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Keywords:

  • Antiepileptic drugs;
  • Epilepsy;
  • Pregnancy;
  • Women;
  • In utero exposure;
  • Cognitive development

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Appendix

Purpose: In this prospective study the early cognitive development of children born to women with epilepsy (n = 198) was assessed and compared to a group of children representative of the general population (n = 230).

Methods: The children were assessed when younger than the age of 2 years using the Griffiths Mental Development Scales, either in their local participating hospital or in their home. The assessments were completed by an assessor who was blinded to whether the child’s mother had epilepsy and to antiepileptic drug type.

Results: Children exposed to sodium valproate had a statistically significant increased risk of delayed early development in comparison to the control children. Linear regression analysis showed a statistically significant effect of sodium valproate exposure on the child’s overall developmental level that was not accounted for by confounding variables. Delayed early development is also noted for children within an ad hoc group of less commonly utilized antiepileptic drugs, although conclusions cannot be drawn due to the size of this group (n = 13). Children exposed to either carbamazepine or lamotrigine in utero did not differ significantly in their overall developmental ability. Differences noted in specific developmental areas for these two groups were not statistically significant after the control for confounders such as socioeconomic status and maternal IQ.

Discussion: Women with epilepsy should be informed of the risks posed to their potential offspring prior to pregnancy to allow for informed decisions regarding treatment. Children exposed in utero to antiepileptic drugs should be monitored throughout childhood to allow for early intervention when necessary.

There is evidence that in utero exposure to antiepileptic drugs (AEDs) poses an increased risk of poorer cognitive abilities (Jones et al., 1989; Adab et al., 2004; Gaily et al., 2004; Kantola-Sorsa et al., 2007; Thomas et al., 2008; Meador et al., 2009). Consistent with findings regarding malformation incidence, the largest risk appears to be associated with exposure to sodium valproate (Adab et al., 2004; Gaily et al., 2004; Kantola-Sorsa et al., 2007; Thomas et al., 2008; Bromley et al., 2009a; Meador et al., 2009). Despite the fact that several studies have aimed at addressing the relative risks of the different AEDs, firm conclusions are lacking due to methodologic flaws (Nicolai et al., 2008). Key methodologic limitations include the numbers of children enrolled and the control of confounding variables. The effects of confounding variables such as socioeconomic status, maternal IQ/ability, and gestational age at birth are of paramount importance in any research involving children. Without statistical control over such influences, unreliable conclusions are likely. The assessment of children at school age allows for more reliable conclusions, but often research focuses on preschool children. No study to date has documented prospectively the development of children exposed to carbamazepine (CBZ), sodium valproate (VPA), lamotrigine (LTG), or polytherapy treatments from early childhood to school age in comparison to a control group representative of the general population. In 2000 the Liverpool and Manchester Neurodevelopment Group established a prospective study to document the long-term development of children exposed to AEDs in utero. The early cognitive development of this cohort is reported here in children younger than 24 months of age.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Appendix

Prospective recruitment

Detailed information regarding the recruitment of mothers into this cohort has been reported elsewhere (Mawer et al. 2010). This cohort comprises a prospectively ascertained population, which differs from our group’s previously reported cohort (Adab et al., 2004; Vinten et al., 2005). Women were recruited from antenatal clinics at 11 different National Health Service hospitals within Merseyside and Greater Manchester, United Kingdom between 2000 and 2006. Ethical approval was given by the relevant ethical committees within the local area. Control women without epilepsy were recruited from the same antenatal clinics. They were matched to the women with epilepsy (WWE) for age, within a 5-year band, and for parity. This was an observational study with the investigators playing no part in clinical management. An epilepsy specialist (GM) ascertained seizure type, syndrome diagnosis, current seizure frequency, and AED regimen. The epilepsy syndrome was classified as focal (localization-related), idiopathic generalized, or unclassified. Seizures were recorded as generalized tonic–clonic or nonconvulsive (simple or complex partial, myoclonic, absence). AED dose was recorded at preconception and throughout pregnancy. Analysis with both preconceptual dose and a cumulative dose over the entire gestation was conducted. Exact information regarding AED prescription (e.g., b.i.d or t.i.d) was not available.

