Review
Treating epilepsy in pregnant women Mervyn J Eadie 1.
Introduction
School of Medicine and Biomedical Science, University of Queensland, Brisbane, Australia
2.
Maternal factors
3.
Foetal factors
4.
The management of epilepsy
Introduction: The management of epilepsy during pregnancy involves achieving the best compromise between the sometimes competing aims of maintaining the well-being of the prospective mother and that of her foetus. Recently available knowledge helps achieve this by providing a better understanding of the hazards that intrauterine exposure to antiepileptic drugs holds for the development of the body structure and aspects of the intellect of the human foetus. The newer knowledge also helps explain why maternal seizure control may deteriorate during pregnancy, and how this risk may be avoided. Areas covered: A survey of the relevant English language literature concerning human epilepsy and pregnancy, foetal outcomes from pregnancy in women with epilepsy, and antiepileptic drug pharmacokinetics and clinical efficacy during pregnancy was carried out Expert opinion: A mother’s past history of foetal malformations, and the intake of valproate during a pregnancy, are significant factors in increasing the hazard of malformations during that pregnancy. Therefore, as far as reasonably possible, valproate use during pregnancy is better avoided. Full seizure control in the pre-pregnancy year, and adjusting antiepileptic drug doses to maintain plasma drug concentrations throughout pregnancy at values associated with seizure control before pregnancy, have major influences in preserving seizure control during pregnancy.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 05/24/14 For personal use only.
during pregnancy 5.
Conclusion
6.
Expert opinion
Keywords: antiepileptic drugs, epilepsy, foetal malformations, neurodevelopment, pregnancy, seizures, teratogenesis Expert Opin. Pharmacother. (2014) 15(6):841-850
1.
Introduction
Treating epilepsy in pregnant women involves considerations additional to those that apply in treating epilepsy in women outside pregnancy. In pregnancy two living beings are involved simultaneously in the treatment processes, with the welfare of the younger almost wholly dependent on the welfare of the older. Epilepsy treatment aims at achieving freedom from all epileptic seizures, and in pregnant women this aim has to be achieved without disadvantaging the foetus both in utero, and in subsequent post-natal life. Some of the extra factors that need to be taken into account in treating pregnant women with epilepsy primarily involve the mother, whose altered physiology in pregnancy may affect both the seizure disorder process, and the body’s disposition of the drugs prescribed to suppress that process. Other factors primarily concern the foetus, for example, the effect of the maternal epileptic process on the foetus, and the effects of antiepileptic treatments taken by the mother on foetal intrauterine and post-natal development.
10.1517/14656566.2014.896902 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
841
M. J. Eadie
Effects of pregnancy on antiepileptic drug disposition
2.2
Article highlights. .
.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 05/24/14 For personal use only.
.
. .
.
A history of a malformed foetus in a previous pregnancy increases the risk of bearing a malformed foetus in the next pregnancy. Valproate, used alone or in conjunction with other antiepileptic drugs, is a dose-related teratogen that is better avoided by pregnant women, and the wisdom of its use in females of child-bearing potential needs to be considered if a suitable alternative is available. In most circumstances, the degree of risk of foetal malformation is not high enough to warrant replacement of the other commonly used antiepileptic drugs during pregnancy. Levetiracetam seems to be emerging as the antiepileptic drug of choice for use in pregnant women. Freedom from seizures in the pre-pregnancy year is a major determinant of whether a woman with treated epilepsy will have seizures during pregnancy. Antiepileptic drug dosage adjustments guided by measurement of drug concentrations in plasma seem to help prevent deterioration in seizure control during pregnancy.
This box summarises key points contained in the article.
These factors will be considered subsequently, seriatim, with a particular interest in the post-1990 generation of antiepileptic drugs, for example, lamotrigine, topiramate, levetiracetam, gabapentin, zonisamide, and oxcarbazepine, which are currently coming into increasing use in pregnant women [1-3].
2.
