Managing epilepsy in pregnancy

Abstract

Epilepsy is one of the most common neurological disorders. Although there may be associated fertility issues and many women with epilepsy may choose not to conceive, it is estimated that at least two to five out of every thousand pregnancies in the UK occur in women with active epilepsy. The overwhelming majority of such cases will have an uneventful pregnancy and will deliver a healthy baby. However, there are issues surrounding epilepsy in pregnancy. These issues are multiple, but include the potential teratogenicity of the antiepileptic drugs, in terms of both major structural defects and of neurodevelopmental delay and loss of seizure control, perhaps due to enhanced clearance of the drugs. In addition, obstetric complications may be encountered more frequently, and maternal death, usually linked with loss of seizure control, is also over-represented in this group. This article details what is known about the prevalence of epilepsy in pregnancy and how epilepsy may impact on pregnancy outcome.

Keywords::

• antiepileptic drugs
• congenital malformations
• epilepsy
• pregnancy

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journals/expertob; (4) view/print certificate.

Release date: 1 November, 2011; Expiration date: 1 November, 2012

Learning objectives

Upon completion of this activity, participants will be able to:

• • Analyze best practices in preconception counseling for women with epilepsy

• • Distinguish the AED associated with the highest risk for causing congenital malformations

• • Evaluate how epilepsy affects the course of pregnancy and the health of the newborn

• • Assess how to manage epilepsy during pregnancy

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P. Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine.

Disclosure:Charles P. Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Ellen Mawhinney, MRCP(UK)

Department of Neurology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.

Disclosure:Ellen Mawhinney, MRCP(UK), has disclosed no relevant financial relationships.

Jim Morrow, MD

Department of Neurology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.

Disclosure:Jim Morrow, MD, has disclosed the following relevant financial relationships: Received educational grants from: Eisai Inc.; GlaxoSmithKline; Novartis Pharmaceuticals Corporation; sanofi-aventis; Pfizer Inc; UCB Pharma, Inc.

Prevalence of epilepsy in pregnancy

A meta-analysis of incidence studies of epilepsy reported an overall incidence rate of epilepsy of approximately five per 10,000 per year [1]. The UK national child development study cohort, based on over 17,000 children born in March 1958, found the cumulative incidence of confirmed epilepsy was 8.4 per 1000 by the age of 23 years, with an active prevalence of 6.3 per 1000. Lifetime prevalence has been estimated at 2–5%; however, the prevalence of epilepsy in the pregnant population is usually considered to be less than the above estimates. This may be because the seizures are only one aspect of a spectrum of other conditions which in themselves may mitigate against pregnancy, or because some women with epilepsy may choose not to become pregnant due to fears surrounding the seizures and/or the drugs used to treat them. Estimates suggest that between 0.2 and 0.5% of pregnancies that occur involve a woman with active epilepsy [2–5].

Preconceptual counseling

There is a growing awareness of the potential teratogenic and other effects of antiepileptic drugs (AEDs) taken during pregnancy. Although there have been studies from as early as the 1960s suggesting links between major congenital malformations (MCMs) and the use of AEDs during pregnancy [6–9], the advent of the large prospective, albeit observational, epilepsy and pregnancy registries have recently added much information on the relative risks associated with the individual AEDs [5,10–17]. The key to a successful outcome in this respect is knowledge of the individual risks and imparting these risks through preconceptual counseling, enabling women to make informed choices and allowing any alteration in therapy to be made prior to pregnancy.

Traditionally women with epilepsy have complained about the lack of information they have received about epilepsy in general and the availability of preconceptual counseling in particular [18]. As an objective measure of the effectiveness of preconceptual counseling in the UK, one recently published study from the UK Epilepsy and Pregnancy register demonstrated that only 32% of women with epilepsy received the recommended daily (5 mg) folic acid preconceptually [19]. Most regional neurology centers now have access to specialized epilepsy nurses and it is through these professionals that preconceptual counseling is probably best delivered. If pregnancy is being actively planned then specialist review is warranted and a timely referral to local specialist epilepsy center should be made.

Preconceptual counseling should aim to raise awareness among women with epilepsy that the best outcome for any pregnancy may be secured if the pregnancy is planned in advance. This will allow the necessary time for any changes or discontinuation of antiepileptic treatment to be carried out, or, if necessary, for seizure control to be optimized prior to pregnancy [20,21].

Abrupt cessation of AED therapy should be avoided at all costs because of the risk of uncontrolled epileptic seizures [22]. In some cases, drug withdrawal may be considered as a proportion of women with epilepsy who have been seizure free for 2 years on medication could successfully withdraw from treatment without relapse [23]. If during the reassessment of the epilepsy, the risk of complete drug withdrawal is considered too high it may still be possible to reduce the drug load and in particular to reduce the number of AEDs that are prescribed.

The dose of individual AEDs may also be considered as there is some evidence to suggest that there is an association with dose and congenital malformation with all of the commonly prescribed AEDs [10,24]. The effect of dose for sodium valproate in particular, may be of clinical importance in determining the size of the teratogenic risk, with the highest risk in those taking over 1000 mg per day [6,7,10].

It is generally accepted that women with epilepsy are at increased risk of having a child with a MCM. Risks of between 3 and 9% are generally quoted – these figures have often been derived from a number of epidemiological studies [2,7,25–28]. However, many of these studies contain methodological flaws. They are often retrospective, they may have emanated from specialized epilepsy centers and usually contain insufficient numbers of patients taking individual drugs in monotherapy to make accurate statistical comparisons about the relative risks of the individual drugs.