Neuropsychological assessment before 2 years of age

Mothers enrolled in the study were offered an appointment for the first assessment of their child between 4 months and 2 years of age. Children recruited at the Manchester sites were often seen earlier than those recruited at the Liverpool sites due to staff availability. This appointment was initially offered by letter and then by a follow-up phone call. Nonresponders were sent a further letter. Each child was assessed using the Griffiths Mental Development Scales (Huntley, 1996) in either their local hospital or their home. Each mother was asked to complete the National Adult Reading Test (Nelson, 1990), a validated tool used to inform on maternal intellectual ability. The children were assessed by an assistant psychologist blinded to not only what AED the child may have been exposed to but whether they were born to a WWE. Feedback on the child’s development was provided to the families, and, where necessary, referrals to specialist services were made. Additional data were also collected regarding growth parameters and dysmorphic features and will be reported in future publications. The results of the Griffiths Mental Development Scales were analyzed as differences between the groups and then separately by the number of children falling below the average range (score of <84). This allowed for a more detailed understanding regarding the numbers of children experiencing difficulties in their early development, in addition to information on group differences.

Data analysis were completed using R (version 2) by author XS. Group comparisons were completed with Kruskal-Wallis with a stringent significance level of 0.01. Demographic and maternal epilepsy variables and their relationship with Griffiths Mental Development Scale scores were identified through a correlational analysis. Variables showing a statistically significant or near statistically significant relationship (<0.1), or that are known to influence early child development (e.g., maternal IQ, socioeconomic status, gestational age) were entered into the linear regression analysis in a hierarchical fashion. This acted statistically to control for the influence of these confounders. AED exposure type was entered into the linear regression model, with the control group set as the reference. The significance level of the regression model was set at 0.05 due to the strict control over demographic confounding variables.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Appendix

In total, 428 children completed this first neuropsychological assessment, representing 73% of children whose mothers were actively enrolled into this study during pregnancy (n = 592). Twenty-seven percent of participants failed to complete the first neuropsychological assessment for the following reasons: 80% could not be contacted; 15% attended the appointment, but the assessment could not be completed; and 5% no longer wished to participate. Those mothers who brought their child for the first assessment were significantly older (p = 0.005) than those who did not attend, but there were no statistically significant differences in socioeconomic status.

Of the 428 children assessed, 198 were children born to WWE and 230 children were born to women without epilepsy. Four children from the 198 children born to WWE were excluded from this analysis because of coexisting conditions likely to affect cognitive ability: namely, Di George syndrome; Down syndrome; spina bifida with hydrocephalus; and neonatal meningitis with complications. No children born to control women required exclusion. Therefore, 424 children are included in the analysis: 194 children born to WWE and 230 children born to control women. All numbers, percentages, and analysis results reported from this point onward are without the data from the excluded children and their mothers.

Within the group of 194 children born to WWE, 167 children (86%) were exposed to AEDs in utero and 27 (14%) were not exposed. Of the children exposed to AEDs in utero, 137 were exposed to monotherapy and 30 to polytherapy (17 including VPA). Of the monotherapy group, 48 children were exposed to CBZ, 42 to VPA, 34 to LTG, and the remaining 13 had other monotherapy exposures (including 7 children exposed to phenytoin, 2 to topiramate, 2 to gabapentin, 1 to vigabatrin, and 1 to oxcarbazepine).

Of the 194 children born to WWE, 94 (48%) of their mothers had focal epilepsy, 72 (37%) had idiopathic generalized epilepsy (2 juvenile absence, 9 juvenile myoclonic, 1 photosensitive reflex, 1 generalized tonic–clonic on waking, and 59 without further classification), and 28 (14%) had an unclassified epilepsy. The majority of children born to women with focal epilepsy were exposed to CBZ in utero (37%), with VPA being the most prevalent in the idiopathic generalized epilepsy group (44%). The unclassified epilepsy group had a more equal distribution of AED usage (25% CBZ, 21% LTG, and 18% VPA), with 32% being untreated.