Maternal factors
Effects of pregnancy on maternal seizure disorders
2.1
Since the publications of Knight and Rhind in 1975 [4] and Schmidt in 1982 [5], there has been continuing disagreement as to whether epileptic seizure disorders worsen during pregnancy. Reasonably effective antiepileptic drug therapy, first in the form of potassium bromide, has been available since 1857 [6]. Consequently, the question of the effects of pregnancy on epilepsy contains within it another question, namely, does pregnancy alter the effectiveness of antiepileptic therapy? Evidence for that possibility has been available since the 1970s [7,8], and there is now fairly widespread acceptance that the lowered circulating antiepileptic drug concentrations relative to drug dose that often develop during pregnancy, sometimes made worse by deliberate non-compliance with prescribed drug dosage, is the major factor responsible for any worsening of seizure disorders that occurs in pregnancy [9]. Whether pregnancy per se contributes more directly to a worsening of seizure control remains uncertain. The review of Harden et al. [10] concluded that no definite opinion concerning the matter was justifiable. 842
The altered physiology of the female body during pregnancy has implications for various aspects of antiepileptic drug disposition, particularly drug clearance [11]. The increased body fluid volume of the maternal--foetal unit may have a diluting effect that reduces plasma and biophase drug concentrations, especially for drugs with relatively small apparent volumes of distribution. In later pregnancy decreased plasma albumin concentrations of drugs that are normally bound to plasma proteins may produce higher plasma water and biophase concentrations of drug relative to concentrations in whole plasma. This effect may confound the interpretation of conventional whole plasma drug concentration measurements. Overall, the above changes are usually of little clinical consequence in relation to antiepileptic drugs. In contrast, the increased clearances of antiepileptic drugs that occur in most pregnant women may have substantial effects. Renal function and glomerular filtration rate are increased in pregnancy, leading to increased losses from the body of drugs which are cleared mainly by renal excretion in un-metabolised form, for example, gabapentin and levetiracetam [12]. Consequently, plasma concentration--dose ratios for these drugs fall during pregnancy. However, biotransformation is the main route of clearance of most antiepileptic drugs, as indicated by their low proportions of dose excreted intact in urine. In pregnancy, increased clearances occur for drugs whose first stage of metabolism is through cytochrome P450 activity or glucuronidation. Induction of the responsible enzymes usually begins in early pregnancy and continues until near term. The consequent effects on the ratio of plasma drug concentration to dose become noticeable at different times in different women, sometimes appearing in the initial weeks of pregnancy. There is considerable inter-individual variation in the magnitude of the clearance change for a given drug, and between drugs. Overall, drugs cleared by glucuronidation as a Phase I mechanism, for example, lamotrigine, show the greatest changes [13]. The extents of the clearance increase can show considerable variation between pregnancies in the same woman [14]. For antiepileptic drugs as a class, these increased drug clearance processes cause plasma and biophase drug concentrations, and hence pharmacological activity, to decrease relative to drug dose during pregnancy. This may compromise seizure control during pregnancy [14] unless appropriate drug dosage adjustments are made. Such dosage adjustments, guided by plasma drug concentration measurements, can prevent the worsening of seizure control [9,15]. Details of the clearance mechanisms and certain pharmacokinetic parameters for the antiepileptic drugs currently in common use and those obtaining a foothold in the market, are shown in Table 1. The more recently introduced of these agents have not yet attained widespread use in pregnant women, largely because adequate information on their human teratogenic potentials is not available. More detail concerning
Expert Opin. Pharmacother. (2014) 15(6)
Treating epilepsy in pregnant women
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 05/24/14 For personal use only.
Table 1. Pharmacokinetic values for antiepileptic drugs. Drug
% protein bound
Carbamazepine Carbamazepine-10,11-epoxide Clobazam Desmethyl clobazam Clonazepam Ethosuximide Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Monohydroxy- carbazepine Phenobarbitone Phenytoin Pregabalin Primidone Tiagabine Topiramate Valproate
~ 75 85 82 -- 90
Vigabatrin Zonisamide
0 40 -- 60
86 0 0 55 0 ~ 40 40 ~ 55 ~ 90 0 0 -- 20 > 95 9 -- 17 85 -- 95
M:P ratio
% unchanged in urine
0.3 -- 0.4 ~ 0.5
1 1 -- 2 Low 1 17 -- 38 > 0.93 0.10 0.66 Low
08 -- 0.9 0.7 -- 1.3 0.06 -- 1.47 0.76 -- 1.55 0.5 0.5 0.3 -- 0.4 0.18 -- 0.45 0.86 -- 1.1 ~ 1.0 0.01 -- 0.1
< 25
Treating epilepsy in pregnant women Mervyn J Eadie 1.
