and FJE Vajda2
(1)
Clinical Neurology and Neuropharmacology, University of Queensland, and Honorary Consultant Neurologist, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
(2)
Department of Medicine and Neurology Director of the Australian Epilepsy and Pregnancy Register, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia
Abstract
This chapter draws on material discussed in earlier chapters in an attempt to provide a scientifically based discussion of the management of antiepileptic drug therapy in women with epilepsy who are planning pregnancy, while pregnant and in the postpartum period. The aim of the management is to maintain optimal control of epileptic seizures at all times while also minimising the risks to the foetus from developing structural malformations while still in utero and from encountering neurodevelopmental problems during infancy and childhood. The information regarding the management of antiepileptic drug therapy in pregnant women with epilepsy should also, for the most part, be applicable to the use of these drugs in pregnant women for indications other than epilepsy.
Managing epilepsy in women presents potentially more complex problems than managing the same disorder in men. This is so particularly because of issues related to pregnancy, a situation where appropriate management must take into account the welfares of both the woman concerned and that of her baby. Although epileptic seizure disorders may become manifest for the first time during the course of pregnancy, the great majority of women with epilepsy who enter pregnancy do so with the therapeutic management of their seizure disorders already instituted.
The following account attempts to consider the use of antiepileptic drugs in the woman who already possesses, or is likely to possess in the reasonably near future, reproductive capacity. It deals with her situation (i) before pregnancy, (ii) during pregnancy and (iii) in the postpartum period.
Before Pregnancy
Prior to pregnancy, it is desirable to have organised the antiepileptic drug treatment of the woman with epilepsy so that it provides the greatest advantage it can for her and for any baby that she may subsequently carry in her uterus. As well, the potential mother needs to have been provided with an understanding of the issues that are likely to arise in relation to her antiepileptic drug therapy during her pregnancy, and afterwards, and of how these issues may be managed.
The burdens that may result from having suffered epileptic seizure include the uncertainties arising from the possibility of further seizures occurring, the possibly of seizures causing physical injury, the small increased risk of sudden unexplained death occurring, the restrictions imposed on various aspects of daily living including vehicle driving and participation in sporting and certain recreational activities, the limitation of alcohol intake and the possibility that prescribed antiepileptic medications may cause adverse effects. Discrimination in relation to employment and employment prospects may still be encountered today by those with epilepsy. This situation exists despite the best efforts made by the medical profession, by recognised epilepsy associations whose memberships include scientists and paramedical personnel and by patient advocacy groups to remedy this situation, mainly through better educating the general community. A further major burden appears to arise from the fears of women with epilepsy that the children to whom they give birth may inherit their disorder and also may be born with physical malformations or with lower than average intellects.
The Initiation of Antiepileptic Drug Therapy
After adequate discussion of these issues with the woman concerned, if it is agreed that antiepileptic drug treatment is expected to hold overall advantages for her and her prospective offspring in any pregnancy that occurs, the matter of the most appropriate antiepileptic drug therapy in her situation has to be considered, even if she is already taking an antiepileptic drug, or drugs. If future pregnancy was not an issue, the decision about the choice of drug would be based mainly on the type of epileptic seizure disorder that was present and required treatment. However, in women who could become pregnant during the anticipated durations of their antiepileptic drug intake, the welfare of any foetuses that are conceived must also be considered in choosing the most appropriate drug. It will nearly always be easier to organise this choice of agent at the outset of treatment or early in its course than to attempt it later, often when pregnancy either is imminent, or already exists.
From the foetal harm point of view, it appears desirable that the antiepileptic drug that is chosen is not valproate and also probably not topiramate , if that is at all possible. The degree of teratogenicity associated with the other antiepileptic drugs in contemporary use is relatively small, perhaps virtually negligible, and there is no consistent evidence that it is dose related, unlike the situations in relation to valproate and topiramate.