Seizures during pregnancy were experienced by 77 WWE (40%). Women with focal epilepsy (49%) experienced more seizures than those with either idiopathic generalized epilepsy (31%) or unclassified epilepsy (32%). Differences in seizure frequency between the maternal epilepsy types across the total duration of the pregnancy were not statistically significant (p = 0.054).

Data regarding maternal consumption of alcohol and nicotine during pregnancy were analyzed. More control women consumed alcohol during pregnancy (28%) in comparison to the WWE (17%) (p = 0.008). In the WWE, 27% smoked in comparison to 22% of control women, a difference that was not statistically significant (p = 0.230). Information on maternal lifestyle was missing for three cases (0.7%).

The ages of the children at assessment ranged from 2 months to 24 months, with a mean of 10 months. The age at assessment did not differ significantly by AED group (p = 0.144). In terms of gender, 48% were female and 52% were male (p = 0.497). Four percent of children were siblings of children already assessed, with five of these being the second of a twin pair. The cognitive abilities of 59 children (14%) at 3 years have previously been reported as part of the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study (Meador et al., 2009).

The gestational age of the children at birth ranged from 29–42 weeks, with the mean falling at 39 weeks for the overall cohort. No statistically significant differences in gestational age were found between the children of WWE and the control children (r = 0.200).

Overall development

In terms of their overall development, children exposed to AEDs had scores that were statistically poorer than control children (p < 0.001). There was a statistically significant difference in overall developmental ability in children exposed to monotherapy AED treatments in comparison to the control children (p = 0.001), but no statistically significant difference was found for the polytherapy group in comparison to the control group (p = 0.058). Comparison between the overall development of children exposed to monotherapy relative to those exposed to polytherapy did not reveal any statistically significant group differences (p = 0.926). See Table 1 for individual group mean scores and Table 2 for statistical comparisons between the AED groups Fig. 1.

Table 1.   Mean scores and confidence intervals by AED type across all developmental areas
 VPA (n = 42) mean (CI)CBZ (n = 48) mean (CI)LTG (n = 34) mean (CI)Other (n = 13) mean (CI)Polytherapy (n = 30) mean (CI)No med (n = 27) mean (CI)Control (n = 230) mean (CI)
Locomotor91 (85.9–96.4)94 (89.0–98.5)100 (94.0–105.2)93 (82.2–104.7)92 (81.4–102.7)102 (95.9–108.3)98 (96.9–99.5)
Personal & social90 (84.7–94.9)100 (95.4–104.8)100 (94.5–105.9)89 (77.9–100.7)90 (81.3–98.2)97 (91.6–102.8)97 (94.9–98.4)
Hearing & language97 (91.5–103.1)103 (98.2–108.2)104 (97.8–109.7)96 (84.16–108.5)103 (94.2–111.6)109 (104.9–113.7)105 (102.7–106.3)
Hand & eye coordination89 (83.7–95.1)96 (90.6–101.7)90 (83.5–97.1)88 (79.2–97.7)89 (81.3–96.4)105 (100.4–108.8)101 (98.4–102.7)
Nonverbal performance92 (87.3–97.1)100 (95.3–105.0)97 (91.3–102.8)96 (89.3–103.0)95 (86.9–102.6)105 (100.8–109.9)102 (99.7–103.7)
Total development quotient92 (87.2–96.4)98 (94.0–102.5)99 (94.2–103.2)92 (83.3–101.4)94 (86.5–102.2)104 (100.5–107.6)100 (98.9–102.1)
Table 2.   Comparisons between the groups in terms of overall developmental ability and over the specific skill domains
ComparisonOverall abilities p-valueLocomotor p-valuePersonal and social p-valueHearing and language p-valueHand and eye coordination p-valueNonverbal reasoning p-value
Control vs. CBZ0.3420.0590.0850.6840.1300.588
Control vs. LTG0.2100.7330.3790.4760.0100.104
Control vs. VPA<0.0010.0150.0030.008<0.001<0.001
Control vs. OTHER0.0330.4470.0450.0490.0070.090
Control vs. polytherapy0.0580.0500.0480.7880.0030.007
Control vs. no medication0.1260.0480.8490.1120.2960.237
CBZ vs. LTG0.7630.1110.7450.8730.2470.311
CBZ vs. no medication0.1000.0840.7200.3070.0030.517
CBZ vs. polytherapy0.3110.4350.0100.8900.1970.175
CBZ vs. VPA0.0280.6020.0020.1200.1150.022
LTG vs. VPA0.0870.0370.0080.2520.6760.277
LTG vs. no medication0.1550.4700.6580.1550.0020.086
LTG vs. polytherapy0.5050.0660.0370.8350.7620.788
VPA vs. polytherapy0.3120.7790.5750.1760.8950.468
VPA vs. no medication0.0100.0600.1700.0270.0040.088
image

