the treatment of epilepsy || reproductive aspects of epilepsy treatment

323

25 Reproductive Aspects of Epilepsy TreatmentTorbjörn TomsonKarolinska University Hospital, Stockholm, Sweden

While reproductive health is regarded as one of the most impor-tant health issues for women with epilepsy, surveys in different countries have repeatedly revealed marked defi ciencies in the pro-vision of health care and advice on this issue. Only a minority of women with epilepsy who plan to have children have any pre-pregnancy counselling and knowledge among health-care provid-ers about the reproductive health of women with epilepsy is often inadequate. To be worthwhile, counselling should ideally be pro-vided long before pregnancy in order to allow for adequate treat-ment measures which reduce risks. Reproduction may be more complicated for people with epilepsy for a number of reasons related to epilepsy and to its treatment. Although most women with epilepsy will be able to give birth to perfectly normal chil-dren, a number of questions are raised when they consider becom-ing pregnant, and these need to be addressed early in the pregnancy planning.

Fertility may be altered, and the effi cacy of steroid oral contra-ceptives may be reduced by certain antiepileptic drugs (AEDs). Epilepsy might affect the outcome of pregnancy and there may be increased risks of obstetric complications. Seizure control may change during pregnancy and treatment may need to be adjusted because of altered pharmacokinetics of AEDs. Fetal risks associ-ated with uncontrolled seizures during pregnancy need to be weighed against the teratogenic effects and other potential devel-opmental toxicity of AEDs. The possibility for a woman on AEDs to nurse her child also needs to be discussed.

Fertility

Studies indicate lower fertility rates among men and women with epilepsy than in the general population [1]. There are many pos-sible causes for reduced fertility rates among people with epilepsy. Social isolation and stigmatization may contribute, which also explain why marriage rates are reported to be lower. Women may also refrain from pregnancy because of fears of deterioration in their epilepsy or risks to the fetus incurred by seizures or the drug treatment. The lesion causing epilepsy and the epileptic activity as such may also induce endocrine dysfunction that could affect fertility. Some studies, however, suggest that concurrent disabili-ties and co-morbidities (e.g. learning disabilities or cerebral palsy) could be the major cause [2,3]. Fertility rates among people with

epilepsy were essentially normal in two population-based studies from Iceland and Finland when people with such severe co-mor-bidities were excluded [2,3]. Treatment with AEDs has also been considered to contribute to lower fertility and other reproductive dysfunction.

Reproductive dysfunctionReproductive dysfunction and endocrine disorders are common among both men and women with epilepsy. In men, this will manifest itself as loss of libido, reduced potency and infertility; in women, by menstrual dysfunction, hirsutism and infertility. In some studies, between 40% and 70% of men with epilepsy report decreased potency and hyposexuality, but this apparently high fi gure needs to be related to the proportion among control popu-lations [4]. Rättyä et al. [5] evaluated sexual function, including libido, potency, satisfaction with erection and orgasm, in men, 18–50 years of age, under treatment with an AED in monother-apy. Of these, 77% were considered to have a normal sexual function compared with 88% among healthy age-matched control subjects. Menstrual disorders are more common among women with epilepsy, occurring in one-third compared with 12–14% in the general population [6].

Whether reproductive dysfunction is related to the underlying epilepsy is still controversial, but it has been suggested that epi-leptiform discharges may promote the development of reproduc-tive endocrine disorders by disruption of normal temporo-limbic modulation of hypothalamopituitary function [6]. This hypothe-sis is supported by observations of lower testosterone levels in men with temporal as compared with extratemporal foci and that successful temporal lobe epilepsy surgery may lead to a normal-ization of low preoperative serum androgen concentrations [7].

Treatment with AEDs can also contribute to reproductive dys-function. Enzyme-inducing drugs such as carbamazepine, phe-nytoin and phenobarbital may increase the concentration of sex hormone-binding globulin (SHBG) and reduce the unbound, bio-logically active concentrations of testosterone [8]. In a cross-sec-tional study, monotherapy with carbamazepine was associated with decreased serum androgen levels and high SHBG concentra-tions in men with predominantly partial seizures. Oxcarbazepine treatment in doses of at least 900 mg/day was associated with similar endocrine effects. In contrast, serum androgen levels were increased in 12 out of 21 men treated with valproic acid for gen-eralized or partial seizures [5].

Infertility in men may also be related to impaired spermatogen-esis or sperm function. Poor sperm motility was noted in epileptic patients with long-term AED treatment and in vitro studies

The Treatment of Epilepsy, Third Edition Edited by S. Shorvon, E. Perucca and J. Engel© 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-18383-3

CHAPTER 25

324

suggest a direct effect of phenytoin, carbamazepine and valproic acid on sperm membrane function [9]. A cross-sectional small study of men with epilepsy suggested that all investigated drugs, carbamazepine, oxcarbazepine and valproic acid, were associated with an increase in abnormal sperm morphology [9], although the clinical relevance of these fi ndings remains to be shown.

The discussion on reproductive endocrine disorders in women with epilepsy has focused on polycystic ovaries (PCO) and polycystic ovarian syndrome (PCOS). PCO, which is normally a diagnosis made on ultrasound examination and which may be asymptomatic, is a common condition with an estimated preva-lence of about 20% in the general population. PCOS has been defi ned as ovulatory dysfunction with clinical evidence of hyper-androgenism and/or hyperandrogenaemia in the absence of iden-tifi able adrenal or pituitary pathology, although criteria vary between researchers. PCOS is a syndrome with multiple aetiolo-gies and a prevalence ranging from about 4% up to 18% in the general female population, depending on the criteria and the population studied and probably higher, 10–20%, in women with epilepsy [6]. Genetic as well as environmental factors can contrib-ute to the development of this syndrome.