Few studies have included the epilepsy syndrome or seizure types and seizure frequency as potential confounding variables when determining the relative risk of major malformation with in utero exposure to AEDs.

There are no randomized controlled trials of AEDs in pregnancy. In fact, women of childbearing age are often routinely excluded from randomized controlled trials, as studies to examine human teratogenic risks would generally be considered unethical. Recently, a number of prospective population-based epilepsy and pregnancy registers have emerged from which it is hoped to derive more accurate information regarding the relative risks of the AEDs when used in pregnancy [10,15–17]. The results from pregnancy registers, however, while having a number of advantages (e.g., they enable sufficient numbers of patients on individual drugs to be recruited and followed-up), must be interpreted in the light of the fact they are neither randomized nor controlled and therefore the reasons for prescribing certain AEDs may vary, and be influenced by other factors, such as epilepsy syndrome or seizure type. This is particularly true for the idiopathic generalized epilepsies, for which the choice of AED may be much more restricted than for partial or secondary generalized seizures.

A common theme emerging from the preliminary data from epilepsy and pregnancy registers is that sodium valproate appears to carry an elevated risk of MCM and perhaps neurodevelopmental delay compared with other AEDs [10,12,13,15–17].

The UK Epilepsy and Pregnancy Register suggested that mothers taking sodium valproate were at increased risk of having a child with a major malformation (6.2%; 95% CI: 4.6–8.2%) compared with other drugs used in monotherapy [10]. In September 2003, following a review of available information including preliminary data from the UK Epilepsy and Pregnancy Register, the Committee on the Safety of Medicines recommended that women of childbearing age should not be started on sodium valproate without specialist neurological advice [11].

Outcomes for a cohort of 149 pregnancies exposed to sodium valproate have been published by the North American Antiepileptic Drug Pregnancy Registry. A total of 16 (10.7%; 95% CI: 6.3–16.9%) MCMs were recorded, of which three had lumbosacral spina bifida [12]. In a smaller number of cases, the Australian registry has also suggested an increased risk in mothers taking sodium valproate and reported a dose–effect relationship in that doses in excess of 1100 mg/day were associated with an enhanced rate of malformations [13].

It is also generally accepted that exposure to polytherapy with AEDs is associated with an overall greater risk of MCMs. Studies have demonstrated that combination therapy including sodium valproate is again particularly associated with an elevated risk compared with other combinations [10]. Data reported from the International Lamotrigine Pregnancy Registry showed that, among 150 pregnancies exposed to polytherapy including sodium valproate in the first trimester, 16 MCMs (10.7%; 95% CI: 6.4–17.0%) were observed. In comparison, among 430 pregnancies exposed to polytherapy including lamotrigine but not sodium valproate, only 12 MCMs (2.8%; 95% CI: 1.5–5.0%) were recorded [14].

A recent paper from the EUROCAT malformation registry has highlighted an over-representation of not only neural tube defects, but also facial clefts, hypospadias, atrial septal defects and some skeletal abnormalities in association with in utero exposure to sodium valproate [29].

In recent years many neurologists and others have preferred to prescribe lamotrigine in place of sodium valproate in women of child-bearing years. Pregnancy outcome data for this drug has generally been reassuring. The International Lamotrigine Pregnancy Registry has published 414 first trimester monotherapy exposures to lamotrigine, 12 MCMs (2.9%; 95% CI: 1.6–5.1%) were observed. No pattern of malformation was observed in any group [14]. The UK Epilepsy and Pregnancy Register has reported very similar results with MCMs in 3.2% (95% CI: 2.1–4.9%) of 647 children [10].

A publication from the North American registry again demonstrated a low teratogenic risk but suggested an increased risk of nonsyndromic cleft palate among infants exposed in utero to lamotrigine [28]. Three isolated cleft palate and two isolated cleft lip were identified among 564 exposed pregnancies, a rate of 8.9 per 1000. In comparison, their control population rate was 0.6 per 1000, giving a relative risk of approximately 15. This association has not been demonstrated in the other available registries’ data nor in a recent analysis by the EUROCAT registry [30]. A population-based cohort study of 837,795 from Denmark [31] has suggested that all of the newer generation AEDs carried a lesser teratogenic risk that was not increased above the unexposed population. The evidence for low teratogenic risk is strongest for lamotrigine and carbamazepine, with other studies also confirming some encouraging preliminary data on levetiracetam [32]. However, the results of this Danish study are in conflict with preliminary data on the effects of topiramate exposure in utero. Topiramate has been demonstrated to be teratogenic in mice, rats and rabbits at high doses. Both the UK and the North American registries, although the data is preliminary and the numbers small suggest that this drug should be viewed with caution in respect of its teratogenic potential, and have suggested a possible association with increased rates of cleft lip and palate (monotherapy MCM rates of 4.8 and 3.8%, respectively) [33,34]. In line with these findings, recent advice issued by the US FDA has classified topiramate as a category D drug (see Table 1 for a summary of published MCM rates) [101].

The role of folic acid

Neural tube defects have been associated with exposure to AEDs in utero, for example, with sodium valproate and carbamazepine [29]. In the general population, folic acid supplementation has been shown to have a protective role in a primary prevention of neural tube defects. In a secondary prevention trial, which included women who had previously given birth to an infant with a neural tube defect, or who had a first degree relative with a child with a neural tube defect – and were therefore considered at high risk, carried out in the UK by the Medical Research Council, it was found that a higher dose of folic acid (4 mg per day) prior to conception was associated with a 72% protective effect [35].