Introduction
School of Medicine and Biomedical Science, University of Queensland, Brisbane, Australia
2.
Maternal factors
3.
Foetal factors
4.
The management of epilepsy
Introduction: The management of epilepsy during pregnancy involves achieving the best compromise between the sometimes competing aims of maintaining the well-being of the prospective mother and that of her foetus. Recently available knowledge helps achieve this by providing a better understanding of the hazards that intrauterine exposure to antiepileptic drugs holds for the development of the body structure and aspects of the intellect of the human foetus. The newer knowledge also helps explain why maternal seizure control may deteriorate during pregnancy, and how this risk may be avoided. Areas covered: A survey of the relevant English language literature concerning human epilepsy and pregnancy, foetal outcomes from pregnancy in women with epilepsy, and antiepileptic drug pharmacokinetics and clinical efficacy during pregnancy was carried out Expert opinion: A mother’s past history of foetal malformations, and the intake of valproate during a pregnancy, are significant factors in increasing the hazard of malformations during that pregnancy. Therefore, as far as reasonably possible, valproate use during pregnancy is better avoided. Full seizure control in the pre-pregnancy year, and adjusting antiepileptic drug doses to maintain plasma drug concentrations throughout pregnancy at values associated with seizure control before pregnancy, have major influences in preserving seizure control during pregnancy.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 05/24/14 For personal use only.
during pregnancy 5.
Conclusion
6.
Expert opinion
Keywords: antiepileptic drugs, epilepsy, foetal malformations, neurodevelopment, pregnancy, seizures, teratogenesis Expert Opin. Pharmacother. (2014) 15(6):841-850
1.
Introduction
Treating epilepsy in pregnant women involves considerations additional to those that apply in treating epilepsy in women outside pregnancy. In pregnancy two living beings are involved simultaneously in the treatment processes, with the welfare of the younger almost wholly dependent on the welfare of the older. Epilepsy treatment aims at achieving freedom from all epileptic seizures, and in pregnant women this aim has to be achieved without disadvantaging the foetus both in utero, and in subsequent post-natal life. Some of the extra factors that need to be taken into account in treating pregnant women with epilepsy primarily involve the mother, whose altered physiology in pregnancy may affect both the seizure disorder process, and the body’s disposition of the drugs prescribed to suppress that process. Other factors primarily concern the foetus, for example, the effect of the maternal epileptic process on the foetus, and the effects of antiepileptic treatments taken by the mother on foetal intrauterine and post-natal development.
10.1517/14656566.2014.896902 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
841
M. J. Eadie
Effects of pregnancy on antiepileptic drug disposition
2.2
Article highlights. .
.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 05/24/14 For personal use only.
.
. .
.
A history of a malformed foetus in a previous pregnancy increases the risk of bearing a malformed foetus in the next pregnancy. Valproate, used alone or in conjunction with other antiepileptic drugs, is a dose-related teratogen that is better avoided by pregnant women, and the wisdom of its use in females of child-bearing potential needs to be considered if a suitable alternative is available. In most circumstances, the degree of risk of foetal malformation is not high enough to warrant replacement of the other commonly used antiepileptic drugs during pregnancy. Levetiracetam seems to be emerging as the antiepileptic drug of choice for use in pregnant women. Freedom from seizures in the pre-pregnancy year is a major determinant of whether a woman with treated epilepsy will have seizures during pregnancy. Antiepileptic drug dosage adjustments guided by measurement of drug concentrations in plasma seem to help prevent deterioration in seizure control during pregnancy.
This box summarises key points contained in the article.
These factors will be considered subsequently, seriatim, with a particular interest in the post-1990 generation of antiepileptic drugs, for example, lamotrigine, topiramate, levetiracetam, gabapentin, zonisamide, and oxcarbazepine, which are currently coming into increasing use in pregnant women [1-3].
2.
