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Fetal antiepileptic drug exposure and cognitive outcomes
Accepted Manuscript Title: Fetal antiepileptic drug exposure and cognitive outcomes Author: Rebecca L. Bromley Gus A. Baker PII: DOI: Reference:
S1059-1311(16)30174-1 http://dx.doi.org/doi:10.1016/j.seizure.2016.10.006 YSEIZ 2807
To appear in:
Seizure
Received date: Accepted date:
17-9-2016 3-10-2016
Please cite this article as: Bromley Rebecca L, Baker Gus A.Fetal antiepileptic drug exposure and cognitive outcomes.SEIZURE: European Journal of Epilepsy http://dx.doi.org/10.1016/j.seizure.2016.10.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Fetal antiepileptic drug exposure and cognitive outcomes
Rebecca L. Bromley1,2 & Gus A. Baker3
1 Division of
Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health,
University of Manchester, UK. 2
Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS
Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. 3
Department of Molecular and Clinical Pharmacology, University of Liverpool, UK
Correspondence to:[email protected].
1
Abstract
Purpose: Data highlighting valproate as a human teratogen put in context the need to balance both maternal and fetal needs; maximising maternal health whilst minimising fetal risk. This led to increased research efforts to understand the associated risks with AED treatments. Methods: A review of currently published literature was undertaken. Results: In utero exposure to valproate was associated with a range of poorer neurodevelopmental outcomes when compared to control children and children exposed to other AEDs. Children exposed to carbamazepine were not found by the majority of studies to have poorer early development, although there is a lack of evidence regarding specific cognitive skills later in childhood and adolescence. Research regarding lamotrigine is limited to a small number of studies but suggests early global development or school aged IQ does not differ from control children, but less is known about specific cognitive skills. Evidence for the other AEDs including levetiracetam and topiramate were significantly limited. Conclusions: Despite an improvement in momentum the evidence remains incomplete for neurodevelopmental outcomes and this limits the evidence-based decision making. Further efforts are required to enhance the treatment of women by giving them the confidence that both the risks and the benefits of commonly used AEDs are known. Future research should also seek to increase our understanding of the children who experience neurodevelopmental
2
difficulties in the context of exposure in the womb to AEDs and what interventions may be successful in maximising the outcome of these children.
Keywords: Epilepsy, Neurodevelopment
Pregnancy,
In
Utero,
Antiepileptic
Drugs,
1. Introduction
The treatment of women with epilepsy in the potential childbearing years has received increasing focus over the last decade. Data highlighting valproate as a human teratogen put in context the need to balance both maternal and fetal needs; maximising maternal health whilst minimising fetal risk. This finding led to increased research efforts to understand the possible risks associated with AED treatments. Whilst there have been improvements in the level of evidence there are still significant limitations to our current knowledge. The establishment of pregnancy registers (1-3) increased the speed at which information on congenital malformations was generated, however investigations into the neurodevelopmental outcomes of children exposed to antiepileptic drugs (AEDs) continues to lag behind.
In utero exposure to valproate (VPA) is linked to an increase in diverse major congenital malformations including spina bifida, cardiac and skeletal malformations (4, 5). Carbamazepine (CBZ) too has a reported association with spina bifida and cardiac malformations, although to a lesser extent than VPA (4, 5). An association with specific malformation types has been reported for
3
topiramate (TPM) and phenobarbital (PB); for cleft malformations and cardiac malformations respectively (3, 4, 6). Phenytoin (PHT) has been shown to be associated with an increased risk of major congenital malformation, although the exact malformation types increased following exposure are less clear(4). A previous, finding linking lamotrigine (LTG) exposure to oral clefts has not been upheld by increasing data (3); however dose of LTG may be an important consideration(7). To date levetiracetam (LEV) exposure is has not been found to be associated with an increased risk in major congenital malformations (1-3); however cohort numbers are relatively small and little is known about a potential association with specific malformation types (4). Therefore there are known risks to the physical development of the fetus from certain AEDs. The period of organogenesis spans the first 12 weeks of gestation and after this time, exposure to a teratogen cannot induce a major structural malformation (8). The brain however, continues its development throughout the entire period of gestation (and beyond) thereby opening it up to a longer period of susceptibility to teratogens(8). The available data regarding neurodevelopmental outcomes following exposure is substantially less for all AEDs (9), despite this extended period of susceptibility and the lifelong significance of the potential deficits. Early case reports of children with a major congenital malformations following prenatal exposure often reported neurodevelopmental difficulties (10-12), however it took until the turn of the century to see an increased interest on neurodevelopment as a primary outcome. Reasons for this delay are complex but are hypothesized to include; longer follow up time, specialist assessment and the financial resource requirement such follow up requires. The brain is a complex organ and its functional outputs are diverse. The trajectory of neurodevelopment
4
is dynamic across childhood with rapid phases of increase skill acquisition. This complex and dynamic nature of neurodevelopment poses additional challenges to the creation of a comprehensive evidence base. This invited paper reviews the data currently available on the neurodevelopmental outcomes for each of the more commonly used AEDs. A discussion is then undertaken regarding the limitations within this current knowledge base and proposals for future progress are outlined.
2. Review of the available studies
2.1. Carbamazepine (CBZ)
Children exposed to CBZ have in the main not been found to be at risk of global neurodevelopmental difficulties when assessed in infancy in comparison to control children, (13-16). However, two studies demonstrated poorer neurodevelopmental outcome (17, 18) as did one meta-analysis study (9). Of note, Ornoy and Cohen (1996)(18) found poorer infant development in children exposed to CBZ who displayed dysmorphic features; an association which was not replicated (19). At school age when the intelligence quotient (IQ) and other cognitive skills being measured are more complex the picture is unclear. Adab et al (20) and Gaily et al(21) failed to find an association between exposure to CBZ and reduced global IQ (FSIQ), verbal IQ (VIQ) or performance/non-verbal IQ (PIQ) in comparison to control children. However, data from two linked studies (22, 23) documented vulnerability in the VIQ domain following CBZ exposure. However, a meta-analysis study of prospective studies, reported no significant
5
differences in ability for children exposed to CBZ in comparison to children born to women without epilepsy in terms of their VIQ(9). A similar conclusion was reported with regards to FSIQ both in comparison to women without epilepsy and also children of women with untreated epilepsy(9).
In comparison to other AEDs, meta-analysis regarding the early development of children exposed to CBZ (n=210) in comparison to those exposed to VPA (n=160) failed to find a difference(9). However, IQ outcomes in the children exposed to CBZ (n=191) in comparison to those exposed to VPA (n=112) demonstrated a nine-point difference in the mean scores favouring the CBZ exposed children(9); highlighting that differences in neurodevelopment may not become apparent until later in childhood. CBZ was not found to be associated with poorer outcomes in comparison to PHT when the outcome being assessed was DQ or IQ (9, 14, 15, 20) and in comparison to LTG, there was no evidence of a difference between neurodevelopment in infancy or at school age (9, 13, 2224).
Neurodevelopment is more than simply early global development (referred to as the developmental quotient (DQ)) or IQ. The functioning of the memory, language, attentional, executive systems as well as motor skills are critical for good outcomes in childhood. The available evidence is more limited particularly for skills such as memory and attention. Gopinath et al (25)and Kantola Sorsa and colleagues (26) investigated the memory and attentional abilities of children exposed to CBZ, however the results were not reported independently from other AED exposures. Language skills of children exposed to CBZ were reported
6
not to differ from control children (13, 27-29) with one exception(30), and five studies have failed to find poorer motor outcomes (13, 14, 18, 28, 31). However, data from the NEAD study showed a dose-dependent association between CBZ and poorer motor skill outcome at three years of age (32) and Veiby (28) documented increased parental concern about fine motor skills at 18 but not 36 months. Adaptive behaviour skills such as communication, daily living and socialisation skills were reported not to be associated with CBZ exposure in school aged children (33, 34) but, Cohen found poorer adaptive behaviour to be associated with increasing dose of CBZ in younger children(32). The adaptive behaviour of children exposed to CBZ is reported to be higher than the children exposed to VPA and not significantly different from the children exposed to LTG (32, 33). Children exposed to CBZ have not been found to require significantly increased levels of educational support (22, 35) and three studies have failed to find an association between prenatal exposure to CBZ and an increased risk of autistic spectrum disorder (36-38, 54).
No dose effect has been consistently found for CBZ exposure in pregnancy and outcome measured as child DQ or IQ (9, 18, 21-23, 30), however the NEAD study did demonstrate an association between increasing CBZ dose and motor abilities in three year old children (32).