Extrapolations have been made from these and other published studies to the epilepsy population. As the children born to women taking valproate and carbamazepine in particular may be at increased risk, it has previously been recommended that a daily dose of 5 mg of folic acid is prescribed for all women taking AEDs, usually starting before conception and continuing until at least the end of the first trimester [36]. Some recent studies have failed to demonstrate added protective value from folic acid in this population group [37], and a practice parameter published by the American Academy of Neurology found only two adequately sensitive class III studies confirming a reduction in the risk of MCMs [38]. However, as there is no evidence of harm, it is still generally recommended that all women with epilepsy planning pregnancy should receive preconceptual folic acid at a dose of at least 0.4 mg daily. There is little evidence to confirm that higher dose folic acid offers more protective effects than low dose, but as this may be of benefit and risks are low many clinicians continue to use the higher dose routinely.

Neurodevelopmental delay

While an association between major and minor structural abnormalities with epilepsy and the AEDs is now generally accepted and the relative risks associated with the individual AEDs is slowly emerging, the effect of the AEDs on neurodevelopment remains a controversial issue. The first study to report an association between intrauterine AED exposure and developmental delay was over 30 years ago [39]. Although the effects of intrauterine AED exposure on neurodevelopment have been investigated over the years, there remains much controversy concerning the overall incidence and relative risks associated with specific agents.

Although extensive medical literature on this topic exists, it has been difficult to draw any meaningful conclusions regarding the relative risks of AEDs on neurodevelopment due to many conflicting results. Some studies have, for example, suggested a high prevalence of developmental delay in exposed children in the early years, yet other studies have reported little or no effect on development.

These conflicting results may have arisen due to a number of factors which would include differences in methodology and differences in neuropsychiatric tests administered. Many studies may be criticized for having inadequately sized study populations, for lack of a control population, for being retrospective and for the lack of appreciation of confounding variables.

One major limiting factor common to many earlier papers is that studies have tended to deal with the epilepsy population as a whole, and to attempt to assess the risks associated with exposure to individual AEDs. The question of which AED is the safest drug to take during pregnancy with respect to risk of any neurodevelopmental delay therefore remains uncertain.

The prevalence of significant cognitive impairment has varied between 10–30% in reported studies [40–42]. Some small case series have also found an association between in utero AED exposure and behavioral disorders, with evidence of a higher proportion of children showing inattention or hyperactivity [41,43]. For all studies in this area, however, it remains difficult to disentangle the effects of confounding variables such as, seizures, maternal and paternal IQ and social class.

However, some studies assessing children born to women with epilepsy who have been seizure free and not on AED treatment during their pregnancy, have found no difference in the IQ of these children when compared with matched controls in the general population – suggesting that AED exposure in utero may be the responsible factor for any cognitive difficulties [44].

With regard to the risk associated with individual AEDs, several early studies demonstrated an association of poor neurodevelopmental outcome in the children exposed in utero to phenytoin, phenobarbitone and carbamazepine [40,45–47]. However, once again studies are conflicting with more recent studies not confirming these findings [48–50].

Overall, there have recently been fewer studies of children exposed to sodium valproate in utero but the studies that do exist have generally suggested an association with a significant percentage of children having some degree of developmental delay or learning difficulties [50–52]. In a study from Liverpool, UK the longer term outcome of children born to mothers with epilepsy was examined [48]. In total, 249 children aged 6 years and over were studied, 41 of whom had been exposed to sodium valproate, 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy and 80 were unexposed. In this study, it was noted that mean verbal IQ was significantly lower in the valproate exposed group compared with the unexposed and other monotherapy groups. A multiple regression analysis showed that both valproate exposure and frequent tonic clonic seizures in pregnancy were significantly associated with the lower verbal IQ. After adjusting for other confounding factors, this study identified valproate as a drug carrying potential risks for developmental delay and cognitive impairment. It was also the first to suggest that tonic clonic seizures may have a similar effect. The study, like many others in this field, may be criticized for some methodological flaws, in particular perhaps, the potential of ascertainment bias. Nevertheless, this study has heightened continuing concerns regarding the risks of in utero exposure to sodium valproate during pregnancy.

With regard to the newer AEDs, there is some emerging literature to support the safety of lamotrigine and levetiracetam with respect to neurodevelopment.

A multicenter, prospective, observational study comparing neurodevelopmental outcomes after exposure to AEDs in utero was published in 2009. This compared 258 children exposed to AED monotherapy in utero (73 carbamazepine, 84 lamotrigine, 48 phenytoin and 53 valproate) and confirmed that in utero exposure to valproate was associated with a dose-dependent reduction in neurodevelopmental outcomes. IQ in the valproate group was on average 9 points lower than the lamotrigine group (92–101; p = 0.009), 7 lower than the phenytoin group (92–99; p = 0.04) and 6 points lower than the carbamazepine group (92–98; p = 0.04) at 3 years of age. This clearly supports the recommendations that valproate should not be used as a first-line drug in women of childbearing potential [53].