Figure 1.   Mean child overall development score with 95% confidence intervals.

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Comparisons of overall developmental ability of the individual AED groups in comparison to control children found that the children exposed to VPA in utero scored significantly poorer than control children (p < 0.001). No other groups differed statistically in comparison to the control children (see Table 2). Comparisons between the individual AED groups revealed a significant higher performance for the children not exposed to medication but whose mothers had epilepsy in comparison to the children exposed to VPA (p = 0.010). A trend toward significance is noted between the children exposed to CBZ and the children exposed to VPA (p = 0.028).

A dose-dependent relationship was found for VPA exposure, with preconceptual doses >900 mg daily being associated with statistically poorer overall developmental scores (p < 0.001). No other AED showed a statistically significant relationship with overall development and preconceptual dose. Cumulative dose across gestation (taking into account dose changes) was not significantly correlated with overall development for any of the three main AED monotherapy groups.

For overall early development, 29% of children exposed to VPA in utero fell below the average range (a score of <84), which was statistically higher than the control children (8%, p < 0.001). The relative risk of delayed overall development was 3.6 [confidence interval (CI) 1.760–7.571, p < 0.001] for children who were VPA exposed. A statistically significant higher percentage (30%) of children within the other monotherapy group fell below average in comparison to control children (p = 0.007), with a relative risk of 3.5 (CI 1.170–10.700, p = 0.007). In no other group was there a statistically significant difference in comparison to control children in the rate of below average performance for their overall developmental ability score, although a strong trend (p = 0.011) is noted for the polytherapy group (see Table 3).

Table 3.   Percentages of children falling below the average range (≤84) on the Griffiths Mental Development Scales and the significance level in comparison to the control children
Exposure groupPercentage of children with below average performance
Overall ability (%)p-valueLocomotor (%)p-valuePersonal and social (%)p-valueHearing and language (%)p-valueHand and eye (%)p-valueNonverbal (%)p-value
CBZ160.07435<0.001200.597120.781350.010180.303
LTG150.22390.666180.767150.309380.004290.004
VPA29<0.00136<0.00138<0.001240.006330.014290.003
Other Monotherapy300.007230.204460.005150.455310.205150.655
Polytherapy200.01140<0.001170.584200.040270.150200.066
No medication70.404180.592250.38370.34170.073140.976
Control children8 11 16 9 17 11 

Linear regression analysis for the child’s overall developmental ability was undertaken controlling for maternal IQ, maternal age, maternal epilepsy type, socioeconomic status, child’s age, and gestational age at birth. Exposure to seizures, alcohol, nicotine, or the gender of the child was not found to correlate with cognitive ability, and, therefore, were not included within the linear regression model. Exposure to VPA in utero (p = 0.026) was significantly associated with a poorer level of developmental ability in children younger than 24 months of age. In no other AED exposure was there a statistically significant association with outcome following the control of the maternal and child variables listed earlier.

