 (27.9)
No
131 (100)
27 (57.4)
31 (72.1)
Yes
39 (33.3)
13 (27.7)
11 (25.6)
No
78 (66.7)
34 (72.3)
32 (74.4)
16 (13.7)
6 (12.8)
13 (30.2)
101 (86.3)
41 (87.2)
30 (69.8)
Professional
27 (23.3)
22 (45.8)
15 (34.9)
Skilled
11 (9.5)
13 (27.1)
11 (25.6)
0.2e
32 (14.5) 189 (85.5)
Alcohol 0.6d
63 (30.4) 144 (69.6)
Smoking Yes No
0.03d
35 (16.9) 172 (83.1)
SES
Manual/unemployed Nf
78 (67.2) 131
13 (27.1)
17 (39.5)
53
44
,0.001d,g
64 (30.9) 35 (16.9) 108 (52.2)
—
228
Abbreviations: LEV 5 levetiracetam; SES 5 socioeconomic status; VPA 5 sodium valproate. a p Values are from a t test. b p Values are from a Mann-Whitney U test. c Number of missing data for each outcome variable: motor, n 5 25 (11.0%); personal, n 5 18 (7.9%); hand and eye, n 5 10 (4.4%); performance, n 5 6 (2.6%); practical, n 5 12 (5.3%); comprehension, n 5 8 (3.5%); expressive, n 5 11 (4.8%); total, 36 (15.8%). d p Values are from a x2 test testing for differences in the variable groups across the drug groups. e p Values are from a x2 test testing for differences in the variable groups across the LEV and VPA groups only. f Group totals include individuals with missing values for some of the binary/categorical variables listed. g Significant.
measures of gross locomotor, comprehension, and expressive language skills, suggesting that LEV exposure may be a preferential antiepileptic drug (AED) during pregnancy if seizures can be controlled. 216
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While research into the effects of LEV in utero upon child development remains extremely limited, the results reported in the current study are supported by previous human10 and animal research.7 The current
Table 2
Results of the multivariate analysis Gross motor
Personal and social
Explanatory variable/group
Coefficient (SE)
Control
Reference group
pa
95% CI
Coefficient (SE)
Hand-eye coordination pa
95% CI
Performance
Coefficient (SE)
95% CI
pa
Coefficient (SE)
95% CI
pa
Treatment LEV
4.1 (4.0)
23.8, 11.9
0.3
1.2 (3.3)
25.4, 7.8
0.7
0.8 (2.8)
24.8, 6.4
0.7
2.7 (3.2)
23.6, 9.0
0.4
VPA
211.7 (3.9)b
219.4 to 24.1b
0.003b
26.5 (3.2)
212.8 to 20.2
0.04
21.2 (2.7)
26.6, 4.2
0.7
3.6 (3.1)
22.5, 9.7
0.3
Treatment LEV
Reference group
VPA
215.8 (4.4)b
224.5 to 27.1b
,0.001b
27.7 (3.8)
215.2 to 20.2
0.04
22.0 (2.9)
27.8, 3.8
0.5
0.9 (3.5)
26.1, 7.9
0.8
Seizures
219.2 (4.8)b
228.5 to 29.8b
,0.001b
212.2 (4.0)b
220.1 to 24.3b
0.002b
211.4 (3.1)b
217.6 to 25.3b
,0.001b
212.9 (3.8)b
220.4 to 25.5b
,0.001b
Gestational age
1.7 (0.7)
0.4, 3.0
0.01
—
—
—
1.2 (0.5)
0.3, 2.0
0.01
1.8 (0.6)b
0.7, 2.8b
0.001b
—
—
—
Covariates
Age at assessment Sex
—
—
—
—
—
—
b
b
21.1 (0.2) 7.8 (2.3)
21.6 to 20.6
b
3.2, 12.4
b
,0.001
b
,0.001
b
—
—
5.5 (1.9)
b
—
1.7, 9.3
b
b
0.005
—
Neurology 82 January 21, 2014
0.005b
0.6 (0.3)
0.1, 1.1
0.01
0.4
—
—
—
0.01
—
—
—
Coefficient (SE)
95% CI
pa
5.5 (2.6)
0.4, 10.5
0.03
24.1 (2.4)
28.7, 0.6
0.09
—
—
—
—
—
—
0.2 (0.09)
0.02, 0.4
0.03
0.3 (0.1)
Maternal age
—
—
—
—
—
—
—
—
—
SES 1 (professional)
Reference status
SES 2 (skilled employment)
—
—
—
—
—
—
2.3 (3.0)
23.6, 8.1
SES 3 (manual/unemployed)
—
—
—
—
—
—
26.0 (2.5)
210.9 to 21.2
Explanatory variable/group
Comprehension of language
—
0.09, 0.5
Maternal IQ
Practical reasoning
— b
b
Expressive language
Coefficient (SE)
95% CI
pa
Coefficient (SE)
95% CI
22.5 (2.9)
28.3, 3.2
0.4
22.3 (2.3)
26.8, 2.2
pa
Control Treatment LEV VPA
b
0.3 b
,0.001
b
25.6 (3.0)
211.6, 0.3
0.06
28.7 (2.1)
212.9, 4.5
23.1 (3.5)
210.0, 3.8
0.4
26.4 (2.3)b
211.0 to 21.8b
0.005b
29.5 (2.6)b
214.7 to 24.4b
,0.001b
—
—
—
27.6 (0.002)b
212.5 to 22.8b
0.002b
26.1 (2.8)
211.5 to 20.7
0.02
1.0 (0.4)
0.3, 1.8
0.008
Treatment LEV VPA Covariates Seizures Gestational age
b
1.7 (0.5)
b
0.7, 2.7
b
,0.001
1.1 (0.4)
b
0.4, 1.8
b
0.002
b
217
Continued
Neurology 82
0.01 212.5 to 21.4 26.9 (2.8) SES 3 (manual/unemployed)