In another blinded cohort study with control, subjects being children prospectively ascertained through the UK Epilepsy and Pregnancy Register, it was found that of 186 children aged 8 years or less (142 being exposed to AEDs in utero) those children exposed to sodium valproate in utero were more likely to have evidence of neurodevelopmental delay than controls; control population: two out of 42 (4.8%). There was one significant delay, one mild. Sodium valproate population: 23/58 (39.6%). There were five significant delays, 18 mild. Children exposed to carbamazepine in utero also demonstrated some degree of neurodevelopmental delay; ten out of 49 (20.4%); two significant, eight mild. However, those children exposed to lamotrigine in utero appeared to produce similar results to the control subjects (one out of 35 [2.9%]) [54].

Furthermore, another recently published study comparing children exposed to either levetiracetam (55 children) or sodium valproate (44 children) in utero with controls (97 children), confirmed high rates of neurodevelopmental delay in the sodium valproate exposed group, but no significant difference between the levetiracetam and control groups (40% of children in sodium valproate group were in the below average range, compared with 8% in levetiracetam group and 12% in control group; relative risk 3.38 for sodium valproate). The levetiracetam results are clearly very reassuring, and would suggest that in the future, this may be the drug of choice for women of childbearing age with epilepsy [55].

Overall, there is growing evidence for an association between in utero exposure to AEDs (at least when used to treat epilepsy) and neurodevelopmental delay or behavioral change in the child. There are suggestions that these changes are more common with in utero exposure to sodium valproate. However, opinions between clinicians differ on how conclusive the current literature is. A recent review published in 2008 concluded that although the available studies raise concerns, particularly for valproate, a valid risk estimate for AED use during pregnancy on neurodevelopment is not possible, and no definite conclusions can be drawn [56]. There is little doubt, however, that the issue remains controversial and it is likely that large, well controlled prospective studies with longer term follow-up will be required to answer this important question.

Fetal anticonvulsant syndrome

Although reports of fetal anticonvulsant syndromes have been published in the literature since the 1970s and 1980s, this concept was probably first brought to the attention of the majority of physicians in a series of case reports by Clayton-Smith and Donnai in 1995, which specifically defined the condition [57]. It has been proposed that a syndrome of dysmorphic features, combined with one or more of six features including neonatal withdrawal symptoms, major malformation, developmental delay, behavioral problems, learning difficulties and general medical problems, are criteria for a syndrome termed the fetal anticonvulsant syndrome, resulting from the in utero exposure to AEDs [58,59]. Evidence regarding the frequency of these abnormalities among children exposed to AEDs in utero remains limited, but it has been suggested that these features are more common in children exposed to sodium valproate than to the other AEDs [48].

Sudden unexpected death in epilepsy & maternal death

Mortality rates in people with epilepsy are higher than the general population. Outwith the risks from accidents, intercurrent infections, suicide and status epilepticus, there are estimated to be up to 500 deaths per year in otherwise healthy people with epilepsy. These deaths are termed sudden unexplained death in epilepsy (SUDEP) [60].

The exact cause of SUDEP is unknown although it has been postulated that a cardiac arrhythmia or a respiratory failure induced by the seizure activity may be responsible. It is recognized that patients whose epilepsy is well controlled are at lower risk of SUDEP.

The Confidential Enquiry into Maternal Death has demonstrated that maternal mortality rates are increased in women with epilepsy (women with epilepsy are approximately ten-times more likely to die during pregnancy than the general population). Poor seizure control, accidents related to the epilepsy and/or SUDEP may account for this increased risk (see Table 2) [60].

Effect of pregnancy on epilepsy

An observational study encompassing over 300 countries has indicated that the majority of women with epilepsy who normally have a good degree of seizure control maintained this control throughout the pregnancy (63.6%), while 5.9% actually experienced improved control and only 17.9% experienced an increase in seizure frequency [15]. By contrast, mothers who normally experience more than one seizure per month preconceptually may be more likely to deteriorate throughout gestation [61].

Reduced seizure control may be the consequence of reduced serum AED levels as a result of nausea and vomiting in early pregnancy, poor compliance with medication (perhaps related to fears of teratogenicity), pharmacokinetic changes resulting from pregnancy specific physiological changes (see later), lack of sleep towards term, or hyperventilation during labor [61].

New onset epilepsy in pregnancy is not unusual – approximately 20–30 per 100,000 women present with new-onset epilepsy during their childbearing years. This may be explained by the fact that particular latent conditions have a tendency to present during pregnancy as a result of specific hormonal and physiological changes. It should be borne in mind that epilepsy may, in these cases, be the presenting feature of the underlying disorder. The new onset of epilepsy, however, needs to be distinguished from eclampsia which usually presents after the 20th week of pregnancy [3].

Effects of pregnancy on AEDs

A number of physiological changes that occur during pregnancy may affect drug levels and subsequently such alterations may impact on maternal seizure control.

Total maternal blood volume increases by between 30 and 50% due to a combined increase in plasma and red blood cell volume [62]. This is subsequently associated with an increase in cardiac output, resulting in a reduction in serum drug levels due to the increased volume of distribution and increased glomerular filtration rate and renal drug clearance [63]. Altered hepatic enzyme activity during pregnancy is also known to lead to enhanced drug clearance [64,65]. During pregnancy albumin concentration of maternal plasma is reduced and hence the drug protein-binding capacity of the blood is also reduced, with the consequence of higher free-drug levels [63]. The effect of reduced protein binding, however, is usually outweighed by the effect of increased drug clearance and volume of distribution, and so overall drug levels during pregnancy tend to fall rather than increase [61]. The increase in drug clearance during pregnancy, however, may be of more clinical relevance with some drugs than others.