The Initial Choice of an Antiepileptic Drug
Information on the selection of so-called first-line drugs for treating the two main categories of epilepsy syndromes, genetic generalised and focal (partial) epilepsies, is widely available but needs to be adapted to individual patients’ situations. The use of the more recently introduced second-generation antiepileptic drugs, with their improved tolerability profiles and comparable efficacies, increases the chances of achieving successful therapy, but it also poses a challenge for making the most appropriate choice of agent for the woman who may become pregnant (Pennell 2005; Perucca 2005). These newer drugs have not yet been thoroughly evaluated for their human teratogenicity over sufficiently long periods. As well, not all second-generation antiepileptic drugs are available worldwide. Regional and traditional prescribing differences, cost factors and lack of availability of specialist care may further complicate decisions as to choice of appropriate agent for a given woman (Tomson et al. 2007a).
Women with Genetic/Idiopathic Generalised Epilepsies
Valproate: Valproate, often marketed as its sodium salt, is generally accepted as being the most effective agent for preventing the seizures of the genetic generalised epilepsies . Unfortunately, valproate is also the antiepileptic drug with the greatest potential for being associated with foetal malformations (Chaps. 8 and 9) and also with cognitive and other neurodevelopmental problems in the offspring of pregnancy (Chap. 10). There is therefore reason to consider the relative expected efficacies of all the available appropriate drugs and also the disadvantages their use entails from the foetal standpoint, before deciding to prescribe valproate in preference to alternative agents in women with epilepsy who may become pregnant while they continue to need seizure-suppressing drug therapy.
Lamotrigine : The relative safety of lamotrigine from the standpoint of teratogenesis clearly favours this drug over valproate , but unfortunately lamotrigine is overall less effective in achieving seizure control in pregnant women as compared not only with valproate but also with another relatively new antiepileptic drug, viz. levetiracetam (Vajda et al. 2014). Early reviews of lamotrigine and its clinical application in epilepsy suggested that the drug would probably provide an excellent treatment option for patients with generalised epilepsies in pregnancy, a view that for a time subsequently became generally accepted (Choi and Morrell 2003). However, the increasingly reported problem of plasma lamotrigine levels falling relative to drug dose in each trimester (Pennell et al. 2008), the need for the drug’s slow introduction and its lesser seizure-preventing efficacy have tended to make its use less attractive (Vajda et al. 2006a). As well, Morrow et al. (2006) reported that in utero lamotrigine exposure could be associated with the occurrence of dose-related foetal malformations, and other studies have suggested that the drug is not free of responsibility for producing foetal malformations, though the degree of hazard is low, compared with that which applies for valproate (see Chap. 9).
Ethosuximide : Ethosuximide , an older drug for which there is virtually no evidence of teratogenicity (see Chap. 9), may be used to treat absence seizures in preference to valproate , if absences are the only type of seizure that is present (Glauser et al. 2013). In a controlled clinical trial, randomly allocated ethosuximide (N = 156), valproic acid (N = 148) and lamotrigine (N = 149) were compared in treating childhood absence epilepsy. Drug doses were incrementally increased until seizure freedom was obtained, or the maximal allowable or highest tolerable dose was reached, or a criterion indicating treatment failure was met. Freedom-from-failure rates for ethosuximide and valproic acid were similar (53 and 58 %, respectively), both being higher than the rate for lamotrigine (29 %). There were no significant differences among the three drugs with regard to discontinuation of intake because of adverse events. Attentional dysfunction was more common with valproic acid than with ethosuximide (in 49 % of the children compared with 33 %). The findings of this study suggests that, in women of childbearing potential who have genetic generalised epilepsies that are manifested only as absence seizures , itself an uncommon situation, ethosuximide may provide more appropriate monotherapy than lamotrigine in relation to seizure control efficacy and be safer than valproate in relation to avoiding teratogenesis . However, there is not enough evidence to know the situation regarding ethosuximide and neurodevelopmental impairment.
Other possibilities: Levetiracetam , zonisamide and topiramate appear to be less effective than valproate in treating genetic generalised epilepsies , though on the basis of currently available evidence in terms of teratogenicity the first two appear to be more acceptable. However, the evidence regarding relative teratogenic hazards is not as extensive as might be desirable. Topiramate probably is less well tolerated than levetiracetam and zonisamide, and the evidence that it is a dose-related teratogen further deters its use.
