The Management of Epilepsy During Pregnancy

Keywords::

• epilepsy
• malformations
• seizures

In 1901, Sir William Gowers [1] wrote regarding epileptic attacks that “pregnancy sometimes makes no difference to the disease, but, on the other hand, in the majority of cases they are less frequent during gestation”. In contrast, 6 years later WA Turner [2], a fellow London consultant, when considering the effects of pregnancy on epilepsy commented “it is more common to find a relapse of the attacks, or the conversion of a minor type of the disease into the combined major and minor type”. The passage of a century has not fully reconciled these views.

When Gowers and Turner wrote, potassium bromide was the only even modestly effective and not unacceptably toxic antiepileptic drug that was available. Neither they nor their immediate successors seemed to consider that pregnancy might alter the body's handling of this drug and thereby influence the situation they were considering. Nor did they seem to give thought to the welfare of the fetus that was involved.

Since then, the situation has changed. Potassium bromide has been replaced by better and safer agents. It has become clear that pregnancy alters the dispositions of most antiepileptic drugs. An increasing awareness of drug-related fetal malformation has followed the experience of the thalidomide tragedy, while evidence of post-natal neurodevelopmental consequences of intrauterine exposure to certain antiepileptic agents is becoming available.

Pregnancy appears to increase the clearances from the body of all of the more commonly used antiepileptic drugs. This reduces the circulating and biophase concentrations of these drugs relative to their doses, thus potentially compromising seizure control if the concentration decrease is sufficient. The plasma protein binding of certain of the drugs is reduced in later pregnancy, while the expanded body volume of the overall materno–fetal unit has a diluting effect on biophase drug concentrations. The capacities of the existing metabolic pathways of drugs that are cleared predominantly by biotransformation tend to be enhanced, though, so far, there appears to be no evidence that new metabolic pathways develop. There is increased urinary excretion of drugs that are cleared predominantly in unmetabolized form because of the increased glomerular filtration rate that occurs during pregnancy. These increased drug clearances mechanisms tend to reduce circulating drug concentrations to different extents and at different stages of pregnancy, and also vary between individuals, but tend to have their maximum effects before the final trimester of pregnancy. The increased clearances tend to revert to their nonpregnant values at different times in the weeks following childbirth. Clinicians have a strong impression that adjusting antiepileptic drug dosages to maintain circulating plasma (or better, plasma water) drug concentrations at prepregnancy values throughout pregnancy usually avoids lessened seizure control at that time.

This impression is in keeping with the notion that, in general, epilepsy does not become worse during pregnancy. However, a study of pregnant women with epilepsy who did not take antiepileptic drugs in the weeks before and at least during the earlier months of pregnancy found that more of these women experienced seizures during pregnancy than in their prepregnancy year [3]. Knowledge of this finding may be important for women who contemplate ceasing antiepileptic drug therapy in preparation for pregnancy.

Awareness of altered drug disposition during pregnancy has led to a policy of monitoring circulating antiepileptic drug concentrations at appropriate intervals from early in pregnancy and adjusting drug dosages to maintain the concentrations that were associated with satisfactory seizure control before pregnancy, or in an attempt to achieve such control in pregnancy. Falling drug concentrations in pregnancy are not inevitably associated with seizure disorder worsening. The lowered concentration may still exceed the individual's seizure control threshold concentration. However, maintaining the concentrations at satisfactory prepregnancy values should not produce overdosage-type drug toxicity. Antiepileptic drug concentrations may rise quite quickly in the postnatal weeks, and reasonably frequent plasma drug concentration monitoring and dosage adjustments may be required to avoid overdosage-type adverse effects occurring and being incorrectly attributed to maternal tiredness and interrupted sleep when coping with a newborn infant.