For older agents such as sodium valproate and carbamazepine there is only limited literature available. In regards to carbamazepine there are two relevant studies demonstrating a maximum decline from baseline in the region of 10–12% in the third trimester [66,67]. Unfortunately these studies did not address seizure control in pregnancy or give any indication as to whether carbamazepine dose increases were required in any patients.

For sodium valproate the decline in serum is most pronounced in the third trimester where the reduction in serum valproate concentration is, on average, observed to be in the region of 50% of the baseline serum concentration [15,66]. However, sodium valproate does not demonstrate linear pharmacokinetics given that, as the levels of protein-bound drug decrease, such as in late pregnancy, a rise in the free-drug concentration is observed [68], that is, the unbound fraction appears to be inversely correlated to the concentration of serum albumin. However, it is this unbound or free fraction that is pharmacologically active and hence this in turn may outweigh the effect of falling serum valproate concentrations [66].

Two recent studies have suggested that despite the previous suggestion of falling serum levels of carbamazepine and/or sodium valproate seizure control is generally maintained throughout pregnancy in women taking these agents [16,69].

There has been a change in recent years with regards to the prescription of AEDs in women. There has been a reduction in the prescription of sodium valproate, and lamotrigine has emerged as a first-line therapy for women of childbearing age. It has been noted that lamotrigine clearance increases during pregnancy, resulting in a decline in lamotrigine serum levels [70]. This finding was followed by the observation that preconceptual seizure control may not be maintained during pregnancy in a significant subgroup of women [71]. It seems reasonable therefore that the loss of seizure control, or seizure breakthrough, in this subgroup of epileptic mothers can be attributed to this fall in lamotrigine serum concentration, as has been suggested.

One study to investigate this association employed a regular lamotrigine serum level monitoring, with dose increases made accordingly, in an attempt to maintain relatively stable serum concentrations in the patients involved, with the ultimate aim of maintaining tight seizure control [71]. On average, it was found that two dosage increments were necessary in response to falling serum concentrations and a mean daily dose of 572 mg was reached during pregnancy, in comparison to the mean preconceptual daily dose of just 286 mg.

Considerable interpatient discrepancy was observed, however, in the Petrenaite study, with one patient requiring almost an eight-fold increase in dose while another patient required no adjustments at all to their medication [71]. Regardless of these dosage manipulations, 45% of the mothers still experienced deterioration in their seizure control. In these cases the deterioration was primarily observed in the second trimester, when concentration/dose ratio decreased by more than 60%, and control continued to deteriorate in the third trimester despite the subsequently raised dose. Pennell et al. also observed deterioration in control to consistently occur when concentrations fell by 65% or more from the preconceptual baseline level [67]. On average, in this study, plasma concentration/dose ratios fell by 26.5, 65.1 and 65.8% in the first, second and third trimester, respectively.

A larger, retrospective study of lamotrigine in monotherapy analyzed serum level measurements that had been monitored on a monthly basis, throughout 42 pregnancies [72]. In this case lamotrigine dose was increased by 20–25% as standard protocol if serum levels fell below prepregnancy baseline levels. It was found that, on average, three dose adjustments were necessary throughout the pregnancy in order to counteract declining serum levels. However, despite this careful monitoring regime, the incidence of deteriorating seizure control was not significantly lower than what had previously been reported in other less attentively monitored AED regimens. The data, collated from the EURAP database between the years 2003 and 2008, demonstrated an increase in seizure frequency, or seizure breakthrough, in 19% of the 42 pregnancies included.

Several studies included within two separate literature reviews, demonstrate that this observed increase in lamotrigine clearance steadily progresses throughout gestation, reaching a peak in the third trimester in approximately the 32nd week [62,72]. In one study, a maximal increase in lamotrigine clearance of as much as 330% from baseline was noted [73]. This observation is further supported by a more recent review in which four separate studies demonstrated clearance to increase by as much as 300% during gestation [68]. It is noteworthy, however, that such pronounced increases in clearance were not demonstrated in those pregnancies in which the mother was concomitantly medicating with sodium valproate [68]. This may be due to the inhibitory effect that valproate has on lamotrigine glucuronidation, which is known to reduce clearance by approximately 50% and increase serum lamotrigine concentration [74].

In a further small study it was found that, with such pronounced changes in lamotrigine clearance, dosage increases were necessary in all nine pregnancies in order to maintain preconceptual seizure control [75]. These dosage increments were, on average, in the order of 315%, and hence the authors advocate as much as a three-fold prophylactic increase in lamotrigine dose to maintain stable control [75].

In parallel with the aforementioned, studies directly examining seizure control throughout pregnancy have consistently suggested that seizure control is more likely to be lost in those women taking lamotrigine rather than carbamazepine or sodium valproate throughout pregnancy [16,69].

At least partially owing to the awareness of the potential for loss of seizure control during pregnancy with lamotrigine, neurologists and others are increasingly prescribing newer agents such as levetiracetam and topiramate.

There is as yet only preliminary data available on levetiracetam clearance during pregnancy. However, in the available literature, the clearance of levetiracetam does appear to increase significantly during pregnancy, with several studies showing a decline in serum concentration/dose ratio in the third trimester to be in the order of 50% of baseline [66,76,77].

There are two studies examining topiramate serum levels in pregnancy [78,79]. From these two studies it is apparent that topiramate levels do decline, particularly in the second and third trimesters, although not to the same extent as lamotrigine or levetiracetam. However, interpatient variability is considerable and, as with levetiracetam [77], no correlation could be found between declining serum levels and deteriorating seizure control [79].

