Ms. No. 5075ETS

The treatment of epilepsy in pregnancy: the neurodevelopmental risks associated with exposure to antiepileptic drugs.

Bromley R1,2.

1 Institute of Human Development, Faculty of Medical & Human Sciences, University of Manchester; 2 Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL. Rebecca.bromley@manchester.ac.uk.

Abstract

A number of antiepileptic drugs (AEDs) have been confirmed as teratogens due to their association with an increased malformation rate. The majority of research to date does not find an association between prenatal exposure to monotherapy carbamazepine, lamotrigine or phenytoin and neurodevelopmental outcome in comparison to control children and noted higher abilities in comparison to children exposed to valproate; but further work is needed before conclusions can be drawn. Data for levetiracetam was limited to one study, as was the evidence for topiramate. Sodium valproate exposure appeared to carry a dose dependent risk to the developing brain, with evidence of reduced levels of IQ, poorer verbal abilities and increased rate of autistic spectrum disorder both in comparison to control children and children exposed to other AEDs. The severity of the neurodevelopmental deficits associated with prenatal exposure to valproate highlight the critical need to consider neurodevelopmental outcomes as a central aspect of teratological research.

1. Introduction

The need to optimize seizure control whilst limiting the potential risk to the fetus can be a challenge. Given the nature of the condition pharmacological treatment during pregnancy is typically required and it is estimated that 0.5-2.5% of pregnancies are exposed to AEDs for epilepsy and other indications (1-4). Prescription patterns in women with epilepsy have changed over the last two decades, with a decrease in the older AEDs such as phenytoin, phenobarbital, carbamazepine and valproate, and an increase in ‘newer’ therapies such as lamotrigine and levetiracetam in women of childbearing age (2, 3, 5).

The older AEDs have been demonstrated to be associated with a significant increase in risk of major congenital malformation. Valproate is reported as the AED with the highest level of teratogenicity (6) and is associated with neural tube (7-9), cardiac (9, 10), orofacial clefts (9, 11, 12) and skeletal or limb malformations (9, 11); with levels of risk being clearly dose dependent (6, 13, 14). Carbamazepine has been associated with an increased risk of major malformation (6), with a higher rate of spina bifida and cardiac malformations

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reported (6, 13, 14). Phenobarbital has been associated with an increased overall rate of malformations (6, 15), and specifically with cardiac malformations (6, 16) and oral clefts (17). Finally, phenytoin is also reportedly associated with an increased rate of malformations (15, 18).

Prenatal exposure to lamotrigine has been found by the majority of pregnancies registers and population-based studies to not be associated with an increased risk of malformation (16, 19-22). To date no specific pattern of malformations have been reported following exposure to lamotrigine (6). A previously reported association with oral clefts in data from the North American Pregnancy Register (23) has not been maintained with increased study population (16). Although the majority of studies have not documented a dose response, the largest study to date does find an association between dose of lamotrigine and prevalence of malformations (6). Data is more limited pertaining to exposure to levetiracetam. Pregnancy register data from UK, US and Australia failed to find an association with malformation status of the child (16, 20, 24) as did a small population based study (21). There is consistent evidence of a specific risk of oral clefts following in utero exposure to topiramate (25, 26). There is no evidence of an increased rate of malformation in children exposed to gabapentin (21, 27), oxcarbazepine (21) or zonisamide (16), however data is limited for conclusions to be drawn.

There is therefore increased risk to the physical development of the fetus following exposure to certain AEDs. Additionally, there are further risks that should be considered, which convey lifelong impact to the fetus and the later child. Early reports of malformations following prenatal exposure to an AED often also reported neurodevelopmental difficulties (28-32), however it took until the turn of the century to see an increased international interest on neurodevelopment as a primary outcome (33-39) and also the utilization of the already established epilepsy and pregnancy registers for the ascertainment of neurodevelopmental data (38, 40-42). Neurodevelopmental outcomes when affected can be substantial and therefore a comprehensive understanding of any association between a drug exposure and impaired neurodevelopmental outcome should be sought as quickly as possible. Below, the evidence pertaining to the neurodevelopment in children exposed to AEDs is reviewed and the approaches taken to understanding these risks are discussed.