Cross-sectional studies from Finland, Norway, the Netherlands and the UK have indicated that polycystic ovaries and hyperan-drogenism, and PCOS are related to the drug treatment and spe-cifi cally to treatment with valproic acid [8]. In these studies 30–40% of patients treated with valproic acid had polycystic ovaries and hyperandrogenism, compared with 5–15% among those taking carbamazepine or lamotrigine. However, two studies from other epilepsy populations found no difference between women taking valproic acid and carbamazepine in this respect [10,11]. A randomized open-label study compared the develop-ment of PCOS after 12 months on valproic acid and lamotrigine [12]. Hyperandrogenism and ovulatory dysfunction was found in 44% of those randomized to valproic acid compared with 23% of those on lamotrigine if treatment was initiated before 26 years of age, whereas the rates were similar (24% versus 22%) if treat-ment was started above 26 years.

In many patients, reproductive endocrine dysfunction appears to be reversible on withdrawal of or change in AED treatment. A switch from valproic acid to lamotrigine in women with poly-cystic ovaries and hyperandrogenism whilst on valproic acid was associated with normalization [8], and so was withdrawal of valproic acid in a large proportion of patients in a 5-year follow-up study [13]. Taken together, these observations confi rm that valproic acid can indeed induce polycystic ovaries and hyperan-drogenism, although the role may not be as important as reported in the initial cross-sectional studies from Finland.

Withdrawal of carbamazepine in seizure-free male and female patients has also been associated with normalization (increase) of serum testosterone and free androgen index [14].

Two cross-sectional studies assessed endocrine function in a younger female population with epilepsy [15,16]. A cohort of 77 girls, 8–18 years of age, under treatment with valproic acid (n = 40), carbamazepine (n = 19) or oxcarbazepine (n = 18) were compared with 49 healthy age-matched controls. No difference was observed in linear growth and sexual maturation [15]. When 41 girls on valproic acid were compared with 54 healthy controls, hyperandrogenism was observed more frequently among the val-

proic acid-exposed girls, but the incidence of polycystic ovaries or menstrual disturbances was not increased [16]. A long-term follow-up of these cohorts revealed normal endocrine function in those that had come off medication but an increased prevalence of endocrine disorders including PCOS among those remaining on AEDs into adulthood [13].

Choice of antiepileptic drugGiven the partly confl icting data concerning the association between valproic acid and reproductive dysfunction, and the excellent effectiveness of this drug, particularly in idiopathic gen-eralized epilepsies, valproic acid is still a reasonable fi rst choice in young women with these types of epilepsy, unless they can be assumed to become pregnant while on treatment (see below). However, based on the intriguing observations discussed above, the patients should be monitored closely. If adverse effects such as considerable weight gain or menstrual disturbances occur, a change in drug therapy should be considered. The potential role of AEDs always needs to be considered in women and men with epilepsy with reproductive dysfunction, and in such cases it may be necessary to reassess the choice of treatment [17].

Birth control

Contraception in women with epilepsy is complicated by the bidirectional pharmacokinetic interactions between AEDs and steroid oral contraceptives. Enzyme-inducing AEDs may reduce the effectiveness of oral contraceptives by inducing the metabo-lism of the oestrogen and progestagen components, and possibly also by increasing the hepatic synthesis of SHBG, thus decreasing the unbound, active concentration of progestagen. This may lead to contraceptive failure and an increased frequency of unplanned pregnancies [18]. AEDs with and without known inducing effects on oral contraceptives are listed in Table 25.1.

Depot injections of medroxyprogesterone, hormone-releasing intrauterine systems and other intrauterine contraceptive devices seem to be unaffected by enzyme inducers and could be good alternatives for some women [18].

If this is not an alternative, patients treated with enzyme-induc-ing AEDs are often recommended oral contraceptives with an oestrogen content of at least 50 μg. Whether this dose is suffi cient, however, is uncertain. Others, therefore, recommend either the use of a combined oral contraceptive with a progestin dose well above the dose needed to inhibit ovulation, or continuous use of combined contraceptive pills without a pill-free interval [19]. Where available, tricycling is another alternative. These are com-bined oral contraceptives given continuously for three sets of 21 days followed by 7 days’ pause.

Estradiol-containing oral contraceptives, on the other hand, induce the elimination of lamotrigine. Lamotrigine serum concen-trations decline by approximately 50% when such contraceptives are introduced. This can lead to breakthrough seizures unless the lamotrigine dose is adjusted. These changes occur rapidly and hence lamotrigine levels rise during the pill-free week if sequential pills are used [20]. This may induce toxic symptoms. Preliminary data suggest that estradiol may have a similar effect on serum concentrations of valproic acid. Pure progestagen-containing pills

REPRODUCTIVE ASPECTS OF EPILEPSY TREATMENT

325

do not seem to affect lamotrigine serum concentrations, and concomitant use of valproic acid appears to block the estradiol-induced effects on lamotrigine kinetics [21].

Women need to be informed about these clinically relevant bidirectional interactions. Enzyme-inducing properties should be taken into account when choosing an AED for a woman on oral contraceptives. Given the choice of two drugs similar in all other important respects it is reasonable to select a drug known not to interact with oral contraceptives. The possibility of using comple-mentary or alternative contraceptive methods should also be dis-cussed, and it should be stressed that the effectiveness of many contraceptive methods other than the intrauterine device may actually be lower than that of an oral contraceptive taken together with enzyme-inducing drugs. Women on lamotrigine who are started on estradiol-containing pills should have their dosage increased guided by drug level monitoring, and pills are best avoided.

Pregnancy in women with epilepsy

In the treatment of epilepsy during pregnancy, maternal and fetal risks associated with uncontrolled seizures need to be weighed against the increased risk of adverse outcomes in the offspring due to maternal use of AEDs.

