Over the course of some 30–40 years, medicine has accumulated a good deal of information concerning antiepileptic drugs and their use in pregnant women. From a practical standpoint, perhaps the most important items of knowledge that have emerged from this work are that (i) nearly all antiepileptic drugs are cleared from the maternal body more rapidly during pregnancy, whether or not this increased elimination is due to heightened metabolic activity or to greater renal excretion of un-metabolised drug and (ii) intrauterine exposure of the foetus to at least some of these drugs results in the hazard of physical malformation occurring in the foetus and, after birth, in the possibility of disordered neurodevelopment in the infant. At least in theory, the application of this knowledge should have ensured better control of antiepileptic drug-treated seizure disorders during pregnancy, and the avoidance to some extent of the hazards that an injudicious choice of antiepileptic drug therapy may impose on the physical, intellectual and behavioural development of the foetus and infant.

As mentioned at several places earlier in this book, there are reports that the attempted adjustment of antiepileptic drug dosages at appropriate stages during the course of pregnancy, particularly if guided by knowledge of circulating concentrations of antiepileptic drugs and pre-pregnancy reference drug concentration values, appears to have had some success in preventing any worsening of epileptic seizure control in pregnant women. Through this means, some of the disadvantages that having active epilepsy is likely to produce for the prospective mother’s pattern of living may be minimised, or avoided entirely. The recognition that certain antiepileptic drugs that are currently in common use during pregnancy in Western countries, notably valproate and topiramate , are particularly prone to be associated with the occurrence of foetal malformations, and for the hazard of such malformations to worsen as the dosages of these drugs increase, has altered prescribing practice in relation to valproate, at least among those sections of the Australian medical profession who have appreciated the drug’s dangers for the foetus. As illustrated in Fig. 9.​2, over the years during which the Australian Pregnancy Register has been collecting information, both the mean daily valproate dose in those women with epilepsy prescribed the drug and the proportion of pregnant women receiving the drug have tended to fall progressively, accompanied by a degree of downward trend in the numbers of malformed foetuses reported to the Register . Unfortunately, from this register ’s data, it is impossible to know whether there has been a similar change in prescribing behaviour among the Australian medical profession more generally, let alone among medical practitioners globally. It is also impossible to know whether those who are using the drug to treat disorders other than epilepsy, especially various psychiatric conditions, have been influenced by this knowledge concerning the foetal hazards arising from intrauterine valproate exposure. Valproate dosages used in psychiatry and in some other medical specialties sometimes appear to be high relative to those likely to be used in treating epilepsies. If so, there may be a particular danger of foetal malformations occurring if women treated with such dosages find themselves pregnant unexpectedly. They then face the possibility of abrupt withdrawal of potentially teratogenic medication, a process that may produce its own problems, without any certainty that this course of action is not being taken already too late to avoid foetal damage. The information concerning topiramate and its teratogenic potential is too recent to have yet had time to exert any widespread influence.

As well as these practical dividends, the accumulated information that has been obtained regarding the behaviour of antiepileptic drugs in human pregnancy has raised a number of interesting scientific questions whose answers, though they may not yield immediate practical dividends for women with epilepsy, may open future possibilities. For instance, although there is already a reasonable general understanding of the mechanisms responsible for the increased antiepileptic drug clearance that occurs during pregnancy, neither the detailed renal nor the metabolic mechanisms involved in the clearance increases have been anything like thoroughly explored.

There has been little attempt to study the possible relationships between circulating concentrations of antiepileptic drugs and the risks of developing specific patterns of foetal malformation. Such attempted correlations in the past certainly paid dividends in improving the control of epileptic seizures. However, in practice, there would probably be considerable difficulty in organising the drug concentration measurements so that they were carried out not only at the appropriate time in the first weeks of pregnancy but also at the appropriate stage of the dosage interval, because it is not known, for instance, when are the critical times for particular patterns of foetal damage to occur. Is it the time of peak circulating drug concentrations or the time of the trough steady-state ones, that would be more relevant? Further, it is not certain whether the teratogenic potential of a drug resides in the parent substance, or in a drug metabolite, or metabolites. Up to perhaps 50 women would have to be studied to obtain the relevant drug concentration data for correlation with a single incidence of a malformation. The logistics of such a study, carried out in a sufficient number of pregnancies, would probably prove both challenging and expensive.