2.2. Lamotrigine (LTG)
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Despite the widespread use of LTG in women of childbearing age (39), significantly limited data pertaining to the outcomes of children exposed to LTG with comparison to control children was available. In infancy, neurodevelopment was not found to differ in two studies (13, 17) and Veiby and colleagues(28) reported no parental concerns about the development of LTG exposed children at 6 or 18 months. In school-aged children where neurodevelopment was measured as IQ, no difference in ability was reported between those exposed to LTG and controls (22, 40).
When compared to other AEDs, children exposed to LTG were documented to have improved early development in comparison to those exposed to VPA and to be no different than those exposed to CBZ in utero (13, 17, 24); a pattern which is stable into the school aged years(22, 23). Meta analysis found the pooled IQ of children exposed to LTG to be comparable to that of children exposed to CBZ; although data was limited to 78 children exposed to CBZ and 84 exposed to LTG(9). Children exposed to LTG (n=84) were reported to have an improved IQ outcome when compared to children exposed to VPA (n=74) with the difference being around 10 points(9); although the data came from just two studies (22, 23). It is of note that Rihtman and colleagues(40) did not reproduce this discrepancy between LTG and VPA exposed children.
For specific cognitive skills, children exposed to LTG have been reported to be poorer on motor and sensory integration type tasks(40) and hand and eye coordination tasks in infancy when compared to control children(13). In the NEAD study however, children exposed to LTG were found to have significantly
8
improved non-verbal abilities in comparison to children exposed to VPA(23) but no control group was available for comparison. Language functioning was higher in the LTG exposed group than the VPA group in two studies(23, 29) but Veiby(28) noted parental concerns about sentence skills at 36 months. Adaptive behaviour and motor development in children exposed to LTG were noted to be superior to the children exposed to VPA (32, 33). The motor development of young infants were not significantly different (13, 28), however, Rihtman (40)reported reduced motor abilities. No association between LTG exposure in utero and an increased risk of neurodevelopmental disorders have been documented (37, 38), however, Veiby et al (28) noted increased parental concerns about autistic traits at 36 months. Baker and colleagues(22) did not find an increased rate of educational support in children exposed to LTG. Finally, neither the NEAD study (23, 24, 32) or the study by Baker et al (2015) found an association with dose, however, Rihtman et al (2013)(40) report an association between dose and reduced motor and sensory functions.
2.3. Levetiracetam (LEV)
There were only three published studies regarding the neurodevelopmental outcomes pertaining to children exposed to LEV in utero and they come from a single research group and involve a partial overlap in the reported cohorts. Under the age of two years the children exposed to LEV (n = 51) were not found to differ from children born to women without epilepsy (n = 97) for their early global neurodevelopment and specific areas of early development such as motor skills, early language skills and hand and eye coordination(41). In children aged
9
between three and four years of age exposure to LEV (n=53) was not associated with developmental outcome (32% of this group had been reported in the earlier publication(42)). This pattern of no effect continued when a group of children exposed to LEV (n=42) were assessed for IQ outcomes at school age in comparison to control children (n=55) (43). No effect of LEV exposure on memory, language or attention was also reported from this school aged cohort(43). No effect of dose was documented in these studies (41-43). This study series also compared the children exposed to LEV to children exposed to VPA and found improved levels of early and preschool development in the children exposed to LEV(41-43). No further comparisons were available and there was no data comparing the cognitive and neurodevelopmental outcome of children exposed to LEV in comparison to children exposed to other AEDs.
2.4. Phenobarbital (PB)
There was limited evidence from monotherapy PB exposure. Dean and colleagues(44) failed to find an increase in ‘developmental delay’ in 61 children exposed to PB; however no formal assessment of neurodevelopment was undertaken which undermines the sensitivity of this data. Leavitt et al (16) reported no difference in DQ scores in comparison to controls, but the number of PB exposed children was unclear. Data from the Kerala Pregnancy Register failed to find a significant difference between children exposed to PB (n = 41) and control children (n = 32) in infancy and again at school age (31, 45) but in middle childhood the children exposed to PB were noted to have poorer FSIQ levels (25).
10
Van der Pol (1994)(46) found specific learning difficulties around arithmetic and spelling in 13 PB monotherapy cases. Memory and attention abilities were assessed in one study but not reported separately from other AEDs(25). Studies by Reinish et al (1995)(47) and Dessens et al (2000)(48), although including monotherapy and polytherapy cases, found significant differences in the IQ and learning of adults with prenatal PB exposure and highlights the potential longer term impact of prenatal exposure. Little data was available pertaining to dose and an increased risk of neurodevelopmental outcomes, however, Dean et al (2002)(44) found no association.
2.5. Phenytoin (PHT)
Children prenatally exposed to PHT were demonstrated to have comparable global neurodevelopment, measured as DQ, to children born to control women when assessed in infancy (9, 15, 16, 31, 49). However, Scolnik et al (1994)(27) found poorer DQ scores in comparison to control children. In school aged children, those exposed to PHT were found to have comparable FSIQ, VIQ and PIQ to control children in the study by Adab and colleagues(20), which is consistent with others(25), however Vanoverloop et al (1992)(50) reported poorer IQ in comparison to control children; however this cohort included polytherapy PHT cases. The amount of data available regarding in utero exposure to monotherapy PHT was limited significantly by cohort size(9).
11
In comparison to other AEDs, children exposed to PHT were found to have increased neurodevelopment in comparison to children exposed to VPA, both in infancy(24) and at school age when skills were measured as IQ (23). Metaanalysis including data from the NEAD and other studies found that exposure to PHT (n=80) was associated with a higher level of development in infancy in comparison children exposed to VPA (n=108) with the mean difference being 7 DQ points but no significant difference was documented in comparison to children exposed to CBZ either in infancy or school age (9). Only a single study made comparisons to children exposed to PHT and no difference was reported in infancy or at school age (23, 24).
Investigation of specific cognitive skills such as memory, language and attentional skills is limited. There was evidence of poorer language skills in in comparison to control children (30), however, the school aged verbal abilities of children exposed to PHT surpassed those of the VPA exposed children in the NEAD study(23). Arulmozhi and colleagues(51), found exposure to PHT to be associated with poorer early motor milestones and which has been replicated in older pre-schoolers(14), but the NEAD study did not find poorer motor outcomes in comparison to CBZ or LTG (32). Adpative behaviour was not found to differ from controls and was not poorer than children exposed to CBZ and LTG and
The potential for a relationship between dose of PHT and poorer neurodevelopmental outcome was investigated by three studies (23, 24, 27, 30,32) and no dose response was documented.
12
2.6. Topiramate (TPM)
Investigations into the neurodevelopment of children exposed to TPM in utero are limited to two published studies(43, 52). Rihtman et al (2011)(52) demonstrated poorer IQ and other specific cognitive skills in nine children exposed to TPM prenatally. In contrast, Bromley et al (2016)(43) reported no significant difference between the IQ, memory, language or attentional abilities of 27 TPM exposed children in comparison to 55 control children, following the adjustment for key confounding variables. Only the more recent study made a comparison to children exposed to other AEDs and topiramate was not found to differ from the children exposed to LEV and were found to have a higher IQ than the children exposed to VPA(43). When dose was considered, there was no association between dose of TPM and poorer IQ and higher doses of TPM were reportedly associated with better outcomes when compared to higher doses of VPA (43).
2.7. Valproate (VPA)
There was relatively consistent evidence that VPA was associated with reduced neurodevelopmental outcomes from the reviewed evidence. In infancy the differences in developmental trajectory were already noticeable with infants scoring below their peers on measures of DQ following adjustment for confounding variables (13, 17, 41). Meta-analysis found that the mean DQ of children exposed to VPA (n=123) was 8 points lower in comparison to children
13
born to untreated women with epilepsy (n=58)(9). IQ in school aged children was also reported to be lower in comparison to that of control children following adjustment(20-22, 53), with meta-analysis finding a similar level of difference as that reported in the infant years both in comparison to general population controls and children born to women with untreated epilepsy(9). Rihtman and colleagues (2013)(40) and the small cohort by Thomas et al (2007)(45) failed to replicate this association however.
In comparison to other AEDs, children exposed to VPA have been associated with poorer outcomes in comparison to CBZ, both in infancy (13, 24) and at school age (21-23); although these differences may be clearer in the school aged years(9). Poorer outcomes are also reported in comparison to children exposed to LTG, LEV or PHT in infancy (13, 17, 24, 41, 42) and later in childhood (20, 22, 23, 43); although there is inconsistent data pertaining to the comparison to LTG at school age(40). Comparisons to children exposed to TPM are limited to a single study, however VPA remained associated with poorer outcomes (43).