Effects of maternal seizures on the fetusEpileptic seizures in a pregnant woman may have adverse effects on the fetus, in addition to risks for the woman. With respect to the risks to the fetus, effects of generalized tonic–clonic seizures are probably different from effects of other types of seizures [22]. Tonic–clonic seizures are associated with transient lactic acidosis, which is likely to be transferred to the fetus. Prolonged decrease in fetal heart rate, which is a common response to acidosis, has been reported after maternal tonic–clonic seizures. Furthermore, generalized tonic–clonic seizures induce alterations in blood pres-sure and blood fl ow, but it is presently not known to what extent this affects uterine blood fl ow and thus the fetus. Seizure-related

maternal abdominal trauma could also, theoretically, cause injury to the fetus or placental abruption. Despite these effects, intra-uterine fetal death as a result of a single seizure appears to be rare and only a few such reports have been published. In contrast, prolonged seizure activity, such as status epilepticus, may be a serious threat to the fetus as well as to the woman. In an early review, fetal death was reported in about 50% of cases with status epilepticus during pregnancy, and in 30% of the mothers [23]. This is in contrast to the results of a recent large prospective study, which reported only one case of intrauterine death and no maternal mortality among 36 women with status epilepticus (12 of whom were convulsive) [24]. According to most prospective studies, seizures during early pregnancy are not associated with an increased risk of birth defects. However, occasional reports have indicated an increased risk for cognitive dysfunction in the offspring of women who have had more than fi ve convulsive sei-zures during pregnancy [25], although conclusive evidence for a causative role of the seizures is lacking.

Other types of seizures are in general unlikely to affect the fetus when they occur during pregnancy unless they lead to a second-arily generalized tonic–clonic seizure. However, they may cause some risks if the seizure results in injury or trauma.

Generalized tonic–clonic seizures during labour can cause fetal asphyxia. Partial seizures that impair consciousness may also impose risks since the mother’s ability to co-operate during the delivery is lost. In such situations, Caesarean delivery should be considered.

In conclusion, our knowledge concerning fetal risks associated with maternal seizures is based on case reports rather than sys-tematic studies and we lack quantitative risk estimates. Neverthe-less, there is a general consensus among physicians that in particular generalized tonic–clonic seizures should be avoided during pregnancy for the sake of the well-being of the fetus as well as the mother.

Seizure control during pregnancy and deliveryThe largest prospective study of seizure control in pregnancy to date reported that 59% of 1736 women remained seizure free throughout pregnancy [24]. Earlier studies, mainly from special-ized epilepsy centres, indicated that approximately one-third of women with epilepsy will experience an increase in seizures during pregnancy [26]. Prospective studies of fewer selected women with epilepsy suggest that the proportion of women who deteriorate is smaller [22]. Some of the observed changes in seizure frequency are likely to be explained by the normal spon-taneous fl uctuations in seizure occurrence, but it appears that some periods of pregnancy are associated with a signifi cant increase in seizures. A generalized tonic–clonic seizure occurs during labour in about 1–2% and within 24 h after delivery in another 1–2% [22]. Taking all seizure types together, roughly 5% of women with epilepsy will experience seizures during labour, delivery or immediately thereafter.

Status epilepticus occurs in less than 1% of all pregnancies of women with epilepsy and does not seem to occur more frequently during pregnancy than in other periods of life.

Most studies report that patients with a satisfactory seizure control before pregnancy are less likely to deteriorate than patients with uncontrolled epilepsy [27]. There are observations

Table 25.1 Pharmacokinetic interactions between steroid oral contraceptives and antiepileptic drugs.

Drugs which increase the clearance of oral contraceptives

Drugs which do not affect the clearance of oral contraceptives

Drugs in which the clearance is induced by estradiol-containing oral contraceptives

CarbamazepineFelbamateLamotriginea

OxcarbazepinePhenobarbitalPhenytoinTopiramate (at dosages

>200 mg/day)

BenzodiazepinesGabapentinLevetiracetamPregabalinTiagabineValproic acidVigabatrinZonisamide

LamotrigineValproic acid

a Lamotrigine does not affect estradiol concentrations but has a modest effect (18% reduction in plasma concentration) on the norgestrel component of the combined oral contraceptive.

CHAPTER 25

326

suggesting that those women who fail to have prepregnancy coun-selling are most at risk of deterioration during pregnancy. This agrees with several reports indicating that poor compliance with the drug treatment, often due to fear of the teratogenic effects, is a major cause of loss of seizure control during pregnancy.

Some women may experience onset of a seizure disorder during pregnancy, and they should be investigated according to the same general principles as non-pregnant patients with new-onset epi-lepsy, although there are some causes of seizures that need to be considered more specifi cally. If seizures occur for the fi rst time during the last 20 weeks of pregnancy, eclampsia needs to be excluded. Stroke and cerebral venous thrombosis also occur at a higher frequency during pregnancy. The general principles for initiation and choice of AED treatment also apply for women in pregnancy, although treatment is often withheld during the fi rst trimester unless the risk is high for recurrent tonic–clonic seizures.

Pharmacokinetics of antiepileptic drugs during pregnancyThe pharmacokinetics of many drugs undergoes signifi cant changes during pregnancy, which may have consequences for maternal seizure control as well as for fetal drug exposure [28]. At constant drug dosages, serum levels of most of the older AEDs tend to decrease during pregnancy, and return to prepregnant levels within the fi rst month or two after delivery. This appears to be due mainly to a decrease in drug binding to plasma proteins and/or an increase in drug metabolism and elimination. A decrease in protein binding will result in lower total drug levels but leave unchanged the unbound, active concentration of the drug.