Valproate and the European Medicines Authority : In 2014 the European Medicines Authority issued a statement which in its effect has restricted physicians’ choice of antiepileptic medications within the European Union. The statement declared that it is inadvisable to prescribe valproate for women of childbearing age who suffer from epilepsy and also for such women at earlier stages in their lives, because of the documented teratogenicity of the drug. The wording employed was ‘This medicine should not be used in women of child-bearing potential unless clearly necessary’ and should only be used in situations ‘where other treatments are ineffective or not tolerated’. References were cited in the declaration that supported this statement, but comments by the European Pregnancy Registry (EURAP ) and a statement from the International League Against Epilepsy, which represents all countries worldwide in terms of epilepsy management, were not included (Meador et al. 2008, 2009, 2013; Bromley et al. 2008; Cummings et al. 2011; Thomas 2011; Christensen et al. 2013; Cohen et al. 2013).
This action by the European Medicines Authority is appropriate up to a point, but the statement may have different implications in Europe than in other parts of the world. From a regulator’s perspective such a statement is understandable, but it fails to give appropriate weight to the harm that may result from failure to employ the most effective available therapy for a major type of epilepsy. To limit prescription of the drug to situations where all other potential useful therapy has first been found wanting may endanger women’s lives and the lives of their foetuses if, for instance, otherwise avoidable status epilepticus were to occur.
Women with Focal (Partial) Epilepsies
Overall, focal epilepsies are more difficult to treat effectively than genetic generalised ones, but a wider choice of reasonably satisfactory antiepileptic drugs is available for their management. The choice between these drugs in women with epilepsy is based on a comparison of the risk–benefit ratio that would be expected to apply in each given individual. Initially, antiepileptic drug monotherapy is almost always tried, and if this fails combinations of antiepileptic drugs, preferably drugs with different mechanisms of action, are employed. In the future, the choice of drug may be made more efficiently if more robust documentation of efficacy of newer antiepileptic drugs can be obtained from epilepsy syndrome-oriented trials than was possible from, as in the past, trials based on seizure types.
There is little persuasive evidence that any one of the rather substantial number of antiepileptic drugs that are effective in managing focal epilepsies is appreciably more effective than its fellows. However, there is rather widespread acceptance that the older agents such as phenobarbitone and phenytoin probably have more adverse effects and are often more difficult to use, than the newer agents. Carbamazepine , despite being available for half a century, still enjoys substantial use but valproate ’s adverse effects on the foetus limit its use for focal epilepsies because there are a number of at least equally effective alternatives. Inevitably, in more affluent countries, the more recently introduced antiepileptic drugs are becoming the preferred agents for managing focal epilepsies , though globally phenobarbitone probably remains the most widely used antiepileptic agent (Kwan and Brodie 2004).
Lamotrigine is of particular interest in relation to women with focal epilepsies . It was originally introduced into therapeutics in 1994 for the treatment of this type of epilepsy, but its indications were later extended to include genetic generalised epilepsies (see above). Some adverse effects attributable to the drug may be serious, including rashes and immunological disturbances ranging as far as a full-blown Stevens–Johnson syndrome, which may be fatal. Slowly incremented dosages of the drug may reduce its unwanted effects. A desirable feature is that lamotrigine administration may produce a mood elevation. There is no generally accepted therapeutic range of plasma concentrations of the drug, and an individual therapeutic window needs to be established for each patient who takes the drug (Vajda et al. 1999; Perucca 2001).
Levetiracetam , marketed in 2005, has a pharmacokinetic profile which approximates to the ideal characteristics for an antiepileptic drug. It is involved in few known drug interactions and has a considerable margin of safety (Patsalos 2000; Mula et al. 2003) and probably possesses greater antiepileptic efficacy than the other new antiepileptic drugs (Tomson et al. 2007b; Weintraub et al. 2007). In clinical practice, its use may be associated with dose-related cognitive slowing and emotional disturbances, which are less than ideal for women with epilepsy, who may already be emotionally stressed.