2. Neurodevelopment

With the interchangeable terminology of neurodevelopment, neurobehavioral, intelligence and cognitive development, the term neurodevelopment is utilized here to refer to the functional outputs of the brain ranging from motor performance, intelligence, speed of information processing, social functioning as well as other cognitive skills. The brain is a complex organ, its functional outcomes diverse and therefore the measurements employed to test cognitive functioning are numerous. The trajectory of neurodevelopment over childhood is dynamic with increasing skill acquisition over time and increasing capacity for

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processing, reasoning, attending, recalling and communicating. Therefore the outcome ‘neurodevelopment’ is wide and is constantly evolving as the child ages. Due to this diversity and evolution there are numerous approaches to the measurement of neurodevelopment. Measured most commonly as a global cognitive ability score either as an intelligence quotient (IQ) or by the developmental quotient (DQ) for younger children, these scores provide a summary of global cognitive development or intellectual reasoning respectively. The IQ and the DQ actually measure distinct skills; with the later much more about the emergence of new skills in early childhood (e.g. Bayley Scales of Infant and Toddler Development)(43). Data is often less for specific cognitive skills such as memory, attention or language functioning or educational measures such as reading proficiency; but the impact of specific deficits in these areas should not be considered minimal. Numerous post-natal environmental influences impact on neurodevelopmental outcomes and should be considered. The hereditary genetic contribution to neurodevelopment, particularly IQ, highlights the need for adjustment for parental IQ in studies investigating neurodevelopmental outcomes in children exposed to AEDs. The impact of parental education, occupation, health variables, age at conception as well as child factors of gestational age at birth, breastfeeding, age at assessment, concomitant medication exposure, access to adequate nutrition and stimulation also require consideration. Additionally, considerations from a teratology point of view are also required when interpreting data in this area. Investigation of a single group of mixed AED exposures will not provide reliable data and outcomes are likely to differ depending on the groups composition. Dose of the AED is also likely to be a key concept as is timing and duration of exposure.

Considering these points, the evidence pertaining to neurodevelopmental outcome is reviewed below for each monotherapy AED, summarizing outcomes in infancy and childhood both for global cognitive measures (IQ and DQ) and specific outcomes.

2.1. Carbamazepine

In infancy, a number of studies have failed to find an association between exposure in utero to carbamazepine and infant neurodevelopment measured by the Bayley Scales of Infant and Toddler Development in comparison to control children representative of the general population (34, 36, 37, 44, 45). However, a significantly poorer level of neurodevelopment was found for the children exposed to carbamazepine (n=163) in comparison to children born to women with an untreated epilepsy (n=58, MD (mean difference) -7.22 (95% CI -12.76 to -1.67)(45). Numbers of included assessments are relatively small in these comparisons and probably accounts for the contrasting finding across the different control groups.

In school aged children Gaily and colleagues(35) found comparable IQ in children exposed to monotherapy carbamazepine (n=86) in comparison to general population control children (n=141) when level of maternal education was taken into account; which is consistent with reports from a UK prospective

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dataset (46). In a meta-analysis study combining these two studies with others prospective studies, no significant differences in ability were found for children exposed to carbamazepine in comparison to children born to women without epilepsy (n=150 vs. n=552, MD -0.03, 95% CI -3.08 to 3.01) and also children of women with untreated epilepsy (n=163 vs. n=87, MD 1.84, 95% CI -2.13 to 5.80)(45). Consistently, the retrospective study of Adab and colleagues(47) also found no significant difference between the IQ of children exposed to carbamazepine (n=52) and children born to women with untreated epilepsy (n=80).

In comparison to other AEDs, carbamazepine exposed children (n=210) were not different in their early development from 160 valproate exposed children (45). In older children however, the vast majority of studies find improved IQ scores for children exposed to carbamazepine versus those exposed to valproate (35, 46, 48), with a meta-analysis demonstrating around a nine point higher mean score (MD 8.69, 95% CI 5.51 to 11.87) for children exposed to carbamazepine (n= 191) in comparison to valproate exposed children (n = 112)(45). No difference in the global cognitive development of children exposed to carbamazepine has been noted in comparison to children exposed to lamotrigine either in infancy or in the school-aged years (33, 34, 40, 45, 48, 49). In comparison to children exposed to phenytoin a non-significant difference is reported (33, 36, 45, 48). There is currently no direct comparison to children exposed to levetiracetam, topiramate or other newer AEDs.