By the end of pregnancy, total and unbound concentrations of phenobarbital decline by up to 50% [28]. Total concentrations of carbamazepine decline to a lesser extent and the changes in unbound concentrations are insignifi cant [28]. Marked decreases in total phenytoin concentrations to about 40% of prepregnancy levels have been reported [28], whereas free concentration decreased to a much lesser extent. For valproic acid, no signifi cant changes were noted in unbound concentrations despite a fairly marked decrease in total concentrations [28]. Hence, for highly protein-bound drugs such as valproic acid and phenytoin, total plasma concentrations may be misleading during pregnancy, underestimating the pharmacological effects of the drugs.

The most pronounced changes have been reported with lamotrigine. In some patients, serum concentrations may decline in late pregnancy to 30% of prepregnancy levels with normaliza-tion within a few days post partum [28]. Such alterations in serum concentrations have frequently been associated with deterioration in seizure control [29]. Preliminary data suggest a similar decline in serum concentrations of the active moiety of oxcarbazepine [28] and a fall in serum concentrations of levetiracetam of up to 50% has also been reported [30].

The fi gures quoted above represent average changes for groups of patients, while the effect of pregnancy varies between individu-als. The decline in plasma concentration may be insignifi cant in some patients and pronounced in others, prompting dosage adjustments to maintain seizure control. Monitoring drug levels is therefore recommended during pregnancy. For highly protein-bound AEDs such as valproic acid and phenytoin, unbound drug

levels should ideally be measured. A single drug level is of limited value since the optimal concentration is individual. When preg-nancy is planned in advance, it is therefore advisable to obtain serum drug concentrations before pregnancy, when seizure control is optimal, in order to establish a baseline to be used for com-parison purposes.

Obstetric complications during pregnancy and deliveryThe literature on rates of obstetric complications in pregnant women with epilepsy is somewhat confl icting. Earlier studies suggest that induction of labour and instrumental deliveries are more frequent in women with epilepsy. This may be a conse-quence of fear of seizures and unfamiliarity with epilepsy among obstetricians rather than a refl ection of an increased rate of obstetric complications. More recent studies suggest that, with modern management, there is no signifi cant increase in common obstetric complications among women with well-controlled epi-lepsy [22,31,32]. However, a Caesarean section might be needed if frequent seizures greatly impair co-operation in the forthcoming labour and delivery or if a generalized tonic–clonic seizure occurs during labour [22]. For these reasons, pregnant women with epi-lepsy should be counselled by obstetricians who are familiar with epilepsy-related problems and delivery should take place in well-equipped obstetric units.

Developmental toxicity of antiepileptic drugsThe fi rst reports of adverse effects of AEDs on the fetus were published in the 1960s. Since then, all of the major old-generation AEDs, such as phenobarbital, phenytoin, valproic acid and car-bamazepine, have been shown to be teratogenic. Adverse effects reported in exposed infants include major congenital malforma-tions, minor anomalies and dysmorphism, growth retardation and impaired postnatal cognitive development. Although the pathogenesis is likely to be multifactorial, including genetic pre-disposition, socioeconomic circumstances, seizures and epilepsy, the available data strongly suggest that AEDs are the major cause of the increased risks.

Major congenital malformationsA large number of retrospective and prospective cohort studies have confi rmed an increased frequency of major malformations in offspring of women treated with AEDs. The prevalence of major congenital malformations has ranged from 4% to 10%, corresponding to a two- to fourfold increase compared with the expected [22,33,34]. Differences in treatment strategy, study populations, controls and criteria for malformations can account for the variation in outcome [34]. Some studies have included untreated women with epilepsy as additional controls. In general, such studies have not found an increased malformation rate among children of mothers with untreated epilepsy [35], suggest-ing that the increased risk for major malformations in the off-spring of women taking AEDs is due to the drug therapy rather than the epilepsy.

Although all major older generation AEDs have been shown to be teratogenic, it is not until recently that suffi ciently large studies have been carried out to compare different AEDs with respect to their teratogenic potential. The prevalence of major malforma-


327

tions in some recent large studies are summarized for the most frequently used drugs in Table 25.2 [36–43]. Malformation rates in association with exposure to a specifi c AED as monotherapy vary between studies, which could be explained by differences in methodology. However, the prevalence of malformations among children exposed to carbamazepine is consistently fairly low (2.2–4.0%). This observation indicates that with monotherapy and modern management the risks might not be as greatly increased as previously thought. Second, it appears that malfor-mation rates are higher in association with valproic acid than with carbamazepine, and that the risk of major malformations with lamotrigine is similar to that of carbamazepine. Unfortu-nately, the numbers of pregnant women on other newer genera-tion drugs are still too small to allow a meaningful analysis. Even within-study comparisons of malformation rates need to be inter-preted with caution considering the possible effects of confound-ing factors in these observational studies. Even larger studies are needed to analyse the contribution of seizure control, type of epilepsy, family history of birth defects, and so on.

The drug dosage also needs to be considered in any compari-son. A dose–effect relationship has been demonstrated for val-proic acid, with signifi cantly higher risks for birth defects with doses exceeding 800–1000 mg/day [22,27,33,37]. One recent study also reported a positive dose–response for malforma-tions with lamotrigine exposure. Doses above 200 mg/day were associated with higher risks [38]. This, however, was not con-fi rmed in the manufacturer’s own lamotrigine pregnancy registry [39]. Polytherapy has consistently been associated with a higher risk for major congenital malformations than monotherapy [22,33].

Pregnancy registries have generally compared overall malfor-mation rates, but the pattern of birth defects differs between drugs [22]. Orofacial clefts, congenital heart defects and distal digital defects are more common in children exposed to phenytoin and barbiturates. Valproic acid exposure has been associated with an increased risk of neural tube defects, reported to occur in 1–2% of exposed infants. Valproic acid has also been associated with skeletal abnormalities including radial aplasia. A risk of neural tube defects of 0.5–1% has also been reported after carbamaze-pine exposure. Carbamazepine is also associated with an increased risk of congenital heart defects and, recently, lamotrigine was reported to be associated with a signifi cant increase in the risk of oral clefts [42].