Topiramate is approved in a number of countries for the treatment of both focal and genetic generalised epilepsies , though the growing evidence of its teratogenicity does not yet seem to have been perhaps sufficiently been taken into account. Oxcarbazepine has been used safely in Scandinavia for over two decades. In focal seizures it has an efficacy comparable to that of valproate and phenytoin , in both adults and in children. It is generally better tolerated than carbamazepine , but its use is associated with a higher incidence of laboratory abnormalities, especially hyponatraemia . Insufficient data are available in regards to its effectiveness, acceptability and foetal safety in pregnancy. Gabapentin is generally perceived to be less effective than the other alternatives for focal epilepsies but appears remarkably safe at usual dosages. Little information is available regarding its efficacy in pregnancy. Zonisamide appears to have no significant associated teratogenicity as yet reported. Lacosamide has not been extensively used in pregnancy and little information is available concerning its teratogenicity. As mentioned above, all the drugs named in this paragraph are coming to be used increasingly in focal epilepsy in pregnant women, being prescribed according to individual needs and preferences (Boon et al. 2012). However, they have not yet found their definitive places in the management of focal seizure disorder in pregnant women.
The Further Management of Antiepileptic Drug Therapy Before Pregnancy
It is hoped that, once the woman with epilepsy is established on appropriate antiepileptic drug therapy, there will be sufficient time before pregnancy occurs to ascertain that the aim of her treatment has been achieved. Ideally, she should have been kept free of all clinical manifestations of her epilepsy and have experienced no adverse effects from her drug therapy. She should also be in a situation where her treatment offers her the least risk of worsened seizure control in any pregnancy that she undertakes and also in a situation in which any foetus that she carries will not suffer physical or intellectual maldevelopment because of her antiepileptic drug intake.
Seizure control during pregnancy has been shown to be better when no seizures have occurred in a woman’s pre-pregnancy 9 months or year (Chap. 7). Control over shorter periods before pregnancy is still associated with advantages from the standpoint of seizure freedom during pregnancy, while the data of Fig. 7.1 suggest that no considerable additional dividends may accrue from having periods of pre-pregnancy seizure control that exceed 1–2 years. It is often stated in the literature that, if valproate is to be used, it should be employed in the lowest possible dose, though in practice achieving this endpoint may require months of dosage adjustments. This advice may be prudent but, if the possible alternatives to its use have already proved unsatisfactory in a woman, she may have an epilepsy that is rather difficult to control. In this case, relatively high valproate doses may be required to obtain seizure control. After that control is achieved, the effort to find the lowest effective dose of the drug may involve trialling dose reductions that in the end compromise earlier hard-won seizure suppression and, if pregnancy occurs, may still leave her foetus with a significant risk of being born malformed. In a way, the situation may be easier to manage if the woman’s epilepsy has been impossible to control for some time despite the best therapeutic endeavours. From the social disadvantage standpoint, paradoxically, such a woman has less to lose than the woman whose controlled seizures have been permitted to recur while seeking the lowest effective valproate dose. If valproate must be used in a woman with an intractable seizure disorder, it may be realistic to keep its dosage low enough to avoid worsening of seizure control during pregnancy rather than attempting to obtain complete seizure control, even though this policy may expose the woman to the hazards of injury or rarely death, in relation to seizures, in the hope of minimising foetal harm.
To obtain seizure control prior to pregnancy, if the first antiepileptic drug that was prescribed has failed, ideally various other potentially appropriate antiepileptic drugs would be tried in monotherapy before drug combinations were employed. In practice, rather than abruptly ceasing the first drug and immediately commencing intake of a second one, a progressive transition between the two agents is often arranged. If a completely satisfactory clinical situation is attained during the transition, the patient may be left taking a combination of agents. There has been considerable mention in the literature that the use of antiepileptic drug combinations , i.e. polytherapy , is associated with increased risks of foetal malformations occurring (Nakane et al. 1980; Kaneko et al. 1992; Lindhout and Omtzigt 1992; Samrén et al. 1997; Morrow et al. 2006). However, as discussed in Chap. 8, several relatively recent studies have demonstrated that the heightened malformation risk is determined by the presence of valproate in the combinations and not simply by the presence of any two or more antiepileptic drugs (Artama et al. 2005; Vajda et al. 2010b; Mawer et al. 2010; Holmes et al. 2011). As mentioned in Chaps. 8 and 9, there is now evidence that topiramate may play a similar role to valproate in antiepileptic drug combinations . Further, the possibility of pharmacokinetic interactions occurring between members of other antiepileptic drug combination may make a scientific approach to their handling more difficult to apply in practice. The magnitudes of such interactions may change as drug disposition parameters alter during the course of pregnancy and afterwards (see Chap. 3).