After the thalidomide tragedy, suspicion began to fall on antiepileptic drugs as possible teratogens. Probably the first to be incriminated was troxidone (trimethadione), used for absence seizures. This drug disappeared from the market after reports of facial malformations in infants and the advent of the more effective and less toxic ethosuximide. Subsequently there were sometimes conflicting reports concerning fetal abnormalities associated with intrauterine exposure to different more commonly employed antiepileptic drugs, but these were based on comparatively small datasets. With more extensive information, usually derived from whole population birth defect collections or special registers that record the outcomes of antiepileptic drug use in pregnancy, the position became reasonably clear. There is sufficient evidence to incriminate valproate as a dose-related teratogen [4–7] and evidence suggesting that topiramate possesses a dose-related teratogenicity capacity, at least when used combined with other antiepileptic drugs [8]. It is not yet clear whether the latter teratogenicity relates to products of a drug–drug interactions, or whether it simply results from insufficient data because the drug is not often used in monotherapy, at least in higher dosages. Some not entirely persuasive evidence suggests that carbamazepine may possess some relatively weak teratogenic capacity [7,9,10]. There are grounds to exculpate levetiracetam, clonazepam and probably lamotrigine. Phenobarbitone was sometimes considered teratogenic but is so little used in contemporary practice that the pregnancy registers do not contain sufficient information to permit a soundly based interpretation. There does not appear to be sufficient information available to exclude the other longer established antiepileptic drugs in contemporary use from teratogenic roles, though at the worst they are unlikely to be highly teratogenic. The earlier idea that antiepileptic drug combinations increased the teratogenicity hazard has been shown to depend on the presence of valproate or topiramate in the combinations [11–13].

Unlike the situation that applied for thalidomide, which produces a particular pattern of fetal malformation, the teratogenesis of antiepileptic drugs involves a wide range of organs and organ systems and produces abnormalities that range in severity from the quite minor to the devastating.

In recent years there have been reports of a relationship between intrauterine antiepileptic drug exposure and disorders of neurodevelopment which become manifest in childhood. There is evidence of such an association between valproate, but not other commonly prescribed antiepileptic drugs, and lowered intelligence quotients and autism spectrum disorders [14,15]. At present, the stage of pregnancy at which valproate initiates these abnormalities is unclear.

Currently, newer antiepileptic drugs such as lacosamide, perampanel, zonisamide and breviracetam are coming into increasing clinical use and their names are beginning to appear in pregnancy registers. Sufficient knowledge of pharmacokinetic principles is available to predict what is likely to happen to their dispositions during pregnancy, and for their dosages to be adjusted, if necessary, on this basis. Nevertheless, whether the predictions hold true in clinical practice needs to be determined. The potential of these newer agents for human teratogenicity is uncertain, and awaits the accumulation and analysis of sufficient data. Paradoxically, the lack of this knowledge is likely to deter the responsible use of these agents in pregnancy, thus delaying the accumulation of the desired teratogenicity information. Particularly if safety concerning neurodevelopment is an issue, by the time these drugs are shown safe for the fetus they may have become superseded in general use by better agents. So far, preclinical testing during drug development seems incapable of detecting what has subsequently proved to be significant human teratogenicity, though it may have detected teratogenicity sufficient to preclude drugs reaching the market place. Currently, no easy solution to the issue seems in sight.

Another contemporary issue concerns valproate and teratogenicity. The extent of the drug's teratogenicity, relative to that of other antiepileptic agents, has resulted in the view that valproate's use should be avoided, as far as practicable, both in women who are pregnant and in women who are likely to, or even who may at some future time, become pregnant. If valproate's use is unavoidable, because there is no adequate alternative, it seems prudent to prescribe it in the lowest dose that will achieve a tolerable compromise between control of seizure activity and fetal safety. There has lately been a proposed strengthening of an EMA statement concerning this matter. The proposed new version seems to mandate that the drug not be used in pregnancy (except perhaps as a last resort), and not used at all in females of child-bearing capacity unless contraceptive measures are employed, or no satisfactory alternative exists [16]. Certainly, these situations are ones where good will and some nicety of judgement on the part of all concerned are desirable to attain the best achievable compromise between the welfare of mother and fetus, but the proposed almost absolute prohibitions seem rather too inflexible and set the balance between the interests of mother and fetus a little too much in favor of the latter. Their acceptance may also encourage litigation. Who would be held blameworthy if a pregnant woman with seizures that were previously fully controlled by valproate, and also her fetus, were to die in a seizure that occurred after the drug was withdrawn?

Problems in managing epilepsy during pregnancy continue to trouble the clinician.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.