Minor anomalies and fetal antiepileptic drug syndromesMinor anomalies are structural variations that are visible at birth but without medical, surgical or cosmetic importance. Such anomalies are common in normal unexposed infants but have been reported to occur more frequently in infants of mothers treated for epilepsy during pregnancy. Combinations of several anomalies are less frequent and can form a pattern, or a dysmor-phic syndrome, which may indicate a more severe underlying dysfunction. Facial features such as hypertelorism, depressed nasal bridge, low-set ears, micrognathia and distal digital hypo-plasia, sometimes in combination with growth retardation and developmental delay, were fi rst reported in association with expo-sure to phenytoin. Subsequently, however, similar patterns have been associated with exposure to carbamazepine. Valproic acid exposure has been claimed to cause a somewhat different dysmor-phic syndrome characterized by thin arched eyebrows, broad

Table 25.2 Malformation rates (%) in infants exposed in utero to antiepileptic drugs in monotherapy recently reported from pregnancy registries (n = offspring with malformations).

Study Carbamazepine Lamotrigine Phenobarbital Phenytoin Valproic acid

Total outcomes

n % Total outcomes

n % Total outcomes

n % Total outcomes

n % Total outcomes

n %

Swedish Medical Birth Registry [36]

703 28 4.0 90 4 4.4 103 7 6.8 268 26 9.7

Finnish Drug Prescription Registry [37]

805 22 2.7 38 1 2.6 263 28 10.6

UK Epilepsy and Pregnancy Register [38]

927 20 2.2 684 21 3.1 85 3 3.5 762 44 5.8

GSK International Lamotrigine Registry [39]

802 22 2.7

Australian Epilepsy and Pregnancy Register [27]

234 7 3.0 146 2 1.4 17 1 5.9 166 22 13.3

North American Epilepsy and Pregnancy Registry [40]

77 5 6.5


564 15 2.7


873 23 2.6


149 16 10.7

CHAPTER 25

328

nasal ridge, short anteverted nose and thin upper lip [44]. However, there is a considerable overlap in the various dysmor-phisms and their drug specifi city has been questioned [45]. A more general term of fetal or prenatal AED syndrome has there-fore been suggested. In addition, the pathogenesis is still some-what controversial, and Gaily et al. [46] attributed most of the minor anomalies to genetic factors rather than drug exposure. Finally, it should be emphasized that minor anomalies are much more diffi cult to assess objectively than major malformations, and that the incidence of minor anomalies in exposed infants varies markedly between studies.

Growth retardationReduced birth weight, body length and head circumference in the offspring of women treated with phenytoin was reported as early as the 1970s. Reductions in body dimensions, in particular head circumference, have been confi rmed in several subsequent studies of larger cohorts [47,48]. Most studies report a more pronounced effect in infants exposed to polytherapy. However, the association with specifi c AEDs in monotherapy varies. Some investigators found an association with phenobarbital and primidone, whereas others report carbamazepine to be more strongly associated with a small head circumference. In a more recent publication, Wide et al. [49] studied body dimensions in infants exposed to AEDs in utero in a Swedish population over a period of 25 years com-paring data with those of the general population. There was a clear trend towards normalization of the head circumference over the time period in parallel with a shift from polytherapy towards monotherapy despite an increasing use of carbamazepine.

Postnatal cognitive developmentOne of the most important issues is whether exposure to AEDs in utero could adversely affect postnatal cognitive development. Long-term follow-up studies of large cohorts of exposed individu-als are necessary in order to address this issue. Such studies are diffi cult to perform and also complicated to interpret since envi-ronmental factors become more important with increasing age of the child. A Cochrane review concluded that the majority of earlier studies are of limited quality and that there is little evidence about which drugs carry more risks than others to the develop-ment of children exposed [50]. A few studies have been published since then, and indicate that exposure to valproic acid might be associated with specifi c adverse cognitive effects [25,51,52]. A retrospective study from the UK found signifi cantly lower verbal intelligence quotient (IQ) in 41 children exposed to valproic acid than in unexposed and in children exposed to carbamazepine (n = 52) or phenytoin (n = 21) [25]. Multiple regression analysis identifi ed exposure to valproic acid, fi ve or more tonic–clonic seizures in pregnancy and low maternal IQ to be associated with lower verbal IQ also after adjustment for confounding factors. Doses above 800 mg/day were associated with lower verbal IQ than were lower doses. These important signals need to be con-fi rmed or refuted in prospective studies. Two small prospective population-based studies from Finland found similar trends for lower verbal IQ in children exposed in utero to valproic acid, although the studies were too small (13 children exposed to valproic acid monotherapy in each) to demonstrate statistically signifi cant associations [51,52].

Hence, adequately powered prospective studies are urgently needed to assess long-term cognitive effects of exposure to val-proic acid and other AEDs.

Sensitive periodsSensitive periods in embryonic development with reference to some of the more important major malformations associated with AEDs are summarized in Table 25.3. Obviously, adverse effects of this type occur early, often before the woman is aware that she is pregnant. In contrast, drugs may affect growth and cognitive development throughout pregnancy.

BreastfeedingMost drugs pass from maternal plasma to breast milk and are transferred to the nursed infant. In general, the amounts thus transferred are much smaller than those transferred via the placenta during pregnancy. The amount that the infant will be exposed to through breastfeeding depends on the maternal plasma concentration, the extent of transfer to breast milk and the amount of milk intake by the infant. Drug exposure of the suck-ling infant is also dependent on the infant’s absorption, distribu-tion, metabolism and elimination of the drug. In particular, metabolism and excretion may be markedly different in the infant compared with children and adults and also vary with the drug in question. Relevant pharmacokinetic information is summa-rized in Table 25.4 [30,53,54].