0.4 29.5, 4.0 22.8 (3.5)
— SES 1 (professional)
SES 2 (skilled employment)
— — Maternal age
0.2, 0.6
b
January 21, 2014
Abbreviations: LEV 5 levetiracetam; SES 5 socioeconomic status; VPA 5 sodium valproate. a Only p values equal to 0.007 or less were considered to be statistically significant after using the Bonferroni correction when considering multiple comparisons (p 5 0.05/7 5 0.007). b Significant.
0.02 29.4 to 20.8 25.1 (2.2) 0.02 28.5 to 20.8
1.1 (2.6) 0.5 23.2, 6.0 1.4 (2.3)
24.6 (2.0)
0.7 24.1, 6.2
— — — — — —
0.05 0.001, 0.3 0.2 (0.08) 0.04 0.003, 0.3 ,0.001 0.4 (0.1)
b
Maternal IQ
0.01
— — Sex
—
21.0 to 20.1 20.6 (0.2) Age at assessment
Explanatory variable/group
Coefficient (SE)
95% CI
pa
b
0.1 (0.07)
—
— —
— —
— —
— —
— —
Coefficient (SE)
—
pa 95% CI 95% CI
pa
Coefficient (SE)
Expressive language Comprehension of language Practical reasoning
Continued Table 2 218
research is supported by many previous studies documenting the poor developmental outcome, including motor and language development, in children exposed in utero to VPA.1,17,18 Research surrounding apoptosis in the rodent brain may go some way to explaining the developmental differences found between LEV- and VPA-exposed children.19,20,21 Replication of a failure to associate LEV with altered infant neurodevelopment is required. A number of demographic variables were associated with infant neurodevelopment scores, with maternally reported seizures during pregnancy found to be predictive of poorer developmental outcome on several measures. This is consistent with previous research22 and inconsistent with other research.1,17,18,23,24 Therefore, the findings of the current research should be interpreted with some caution, especially as the impact of occurring generalized tonic-clonic seizures upon child development is not well-established. The methodology for the collection of seizure information in the current cohort is a limitation of the study. Due to the methodology of the UKEPR,11 seizure information was collected retrospectively on a “yes/no” basis. No more detail was provided about seizures during pregnancy (frequency, duration, type, severity). Therefore, conclusions cannot accurately be drawn in regards to the effect of seizures during pregnancy upon the developing child. There were no significant differences between LEV- and VPA-exposed children in the number of children exposed to seizures during pregnancy, suggesting that differences between the groups in terms of seizures cannot account for differences in developmental outcome between LEV- and VPA-exposed children. Interestingly, previous research with retrospective collection of seizure information22 also found an association with developmental outcome, while cohorts whereby data were collected prospectively1,18,24 failed to find an association. A larger cohort, with a prospective record of seizures during pregnancy, is needed to extrapolate the relationship between drug type, seizures during pregnancy, and child developmental outcome, which was beyond the scope of the current study. In regards to epilepsy type, Fisher exact test revealed that there are statistically significant differences between the LEV- and VPA-exposed groups in terms of the distribution of different epilepsy types. For example, of mothers prescribed LEV during pregnancy, 46.9% were classified as focal epilepsy, 44.9% generalized epilepsy, and 8.2% unclassified. Of mothers prescribed VPA during pregnancy, 7.0% were classified as focal epilepsy, 79.0% generalized epilepsy, and 14.0% unclassified. Therefore, one cannot rule out from these data that differences observed between drug groups could be fully (or partially)
Figure 2
Treatment group 95% confidence intervals of the adjusted means for developmental outcome
LEV 5 levetiracetam; VPA 5 sodium valproate.