There is more limited evidence when it comes to the potential effects of carbamazepine on specific cognitive skills. Rovet et al(50), Veiby et al (51) and Nadebaum (52) failed to demonstrate a association between exposure and language development in comparison to control children. However, in the longitudinal study by Baker, Bromley and colleagues, early language development in the children exposed to carbamazepine was not discernible from control children however, verbal IQ scores at school age were significantly poorer than control children following adjustment for confounding influences (34, 41, 49). For child motor development, five studies have failed to find poorer outcomes for carbamazepine exposed children in comparison to control children (34, 39, 51, 53, 54), however the NEAD study found a dose related decline in motor skills for the carbamazepine exposed children (n=61). The adaptive behaviour including communication, daily living and socialisation skills, of children exposed to carbamazepine were reported to be comparable to control children; however, in the NEAD study a small but significant dose-related relationship was demonstrated for carbamazepine (55).

No dose effect has been consistently found for carbamazepine exposure in pregnancy and outcome measured as child DQ or IQ (33-37, 42, 45, 46, 48, 50, 53), however the NEAD study did demonstrate an association between increasing carbamazepine dose and poorer verbal abilities (48) and motor abilities (55).

2.2. Lamotrigine

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Data is limited to three prospective observational studies (34, 40, 56) and one questionnaire study (51)when comparisons are being made to control children for global neurodevelopmental outcome following in utero exposure to lamotrigine. All demonstrate comparable neurodevelopment, measured as IQ, or DQ in younger children, in comparison to control children (34, 40, 56); with the controls being children born to women without epilepsy. Two of the three studies adjusted for key confounders including parental education and or IQ, exposure to folate and gestational age at birth. The adaptive behavior of children exposed to lamotrigine is not reported to differ from controls (42) and no relationship between poorer adaptive behavior and higher doses of lamotrigine have been found(55).

In comparison to other AEDs, children exposed to lamotrigine have been reported to have superior neurodevelopment in comparison to children exposed to valproate both in infancy (33, 34, 40) and in school aged children (46, 48). Rihtman and colleagues (56) however, failed to find a significant difference between the IQ of children exposed to valproate (n = 29) and those exposed to lamotrigine (n = 41); but the mean doses in this cohort were substantially lower than that reported valproate doses in the larger NEAD study (546mg/day vs. 1032mg/day), which given valproate’s significant association with dose, may account for this difference in outcome. No difference in global neurodevelopment in comparison to children exposed to carbamazepine has been reported either in infancy or in school aged children (45). To date there has been no published comparison to levetiracetam, topiramate, phenytoin or phenobarbital.

In terms of specific cognitive skills, children exposed to lamotrigine were not at any increased risk of poorer language development in comparison to controls in one study under 24 months of age (34). However in a parental completed questionnaire study parents felt their children had poorer sentence skills at 36 months (51). In comparison to children exposed to valproate, children exposed to lamotrigine have been reported to have superior language/ verbal development (48, 49). There is evidence to suggest that children exposed to lamotrigine do not experience difficulties with motor development in comparison to control children (34, 51, 55) or in comparison to other AED exposed children (55). However, Rihtman and colleagues(56) found a relationship between dose of lamotrigine on fine motor ability, which requires further investigation. No relationship between dose of lamotrigine and child DQ or IQ has been documented by others (33, 34, 46, 48); although numbers remain small across all published studies to date. Two studies have measured the adaptive behavior of children exposed to lamotrigine and failed to find poorer outcomes (42, 55).

2.3. Levetiracetam

Despite its recent increase in use evidence pertaining to the neurodevelopmental outcomes of children exposed to levetiracetam in utero are limited to the series by Shallcross and colleagues (41, 57). Children exposed to levetiracetam (n = 51)

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were assessed under two years of age and were found not to differ from children born to women without epilepsy (n = 97) for their overall neurodevelopmental level. Consistently, there were no differences found between more specific skills across the areas of language, hand and eye coordination, non-verbal reasoning and social development(41).

A linked paper reported the DQ of 53 levetiracetam exposed children between three and four years of age in comparison to children born to women without epilepsy (n = 131); 32% of this levetiracetam group had been assessed under the age of two years and were reported in earlier publication(41). Consistent with the outcome at the younger age assessments the children exposed to levetiracetam did not differ in their performance on tasks of language, motor, social, hand and eye co- ordination and non-verbal skills (57).