The reduced outcomes for the children exposed to VPA in utero are more than DQ and FSIQ related. Poorer outcomes in terms of language functioning(28, 29, 44) have been reported as well as poorer attention, memory and executive functioning skills in comparison to children exposed to CBZ and LTG(23, 26). Poorer levels of adaptive behaviour are also noted for the children exposed to VPA(32-34). Increased diagnosis rates of neurodevelopmental disorders such as autistic spectrum disorder are also reported(20, 36-38, 44) and screening for social communication difficulties found higher levels of dysfunction the children
14
exposed to monotherapy or polytherapy VPA(54); which is consistent with reports of early social difficulties (32). Evidence of an increased need for educational support(22, 35) are to be expected given the magnitude and diversity of the reported impact on IQ.
DQ,
IQ,
language,
memory,
social
skills,
motor
development
and
neurodevelopmental disorders have all been associated with dose of VPA (13, 20-24, 29, 43). Baker et al (2015)(22) demonstrated that the risk to IQ associated with VPA exposure could be limited by reducing the dose of VPA to <800mg daily. Finally, higher doses of VPA were associated with poorer levels of IQ in comparison to higher doses of LEV or TPM(43) .
2.8. Other AEDs There is no published evidence pertaining to the neurodevelopmental outcomes of children exposed other AEDs.
2.9. Polytherapy The data reviewed above is regarding monotherapy however, this is not to say that polytherapy is not an important treatment option for women with epilepsy. The data however is severely limited when the need to consider specific polytherapy combinations. At a simple level there data suggests that outcomes for children exposed to polytherapy are poorer than for children exposed to monotherapy(16, 21, 25, 31). It is however likely that the picture is in fact much more complicated. Nadebaum et al (2011)(55) for example demonstrated that rather than polytherapy per se polytherapies containing VPA were associated
15
with significantly poorer outcomes which has been replicated(22) where following adjustment for confounding variables only polytherapy including VPA was associated with poorer IQ outcome in exposed children.
3. Current levels of evidence
Momentum has gathered published data is building an evidence base from which women and their doctors can make their treatment decisions. This topic still lags behind the study of major congenital malformations however. Methodological progress has been made though with the majority of recent research coming from prospective studies or studies utilising prospective cohorts from one of the national pregnancy registers. This more recent research frequently utilised standardised blinded assessments, employed a control group or made comparison to other AED exposures, analysed single AED groups, investigated potential dose relationships and made statistical adjustment for the influence of key confounding variables such as maternal IQ, socioeconomic status, gestational age at birth, age at assessment, child gender as well as maternal illness variables such as maternal epilepsy type (9, 17, 21-24, 26, 29, 31-34, 40-43, 54, 55). Such improvements in methodological rigour will be welcomed by previous critical appraisers of the area(56) and enhance the evidence base on which treatment decisions can be made. However, there remain substantial gaps in our knowledge, particularly so for LTG, LEV, TPM and other ‘newer’ AEDs. In order to demonstrate these gaps the available evidence is summarised by AED, age at follow up, neurodevelopmental area assessed and comparator group in Table 1 and provides a visual representation that current knowledge falls significantly
16
short of a comprehensive evidence base. References are provided for data pertaining to age or cognitive skill, however certain studies, particularly those which are longitudinal in nature, have more than one publication/reference and this table should not be taken to indicate that these publications from distinct cohorts. IQ assessments in LTG exposed children for example are only available from three studies, two of which have overlap in terms of their cohorts(22, 23). In particular, Table 1 highlights that the longer-term follow up of cohorts is missing. The development of the brain and the expansion of cognitive skills is dynamic and therefore assessment of exposed children in the teenage years when the complexity of cognitive abilities is greater is required to ensure that any and all potential risks are identified and it should be recognised that not all difficulties may be detectable in the infant years. Further, the majority of evidence reports DQ and FSIQ outcomes in isolation. These scores summarise cognitive functioning from a number of more specific skills. Therefore although a useful starting point global cognitive ability should not be the end point of research and should be followed by investigations into specific cognitive systems.
4. Summary and recommendations for the future
It is clear that the last two decades have resulted in advances in our knowledge of the neurodevelopmental effects of exposure to AEDs but there are further and significant amounts of work required to ensure a comprehensive evidence base
17
to advise clinicians and patients to ensure that the risks to the fetus are minimised whilst possible and maternal health is maximised.
The authors believe that the required advances in the field can be summarised as follows:
1. Research is required to investigate any risks to the neurodevelopment of the child or to establish relative safety following exposure to the ‘newer’ AEDs. 2. Further refinement regarding our knowledge of neurodevelopmental outcomes and neuropsychological profiles for children exposed to all AEDs is required. This includes the need for longer-term follow up into the teenage years. This will inform professionals who have in their services children who have been exposed to AEDs in utero. 3. Research is needed that identifies the impact of early intervention (e.g. Speech Therapy, Neuropsychology, Clinical Psychology and Occupational Therapy) for children exposed who have neurodevelopmental difficulties. Such research will be important to determine if the effects of exposure can be ameliorated with intensive interventions. 4. Investigations should also be focused on mechanisms through which the evidence base pertaining to neurodevelopmental outcomes can be generated in a more time sensitive manner to reduce the time between onset of medication use and the generation of first evidence followed by comprehensive evidence.
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5. Finally, research is required to elucidate a greater understanding of the underlying mechanisms that result in neurodevelopmental delay following exposure, which will include both genetic and neuroimaging investigations.
The completion of the above programme of research would mean that the epilepsy community could be confident that the risks of neurodevelopmental delay as a result of exposure to AEDs in utero could be minimised where possible. Further, where neurodevelopmental delay had occurred in the context of a prenatal exposure to AEDs clinician’s would feel that they have the knowledge and understanding of this impact in order to be able to recommend appropriate programmes with proven efficacy to maximise the child’s outcome. Such programmes are likely to represent a multidisciplinary approach that would involve a number of agencies and a number of clinical specialities (e.g Specialist Teaching, Speech Therapy, Neuropsychology, Educational Psychology and Occupational Health). Conflicts of interest: R.
Bromley
has
received
lecture
fees
from
Sanofi
Aventis
(two
occasions),received on one occasion conference travel support from UCB Pharma and a single consultancy fee. She has previously provided expert testimony pertaining to fetal anticonvulsant syndrome.
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G. Baker has received educational grants from Sanofi Aventis and UCB Pharma and lecture speaker fees from Sanofi Aventis, UCB Pharma and GSK and has given expert testimony on fetal anticonvulsant Syndrome. Funding: Dr Bromley is funded by the National Institute for Health Research (NIHR) (PDF2013-06-041).
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memory: Observations from a prospective cohort case control study. Epilepsy research. 2015;117:58-62. 26. Kantola-Sorsa E, Gaily E, Isoaho M, Korkman M. Neuropsychological outcomes in children of mothers with epilepsy. Journal of the International Neuropsychological Society. 2007;13(4):642-52. 27. Scolnik D, Nulman I, Rovet J, Gladstone D, Czuchta D, Gardner HA, et al. Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. 1994;271(10):767-70. 28. Veiby G, Daltveit AK, Schjolberg S, Stoltenberg C, Oyen AS, Vollset SE, et al. Exposure to antiepileptic drugs in utero and child development: a prospective population-based study. Epilepsia. 2013;54(8):1462-72. 29. Nadebaum C, Anderson V, Vajda F, Reutens D, Barton S, Wood A. Language skills of school-aged children prenatally exposed to antiepileptic drugs. Neurology. 2011;76(8):719-26. 30. Rovet J, Cole S, Nulman I, Scolnik D, Altmann D, Koren G. Effects of maternal epilepsy on children's neurodevelopment. Child Neuropsychology. 1995;1(2):150-7. 31. Thomas SV, Ajaykumar B, Sindhu K, Nair M, George B, Sarma P. Motor and mental development of infants exposed to antiepileptic drugs in utero. Epilepsy & Behavior. 2008;13(1):229-36. 32. Cohen MJ, Meador KJ, Browning N, Baker GA, Clayton-Smith J, Kalayjian LA, et al. Fetal antiepileptic drug exposure: motor, adaptive, and emotional/behavioral functioning at age 3 years. Epilepsy & Behavior. 2011;22(2):240-6. 33. Deshmukh U, Adams J, Macklin EA, Dhillon R, McCarthy KD, Dworetzky B, et al. Behavioral outcomes in children exposed prenatally to lamotrigine, valproate, or carbamazepine. Neurotoxicology and Teratology. 2016;54:5-14. 34. Vinten J, Bromley R, Taylor J, Adab N, Kini U, Baker G. The behavioral consequences of exposure to antiepileptic drugs in utero. Epilepsy & Behavior. 2009;14(1):197-201. 35. Adab N, Jacoby A, Smith D, Chadwick D. Additional educational needs in children born to mothers with epilepsy. Journal of neurology, neurosurgery, and psychiatry. 2001;70(1):15-21. 36. Rasalam A, Hailey H, Williams J, Moore S, Turnpenny P, Lloyd D, et al. Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Developmental Medicine & Child Neurology. 2005;47(8):551-5. 37. Bromley RL, Mawer GE, Briggs M, Cheyne C, Clayton-Smith J, Garcia-Finana M, et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. Journal of neurology, neurosurgery, and psychiatry. 2013;84(6):637-43. 38. Christensen J, Gronborg TK, Sorensen MJ, Schendel D, Parner ET, Pedersen LH, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309(16):1696-703. 39. Wen X, Meador KJ, Hartzema A. Antiepileptic drug use by pregnant women enrolled in Florida Medicaid. Neurology. 2015.3;84(9):944-950. 40. Rihtman T, Parush S, Ornoy A. Developmental outcomes at preschool age after fetal exposure to valproic acid and lamotrigine: cognitive, motor, sensory and behavioral function. Reproductive toxicology. 2013;41:115-25.