In an ideal situation, once antiepileptic drug therapy has been adjusted before pregnancy to achieve the best achievable compromise between seizure control and preservation of the welfare of any prospective foetus, knowledge of the steady-state plasma concentration of antiepileptic drugs associated with this satisfactory situation becomes a valuable, perhaps almost essential, guidepost for managing the treatment situation during the course of pregnancy.
Pre-pregnancy Advice
Qualitative research suggests that many women with epilepsy remain uninformed about the risks and other issues associated with epilepsy and pregnancy. They may, as a result, make uninformed and sometimes inappropriate decisions. Evidence suggests that many women with epilepsy want to receive more information – particularly about the risks that exposure to antiepileptic drugs may hold for their offspring – and that they wish to receive it well in advance of beginning to take an antiepileptic drug or to plan pregnancy. Women aged below 35 years, in particular, seem to seek the most information (McGrath et al. 2014). There also may be other matters which have not occurred to them at the stage when they ask for information, but which they should know about. Leaving aside aspects that are predominantly matters of obstetric concern and practice, this information relevant to antiepileptic drug therapy in pregnancy can be provided below in the form of answers to questions that women with epilepsy who are considering pregnancy may well ask.
Will I have a malformed baby ?
Here the first point to be made is that any pregnant woman has some risk of giving birth to a baby with a malformation. The risk is of the order of 2 or 3 per 100, and the malformations can range in severity between the cosmetically almost trivial and the catastrophic, though many of the latter can be detected during pregnancy and appropriate action considered at that stage. The woman with epilepsy needs to realise that the essential matter that she should appreciate is the extent to which her antiepileptic drug use increases her risk of giving birth to a malformed baby above the general population background risk of this happening.
In the present state of knowledge, it is possible to state that, with the exception of valproate and topiramate , the increase risk associated with the longer established antiepileptic drugs that remain in common use is probably a real one but so small that it cannot be demonstrated unambiguously in the available statistics. For practical purposes, it would be almost negligible for the individual woman. Unfortunately, it cannot be stated definitely that any of the newer antiepileptic drugs is associated with less risk of birth defects than the older agents (excluding valproate and topiramate). There simply is not enough information available regarding some of the recently introduced drugs such as lacosamide and perampanel to permit any firm advice. This is a situation that is likely to continue for some time. Further, it needs to be pointed out that there is now evidence that some of the risk of a malformed baby being born to a woman with an antiepileptic drug-treated seizure disorder is related to genetic factors (see Chap. 8). It is therefore important to ascertain whether the woman concerned has a family history or past history of births of malformed babies. Such a history could significantly increase the woman’s hazard of having a malformed baby and may suggest the need for genetic counselling.
If the woman with epilepsy is taking valproate or topiramate , she should be made aware that her risk of a malformed baby due to exposure to the drug is increased and that the risk increases with increasing drug dosages, with higher doses of valproate than are now customarily used being associated in particular with the occurrence of neural tube defects (Vajda et al. 2013). There is no standard pattern of malformation associated with either of these two drugs. Some of the malformations are relatively minor, and they and others may be surgically remediable. In addition to the hazard of giving birth to a malformed baby, the woman taking valproate need to be told that relatively recent investigations have shown that babies born to mothers taking valproate, even if not physically malformed at birth, are more likely to prove less intelligent than their peers and are also more likely to develop behavioural disturbances and autism spectrum manifestations. It is not yet possible to indicate the degree of risk of these latter situations occurring. For topiramate exposure in pregnancy, the dose-related malformations appear to be mainly facial clefts and hypospadias , both at least to an extent remediable surgically. The prospective mother certainly should be made aware of this matter. There does not appear to be sufficient evidence available to permit any definite statement regarding the possibility of neurodevelopmental problems associated with intrauterine exposure to this drug.