Table 25.3 Gestation periods sensitive to specifi c congenital malformations.

Malformation Approximate sensitive period (gestational weeks)

Neural tube defects 3–4Congenital heart defects 4–8Orofacial clefts 6–10

Table 25.4 Antiepileptic drugs in breast milk and in the breast-fed infant.

Antiepileptic drug Milk–maternal plasma concentration ratio

Infant–maternal plasma concentration (%)

Carbamazepine 0.1–0.3 10–20Clobazam 0.1–0.4

Ethosuximide 0.8–1.0 40–60Felbamate ?

Gabapentin 0.7–1.3 4–12Lamotrigine 0.4–0.8 25–50Levetiracetam 0.8–1.3 <20Oxcarbazepinea 0.5–0.8 7–12%Phenobarbital 0.3–0.5 50–100Phenytoin 0.1–0.6 <10Pregabalin ?

Tiagabine ?

Topiramate 0.7–1.1 9–17Valproic acid 0–01–0.1 <5Zonisamide 0.9

a Refers to the active mono-hydroxy metabolite of oxcarbazepine.


329

For carbamazepine, gabapentin, levetiracetam, oxcarbazepine, topiramate and valproic acid, only small amounts are transferred and serum levels in suckling infants are generally so low that pharmacological effects are unlikely to occur. For ethosuximide and lamotrigine, infant serum concentrations may occasionally reach levels at which pharmacological effects can be seen. However, so far there is no clear evidence for the occurrence of adverse effects in nursed infants. Phenobarbital, and phenobarbi-tal as a metabolite of primidone, can accumulate in the suckling infant, and sedation and poor suckling have been reported. Simi-larly, sedation may occur due to exposure to benzodiazepines such as diazepam, clonazepam and possibly clobazam if taken chronically by the nursing mother. However, such adverse effects do not occur in all nursed infants.

The benefi ts of breastfeeding in general are unquestionable. These must be weighed against the possible risks to the infant induced by drug exposure. Taking this into account, women with epilepsy should, in general, be encouraged to nurse their infants, and the risk for adverse effects due to drug exposure through breast milk is, in most cases, negligible.

Women who nurse while taking phenobarbital, primidone, ben-zodiazepines and perhaps also ethosuximide and lamotrigine should be encouraged to monitor their infant for side-effects such as sedation or poor suckling, rather than being advised not to nurse. If suspicion of pharmacological effects arises, this could be confi rmed or rejected by measuring serum drug levels in the infant.

Folate supplementationLow folate intake has been associated with an increased risk of congenital malformations, in particular neural tube defects, in animal studies and in humans. In a randomized study of more than 7000 Hungarian women planning pregnancy, supplementa-tion with 0.8 mg folic acid reduced the risk of neural tube defects signifi cantly [55], demonstrating the effectiveness of folate for prevention of fi rst occurrence of neural tube defects. A random-ized British study [56] assessed the effect of folic acid supplemen-tation on the risk of recurrence of neural tube defects in high-risk pregnancies. More than 1000 pregnancies were included and 4.0 mg/day folate reduced the recurrence risk by 72%. Pericon-ceptional intake of 0.4 mg of folic acid daily has also been shown to reduce the risk of neural tube defects in a public health cam-paign in China [57]. Unfortunately, no randomized study has specifi cally assessed the effectiveness of folic acid supplementation in women with epilepsy. In fact, such patients were excluded from the study in the UK [56].

In the absence of data specifi c for women with epilepsy, recom-mendations have to be drawn from studies based on the general population. In general, women of child-bearing potential are recommended a daily intake of 0.4 mg folic acid, and the most practical way of achieving that is as a daily supplementation. It is reasonable to suggest this also to all women with epilepsy. A higher dose of 4 mg/day is recommended for secondary preven-tion to women with a previous history of giving birth to a child with neural tube defects or with a family history of such mal-formations. However, as AED use is associated with an increased risk of neural tube defects and other malformations, many guide-lines recommend that all women under treatment with such

drugs should take up to 5 mg of folate per day from before conception and throughout the fi rst trimester [22,58]. However, it is essential to inform the patient that it is uncertain whether folate supplementation will reduce this risk induced by AEDs [59], and pregnancy monitoring with prenatal diagnosis should be offered in the same way whether or not high-dose folate is prescribed.

Vitamin K supplementation and neonatal haemorrhageVitamin K defi ciency can cause early neonatal haemorrhage, and neonates of mothers treated with enzyme-inducing AEDs during pregnancy may have an increased risk. Decreased levels of vitamin K-dependent clotting factors are found in the cord blood of newborns of women taking enzyme-inducing AEDs, and supple-mentation with 10 mg/day of vitamin K orally for the last month of pregnancy has been shown to normalize these levels. It remains to be shown that prenatal oral vitamin K supplementation also reduces the risk of neonatal haemorrhage. Hey [60] studied pro-spectively cord blood prothrombin time in 137 babies born to women on phenobarbital, phenytoin or carbamazepine. Only 14 of the babies had prolonged prothrombin time and none an overt bleeding tendency. The abnormality was corrected within 2 h by 1 mg of parenteral vitamin K. Based on these observations, Hey concluded that evidence is lacking for a particular early form of neonatal haemorrhage related to use of anticonvulsants, and that oral vitamin K supplementation during late pregnancy is unjusti-fi ed, where intramuscular injections of vitamin K to the newborn are routine. This notion is further supported by two more recent controlled studies that failed to fi nd an increased risk of neonatal haemorrhage related to the use of enzyme-inducing AEDs [61,62].