To date, the neurodevelopmental abilities of children exposed to levetiracetam have only been directly compared to children exposed to valproate, where significantly higher levels of DQ are reported(41, 57). In models adjusted for a number of confounding factors, including maternal IQ and a number of key child variables, the children exposed to levetiracetam had higher score for their motor development (MD 15.8, 95% CI 24.5 to 27.1), language comprehension (MD 6.4, 95% CI 211.0 to 21.8) and language expression (MD 9.5, 95% CI 214.7 to 24.4) (57).

No dose effect was found in the Shallcross studies (41, 57), but further investigation is required for conclusions to be drawn.

2.4. Phenobarbital

Despite its historical widespread use, the majority of research into children exposed to phenobarbital reported outcomes as part of a single ‘AED exposed group’ rather outcomes from monotherapy phenobarbital exposure (58). Therefore, limited data was available on monotherapy phenobarbital exposure and child neurodevelopmental outcomes. Thomas and colleagues(39), failed to find a significant difference between the neurodevelopment of phenobarbital exposed infants (n = 41) and control children (n = 32), a finding which was consistent with that of another study (44), although the numbers exposed to monotherapy phenobarbital in this latter study were unclear. Data from school aged children was limited for monotherapy phenobarbital, with only one study identified which included just 14 phenobarbital monotherapy cases(59) failing to find a difference in terms of IQ in comparison to control children, whilst another small study including 13 phenobarbital exposed children found differences in reading and handwriting ability in comparison to controls (60). Dean and colleagues (61) failed to find an increased in ‘developmental delay’ in 61 children exposed to phenobarbital; however no formal assessment of neurodevelopment was undertaken. It is of note that Dessens and colleagues (62) report neuropsychological deficits in adults with a prenatal history of phenobarbital exposure; although caution is required as this study also included polytherapy phenobarbital cases. It does however, highlight the long-term nature of

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neurodevelopmental deficits.

2.5. Phenytoin

The neurodevelopment of infants exposed to phenytoin in utero has been demonstrated to be comparable to control children (32, 36, 37, 39, 45, 63); however the majority of cohorts of phenytoin exposed children were sized between 20 and 30 which limits the conclusions. The IQ of school aged children exposed to phenytoin is also reported to be comparable to control children (47).

Meta-analysis of data from prospective observation studies demonstrated comparable levels of early neurodevelopment for children exposed to phenytoin (n=87) in comparison to children exposed to carbamazepine (n=172, MD 3.02 (95% CI -2.41 to 8.46) (45). Wide and colleagues(36) compared the development of 35 children exposed to carbamazepine to 15 children exposed to phenytoin and failed to find a significant difference for overall neurodevelopmental level. Similarly, meta-analysis found no significant differences been phenytoin exposed school aged children and carbamazepine exposed children (n=75) when abilities were measured as IQ (MD -3.30 (95% CI -7.91 to 1.30 ) (45); which is consistent with a retrospective study (47). In comparison to valproate exposed children (n=108) the children exposed to phenytoin (n=80) had a higher level of early development by seven points (MD 7.04, 95% CI 0.44 to 13.65) (45). The NEAD study(48) demonstrated that this difference persisted into school age and demonstrated significantly higher IQ ability for the children exposed to phenytoin (n=55) in comparison to those exposed to valproate (n=62), following adjustment for maternal IQ and other confounding influences.

Very little work has looked at specific cognitive abilities in the phenytoin exposed children. Rovet et al (50) demonstrated significantly poorer language ability in children exposed to phenytoin compared to control children. However, the NEAD study found superior verbal skills for children exposed to phenytoin in comparison to the children exposed to valproate (48). Delays in motor development have also been reported (36, 54), but such findings have not been replicated by others (55).

A relationship between dose of phenytoin and child neurodevelopment has been investigated by, with all failing to find an association with language (50), motor ability (55)or IQ (33, 47, 48).

2.6. Topiramate

The evidence on topiramate is limited to one small published article. Rihtman and colleagues(64) included just nine topiramate exposed children of which only six were born to mothers with epilepsy. IQ was assessed and a significant difference between the nine topiramate exposed children and 18 control children in terms of global cognitive ability (topiramate mean 96.33, SD 10.37 vs.