explained by epilepsy type. However, in a literature review, fetal exposure to VPA in rodents (whereby maternal epilepsy is not a factor) was found to be associated with microcephaly, cerebellar abnormalities, and detrimental impact upon cognitive functions.25 The authors warn that while animal models allow for careful and controlled assessment of AEDs, care must be taken in generalizing to humans. However, the human data available in larger studies with a more equal distribution of epilepsy type across medications support animal data and fail to find an association between maternal epilepsy type and child developmental outcome.18 Limitations of the current study include the retrospective invitation to participate in neurodevelopmental follow-up. However, both the VPA and the LEV group were approached in the same way and
Figure 3
therefore it is not thought that this alone can account for the rise of neurodevelopmental difficulty in the VPA group in isolation. A much poorer level of response was obtained for the VPA group, the reasons for which are unclear. Children exposed to LEV were more likely to have been seen at 1 year of age (32.1%) than children exposed to VPA (11.4%) due to delays in recruiting VPA-exposed children aged 0–24 months. Contact with the family at 1 year of age may have increased participation rates in the current study due to improved relationship with the researcher and higher likelihood of holding a correct address on file. This is one possible explanation; however, this is a potential source of bias and therefore consideration should be given to the generalizability of these findings and replication is required. Details regarding nicotine and
Treatment group 95% confidence intervals of the adjusted means for language
LEV 5 levetiracetam; VPA 5 sodium valproate. Neurology 82
January 21, 2014
219
alcohol use, along with seizure frequency, were all collected retrospectively and may be subject to recall bias. Further bias may appear through the ascertainment of a control group from an alternative source due to resource restrictions and the inability to recruit women without epilepsy from the UKEPR. Several previous studies have not included a control group,18,24 limiting conclusions about less teratogenic AEDs. It was important to have a control group born to women without epilepsy, even if recruited from a different source, to ensure that risk estimates could be calculated for LEV. This follows a similar methodology employed by previous research.26 Despite the limitations of the control group, this cannot account for the significant difference between VPA and LEV. The assessor was unblinded to exposure type and therefore bias is possible. It is of note that analysis of children exposed at 6 years of age is currently being undertaken by the LMNDG, where assessors are blinded to the exposure of the children at assessment. Moreover, the results here pertaining to VPA exposure are consistent with previous research that utilized blinded assessment.1,18,24 The GMDS has been widely used in child development research,27 although consideration is required about the age of its normative sample, which likely accounts for the inflated mean group scores, possibly representing a Flynn effect.28 However, all groups were assessed with the measure and therefore this cannot account for the reported between-group differences. The age of the child at assessment should be considered, as assessment at school age, when cognitive abilities are more complex, may reveal different results. We are unable to report the Griffiths General Quotient as the language subscale was not administered due to administration of the RDLS in its place. It is believed that obtaining a measure of expressive and comprehension of language abilities outweighs obtaining an overall quotient of development, which would fail to highlight specific areas of difficulty. No information was collected on use of folic acid prior to or during pregnancy. Despite limitations, the current research has several strengths. This study provides valuable information in regards to the neurodevelopmental outcome of older infants exposed to LEV in utero. Currently, the use of LEV is increasing, creating an urgent need for reliable risk information on which to base preconception counseling. The enrollment of women during pregnancy into the UKEPR or LMNDG prior to pregnancy outcome limits recall bias surrounding medication type and doses. This research has adequate numbers in both experimental groups, allowing reliable conclusions regarding medium to large effect sizes. Utilization of regression analysis to adjust for a number of influential variables is essential in child research. The generalizability of our cohort is supported by the finding that previously documented 220