Maternal factors
Effects of pregnancy on maternal seizure disorders
2.1
Since the publications of Knight and Rhind in 1975 [4] and Schmidt in 1982 [5], there has been continuing disagreement as to whether epileptic seizure disorders worsen during pregnancy. Reasonably effective antiepileptic drug therapy, first in the form of potassium bromide, has been available since 1857 [6]. Consequently, the question of the effects of pregnancy on epilepsy contains within it another question, namely, does pregnancy alter the effectiveness of antiepileptic therapy? Evidence for that possibility has been available since the 1970s [7,8], and there is now fairly widespread acceptance that the lowered circulating antiepileptic drug concentrations relative to drug dose that often develop during pregnancy, sometimes made worse by deliberate non-compliance with prescribed drug dosage, is the major factor responsible for any worsening of seizure disorders that occurs in pregnancy [9]. Whether pregnancy per se contributes more directly to a worsening of seizure control remains uncertain. The review of Harden et al. [10] concluded that no definite opinion concerning the matter was justifiable. 842
The altered physiology of the female body during pregnancy has implications for various aspects of antiepileptic drug disposition, particularly drug clearance [11]. The increased body fluid volume of the maternal--foetal unit may have a diluting effect that reduces plasma and biophase drug concentrations, especially for drugs with relatively small apparent volumes of distribution. In later pregnancy decreased plasma albumin concentrations of drugs that are normally bound to plasma proteins may produce higher plasma water and biophase concentrations of drug relative to concentrations in whole plasma. This effect may confound the interpretation of conventional whole plasma drug concentration measurements. Overall, the above changes are usually of little clinical consequence in relation to antiepileptic drugs. In contrast, the increased clearances of antiepileptic drugs that occur in most pregnant women may have substantial effects. Renal function and glomerular filtration rate are increased in pregnancy, leading to increased losses from the body of drugs which are cleared mainly by renal excretion in un-metabolised form, for example, gabapentin and levetiracetam [12]. Consequently, plasma concentration--dose ratios for these drugs fall during pregnancy. However, biotransformation is the main route of clearance of most antiepileptic drugs, as indicated by their low proportions of dose excreted intact in urine. In pregnancy, increased clearances occur for drugs whose first stage of metabolism is through cytochrome P450 activity or glucuronidation. Induction of the responsible enzymes usually begins in early pregnancy and continues until near term. The consequent effects on the ratio of plasma drug concentration to dose become noticeable at different times in different women, sometimes appearing in the initial weeks of pregnancy. There is considerable inter-individual variation in the magnitude of the clearance change for a given drug, and between drugs. Overall, drugs cleared by glucuronidation as a Phase I mechanism, for example, lamotrigine, show the greatest changes [13]. The extents of the clearance increase can show considerable variation between pregnancies in the same woman [14]. For antiepileptic drugs as a class, these increased drug clearance processes cause plasma and biophase drug concentrations, and hence pharmacological activity, to decrease relative to drug dose during pregnancy. This may compromise seizure control during pregnancy [14] unless appropriate drug dosage adjustments are made. Such dosage adjustments, guided by plasma drug concentration measurements, can prevent the worsening of seizure control [9,15]. Details of the clearance mechanisms and certain pharmacokinetic parameters for the antiepileptic drugs currently in common use and those obtaining a foothold in the market, are shown in Table 1. The more recently introduced of these agents have not yet attained widespread use in pregnant women, largely because adequate information on their human teratogenic potentials is not available. More detail concerning
Expert Opin. Pharmacother. (2014) 15(6)
Treating epilepsy in pregnant women
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 05/24/14 For personal use only.
Table 1. Pharmacokinetic values for antiepileptic drugs. Drug
% protein bound
Carbamazepine Carbamazepine-10,11-epoxide Clobazam Desmethyl clobazam Clonazepam Ethosuximide Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Monohydroxy- carbazepine Phenobarbitone Phenytoin Pregabalin Primidone Tiagabine Topiramate Valproate
~ 75 85 82 -- 90
Vigabatrin Zonisamide
0 40 -- 60
86 0 0 55 0 ~ 40 40 ~ 55 ~ 90 0 0 -- 20 > 95 9 -- 17 85 -- 95
M:P ratio
% unchanged in urine
0.3 -- 0.4 ~ 0.5
1 1 -- 2 Low 1 17 -- 38 > 0.93 0.10 0.66 Low
08 -- 0.9 0.7 -- 1.3 0.06 -- 1.47 0.76 -- 1.55 0.5 0.5 0.3 -- 0.4 0.18 -- 0.45 0.86 -- 1.1 ~ 1.0 0.01 -- 0.1
< 25