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41. Shallcross R, Bromley RL, Irwin B, Bonnett LJ, Morrow J, Baker GA, et al. Child development following in utero exposure: levetiracetam vs sodium valproate. Neurology. 2011;76(4):383-9. 42. Shallcross R, Bromley RL, Cheyne CP, Garcia-Finana M, Irwin B, Morrow J, et al. In utero exposure to levetiracetam vs valproate: development and language at 3 years of age. Neurology. 2014;82(3):213-21. 43. Bromley RL, Calderbank R, Cheyne CP, Rooney C, Trayner P, Clayton-Smith J, et al. Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate. Neurology. 2016. In Press. 44. Dean JCS, Hailey H, Moore SJ, Lloyd DJ, Turnpenny PD, Little J. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. Journal of medical genetics. 2002;39(4):251-9. 45. Thomas SV, Sukumaran S, Lukose N, George A, Sarma P. Intellectual and language functions in children of mothers with epilepsy. Epilepsia. 2007;48(12):2234-40. 46. van der Pol MC, Hadders-Algra M, Huisjes HJ, Touwen BC. Antiepileptic medication in pregnancy: late effects on the children's central nervous system development. American Journal of Obstetrics & Gynecology. 1991;164(1 Pt 1):121-8. 47. Reinisch JM, Sanders SA, Mortensen EL, Rubin DB. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA. 1995;274(19):1518-25. 48. Dessens AB, Cohen-Kettenis PT, Mellenbergh GJ, Koppe JG, van De Poll NE, Boer K. Association of prenatal phenobarbital and phenytoin exposure with small head size at birth and with learning problems. Acta Paediatrica. 2000;89(5):533-41. 49. Steinhausen HC, Losche G, Koch S, Helge H. The psychological development of children of epileptic parents. I. Study design and comparative findings: Acta Paediatrica, International Journal of Paediatrics. 1994;83(9):955-960. 50. Vanoverloop D, Schnell RR, Harvey EA, Holmes LB. The effects of prenatal exposure to phenytoin and other anticonvulsants on intellectual function at 4 to 8 years of age. Neurotoxicology & Teratology. 1992;14(5):329-335. 51. Arulmozhi T, Dhanaraj M, Rangaraj R, Vengatesan A. Physical growth and psychomotor development of infants exposed to antiepileptic drugs in utero. Neurology India. 2006;54(1):42-46. 52. Rihtman T, Parush S, Ornoy A. Preliminary findings of the developmental effects of in utero exposure to topiramate. Reproductive toxicology. 2012;34(3):308311. 53. Eriksson K, Viinikainen K, Monkkonen A, Aikia M, Nieminen P, Heinonen S, et al. Children exposed to valproate in utero--population based evaluation of risks and confounding factors for long-term neurocognitive development. Epilepsy research. 2005;65(3):189-200. 54. Wood AG, Nadebaum C, Anderson V, Reutens D, Barton S, O'Brien TJ, et al. Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy. Epilepsia. 2015;56(7):1047-55. 55. Nadebaum C, Anderson V, Vajda F, Reutens D, Barton S, Wood A. The Australian brain and cognition and antiepileptic drugs study: IQ in school-aged children exposed to sodium valproate and polytherapy. Journal of the International Neuropsychological Society. 2011;17(1):133-42.
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56. Nicolai J, Vles JSH, Aldenkamp AP. Neurodevelopmental delay in children exposed to antiepileptic drugs in utero: A critical review directed at structural studybias: Journal of the Neurological Sciences. 2008;271(1-2):1-14. 57. Titze K, Koch S, Helge H, Lehmkuhl U, Rauh H, Steinhausen H-C. Prenatal and family risks of children born to mothers with epilepsy: effects on cognitive development. Developmental Medicine & Child Neurology. 2008;50(2):117-22.
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Table 1. Literature pertaining to the neurodevelopmental outcomes of children exposed to AEDs by age and investigation type.
20, 2125, 45, 53, 57
23, 26
22, 23, 29, 37, 38
-
13, 17
22-24, 40
23
43
-
41, 42
43
16,31
NDD
13-18, 27, 31, 49
Adaptive Behaviour
20, 35, 57, 44
Motor
20-23, 25, 26, 29, 3335, 37,38, 44-46, 53)
Rating *
Executive functioning
13-18, 24, 27, 28, 3033, 44
Language
Attention & memory
IQ
Adolescence / adulthood
DQ
Lamotrigine
2, 5, 8, 10, 13, 18, 2025, 27,29, 31-34, 37, 44, 45, 54 13, 22-24, 29, 32-34, 37, 40
School age
Carbamazepine
Neurodevelopmental outcomes^ $
Pre-school
Dose
Age±
13, 14, 23, 26, 28-30, 33, 34, 44, 45 13, 23, 28, 29, 32
23, 26
13,14, 16,18, 28, 3133, 51
32-34
20, 28,32, 3638,44 54
Adequate
23
13, 28, 32, 40
32, 33
28,37, 38
Limited
43
41-43
43
41, 42
-
-
Substantially limited
-
45
-
16,
-
44
23
14, 23, 30, 32, 44, 45
23
14, 31, 51
32, 34
20,44
Limited
Substantially limited Adequate
Levetiracetam
41-43
13, 17, 24, 28, 32, 33, 40 41, 42
Phenobarbital
25, 31, 44, 45
16,22, 31, 44
25, 44, 45,46
44, 48
Phenytoin
20, 23-25, 27, 31, 32, 44, 45
20, 23, 25, 34, 44, 45, 50
57
14-16, 27, 31, 49
Topiramate
43
14, 15, 16, 24, 27, 3032, 44, 50, 51 52
25, 45, 47, 48, 57 20, 2325, 45, 50,57
43
-
-
43,52
43
43
43
52
-
-
Valproate
8, 9, 13, 14, 15, 20-25, 29, 31-33, 35, 37, 39, 40-46, 48, 51, 53, 54, 57
13, 17, 24, 28, 31-33, 40-42, 44
20,21-23, 25, 26, 29, 34, 37, 38, 43-45, 53, 55
44, 57
13, 17, 31, 41, 42
20-25, 40, 43, 45, 5355, 57
23, 26,43
13, 23, 26, 28, 29, 32, 33, 4143, 45
23, 26,43
13, 28, 31-34, 40-42
32-34
20,28, 32, 3638, 44, 54
47,
20,
16, 32,
* Rating Key: Comprehensive – Data is available from more than one well designed and adequately powered cohort, comparing to controls and to other AEDs, across all key neurodevelopmental areas and with clear outcomes pertaining to dose association or a lack there of. Adequate– Data is available from more than one well designed and adequately powered cohort, at each age/time point, across DQ/ IQ and other but25not all
neurodevelopmental areas, with clear outcomes pertaining to dose association or a lack there of. Limited - Data is available from only one well designed and adequately powered cohort, at each age/time point, across DQ/ IQ and other but not all neurodevelopmental areas and there is no consistent evidence pertaining to dose associated effects. Substantially limited - Data is available from a small number of studies, with small cohorts, across one or two of the key neurodevelopmental areas with no consistent evidence pertaining to dose associated effects as yet.