The child’s overall ability score of the Griffiths Mental Development Scales is a summary score of abilities on the specific developmental areas of locomotor skills, personal and social skills, hearing and language, hand and eye coordination skills, and nonverbal performance. Performance differed across the individual developmental areas for the specific AED groups in comparison to the control children and other AED groups (see Table 2). The rate of children falling below the average range (<84) also differed across the individual AED groups by developmental area (see Table 3). Over each of the developmental areas, the children exposed to VPA and the small group of children exposed to other monotherapy treatments had the lowest levels of performance. In both of these groups a statistically significantly increased number of children fell below the average range for specific skill types (see Table 3). For the children exposed to VPA, this increased risk of delayed development appeared to be global, with only hand and eye coordination abilities not reaching statistical significance in comparison to the control children.

Seizures during pregnancy

From the 194 children born to a WWE within this cohort, 77 (40%) were exposed to seizures during pregnancy, with 48 (24%) being exposed to convulsive seizures. The overall development of children who were exposed to seizures during gestation did not differ statistically from the children who were not (p = 0.454). Children who were exposed to convulsive seizures during gestation did not differ significantly from those exposed to nonconvulsive seizures (p = 0.780). In neither the first half of gestation nor the second half did seizure exposure correlate with developmental ability (r = 0.290 and r = 0.581, respectively).

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Appendix

In this study, 73% of women enrolled during pregnancy brought their child for assessment when younger than 24 months of age. The group of women attending this first appointment was similar in socioeconomic status to women not in attendance, but there was a difference in maternal age. This could be due to, in part, a lack of support, feelings of competency. and possibly due to the reported stigma young mothers feel in the British National Health Service (Hirst et al., 2006).

Results here highlight that children exposed to VPA in utero were at an increased risk of poorer development that is global across the areas of early development. For overall development, 29% of children exposed to VPA in utero fell below average (score of <84) with a relative risk of 3.6 in comparison to the control children. These results indicate that the developmental differences reported here are not merely statistical but have clinical significance. Linear regression analysis found a statistically significant effect of VPA exposure after controlling for demographic and maternal epilepsy variables. Exposure to VPA in utero, therefore, presents an increased risk to the child’s early development that is not explained by demographic factors or maternal epilepsy. Exposure to VPA in utero has previously been linked to delayed developmental milestones (Moore et al., 2000), which is supported by the results reported here. These results are also consistent with reports associating the exposure to VPA with neurodevelopmental/cognitive outcome in the young child, which is not accounted for by confounding influences (Meador et al., 2009). Dose analysis indicated that doses >900 mg daily are more likely to cause delays in development, a finding that is consistent with previous reports relating to VPA dose with malformations (Samren et al., 1997) and cognitive outcomes (Adab et al., 2004; Meador et al., 2009). The lack of effect in the analysis for cumulative dose requires consideration in larger cohorts. Larger cohorts will allow for cumulative analysis to separately analyze the effects of dose in the different trimesters, most importantly the third trimester when a wealth of neuronal development occurs (Stiles 2008).

The children within the “other monotherapy” group were found to have an increased risk at a level similar to the VPA-exposed children (relative risk of 3.5). Caution is required with this group, however, due to its size (n = 13). Such a small group size may have lead to an inaccurate inflation of below average performance. Alternatively, there may be genuine concerns about the children within this ad hoc group. The inclusion of a number AEDs within this group (7 children exposed to phenytoin, 2 to topiramate, 2 to gabapentin, 1 to vigabatrin, and 1 to oxcarbazepine) means conclusions cannot be drawn. However, more than half of the patients in this group were exposed to PHT in utero, an AED that has been linked to poorer cognitive outcomes (Rovet et al., 1995). Research into the cognitive functioning of children exposed to newer AEDs is urgently required, as to date, no reports on the risk to the cognitive abilities of the child have been published.