Preconception counsellingSeveral surveys have revealed that women with epilepsy often receive insuffi cient and even inaccurate information concerning issues related to reproductive function. Clinical practical guide-lines for the care of women with epilepsy of child-bearing age have been published in many countries [58]. Unfortunately, many important questions are still unanswered, and many of the recommendations build on rather weak evidence, from observa-tional studies rather than randomized trials. This is refl ected in the slight differences found in the different guidelines. Neverthe-less, they provide useful tools and need to be brought to the attention of health-care providers and utilized in their counsel-ling of women with epilepsy. An optimal management of preg-nancy depends largely on considerations that have to be made, and measures that have to be taken, before conception. Prepreg-nancy counselling is therefore essential, and it is an important challenge to change the present situation whereby such counsel-ling seems to be offered to only a minority of women with epi-lepsy. Preconceptional counselling should cover the issues listed below.• Contraception and fertility. The bidirectional interaction

between hormonal contraceptives and AEDs should be dis-cussed when relevant. The possibility that drug treatment may induce endocrine dysfunction affecting fertility should also be addressed.

CHAPTER 25

330

• Genetic counselling with respect to the risk of giving birth to a child who will develop epilepsy and with respect to birth defects.

• Risks associated with seizures during pregnancy, and informa-tion that such risks to the fetus probably outweigh the risks incurred by an optimized treatment with AEDs.

• Risks of adverse effects of AEDs to the fetus, including a two- to fourfold increase in the incidence of major malformations.

• The option of prenatal diagnosis of birth defects, including possibilities and risks with the different methods.

• General principles of AED use in pregnancy, and the impor-tance of optimizing seizure control and making any major change in drug therapy before pregnancy. The importance of medication compliance during pregnancy and the risks associ-ated with abrupt withdrawal need to be underlined.

• Recommendations concerning folate supplementation, includ-ing information on the lack of evidence for its effectiveness in preventing birth defects related to AED exposure.

• Risk of seizures at delivery and the recommendation that deliv-ery should take place in well-equipped obstetric units.

• Risk for deterioration in seizure control due to sleep depriva-tion after delivery.

• Feasibility of breastfeeding.In conclusion, although there are specifi c risks and problems

associated with pregnancy in women with epilepsy, counselling should focus on the feasibility of reducing risks and on the fact that more than 90% of women with epilepsy can look forward to an uneventful pregnancy and to giving birth to a normal and healthy child.

Some of the issues discussed above (e.g. genetic counselling and the risk for deterioration in seizure control due to sleep deprivation) are also relevant for men with epilepsy who are considering having children, although this is often completely neglected.

Management during pregnancy

Antiepileptic drug treatment during pregnancyThe optimal management of a woman with epilepsy during pregnancy relies on a close collaboration, with exchange of information between the physician responsible for epilepsy care and the obstetrician (Table 25.5). Treatment with AEDs should be optimized before conception, with the objective to use mono-therapy at the lowest effective dosage. Select the AED that is most likely to control seizures (i.e. the appropriate fi rst-line drug for seizure type and epilepsy syndrome). However, accumulating data suggest that valproic acid should be avoided if other equally effective treatment options are available. There is, at present, no simple answer to what the suitable alternative could be for women with idiopathic generalized epilepsies (e.g. juve-nile myoclonic epilepsy). Lamotrigine has a reasonable docu-mentation concerning pregnancy outcomes, but the pronounced pharmacokinetic alterations during pregnancy can result in breakthrough seizures. Levetiracetam may be less problematic in this respect, but data on pregnancy outcomes on the other hand are limited. Although as yet we have no signals of major increase in fetal risks with levetiracetam, the data are insuffi cient

to allow fi rm conclusions. Some prefer carbamazepine. This drug is likely to be effective against generalized tonic–clonic seizures, which is the most important for fetal safety. However, carbamazepine could aggravate myoclonic seizures. Although such seizures are of limited importance during pregnancy, poorly controlled myoclonic seizures can be a major problem after birth when the mother has a newborn infant to care for. Irre-spective of which of the alternatives is considered, it is necessary to allow suffi cient time before conception to assess its effectiveness.

Treatment should aim at complete control of, in particular, generalized tonic–clonic seizures. Other seizure types are prob-ably less hazardous but may, in some patients, signal an increased risk also for tonic–clonic seizures. Complex partial seizures may also compromise maternal co-operation at delivery.

An attempt to withdraw treatment should be considered in women who plan pregnancy and who have been seizure free for 2 years or more. However, this needs to be assessed individually based on the estimated risk of recurrence and potential conse-quences thereof. In the case of polytherapy, conversion to mono-therapy should be considered, and an attempt to titrate the lowest effective dosage be made. All such major changes should ideally be completed several months before conception to allow a reason-able observation period before pregnancy. It may be useful to document the optimal serum drug level before pregnancy to facili-tate interpretation of serum concentration measurements during pregnancy.

Conversion from polytherapy to monotherapy, or changes between AEDs, for the purpose of reducing teratogenic risks,

Table 25.5 Optimizing treatment of epilepsy in pregnancy.

Women seeking advice before becoming pregnantAll attempts at major changes in drug treatment should be accomplished and

adequately assessed before conceptionConfi rm diagnosis of active epilepsy and reassess need for treatment with

antiepileptic drugsFor women in remission, gradual withdrawal of antiepileptic drugs may be

considered if the risk of recurrence is low and the woman is aware of the risks and potential consequences

For women who need treatment, select the appropriate drug for the patient’s seizures or epilepsy syndrome but avoid valproic acid if possible

Aim at monotherapy and try out the lowest effective dosage of the appropriate drug

Document the patient’s optimal drug concentration before pregnancy. Measure unbound concentrations of phenytoin and valproic acid

Prescribe folate at 4–5 mg/day from before conception

During pregnancyOffer prenatal diagnosisMonitor the patient clinically and with serum drug concentrations each trimester,

more frequently in patients with poor seizure control or if lamotrigine is usedAdjust dosage in case of generalized tonic–clonic seizuresIn sensitive patients a dose adjustment may be justifi ed in response to a

signifi cant drop in active drug concentrations also in the absence of seizuresStress the importance of compliance with prescribed treatmentMonitor drug concentrations closely after delivery and re-adjust dosage if

increased during pregnancy


331

should not be attempted during pregnancy. At this stage of pregnancy the potential gain is minor compared with the risks associated with such procedures.