Key: + One cohort may span all age groups but may not provide data analysed by age group. ^ studies referenced only if they reported this data by individual AED type and publications may refer to multiple observations from the same cohort. $- studies may not be adequately powered. NDD – neurodevelopmental disorder; DQ – developmental quotient; IQ – intelligence quotient.
26
S1059-1311(16)30174-1 http://dx.doi.org/doi:10.1016/j.seizure.2016.10.006 YSEIZ 2807
To appear in:
Seizure
Received date: Accepted date:
17-9-2016 3-10-2016
Please cite this article as: Bromley Rebecca L, Baker Gus A.Fetal antiepileptic drug exposure and cognitive outcomes.SEIZURE: European Journal of Epilepsy http://dx.doi.org/10.1016/j.seizure.2016.10.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Fetal antiepileptic drug exposure and cognitive outcomes
Rebecca L. Bromley1,2 & Gus A. Baker3
1 Division of
Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health,
University of Manchester, UK. 2
Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS
Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. 3
Department of Molecular and Clinical Pharmacology, University of Liverpool, UK
Correspondence to:[email protected].
1
Abstract
Purpose: Data highlighting valproate as a human teratogen put in context the need to balance both maternal and fetal needs; maximising maternal health whilst minimising fetal risk. This led to increased research efforts to understand the associated risks with AED treatments. Methods: A review of currently published literature was undertaken. Results: In utero exposure to valproate was associated with a range of poorer neurodevelopmental outcomes when compared to control children and children exposed to other AEDs. Children exposed to carbamazepine were not found by the majority of studies to have poorer early development, although there is a lack of evidence regarding specific cognitive skills later in childhood and adolescence. Research regarding lamotrigine is limited to a small number of studies but suggests early global development or school aged IQ does not differ from control children, but less is known about specific cognitive skills. Evidence for the other AEDs including levetiracetam and topiramate were significantly limited. Conclusions: Despite an improvement in momentum the evidence remains incomplete for neurodevelopmental outcomes and this limits the evidence-based decision making. Further efforts are required to enhance the treatment of women by giving them the confidence that both the risks and the benefits of commonly used AEDs are known. Future research should also seek to increase our understanding of the children who experience neurodevelopmental
2
difficulties in the context of exposure in the womb to AEDs and what interventions may be successful in maximising the outcome of these children.
Keywords: Epilepsy, Neurodevelopment
Pregnancy,
In
Utero,
Antiepileptic
Drugs,
1. Introduction
The treatment of women with epilepsy in the potential childbearing years has received increasing focus over the last decade. Data highlighting valproate as a human teratogen put in context the need to balance both maternal and fetal needs; maximising maternal health whilst minimising fetal risk. This finding led to increased research efforts to understand the possible risks associated with AED treatments. Whilst there have been improvements in the level of evidence there are still significant limitations to our current knowledge. The establishment of pregnancy registers (1-3) increased the speed at which information on congenital malformations was generated, however investigations into the neurodevelopmental outcomes of children exposed to antiepileptic drugs (AEDs) continues to lag behind.
In utero exposure to valproate (VPA) is linked to an increase in diverse major congenital malformations including spina bifida, cardiac and skeletal malformations (4, 5). Carbamazepine (CBZ) too has a reported association with spina bifida and cardiac malformations, although to a lesser extent than VPA (4, 5). An association with specific malformation types has been reported for
3
topiramate (TPM) and phenobarbital (PB); for cleft malformations and cardiac malformations respectively (3, 4, 6). Phenytoin (PHT) has been shown to be associated with an increased risk of major congenital malformation, although the exact malformation types increased following exposure are less clear(4). A previous, finding linking lamotrigine (LTG) exposure to oral clefts has not been upheld by increasing data (3); however dose of LTG may be an important consideration(7). To date levetiracetam (LEV) exposure is has not been found to be associated with an increased risk in major congenital malformations (1-3); however cohort numbers are relatively small and little is known about a potential association with specific malformation types (4). Therefore there are known risks to the physical development of the fetus from certain AEDs. The period of organogenesis spans the first 12 weeks of gestation and after this time, exposure to a teratogen cannot induce a major structural malformation (8). The brain however, continues its development throughout the entire period of gestation (and beyond) thereby opening it up to a longer period of susceptibility to teratogens(8). The available data regarding neurodevelopmental outcomes following exposure is substantially less for all AEDs (9), despite this extended period of susceptibility and the lifelong significance of the potential deficits. Early case reports of children with a major congenital malformations following prenatal exposure often reported neurodevelopmental difficulties (10-12), however it took until the turn of the century to see an increased interest on neurodevelopment as a primary outcome. Reasons for this delay are complex but are hypothesized to include; longer follow up time, specialist assessment and the financial resource requirement such follow up requires. The brain is a complex organ and its functional outputs are diverse. The trajectory of neurodevelopment
4
is dynamic across childhood with rapid phases of increase skill acquisition. This complex and dynamic nature of neurodevelopment poses additional challenges to the creation of a comprehensive evidence base. This invited paper reviews the data currently available on the neurodevelopmental outcomes for each of the more commonly used AEDs. A discussion is then undertaken regarding the limitations within this current knowledge base and proposals for future progress are outlined.
2. Review of the available studies
2.1. Carbamazepine (CBZ)
Children exposed to CBZ have in the main not been found to be at risk of global neurodevelopmental difficulties when assessed in infancy in comparison to control children, (13-16). However, two studies demonstrated poorer neurodevelopmental outcome (17, 18) as did one meta-analysis study (9). Of note, Ornoy and Cohen (1996)(18) found poorer infant development in children exposed to CBZ who displayed dysmorphic features; an association which was not replicated (19). At school age when the intelligence quotient (IQ) and other cognitive skills being measured are more complex the picture is unclear. Adab et al (20) and Gaily et al(21) failed to find an association between exposure to CBZ and reduced global IQ (FSIQ), verbal IQ (VIQ) or performance/non-verbal IQ (PIQ) in comparison to control children. However, data from two linked studies (22, 23) documented vulnerability in the VIQ domain following CBZ exposure. However, a meta-analysis study of prospective studies, reported no significant
5
differences in ability for children exposed to CBZ in comparison to children born to women without epilepsy in terms of their VIQ(9). A similar conclusion was reported with regards to FSIQ both in comparison to women without epilepsy and also children of women with untreated epilepsy(9).
In comparison to other AEDs, meta-analysis regarding the early development of children exposed to CBZ (n=210) in comparison to those exposed to VPA (n=160) failed to find a difference(9). However, IQ outcomes in the children exposed to CBZ (n=191) in comparison to those exposed to VPA (n=112) demonstrated a nine-point difference in the mean scores favouring the CBZ exposed children(9); highlighting that differences in neurodevelopment may not become apparent until later in childhood. CBZ was not found to be associated with poorer outcomes in comparison to PHT when the outcome being assessed was DQ or IQ (9, 14, 15, 20) and in comparison to LTG, there was no evidence of a difference between neurodevelopment in infancy or at school age (9, 13, 2224).
Neurodevelopment is more than simply early global development (referred to as the developmental quotient (DQ)) or IQ. The functioning of the memory, language, attentional, executive systems as well as motor skills are critical for good outcomes in childhood. The available evidence is more limited particularly for skills such as memory and attention. Gopinath et al (25)and Kantola Sorsa and colleagues (26) investigated the memory and attentional abilities of children exposed to CBZ, however the results were not reported independently from other AED exposures. Language skills of children exposed to CBZ were reported
6
not to differ from control children (13, 27-29) with one exception(30), and five studies have failed to find poorer motor outcomes (13, 14, 18, 28, 31). However, data from the NEAD study showed a dose-dependent association between CBZ and poorer motor skill outcome at three years of age (32) and Veiby (28) documented increased parental concern about fine motor skills at 18 but not 36 months. Adaptive behaviour skills such as communication, daily living and socialisation skills were reported not to be associated with CBZ exposure in school aged children (33, 34) but, Cohen found poorer adaptive behaviour to be associated with increasing dose of CBZ in younger children(32). The adaptive behaviour of children exposed to CBZ is reported to be higher than the children exposed to VPA and not significantly different from the children exposed to LTG (32, 33). Children exposed to CBZ have not been found to require significantly increased levels of educational support (22, 35) and three studies have failed to find an association between prenatal exposure to CBZ and an increased risk of autistic spectrum disorder (36-38, 54).