Overall, if the woman with epilepsy that is treated with antiepileptic drugs is not taking valproate or perhaps topiramate or one of the very recently available drugs for which the relevant information is not yet available and has no previous or family history of potentially inheritable foetal malformations, the answer to the question posed above should not be likely to deter her from becoming pregnant.
Will the drugs increase my risk of miscarriage or other pregnancy problem?
In so far as consequences of taking antiepileptic drugs are concerned, as distinct from the effects of seizures occurring, there does not appear to be clear-cut evidence of an increased hazard.
What will happen if I do not take antiepileptic drugs when pregnant?
This question arises out of the widespread community awareness that any therapeutic drug intake during pregnancy is undesirable from the foetal standpoint and from the more specific knowledge that foetal malformation and other hazards may be associated with intrauterine antiepileptic drug exposure.
It seems entirely reasonable to expect that the increased foetal malformation risk associated with antiepileptic drug exposure in utero would be avoided if a woman were to cease her antiepileptic drug intake before the time of conception and continued not to take these drugs during at least the first trimester of pregnancy, the critical stage for organogenesis. Doing this would in practice involve ceasing the drugs before conception occurs, as taking such action once it is realised that pregnancy exists may be too late to achieve the desired outcome. Unfortunately, as far as can be ascertained, there is little published evidence that such cessation of therapy does reduce the malformation risk to the level of the community background one, but on the other hand, there is no evidence that it does not. In so far as foetal neurodevelopmental problems are concerned, an issue that at present mainly concerns valproate , it seems likely that intake of the drug would have to be avoided throughout the entire duration of pregnancy and possibly also while breastfeeding .
The possible benefits for the baby in this scenario have to be balanced against possible disadvantages for the mother, and some of the maternal disadvantages may possibly extend to the baby. There is the likelihood of seizure control worsening, perhaps with status epilepticus occurring and perhaps damaging the mother or foetus or interrupting the pregnancy. Loss of seizure control in more advanced and complicated societies may impose various limitations on the mother, particularly in relation to vehicle driving. This restriction may reduce her capacity to care for other members of her family, as well as the baby whose welfare she has tried to protect by avoiding antiepileptic drug intake.
The possibility might be considered that a more teratogenic drug could be replaced with a less teratogenic but perhaps also less effective antiepileptic one for the duration of the pregnancy or for part of it. In the woman with apparently fully controlled epilepsy before pregnancy, unless the substitution was carried out long enough before conception to be sure that seizure control was maintained, the various limitations imposed by potentially uncontrolled epilepsy would again apply, as well as the further problems that might arise from any return of seizures. If the woman’s epilepsy was already incompletely controlled before pregnancy, the same social disadvantages would already apply, but difficulties could arise from increased frequency or severity of seizures. As well, the substituting drug might produce adverse effects in the woman now taking it.
A decision to interrupt, or modify, antiepileptic drug therapy in preparation for pregnancy needs to be made on the basis of a clear and realistic understanding of the issues likely to be involved. The experience of the Australian Pregnancy Register suggests that some women with epilepsy do take this decision, being prepared to deliberately sacrifice their own welfare for the potential benefit of their foetuses. Thus Vajda et al. (2015) recorded that in the Register , 148 of the women with epilepsy had entered pregnancy when not taking antiepileptic drugs. The intake of these drugs had been ceased in the few months prior to pregnancy in 41.9 % of these women, usually with the explicit aim of avoiding foetal exposure to the effects of these agents. In this subset of the original 148 untreated pregnancies, seizures had been experienced in 48.4 % during the pregnancy, and by term antiepileptic drug intake had been resumed in 56.4 %.
Will I be able to breastfeed ?
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