Further studies with greater numbers of patients using levetiracetam and topiramate in monotherapy are necessary to confirm these findings and in particular whether there is any associated loss of seizure control.

Effect of epilepsy on pregnancy

The evidence suggests that most pregnancies in women with epilepsy are uneventful and most babies that are delivered are healthy. With regard to the pregnancy itself and obstetric complications in particular, previously quoted figures of approximately 1.5–3-times increased risk of common complications of pregnancy such as toxemia, preeclampsia, bleeding and premature labor, and a 1.2–2-times increase in prenatal mortality have been derived from a number of earlier and often retrospective studies. More recent prospective studies have not confirmed these increased risks [36].

There is no evidence that simple partial or complex partial, absence seizures or myoclonic seizures adversely affect the pregnancy or the developing fetus other than through the coincidental effects of trauma. There is also no definitive evidence to suggest that tonic clonic seizures during pregnancy are associated with increased risk of major malformation although clearly the risk of injury may be greater in these seizures. There is some recent evidence, however, linking frequent tonic clonic seizures during pregnancy with cognitive or behavioral changes in childhood [48].

Vitamin K

Expectant mothers taking enzyme inducing AEDs should be advised to protect their baby against hemorrhagic disease of the newborn as this condition carries a mortality rate over 30%. It is due to the deficiency of vitamin K and is more likely to occur in the offspring of women who have taken a hepatic enzyme-inducing drug during pregnancy. It was previously recommended that 10–20 mg per day of vitamin K is given orally to the mother in the last month of pregnancy and the baby should be given intramuscular vitamin K (1 mg at birth and at 28 days postdelivery) [36]. However, more recently and at least partially due to the unavailability of oral vitamin K, the maternal recommendation has been dropped and the current advice is simply that the child receives the intramuscular dosage [21].

Infants should receive intravenous fresh frozen plasma if there is evidence of bleeding or if the concentrations on two or more of the factors 2, 7, 9 or 10 fall less than 25% normal [36].

Joint epilepsy–obstetric clinics

In general terms, pregnancies in women with epilepsy are often considered to be complicated and do require careful management. Arguably, such management may be best delivered by a joint epilepsy–obstetric clinic; however, to date the evidence in support of this development remains controversial [20].

Seizure control should be optimized throughout pregnancy with seizure freedom being the aim. The importance of adherence to medication should be emphasized and women should protect themselves from becoming too tired through not getting enough rest and sleep. Uncontrolled seizures in pregnancy resulting from sudden withdrawal or from nonadherence to antiepileptic medication may present a risk to the developing fetus and indeed the mother herself. Ideally, therefore, if a joint epilepsy–obstetric clinic exists locally then women with epilepsy should be referred to it to allow for a more detailed follow-up of both the pregnancy and seizure control.

Arguably the need for specialist clinics is increasing due to the challenges posed by the changing prescribing habits among neurologists. As the older AEDs, which may be more teratogenic [10,12,13,29], are replaced with newer agents, which may be safer to the fetus [10,14,30–32], it is possible if not probable that increased difficulty will be encountered in maintaining seizure freedom and/or control throughout pregnancy [67,68,70–73,75].

The number of joint epilepsy–obstetric clinics in the UK remains limited. If no joint service exists then pregnant women with epilepsy should be referred early for shared care to the nearest obstetric center that offers high resolution ultrasound scanning and at the same time re-referred to a local epilepsy service. Ideally an obstetrician who specializes in medically complicated pregnancies should be identified if there is no shared service between these specialties [36].

High quality ultrasound scans should be performed during pregnancy along with appropriate blood tests (and possibly an amniocentesis) as required. Given the emerging evidence regarding the specific malformations found in association with the individual AEDs and their incidence [77], it seems likely that over time tailored antenatal investigations may become the norm for individual pregnant women with epilepsy.

Management during labor

Approximately 1–2% of women with active epilepsy will have a tonic clonic seizure during labor and a further 1–2% will have a seizure during the following 24 h [80]. Generalized tonic clonic seizures at this time are more likely to result in a profound hypoxia than in the nonpregnant state because of increased maternal oxygen requirements. This may have a deleterious effect on the fetus. It is therefore recommended that delivery of women with epilepsy takes place in an obstetric unit with facilities for maternal and neonatal resuscitation [20].

Antiepileptic drugs should be continued throughout labor and if necessary the drugs can be given by nasal gastric tube or if available parenterally.

Most women with epilepsy may have normal vaginal deliveries. Over breathing, sleep deprivation, pain and emotional stress increase the risk of seizures during labor. The analgesic pethidine may have a proconvulsant effect and is best avoided if possible [81]. It is appropriate therefore to consider epidural anesthesia early on to minimize these factors. An elective cesarean section may be appropriate if frequent tonic clonic or prolonged complex partial seizures occur in the last weeks of pregnancy. Intravenous lorazepam may be an appropriate acute treatment for serial seizures during labor [36].

Breastfeeding

Many mothers and physicians are concerned that AEDs will be expressed in breast milk and hence possibly adversely affect their child. In fact, breast milk usually contains only a fraction of the serum levels of the AEDs (although some, e.g., lamotrigine, are found in higher concentration than others [70,75]. In general terms earlier concerns regarding traces of the AEDs in breast milk centered around the potential for sedative effects of these drugs on the child. While this may have been a concern for the older drugs such as, phenobarbitone, these effects are much less likely with the conventional and newer AEDs which are not generally associated with the similar degrees of sedation. It is therefore recommended that, while AEDs may be expressed to a limited degree in breast milk, mothers with epilepsy taking AEDs, are encouraged to breastfeed their children [20].