No dose effect has been consistently found for CBZ exposure in pregnancy and outcome measured as child DQ or IQ (9, 18, 21-23, 30), however the NEAD study did demonstrate an association between increasing CBZ dose and motor abilities in three year old children (32).
2.2. Lamotrigine (LTG)
7
Despite the widespread use of LTG in women of childbearing age (39), significantly limited data pertaining to the outcomes of children exposed to LTG with comparison to control children was available. In infancy, neurodevelopment was not found to differ in two studies (13, 17) and Veiby and colleagues(28) reported no parental concerns about the development of LTG exposed children at 6 or 18 months. In school-aged children where neurodevelopment was measured as IQ, no difference in ability was reported between those exposed to LTG and controls (22, 40).
When compared to other AEDs, children exposed to LTG were documented to have improved early development in comparison to those exposed to VPA and to be no different than those exposed to CBZ in utero (13, 17, 24); a pattern which is stable into the school aged years(22, 23). Meta analysis found the pooled IQ of children exposed to LTG to be comparable to that of children exposed to CBZ; although data was limited to 78 children exposed to CBZ and 84 exposed to LTG(9). Children exposed to LTG (n=84) were reported to have an improved IQ outcome when compared to children exposed to VPA (n=74) with the difference being around 10 points(9); although the data came from just two studies (22, 23). It is of note that Rihtman and colleagues(40) did not reproduce this discrepancy between LTG and VPA exposed children.
For specific cognitive skills, children exposed to LTG have been reported to be poorer on motor and sensory integration type tasks(40) and hand and eye coordination tasks in infancy when compared to control children(13). In the NEAD study however, children exposed to LTG were found to have significantly
8
improved non-verbal abilities in comparison to children exposed to VPA(23) but no control group was available for comparison. Language functioning was higher in the LTG exposed group than the VPA group in two studies(23, 29) but Veiby(28) noted parental concerns about sentence skills at 36 months. Adaptive behaviour and motor development in children exposed to LTG were noted to be superior to the children exposed to VPA (32, 33). The motor development of young infants were not significantly different (13, 28), however, Rihtman (40)reported reduced motor abilities. No association between LTG exposure in utero and an increased risk of neurodevelopmental disorders have been documented (37, 38), however, Veiby et al (28) noted increased parental concerns about autistic traits at 36 months. Baker and colleagues(22) did not find an increased rate of educational support in children exposed to LTG. Finally, neither the NEAD study (23, 24, 32) or the study by Baker et al (2015) found an association with dose, however, Rihtman et al (2013)(40) report an association between dose and reduced motor and sensory functions.
2.3. Levetiracetam (LEV)
There were only three published studies regarding the neurodevelopmental outcomes pertaining to children exposed to LEV in utero and they come from a single research group and involve a partial overlap in the reported cohorts. Under the age of two years the children exposed to LEV (n = 51) were not found to differ from children born to women without epilepsy (n = 97) for their early global neurodevelopment and specific areas of early development such as motor skills, early language skills and hand and eye coordination(41). In children aged
9
between three and four years of age exposure to LEV (n=53) was not associated with developmental outcome (32% of this group had been reported in the earlier publication(42)). This pattern of no effect continued when a group of children exposed to LEV (n=42) were assessed for IQ outcomes at school age in comparison to control children (n=55) (43). No effect of LEV exposure on memory, language or attention was also reported from this school aged cohort(43). No effect of dose was documented in these studies (41-43). This study series also compared the children exposed to LEV to children exposed to VPA and found improved levels of early and preschool development in the children exposed to LEV(41-43). No further comparisons were available and there was no data comparing the cognitive and neurodevelopmental outcome of children exposed to LEV in comparison to children exposed to other AEDs.
2.4. Phenobarbital (PB)
There was limited evidence from monotherapy PB exposure. Dean and colleagues(44) failed to find an increase in ‘developmental delay’ in 61 children exposed to PB; however no formal assessment of neurodevelopment was undertaken which undermines the sensitivity of this data. Leavitt et al (16) reported no difference in DQ scores in comparison to controls, but the number of PB exposed children was unclear. Data from the Kerala Pregnancy Register failed to find a significant difference between children exposed to PB (n = 41) and control children (n = 32) in infancy and again at school age (31, 45) but in middle childhood the children exposed to PB were noted to have poorer FSIQ levels (25).
10
Van der Pol (1994)(46) found specific learning difficulties around arithmetic and spelling in 13 PB monotherapy cases. Memory and attention abilities were assessed in one study but not reported separately from other AEDs(25). Studies by Reinish et al (1995)(47) and Dessens et al (2000)(48), although including monotherapy and polytherapy cases, found significant differences in the IQ and learning of adults with prenatal PB exposure and highlights the potential longer term impact of prenatal exposure. Little data was available pertaining to dose and an increased risk of neurodevelopmental outcomes, however, Dean et al (2002)(44) found no association.
2.5. Phenytoin (PHT)
Children prenatally exposed to PHT were demonstrated to have comparable global neurodevelopment, measured as DQ, to children born to control women when assessed in infancy (9, 15, 16, 31, 49). However, Scolnik et al (1994)(27) found poorer DQ scores in comparison to control children. In school aged children, those exposed to PHT were found to have comparable FSIQ, VIQ and PIQ to control children in the study by Adab and colleagues(20), which is consistent with others(25), however Vanoverloop et al (1992)(50) reported poorer IQ in comparison to control children; however this cohort included polytherapy PHT cases. The amount of data available regarding in utero exposure to monotherapy PHT was limited significantly by cohort size(9).
11
In comparison to other AEDs, children exposed to PHT were found to have increased neurodevelopment in comparison to children exposed to VPA, both in infancy(24) and at school age when skills were measured as IQ (23). Metaanalysis including data from the NEAD and other studies found that exposure to PHT (n=80) was associated with a higher level of development in infancy in comparison children exposed to VPA (n=108) with the mean difference being 7 DQ points but no significant difference was documented in comparison to children exposed to CBZ either in infancy or school age (9). Only a single study made comparisons to children exposed to PHT and no difference was reported in infancy or at school age (23, 24).
Investigation of specific cognitive skills such as memory, language and attentional skills is limited. There was evidence of poorer language skills in in comparison to control children (30), however, the school aged verbal abilities of children exposed to PHT surpassed those of the VPA exposed children in the NEAD study(23). Arulmozhi and colleagues(51), found exposure to PHT to be associated with poorer early motor milestones and which has been replicated in older pre-schoolers(14), but the NEAD study did not find poorer motor outcomes in comparison to CBZ or LTG (32). Adpative behaviour was not found to differ from controls and was not poorer than children exposed to CBZ and LTG and
The potential for a relationship between dose of PHT and poorer neurodevelopmental outcome was investigated by three studies (23, 24, 27, 30,32) and no dose response was documented.
12
2.6. Topiramate (TPM)
Investigations into the neurodevelopment of children exposed to TPM in utero are limited to two published studies(43, 52). Rihtman et al (2011)(52) demonstrated poorer IQ and other specific cognitive skills in nine children exposed to TPM prenatally. In contrast, Bromley et al (2016)(43) reported no significant difference between the IQ, memory, language or attentional abilities of 27 TPM exposed children in comparison to 55 control children, following the adjustment for key confounding variables. Only the more recent study made a comparison to children exposed to other AEDs and topiramate was not found to differ from the children exposed to LEV and were found to have a higher IQ than the children exposed to VPA(43). When dose was considered, there was no association between dose of TPM and poorer IQ and higher doses of TPM were reportedly associated with better outcomes when compared to higher doses of VPA (43).
2.7. Valproate (VPA)
There was relatively consistent evidence that VPA was associated with reduced neurodevelopmental outcomes from the reviewed evidence. In infancy the differences in developmental trajectory were already noticeable with infants scoring below their peers on measures of DQ following adjustment for confounding variables (13, 17, 41). Meta-analysis found that the mean DQ of children exposed to VPA (n=123) was 8 points lower in comparison to children
13
born to untreated women with epilepsy (n=58)(9). IQ in school aged children was also reported to be lower in comparison to that of control children following adjustment(20-22, 53), with meta-analysis finding a similar level of difference as that reported in the infant years both in comparison to general population controls and children born to women with untreated epilepsy(9). Rihtman and colleagues (2013)(40) and the small cohort by Thomas et al (2007)(45) failed to replicate this association however.