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control mean 111.39, SD 12.20) was demonstrated. Due to limited cohort size conclusions cannot yet be drawn however. To date there has been no investigation of a relationship between topiramate dose and neurodevelopmental outcome, due to limited cohort size.

2.7. Valproate

As with its malformation risk valproate is the AED with by far the most consistent picture regarding its risk. Children exposed to valproate have been reported to have lower early developmental outcome (33, 34, 40, 48); although this is in contrast with one study(39). Results of these and other studies (including one unpublished) were combined in meta-analysis, which noted a 8.7 point decrease in the mean (MD -8.72, 95% CI -14.31 to -3.31) for the valproate exposed children (n=123) in comparison to the offspring of untreated women with epilepsy (n=58) (45). Consistently, a UK based retrospective study also documented a difference in the IQ if children born to women with an untreated epilepsy (47). In older children, these deficits appear to persist when abilities are measured as IQ and are compared to control children (35, 45, 47-49) with similar levels of difference; indicating that exposure to valproate is associated with a 7-10 point reduction in IQ in comparison to control children. In contrast, Rihtman et al(56) failed to find poorer level of IQ in children exposed to valproate; however it was of note that the mean dose of valproate was low (546.3 mg/day).

In comparison to other AEDs, valproate exposed children have been demonstrated across a number of studies to have poorer neurodevelopmental outcomes than children exposed to carbamazepine (33, 34, 40). At school age the children exposed to valproate are still behind those with carbamazepine exposure with a meta-analysis of five studies including 112 valproate and 191 carbamazepine exposed children, finding a difference of 8.69 point difference (MD 8.69, 95% CI 5.51 to 11.87)(45). Similar, levels of difference are also reported in comparison to lamotrigine exposed children when IQ is the outcome measure (MD -10.79, 95% CI -14.41 to -7.17) for 74 valproate exposed children in comparison to 84 lamotrigine exposed children (45) and in comparison to phenytoin exposed children (n=45 vs. 61 valproate exposed children) (MD, 6.38 95% CI -4.84 to 17.58)(45).

Poorer verbal reasoning abilities and poorer language skills are commonly reported within the valproate exposed children (34, 35, 47-49, 52), as are delays in motor development (34, 41, 45, 55, 56), both in comparison to children exposed to other AEDs and control children. Poorer levels of attention, working memory and slow processing speed have also been reported (65, 66). Further, deficits in adaptive behavior (42, 55) and lower educational attainments are reported for the children exposed to valproate (49, 67).

In addition to the deficits in cognitive development, increased rates of autistic spectrum disorder have been reported in case studies (68, 69), retrospective studies (47, 70) and more recently, prospective observational studies (71-73)

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and population-database studies (74). From the cohort observational studies the prevalence is reported to be around 6-8% (70-72) (background risk is around 1-2% (75))with the risk in the larger population -database study reporting after 14 years follow up the absolute risk to be 4.42% (95% CI, 2.59%-7.46%) for the wider diagnosis autism spectrum disorder and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (74).

The neurodevelopmental outcomes of children exposed to valproate consistently demonstrate an association with dose; with higher doses linked to poorer global cognitive abilities (e.g. DQ or IQ scores) (35, 47-49, 72). Most commonly, doses of 800 to 1000 mg daily are reportedly associated with higher levels of risk. Baker and colleagues(49) split the group of valproate exposed children into equal and below 800mg/day and those above and demonstrated that the associated multiple regression coefficients were almost halved for the lower dose level (4.9 IQ points lower vs. 9.5 IQ points lower than control children). Additionally, a relationship with dose has been reported for verbal/ language abilities (48, 49, 52) and also motor skills (55); this later association was not replicated however (41).

2.8. Other AEDsTo date there is no published experience on the neurodevelopment of children exposed to gabapentin, oxcarbazepine, ethosuximide, zonisamide or other regulatory approved AEDs.