A study published in 2010 including 199 children (42% breastfed) showed no adverse cognitive effects of breastfeeding during AED therapy in children previously exposed to AEDs in utero[82].

A further potential advantage of breastfeeding is that the child will have been exposed to the AEDs in utero and a further and decreasing exposure through breast milk may prove a useful way to wean the child off the AED, thus to avoid the potential for any withdrawal symptoms.

Peurperium

The general practitioner should undertake a postnatal epilepsy review at 6 weeks post delivery, and it would be considered good medical practice for a specialist epilepsy review around 12 weeks post delivery [83].

If, because of increased seizure frequency and/or falling serum levels, the AED dosage has been increased during pregnancy, it is usually advisable to reduce the dosage level gradually over the succeeding few weeks back to prepregnant levels to reduce the risk of maternal toxicity [67]. However, there is as yet no firm consensus as to when this should occur, as there may be increased risk of seizures during the weeks following delivery (which may be related to a number of factors such as hormonal change, lack of sleep and emotional factors). Therefore, if there is no evidence of toxic symptoms from the increased dose (despite the probable rise in serum levels) and there is a sustained benefit on seizure frequency then alternatively the regime may be left unaltered.

Expert commentary

The management of epilepsy in women of childbearing age is far from straightforward, and there are many factors to consider during pregnancy and the perinatal period. With the growing mountain of emerging data in this field, preconceptual counseling remains of paramount importance. It is prudent to identify and discuss these issues at the time of epilepsy diagnosis and to revisit them frequently during routine follow-up. However, to ensure patients are fully informed of the risks involved and the options open to them, all women should be encouraged to attend a medication review and counseling before attempting to conceive.

As far as the choice of AED goes, in clinical practice, the best option is not always clear. It is crucial to consider AED efficacy and tolerability as well as MCM profile in this decision. Sodium valproate exposure is recognized to be associated with higher MCM and neurodevelopmental delay rates than exposure to the majority of other AEDs. However, valproate is also considered the gold standard treatment of primary generalized epilepsy syndromes. We know from the SANAD study that the chance of achieving seizure freedom on lamotrigine is significantly lower in these patients than with sodium valproate. It is important to be aware that use of sodium valproate in women of childbearing age, although sometimes necessary, should be a last resort and only be considered if patients have failed on newer agents such as lamotrigine and levetiracetam. If other treatment options have previously failed, the risk of uncontrolled seizures to pregnancy should be considered before any change of AED treatment. If valproate is to be continued during pregnancy, as a dose related effect has been observed, it is essential to consider reducing total daily dose if epilepsy syndrome and seizure control allows.

All women of childbearing age taking AEDs should be encouraged to take high-dose folic acid if considering pregnancy. However, as outlined previously, some studies have failed to show a significant reduction in MCM rates even with folic acid supplementation in this population group.

During pregnancy, prenatal care should ideally be in a joint epilepsy–obstetric clinic. Monitoring of breakthrough seizures and an awareness of the potential impact of pregnancy on AED drug levels is vital. Appropriate prenatal high quality ultrasound screening for recognized MCMs should also be performed, as discussed earlier.

The overall likelihood of seizures during labor is low, but pain, stress, hyperventilation and sleep deprivation can lower the seizure threshold. Medication factors, such as missed doses and other drugs (e.g., pethidine) can also predispose to seizures. All of these factors should be considered in the perinatal period, and ideally, management should be in a center with facilities for maternal and neonatal resuscitation.

Guidelines suggest general practitioner review of epilepsy at 6 weeks, and epilepsy specialist review at 12 weeks postpartum. Again, due to environmental and pharmacodynamic reasons, it is possible for seizure frequency to increase in the weeks postpartum. Patients requiring medication increases during pregnancy should be advised of toxicity symptoms and medication reduction protocols should these symptoms occur.

Last, it is important for patients to recognize that although there are many factors to consider, the majority of women with epilepsy have uneventful pregnancies and normal, healthy children.

Five-year view

The management of epilepsy in pregnancy is a rapidly evolving field. The recent advent of several national and international observational registries has added a great deal of information on the relative safety of AEDs in pregnancy. Other high quality studies have greatly influenced our understanding of issues such as pharmacokinetics in pregnancy and risks of neurodevelopmental delay. With more data emerging, the next 5 years are likely to see significant changes to the way in which epilepsy is managed in women of childbearing age.

Since the introduction of the epilepsy pregnancy registers, there has been a significant shift away from prescribing conventional drugs (such as sodium valproate) and towards newer agents (such as lamotrigine and levetiracetam). As evidence evolves and our understanding of the risks associated with specific AEDs increases, this shift is likely to continue over time. We would expect to see substantial increases in the use of newer and safer AEDs, with older agents being used only for more difficult cases and medically refractory seizures.

Changes in drug prescribing may lead to new challenges in maintaining seizure control during pregnancy. It is likely that this will increase demand for more specialized antenatal care in joint epilepsy–obstetric clinics. As a result, specialized epilepsy–obstetric clinic numbers are likely to increase substantially to cope with demand for more comprehensive care of both epilepsy and obstetric issues.