The children exposed to CBZ in utero differed significantly from control children in their early locomotor abilities, showing an increased risk of motor delay. As a group, the children exposed to CBZ in utero did not differ from control children in their overall development. An increased risk of below- average performance was found for the children’s locomotor and hand and eye coordination abilities in comparison to control children. The linear regression analysis failed to find a statistically significant effect of CBZ exposure when demographic and maternal epilepsy variables were controlled, suggesting that the differences seen within the group comparisons may be due to confounding variables or that the magnitude of difference is small, requiring a larger cohort. A lack of a significant finding here is consistent with the results of Gaily et al. (2004) and a recent study by Meador et al. (2009), but are inconsistent with other reports (Ornoy & Cohen, 1996). More research is required into the abilities of children exposed to CBZ, using larger groups able to detect possible milder levels of cognitive dysfunction.

The children exposed to LTG in utero did not differ significantly from control children with respect to their overall level of early development but showed specific developmental deficits, which differed in nature from those seen for the children exposed to VPA in utero. The children exposed to LTG in utero appeared to have deficits in their nonverbal abilities, with statistically significant differences in comparison to control children for hand and eye coordination tasks and with a significant increase in the number falling below average for their hand and eye coordination abilities and their nonverbal performance abilities. Linear regression analysis failed to find any statistically significant effect of LTG exposure on early developmental abilities. This group of children exposed to LTG in utero was relatively small (n = 34), which may account for the lack of significant effect of exposure in the regression analysis. Lack of significance may also indicate that the differences noted are due to demographic influences. These results may, however, suggest that there is an increased risk for below-average development of nonverbal abilities for children exposed to LTG in utero. Little research has been published regarding the cognitive abilities of children exposed to LTG in utero. Meador et al. (2009) report that at 3 years of age, children exposed to LTG have a superior full scale IQ in comparison to children exposed to VPA in utero. To date no published research has documented the nonverbal abilities of children exposed to LTG. Further research is required in LTG exposure in utero due to its increasing use in WWE of childbearing age (Ackers et al., 2009).

Polytherapy exposure in utero has more often than not been associated with poorer outcomes in comparison to monotherapy (Adab et al., 2004; Thomas et al., 2008; Titze et al., 2008). In this cohort the children who were exposed to polytherapy did not differ significantly in comparison to monotherapy-exposed children. This difference may be due at least in part to the relatively small number of polytherapy-exposed children included, or may reflect prescribing practices relating to lower doses in polytherapy combinations. Exposure to polytherapy was not found to be associated with overall developmental ability in the linear regression model once maternal and child variables had been controlled. This may be due to the relatively small group size, however.

No statistically significant difference was found between the children who were exposed to seizures and those who were not, and there was no correlation between seizure exposure and developmental ability. This is consistent with the majority of evidence to date (Hattig & Steinhausen, 1987; Kantola-Sorsa et al., 2007; Thomas et al., 2007, 2008; Meador et al., 2009), although inconsistent with a small number of studies (Adab et al., 2004; Gaily et al., 2004). The relationship between AED variables and seizure occurrence should be considered, as the effect of seizures may be confounded by a particular AED, polytherapy treatment, or dose. This was highlighted in the research by Titze et al. (2008).

Strengths of this study include its prospective design, sample sizes, reliable assessment methodology, control for confounding variables, and the fact that the assessors were blinded not just to the exposure of the child but also to whether they were born to a woman with epilepsy. In addition, the most important strength of this research is the utilization of a control group. Research without a control group limits the understanding that can be gained into exposures that may be associated with more minor or mild cognitive deficits. No differences were found between the children born to WWE who were not medicated and the control group, highlighting that a group of children born to WWE who are not medicated may be a reliable control group for future research in this area. However, caution is required given the size of this group (n = 27). Limitations of this research include that 14% of this cohort has been reported as part of the NEAD study at 3 years of age (Meador et al., 2009). This study differs from the NEAD study by its inclusion of a more diverse range of treatment groups and a control group. The inclusion of a group exposed to polytherapy in addition to the presence of the control group and a group of children born to untreated WWE makes comparisons more methodologically reliable. A further limitation is the young age of the children at assessment. This cohort will be followed until the age of 6 years to ensure reliable conclusions can be drawn. The assessment of school-aged children will allow for a more reliable understanding of the longer term impact of in utero exposure to AEDs. Preliminary data from this 6-year follow-up documents a significant effect of VPA exposure on IQ, memory, language, and attentional ability, following control for maternal epilepsy variables and demographic variables (Bromley et al., 2009b). In addition, an increased incidence of autism spectrum disorders has been reported for the children exposed to VPA in utero in this cohort (Bromley et al. 2008). It is noted that the wide age range of the children (4–24 months) is a limitation and that a smaller age range may have provided more detailed information regarding a specific developmental period (e.g., 0–12 months). However, no statistically significant differences were noted in the age at assessment between the groups. In addition, the Griffiths Mental Development Scales control for the age of the child in its computation of scores.