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variables found to be predictive of outcome (i.e., maternal IQ and gestational age) are also predictive of some outcomes in the current research.29 Importantly, the study utilized a control group and assessed children using a comprehensive, appropriate, and widely used battery of neurodevelopmental assessments across the groups to ensure that the abilities of children exposed to LEV were appropriately investigated. The aim of this research is not to imply that VPA should not be used under any circumstances in WWE of childbearing age. This is an important point, as often research of this nature may be misinterpreted. The purpose of the current research is to add to our understanding of the risks associated with both established and newer treatment options for WWE. The current research suggests LEV may be a viable alternative for many WWE, in terms of the later development of the child. WWE should be fully informed of the potential risks associated with VPA should a pregnancy occur, so that they can make evidence-based, informed decisions about the risks and benefits of their treatment. AUTHOR CONTRIBUTIONS Dr. Shallcross: drafting/revising the manuscript for content, study design, interpretation of data, acquisition of data, study coordination. Dr. Bromley: revising the manuscript for content, study design, interpretation of data, study supervision, acquisition of data. Dr. Cheyne: revising the manuscript for content, analysis and interpretation of data, statistical analysis. Dr. García-Fiñana: revising the manuscript for content, study supervision of statistical analysis, interpretation of data. B. Irwin: revising the manuscript for content, acquisition of data. Dr. Morrow: revising the manuscript for content, study design, obtaining funding for the UKEPR. Dr. Baker: revising the manuscript for content, study design, study supervision, obtaining funding.
ACKNOWLEDGMENT The authors thank Arif Shukralla, MRCP, Division of Neuroscience, The University of Liverpool, UK, for classification of seizure types.
STUDY FUNDING An educational grant was provided by UCB Pharma Ltd. Work carried out by the UK Pregnancy and Epilepsy Register is supported by a research grant from the Epilepsy Research Foundation and a number of unrestricted educational grants from pharmaceutical companies (Glaxo-Smith-Kline, Sanofi-Aventis, UCB Pharma Ltd., Janssen-Cilag, Novartis, Pfizer, Eisai). An Internet-based site detailing the aims of the UK Epilepsy and Pregnancy Register was made possible by a grant from Glaxo-Smith-Kline and UCB Pharma Ltd. The Liverpool and Manchester Neurodevelopment Group have received an educational grant from Sanofi-Aventis and grants from Epilepsy Research UK RB219738 (National Lottery Charities Board).
DISCLOSURE R. Shallcross has attended conferences with the support of UCB Pharma Ltd. and has received honorarium for lectures at the bequest of UCB Pharma Ltd. R. Bromley has given expert testimony on fetal anticonvulsant syndrome and honorarium for advisory board presentation for Sanofi-Aventis. C. Cheyne and M. García-Fiñana report no disclosures. B. Irwin has received honorarium for an advisory board with SanofiAventis and has attended meetings with the support of various pharmaceutical companies. J. Morrow has attended meetings with the support of various pharmaceutical companies and has given lectures at the bequest of pharmaceutical companies, for which he has received honoraria. He has given expert testimony on anticonvulsant teratogenicity and has received
a grant from UCB Pharma Ltd. to support this research. G. Baker has given expert testimony on fetal anticonvulsant syndrome, has attended meetings with the support of various pharmaceutical companies, and has received a grant from UCB Pharma Ltd. to support this research. Go to Neurology.org for full disclosures.
14.
Received April 11, 2013. Accepted in final form September 3, 2013.
17.
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In utero exposure to levetiracetam vs valproate: Development and language at 3 years of age R. Shallcross, R.L. Bromley, C.P. Cheyne, et al. Neurology 2014;82;213-221 Published Online before print January 8, 2014 DOI 10.1212/WNL.0000000000000030 This information is current as of January 8, 2014 Updated Information & Services
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