2.9. The influence of the maternal condition

AED teratogenesis rather than the maternal condition per se is thought to be the primary causal element in the uplift in malformation risk (13, 76-80). Although there is less data available, in the main studies have also linked the increase difficulties with neurodevelopment noted for children exposed to valproate to be associated with AED exposure rather than the maternal condition. The studies of Meador (33, 48), Gaily (35)and others (34, 49) have all investigated but failed to find an association between maternal epilepsy type and poorer neurodevelopmental outcome. The neurodevelopment of children born to women with untreated epilepsy has been documented to be comparable to control children (34, 35, 49, 76) and there is animal data from non-epileptic mothers whose offspring have affected neurodevelopment following exposure (81, 82); although there are few such investigations. A further line of investigation is when the father has epilepsy and there has been a failure to find an increased rate of neurodevelopment difficulties for children born to fathers with epilepsy (83, 84). An association between child verbal IQ levels and exposure to seizures was reported by a UK retrospective study (47) and in the study by Shallcross and colleagues (57), however, this finding has not been supported by the majority of prospective studies (33, 35, 48, 49, 72) or Pregnancy Register based studies (40, 42). It is of interest, that in studies which find significantly poorer cognitive outcomes in children exposed to valproate in comparison to the children exposed to lamotrigine, that the seizure frequency of

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the valproate group is substantially lower than the lamotrigine group (42, 49); possibly due to the documented increased efficacy of valproate in comparison to lamotrigine (85). However, seizures were infrequent in all of these studies and it is unclear whether comprehensive seizure diaries were kept and in some cases details on seizure frequency were collected retrospectively which may have led to bias. Therefore more comprehensive investigation of the possible effects of brief seizure exposure during pregnancy is required before firm conclusions can be drawn.

3. Discussion

For both malformations and neurodevelopmental outcomes exposure to valproate presents the highest teratogenic risk of the AEDs and has led to a number of regulatory decisions and guidelines pertaining to the avoidance of valproate treatment in the childbearing years, where safe to do so (86, 87). This presents a difficult decision for women requiring AED treatment during pregnancy. Valproate is an efficacious AED (85) and therefore harms to the fetus need to be considered alongside the treatment of the mother and thus valproate is likely to continue to have a place in the treatment of women (86); particularly, if other treatments have failed and the dose of valproate is kept low (86). What is particularly of concern is the lack of data regarding the alternatives to valproate with limited published evidence pertaining to levetiracetam or lamotrigine and no published neurodevelopmental data for a number of other approved AEDs.

Focus on this area has increased and research methodologies have become more refined, investigating single monotherapy AED groups rather than single exposure groups comprised of a number of different AEDs. Blinded assessment with standardized measures and, more often, undertaking adjustment for confounding variables adds further reliability to the results. An increasing number of studies are focusing on wider aspects of neurodevelopment (i.e. memory, language and attention) but this leads to a larger number of values for statistical analysis and increases the likelihood of chance findings. Given the consistency of the findings pertaining to valproate across studies, it is unlikely that such a situation accounts for the findings for this AED and a number of studies used significance level correction to limit the likelihood of chance findings (34, 41, 47, 49, 51, 57, 65). Longitudinal studies following the children from birth are limited to just a few studies (33, 34, 36, 37, 48, 49, 51, 84, 88) but provide critical and in depth information about the neurodevelopment of children exposed to AEDs. Thus the area has evolved however more research is needed and a lack of evidence of risk to neurodevelopment should not be taken as evidence of safety.

This relative lack of neurodevelopmental data in comparison to the data available regarding malformation risk highlights the historical view of neurodevelopment as a secondary outcome in teratology research. As thalidomide focused attention to the susceptibility of the physical development

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of the fetus to the deleterious effects of certain medications, the case of valproate highlights the significant effects of certain medications on fetal brain development and later child cognitive functioning. Licensed for use in the 1970s, evidence pertaining to the neurodevelopmental outcomes have been slow to accumulate; despite delayed neurodevelopment often being noted in early case reports (28-30, 32, 89). However, an increased risk of autistic spectrum disorders (47, 70, 74) and an average reduction of between 7 and 10 IQ points (45) highlight a significant and substantial effect on neurodevelopment. In a UK prospective study, children exposed to valproate were eight times (RR 8.6, 95% CI 3.1–18.8) more likely to fall below the average range for their IQ (49). The real life significance of this type of deficit is that an IQ below the average range at school age leads to poorer educational attainments (90) which in turn lead to reduced occupational attainment and thus lower socioeconomic status (91) and higher health inequalities (92). Thus, potential deficits in neurodevelopment can be severe, in the case of higher dose valproate, and can have substantial long-term effects on the child and present large costs to society. Considering the significance and the severity of the impact, neurodevelopment should not be thought of as a minor or secondary research outcome. Neurodevelopment should not be seen as a ‘softer’ marker of exposure. The potential severity of a reduction in neurodevelopment should mean that it is researched as a primary outcome and should always be considered central to teratological knowledge for that medication.