A number of genetic studies are currently underway, aimed to advance our understanding of the genetic factors involved in predisposition to MCMs. Advances in this area would revolutionize preconceptual counseling. It is possible that in the future, preconceptual advice could be modified to a woman’s individual genetic susceptibility to the complications of drug exposure.

Emerging data on the specific malformation profiles of individual AEDs will also allow more focused prenatal screening. In the future, high quality ultrasound could be used routinely in tailored antenatal investigations, according to the specific AED risks and genetic susceptibility of individual women.

Table 1. Results for some of the more recent epidemiological studies of antiepileptic drugs associated with teratogenesis.

Study (year)	Exposed			Controls		Ref.
	Children (n)	Major congenital malformation (%)		Children (n)	Major congenital malformation (%)
Samren et al. (1997)	1221	9.0				[7]
Olafsson et al. (1998)	266	5.7		82,483	2.2	[2]
Canger et al. (1999)	444	9.7				[25]
Kaneko et al. (1999)	885	9.0				[26]
Samren et al. (1999)	1441	3.7		2000	1.5	[27]
Holmes et al. (2001)	223	4.5		508	1.8	[84]
Tomson et al. (2004)	1804	5				[15]
Holmes et al. (2004)	77	6.5				[85]
Vajda et al. (2004)	403	6.5				[13]
Wyszynski et al. (2005)	1197	3.9			1.62	[12]
Morrow et al. (2006)	3186	4.2		227	3.5	[10]
Diav-Citrin et al. (2008)	120	6.7		1236	2.5	[86]
Cunnington et al. (2011)	1558	2.2				[14]

Table 2. Confidential enquiry into maternal death, 1985–2008.

Year of enquiry	Maternities (m)	Maternal deaths (n)	Deaths due to epilepsy (n)
1985–1987	2.27	223	3
1988–1990	2.63	238	9
1991–1993	2.32	228	6
1994–1996	2.19	268	16
1997–1999	2.12	242	9
2000–2002	2.00	261	13
2003–2005	2.11	295	11
2006–2008	2.29	261	14

Key issues

• • Epilepsy is one of the most common neurological disorders, with two to five out of every 1000 pregnancies in the UK occurring in women with active epilepsy.

• • Women with epilepsy are at increased risk of having a child with major congenital malformations (3–9%).

• • Sodium valproate appears to carry an elevated risk of major congenital malformation, particularly in doses above 1000 mg daily.

• • Preliminary data suggests that teratogenic risk with some newer antiepileptics drugs (AEDs), such as lamotrigine and levetiracetam, is encouraging. However, topiramate may carry a high risk of cleft lip and palate and should be used with caution.

• • All women taking AEDs should take 5 mg folic acid preconceptually, due to the increased risk of major malformations with some drugs. Further studies are needed to confirm whether this has a protective effect.

• • There may be an association of in utero exposure to AEDs with neurodevelopmental delay. These changes are likely to be more common with sodium valproate exposure.

• • Reduced seizure control in pregnancy may be multifactorial. AED levels may be reduced during pregnancy due to vomiting, compliance issues and pharmacokinetic/physiologic changes. Sleep deprivation in later stages of gestation, and pain and hyperventilation associated with labor, may also predispose to seizures.

• • Reduced seizure control has been noted to be more common with some of the newer AEDs, for example, lamotrigine.

• • Children of women on enzyme-inducing AEDs should receive intramuscular vitamin K to reduce risk of hemorrhagic disease of the newborn.

• • Breastfeeding should be encouraged in mothers taking AEDs. Conventional and newer drugs are not associated with sedation to the same degree as older agents, and drug exposure through breast milk may reduce the potential for withdrawal symptoms following drug exposure in utero.

Acknowledgements

The authors would like to thank Ms Hannah Addley for her work in helping in this literature review.

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Managing epilepsy in pregnancy

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. You are seeing a 24-year-old woman who is considering becoming pregnant. She has a history of epilepsy that has been well controlled on multiple medications. What can you tell her as part of preconception counseling?

• □ A It is usually best to stop antiepileptic therapy (AED) immediately if conception is planned in the next 3 months

• □ B There is no evidence that the dose of AEDs affects the risk for congenital malformations

• □ C Treatment with folate should be initiated at a dose not to exceed 1 mg/day

• □ D Polytherapy with AEDs can promote more congenital malformations compared with monotherapy

2. You review this patient’s medications. Which of the following AEDs is associated with the most significant risk for major congenital malformations?

• □ A Sodium valproate

• □ B Carbamazepine

• □ C Lamotrigine

• □ D Levetiracetam

3. Five months later, the patient returns to your office and has a positive pregnancy test. What should you consider regarding the effects of epilepsy and AEDs during pregnancy?

• □ A There is clear evidence that the maternal use of AEDs during pregnancy results in neurodevelopmental delay in offspring

• □ B Phenytoin is associated with better neurodevelopmental outcomes among offspring compared with other AEDs

• □ C Epilepsy during pregnancy does not increase overall rates of maternal mortality

• □ D Topiramate may promote a higher risk for cleft lip and palate

4. The pregnancy progresses well through the first trimester. What should you consider regarding epilepsy during pregnancy and beyond?

• □ A The course of epilepsy invariably improves during pregnancy

• □ B Serum levels of most AEDs fall during pregnancy

• □ C Even simple partial seizures adversely affect the fetus in the third trimester

• □ D Breastfeeding should be avoided among women receiving AEDs