It is of paramount importance that a full understanding of the risks that exposure to AEDs in utero present is explored and that these risks are communicated effectively to WWE to ensure that they, in conjunction with their neurologists, are able to make informed decisions about treatment when planning a pregnancy. Children exposed to AEDs, and particularly VPA, in utero should be considered “at risk” for poor cognitive development, and routine developmental surveillance should be offered to these children with referral at a young age for more detailed cognitive assessment and early intervention should concerns arise.

Conclusions

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Appendix

This study showed that children exposed to monotherapy VPA in utero are at an increased risk of delayed early development in infancy, with 29% of children demonstrating a level of clinical impairment. The children exposed to CBZ and LTG also showed distinct areas of poorer performance, although this could not be specifically attributed to the drug exposures in the linear regression analysis. The findings of this study have implications for both WWE and their neurologists. Potential mothers with epilepsy should receive appropriate preconceptual counseling informing them of an increased risk of adverse early development.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Appendix

Supported by grants from Epilepsy Research UK RB219738 (National Lottery Charities Board) and Sanofi Aventis (educational grant). In addition, support from the U.S. National Institutes of Health (2 R01 NS038455) has been received as part of the NEAD study. Work carried out within the Department of Genetic Medicine at St Mary’s Hospital Manchester is supported by the UK National Institute of Health Research funding through the Manchester Biomedical Research Centre.

We confirm that we have read the Journal’s position on issues in ethical publication and affirm that this report is consistent with those guidelines.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Appendix

G.A. Baker, R.L. Bromley, J. Clayton-Smith, and G. Mawer have each given expert testimony on fetal anticonvulsant syndrome. G.A. Baker has received educational grants from Sanofi Aventis to support this research. The remaining authors have nothing to disclose.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Appendix
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  • Bromley R, Mawer G, Clayton-Smith J, Baker GA; on Behalf of the Liverpool and Manchester Neurodevelopment Group. (2008) Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology, 71:19231924.
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Appendix

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Appendix

Liverpool and Manchester Neurodevelopment Group (during the period of this work). Alder Hey Children’s Hospital, Liverpool, UK: Alan Fryer, MD, Rachel Kneen, MD; Liverpool University, UK: Gus Baker, PhD, Rebecca Bromley, PhD, Pete Dixon, PhD, Joanne Eatock, BA, Alison Gummery, BSc, James Kelly, BSc, Jennna Love, BSc, Lauren McEwan, BSc, Laura Purdy, BSc, Rebekah Shallcross, BSc, Jacqui Vinten, PhD; St Mary’s Hospital, Manchester UK: Siddharth Banka, MRCP(Ch), Maria Briggs, RGN, Deirdre Cilliers MD, Jill Clayton-Smith, MD, Usha Kini, MD, Mila Kuzmyshcheva, BS, Sam Lucas, PhD, George Mawer, FRCP(E), PhD, Walton Centre for Neurology and Neurosurgery, Liverpool, UK: Loretta Kerr, Kate O’Hanlon, RGN, Lynne Owen, EPTA, Gilla Veling-Warnke, MD, Lynne Wyatt, BSc.