The time taken to collect neurodevelopmental data undoubtedly contributes to its lesser focus; malformation data is available prenatally or at the birth of the child but for neurodevelopmental data longer term follow up is required which is expensive both in terms of time and finance. However, there needs to be an increased interest in, and an acceptance of, the importance of risks posed to neurodevelopment by potential teratogens. The utilization of Pregnancy Registers (39-42, 57) and Teratology Information Services (53, 56, 64, 93) for the collection of neurodevelopmental outcomes data will, and has in the case of levetiracetam, decreased the latency between medication onset and first experience in pregnancy from child neurodevelopmental point of view. However, these studies are far from the norm and few Pregnancy Registers or Teratology Information Services appear to routinely collect neurodevelopment data alongside malformation data.

As well as an increased focus on the importance of understanding neurodevelopment methodologies need to be more refined to ensure the quality of the data collected. Single AED exposure groups should be investigated, with consideration over dose effects. Interpretation of the neurodevelopmental results should be done carefully and considering what exact skills have been assessed and what remains unknown. For example, assessment of neurodevelopment in infancy does not demonstrate a significant difference between children exposed to carbamazepine and those exposed to valproate; however, by school age these differences are very clearly established (45). Therefore early assessment in infancy should not be taken as the final word on neurodevelopment, as there is still much development to occur and as the

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complexity of the workings of the human brain develop over time concluding too early may provide a misleading conclusion.

Due to the complex and diverse nature of cognitive functioning there are a large number of outcomes which require assessment (e.g. reasoning, memory, language, motor functioning) with a larger number of measures which are utilized to assess these outcomes. Up to 2014 over 15 different types of assessments had been utilized in prospective observational studies; leading to a heterogeneous dataset (45). Early global cognitive development, measured as DQ, although predictive of later school aged IQ, is not the same as IQ and should not be considered as such (43). The intelligence quotient is by far the most widely known measure of cognitive function, however IQ should be considered a summary score; a score derived based on a number of other cognitive processes such as speed of information processing, memory and executive functioning skills. Whilst a good and reliable summary statistic, IQ is an insensitive measure for specific cognitive skills (e.g. language, memory, attention). As noted above, there is evidence for example, that following exposure to valproate verbal abilities are disproportionally effected (38, 47-49) and consideration of the full scale IQ in isolation may mask such differential outcomes. Finally, randomized controlled trials are not ethical in this area and therefore the measurement and statistical adjustment for confounding variables is of paramount importance. Data from completed studies highlights that parental IQ, parental age, gestational age at delivery, socioeconomic status, age of child, child gender, dose of AED are important cofounders to consider in this area (33, 35, 40, 47-49, 51). As noted above, it is less clear as to whether there is an association between either maternal epilepsy type or exposure to seizures in additional to the teratological risk of certain AEDs and child cognitive outcome and this data should continue to be investigated in future work.

Considering these issues, to say therefore that there is no association between an agent and neurodevelopmental outcome would mean that adequate investigation had been conducted across all cognitive domains and well into the school age years; something which rarely occurs currently.

4. Conclusions

Given the magnitude of neurodevelopmental impairment which can be found following prenatal exposure to a teratogen such as valproate the cognitive functioning of exposed children should not be considered as a secondary feature or as a milder outcome but, given their lifelong impact and potential severity, should be considered as a central feature of teratological research.

FundingThis report is independent research supported by the National Institute for Health Research (Post Doctoral Fellowship, Dr Rebecca Bromley, PDF-2013-06-041). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the

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Department of Health.

AcknowledgementsRB would like to acknowledge the very useful input on aspects of this manuscript from Dr Laura Yates, UK Teratology Information Service, Newcastle Upon-Tyne, UK.

Conflict of InterestsRB has contributed to studies funded by Sanofi Aventis and UCB Pharma and has received consultancy payment (one occasion) from UCB Pharma for work on an unrelated matter.

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