In comparison to other AEDs, children exposed to VPA have been associated with poorer outcomes in comparison to CBZ, both in infancy (13, 24) and at school age (21-23); although these differences may be clearer in the school aged years(9). Poorer outcomes are also reported in comparison to children exposed to LTG, LEV or PHT in infancy (13, 17, 24, 41, 42) and later in childhood (20, 22, 23, 43); although there is inconsistent data pertaining to the comparison to LTG at school age(40). Comparisons to children exposed to TPM are limited to a single study, however VPA remained associated with poorer outcomes (43).
The reduced outcomes for the children exposed to VPA in utero are more than DQ and FSIQ related. Poorer outcomes in terms of language functioning(28, 29, 44) have been reported as well as poorer attention, memory and executive functioning skills in comparison to children exposed to CBZ and LTG(23, 26). Poorer levels of adaptive behaviour are also noted for the children exposed to VPA(32-34). Increased diagnosis rates of neurodevelopmental disorders such as autistic spectrum disorder are also reported(20, 36-38, 44) and screening for social communication difficulties found higher levels of dysfunction the children
14
exposed to monotherapy or polytherapy VPA(54); which is consistent with reports of early social difficulties (32). Evidence of an increased need for educational support(22, 35) are to be expected given the magnitude and diversity of the reported impact on IQ.
DQ,
IQ,
language,
memory,
social
skills,
motor
development
and
neurodevelopmental disorders have all been associated with dose of VPA (13, 20-24, 29, 43). Baker et al (2015)(22) demonstrated that the risk to IQ associated with VPA exposure could be limited by reducing the dose of VPA to <800mg daily. Finally, higher doses of VPA were associated with poorer levels of IQ in comparison to higher doses of LEV or TPM(43) .
2.8. Other AEDs There is no published evidence pertaining to the neurodevelopmental outcomes of children exposed other AEDs.
2.9. Polytherapy The data reviewed above is regarding monotherapy however, this is not to say that polytherapy is not an important treatment option for women with epilepsy. The data however is severely limited when the need to consider specific polytherapy combinations. At a simple level there data suggests that outcomes for children exposed to polytherapy are poorer than for children exposed to monotherapy(16, 21, 25, 31). It is however likely that the picture is in fact much more complicated. Nadebaum et al (2011)(55) for example demonstrated that rather than polytherapy per se polytherapies containing VPA were associated
15
with significantly poorer outcomes which has been replicated(22) where following adjustment for confounding variables only polytherapy including VPA was associated with poorer IQ outcome in exposed children.
3. Current levels of evidence
Momentum has gathered published data is building an evidence base from which women and their doctors can make their treatment decisions. This topic still lags behind the study of major congenital malformations however. Methodological progress has been made though with the majority of recent research coming from prospective studies or studies utilising prospective cohorts from one of the national pregnancy registers. This more recent research frequently utilised standardised blinded assessments, employed a control group or made comparison to other AED exposures, analysed single AED groups, investigated potential dose relationships and made statistical adjustment for the influence of key confounding variables such as maternal IQ, socioeconomic status, gestational age at birth, age at assessment, child gender as well as maternal illness variables such as maternal epilepsy type (9, 17, 21-24, 26, 29, 31-34, 40-43, 54, 55). Such improvements in methodological rigour will be welcomed by previous critical appraisers of the area(56) and enhance the evidence base on which treatment decisions can be made. However, there remain substantial gaps in our knowledge, particularly so for LTG, LEV, TPM and other ‘newer’ AEDs. In order to demonstrate these gaps the available evidence is summarised by AED, age at follow up, neurodevelopmental area assessed and comparator group in Table 1 and provides a visual representation that current knowledge falls significantly
16
short of a comprehensive evidence base. References are provided for data pertaining to age or cognitive skill, however certain studies, particularly those which are longitudinal in nature, have more than one publication/reference and this table should not be taken to indicate that these publications from distinct cohorts. IQ assessments in LTG exposed children for example are only available from three studies, two of which have overlap in terms of their cohorts(22, 23). In particular, Table 1 highlights that the longer-term follow up of cohorts is missing. The development of the brain and the expansion of cognitive skills is dynamic and therefore assessment of exposed children in the teenage years when the complexity of cognitive abilities is greater is required to ensure that any and all potential risks are identified and it should be recognised that not all difficulties may be detectable in the infant years. Further, the majority of evidence reports DQ and FSIQ outcomes in isolation. These scores summarise cognitive functioning from a number of more specific skills. Therefore although a useful starting point global cognitive ability should not be the end point of research and should be followed by investigations into specific cognitive systems.
4. Summary and recommendations for the future
It is clear that the last two decades have resulted in advances in our knowledge of the neurodevelopmental effects of exposure to AEDs but there are further and significant amounts of work required to ensure a comprehensive evidence base
17
to advise clinicians and patients to ensure that the risks to the fetus are minimised whilst possible and maternal health is maximised.
The authors believe that the required advances in the field can be summarised as follows:
1. Research is required to investigate any risks to the neurodevelopment of the child or to establish relative safety following exposure to the ‘newer’ AEDs. 2. Further refinement regarding our knowledge of neurodevelopmental outcomes and neuropsychological profiles for children exposed to all AEDs is required. This includes the need for longer-term follow up into the teenage years. This will inform professionals who have in their services children who have been exposed to AEDs in utero. 3. Research is needed that identifies the impact of early intervention (e.g. Speech Therapy, Neuropsychology, Clinical Psychology and Occupational Therapy) for children exposed who have neurodevelopmental difficulties. Such research will be important to determine if the effects of exposure can be ameliorated with intensive interventions. 4. Investigations should also be focused on mechanisms through which the evidence base pertaining to neurodevelopmental outcomes can be generated in a more time sensitive manner to reduce the time between onset of medication use and the generation of first evidence followed by comprehensive evidence.
18
5. Finally, research is required to elucidate a greater understanding of the underlying mechanisms that result in neurodevelopmental delay following exposure, which will include both genetic and neuroimaging investigations.
The completion of the above programme of research would mean that the epilepsy community could be confident that the risks of neurodevelopmental delay as a result of exposure to AEDs in utero could be minimised where possible. Further, where neurodevelopmental delay had occurred in the context of a prenatal exposure to AEDs clinician’s would feel that they have the knowledge and understanding of this impact in order to be able to recommend appropriate programmes with proven efficacy to maximise the child’s outcome. Such programmes are likely to represent a multidisciplinary approach that would involve a number of agencies and a number of clinical specialities (e.g Specialist Teaching, Speech Therapy, Neuropsychology, Educational Psychology and Occupational Health). Conflicts of interest: R.
Bromley
has
received
lecture
fees
from
Sanofi
Aventis
(two
occasions),received on one occasion conference travel support from UCB Pharma and a single consultancy fee. She has previously provided expert testimony pertaining to fetal anticonvulsant syndrome.
19
G. Baker has received educational grants from Sanofi Aventis and UCB Pharma and lecture speaker fees from Sanofi Aventis, UCB Pharma and GSK and has given expert testimony on fetal anticonvulsant Syndrome. Funding: Dr Bromley is funded by the National Institute for Health Research (NIHR) (PDF2013-06-041).
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memory: Observations from a prospective cohort case control study. Epilepsy research. 2015;117:58-62. 26. Kantola-Sorsa E, Gaily E, Isoaho M, Korkman M. Neuropsychological outcomes in children of mothers with epilepsy. Journal of the International Neuropsychological Society. 2007;13(4):642-52. 27. Scolnik D, Nulman I, Rovet J, Gladstone D, Czuchta D, Gardner HA, et al. Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. 1994;271(10):767-70. 28. Veiby G, Daltveit AK, Schjolberg S, Stoltenberg C, Oyen AS, Vollset SE, et al. Exposure to antiepileptic drugs in utero and child development: a prospective population-based study. Epilepsia. 2013;54(8):1462-72. 29. Nadebaum C, Anderson V, Vajda F, Reutens D, Barton S, Wood A. Language skills of school-aged children prenatally exposed to antiepileptic drugs. Neurology. 2011;76(8):719-26. 30. Rovet J, Cole S, Nulman I, Scolnik D, Altmann D, Koren G. Effects of maternal epilepsy on children's neurodevelopment. Child Neuropsychology. 1995;1(2):150-7. 31. Thomas SV, Ajaykumar B, Sindhu K, Nair M, George B, Sarma P. Motor and mental development of infants exposed to antiepileptic drugs in utero. Epilepsy & Behavior. 2008;13(1):229-36. 32. Cohen MJ, Meador KJ, Browning N, Baker GA, Clayton-Smith J, Kalayjian LA, et al. Fetal antiepileptic drug exposure: motor, adaptive, and emotional/behavioral functioning at age 3 years. Epilepsy & Behavior. 2011;22(2):240-6. 33. Deshmukh U, Adams J, Macklin EA, Dhillon R, McCarthy KD, Dworetzky B, et al. Behavioral outcomes in children exposed prenatally to lamotrigine, valproate, or carbamazepine. Neurotoxicology and Teratology. 2016;54:5-14. 34. Vinten J, Bromley R, Taylor J, Adab N, Kini U, Baker G. The behavioral consequences of exposure to antiepileptic drugs in utero. Epilepsy & Behavior. 2009;14(1):197-201. 35. Adab N, Jacoby A, Smith D, Chadwick D. Additional educational needs in children born to mothers with epilepsy. Journal of neurology, neurosurgery, and psychiatry. 2001;70(1):15-21. 36. Rasalam A, Hailey H, Williams J, Moore S, Turnpenny P, Lloyd D, et al. Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Developmental Medicine & Child Neurology. 2005;47(8):551-5. 37. Bromley RL, Mawer GE, Briggs M, Cheyne C, Clayton-Smith J, Garcia-Finana M, et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. Journal of neurology, neurosurgery, and psychiatry. 2013;84(6):637-43. 38. Christensen J, Gronborg TK, Sorensen MJ, Schendel D, Parner ET, Pedersen LH, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309(16):1696-703. 39. Wen X, Meador KJ, Hartzema A. Antiepileptic drug use by pregnant women enrolled in Florida Medicaid. Neurology. 2015.3;84(9):944-950. 40. Rihtman T, Parush S, Ornoy A. Developmental outcomes at preschool age after fetal exposure to valproic acid and lamotrigine: cognitive, motor, sensory and behavioral function. Reproductive toxicology. 2013;41:115-25.
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41. Shallcross R, Bromley RL, Irwin B, Bonnett LJ, Morrow J, Baker GA, et al. Child development following in utero exposure: levetiracetam vs sodium valproate. Neurology. 2011;76(4):383-9. 42. Shallcross R, Bromley RL, Cheyne CP, Garcia-Finana M, Irwin B, Morrow J, et al. In utero exposure to levetiracetam vs valproate: development and language at 3 years of age. Neurology. 2014;82(3):213-21. 43. Bromley RL, Calderbank R, Cheyne CP, Rooney C, Trayner P, Clayton-Smith J, et al. Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate. Neurology. 2016. In Press. 44. Dean JCS, Hailey H, Moore SJ, Lloyd DJ, Turnpenny PD, Little J. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. Journal of medical genetics. 2002;39(4):251-9. 45. Thomas SV, Sukumaran S, Lukose N, George A, Sarma P. Intellectual and language functions in children of mothers with epilepsy. Epilepsia. 2007;48(12):2234-40. 46. van der Pol MC, Hadders-Algra M, Huisjes HJ, Touwen BC. Antiepileptic medication in pregnancy: late effects on the children's central nervous system development. American Journal of Obstetrics & Gynecology. 1991;164(1 Pt 1):121-8. 47. Reinisch JM, Sanders SA, Mortensen EL, Rubin DB. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA. 1995;274(19):1518-25. 48. Dessens AB, Cohen-Kettenis PT, Mellenbergh GJ, Koppe JG, van De Poll NE, Boer K. Association of prenatal phenobarbital and phenytoin exposure with small head size at birth and with learning problems. Acta Paediatrica. 2000;89(5):533-41. 49. Steinhausen HC, Losche G, Koch S, Helge H. The psychological development of children of epileptic parents. I. Study design and comparative findings: Acta Paediatrica, International Journal of Paediatrics. 1994;83(9):955-960. 50. Vanoverloop D, Schnell RR, Harvey EA, Holmes LB. The effects of prenatal exposure to phenytoin and other anticonvulsants on intellectual function at 4 to 8 years of age. Neurotoxicology & Teratology. 1992;14(5):329-335. 51. Arulmozhi T, Dhanaraj M, Rangaraj R, Vengatesan A. Physical growth and psychomotor development of infants exposed to antiepileptic drugs in utero. Neurology India. 2006;54(1):42-46. 52. Rihtman T, Parush S, Ornoy A. Preliminary findings of the developmental effects of in utero exposure to topiramate. Reproductive toxicology. 2012;34(3):308311. 53. Eriksson K, Viinikainen K, Monkkonen A, Aikia M, Nieminen P, Heinonen S, et al. Children exposed to valproate in utero--population based evaluation of risks and confounding factors for long-term neurocognitive development. Epilepsy research. 2005;65(3):189-200. 54. Wood AG, Nadebaum C, Anderson V, Reutens D, Barton S, O'Brien TJ, et al. Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy. Epilepsia. 2015;56(7):1047-55. 55. Nadebaum C, Anderson V, Vajda F, Reutens D, Barton S, Wood A. The Australian brain and cognition and antiepileptic drugs study: IQ in school-aged children exposed to sodium valproate and polytherapy. Journal of the International Neuropsychological Society. 2011;17(1):133-42.
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Table 1. Literature pertaining to the neurodevelopmental outcomes of children exposed to AEDs by age and investigation type.
20, 2125, 45, 53, 57
23, 26
22, 23, 29, 37, 38
-
13, 17
22-24, 40
23
43
-
41, 42
43
16,31
NDD
13-18, 27, 31, 49
Adaptive Behaviour
20, 35, 57, 44
Motor
20-23, 25, 26, 29, 3335, 37,38, 44-46, 53)
Rating *
Executive functioning
13-18, 24, 27, 28, 3033, 44
Language
Attention & memory
IQ
Adolescence / adulthood
DQ
Lamotrigine
2, 5, 8, 10, 13, 18, 2025, 27,29, 31-34, 37, 44, 45, 54 13, 22-24, 29, 32-34, 37, 40
School age
Carbamazepine
Neurodevelopmental outcomes^ $
Pre-school
Dose
Age±
13, 14, 23, 26, 28-30, 33, 34, 44, 45 13, 23, 28, 29, 32
23, 26
13,14, 16,18, 28, 3133, 51
32-34
20, 28,32, 3638,44 54
Adequate
23
13, 28, 32, 40
32, 33
28,37, 38
Limited
43
41-43
43
41, 42
-
-
Substantially limited
-
45
-
16,
-
44
23
14, 23, 30, 32, 44, 45
23
14, 31, 51
32, 34
20,44
Limited
Substantially limited Adequate
Levetiracetam
41-43
13, 17, 24, 28, 32, 33, 40 41, 42
Phenobarbital
25, 31, 44, 45
16,22, 31, 44
25, 44, 45,46
44, 48
Phenytoin
20, 23-25, 27, 31, 32, 44, 45
20, 23, 25, 34, 44, 45, 50
57
14-16, 27, 31, 49
Topiramate
43
14, 15, 16, 24, 27, 3032, 44, 50, 51 52
25, 45, 47, 48, 57 20, 2325, 45, 50,57
43
-
-
43,52
43
43
43
52
-
-
Valproate
8, 9, 13, 14, 15, 20-25, 29, 31-33, 35, 37, 39, 40-46, 48, 51, 53, 54, 57
13, 17, 24, 28, 31-33, 40-42, 44
20,21-23, 25, 26, 29, 34, 37, 38, 43-45, 53, 55
44, 57
13, 17, 31, 41, 42
20-25, 40, 43, 45, 5355, 57
23, 26,43
13, 23, 26, 28, 29, 32, 33, 4143, 45
23, 26,43
13, 28, 31-34, 40-42
32-34
20,28, 32, 3638, 44, 54
47,
20,
16, 32,
* Rating Key: Comprehensive – Data is available from more than one well designed and adequately powered cohort, comparing to controls and to other AEDs, across all key neurodevelopmental areas and with clear outcomes pertaining to dose association or a lack there of. Adequate– Data is available from more than one well designed and adequately powered cohort, at each age/time point, across DQ/ IQ and other but25not all
neurodevelopmental areas, with clear outcomes pertaining to dose association or a lack there of. Limited - Data is available from only one well designed and adequately powered cohort, at each age/time point, across DQ/ IQ and other but not all neurodevelopmental areas and there is no consistent evidence pertaining to dose associated effects. Substantially limited - Data is available from a small number of studies, with small cohorts, across one or two of the key neurodevelopmental areas with no consistent evidence pertaining to dose associated effects as yet.
Key: + One cohort may span all age groups but may not provide data analysed by age group. ^ studies referenced only if they reported this data by individual AED type and publications may refer to multiple observations from the same cohort. $- studies may not be adequately powered. NDD – neurodevelopmental disorder; DQ – developmental quotient; IQ – intelligence quotient.
26