The treatment should be monitored more closely during preg-nancy than otherwise. This, too, needs to be tailored to the indi-vidual but in most cases an assessment each trimester, with a last visit at week 34–36, will suffi ce. This should include clinical evaluation and drug level monitoring where appropriate. Where phenytoin and valproic acid are used, monitoring the unbound levels is preferred. More frequent drug level monitoring may be justifi ed with lamotrigine and possibly also oxcarbazepine. A decrease in serum levels of AEDs alone does not automatically justify an increase in dosage, but in particular for lamotrigine, declining plasma concentrations have been linked to deterioration in seizure control [29]. The overall clinical state should be assessed and the individual patient’s optimal drug concentration and sen-sitivity to changes in drug levels documented before pregnancy should be taken into account. If a dosage increment was made during pregnancy, serum drug levels should be monitored during the fi rst weeks after delivery, since a dose reduction may be necessary.

Prenatal diagnosisWomen on antiepileptic drugs should be offered the possibility of prenatal testing if elective termination of pregnancy is acceptable. A malformation-directed ultrasound investigation at 16–20 weeks of gestation has a high sensitivity and specifi city in the detection of major malformations, including more than 90% of neural tube defects, and a high proportion of cardiac malformations, skeletal defects and orofacial clefts [63]. An ultrasound examination is often offered also at week 33–34 for assessment of intrauterine growth retardation.

Vitamin supplementationWomen with epilepsy considering pregnancy should be prescribed 4–5 mg folate/day, but also informed about the lack of evidence for its effi cacy.

Labour and deliveryIn general, labour and delivery do not imply any particular obstet-ric measures. However, delivery should take place in a well-equipped obstetric unit in view of the increased risk of seizures during labour and delivery and the increased risk of neonatal death.

Emergency Caesarean delivery is indicated during labour when seizures induce fetal asphyxia or cause poor maternal co-opera-tion. Intravenous benzodiazepines to the mother are also indi-cated in such cases.

PuerperiumStress and sleep deprivation in the puerperium may sometimes adversely affect seizure control. Furthermore, the new respon-sibilities of the care of the newborn may necessitate special considerations and precautions at home. It is recommended that the mother with epilepsy is given extra support from her partner or others during the fi rst weeks at home, in particular if she is sensitive to sleep deprivation, when seizures are likely to occur. In order to minimize risks to the infant, care for the

child, including breastfeeding, is best carried out on the fl oor, and another person should supervise bathing of the newborn.

Implications for the treatment of women of child-bearing age

The rate of unplanned pregnancies in the general population is high and the fi rst contact with health-care providers is frequently late. These factors are as true for women with epilepsy as they are for anyone else. Therefore, issues related to management during pregnancy will have implications for the treatment of women of child-bearing potential with epilepsy in general. Fur-thermore, the potential adverse effects of epilepsy and drug therapy on reproductive function, pharmacokinetic interactions with oral contraceptives, as well as developmental toxicity of AEDs, need to be included in the overall risk–benefi t equation, which should be the basis for decisions on when and how to treat epilepsy in young women. Thus, it is sometimes reasonable to withhold treatment in new-onset seizures if the indication is weak or ambiguous. If treatment is indicated, it is particularly impor-tant in this patient group to aim at monotherapy with the lowest effective dosage. When treatment is initiated in a woman of child-bearing potential, information must be given concerning drug effects on oral contraceptives, when appropriate, as well as poten-tial adverse effects on endocrine reproductive function and impli-cations in relation to pregnancy. The benefi ts of planning pregnancy should be emphasized. Because of the high rate of unplanned pregnancies, supplementation with folic acid (0.4 mg/day) is reasonable in all women of child-bearing potential who take AEDs. Counselling needs to be iterated at regular intervals. It is also important to inform, at an appropriate age, those women who had onset of their epilepsy as young girls but continue on AEDs beyond puberty.

Based on the considerations above, it is essential to identify young women with epilepsy who are likely to be able to withdraw their treatment without seizure recurrence, and to support them in attempts to taper treatment before they consider pregnancy. Likewise, suitable candidates for epilepsy surgery have the pros-pect of becoming seizure free, eventually without medication, after a successful operation. Hence, it is of particular value to avoid unnecessary delay in assessment for epilepsy surgery in women of child-bearing potential.

Potential adverse effects on reproductive function should be considered, together with all other relevant properties, when selecting an AED for a woman with epilepsy. The most impor-tant property of an AED is its effectiveness in preventing sei-zures, and for women of child-bearing potential the best choice is the drug that is most appropriate for the seizure type or syn-drome. However, the patient should be closely monitored for possible adverse effects on reproductive endocrine function and the treatment reassessed should such side-effects occur. It should also be remembered that drug preferences are likely to change as we gain more information on adverse effects on endocrine function from randomized clinical trials and comparative data on teratogenic effects of different antiepileptic drugs from preg-nancy registries.

CHAPTER 25

332

References

1 Wallace H, Shorvon S, Tallis R. Age-specifi c incidence and prevalence rates of treated epilepsy in an unselected population of 2,052,922 and age-specifi c fertility rates of women with epilepsy. Lancet 1998; 352: 1970–1973.

2 Olafsson E, Hauser WA, Gudmundsson G. Fertility in patients with epi-lepsy: a population-based study. Neurology 1998; 51: 71–73.

3 Viinikainen K, Heinonen S, Eriksson K, Kälviäinen R. Fertility in women with active epilepsy. Neurology 2007; 69: 2107–2108.

4 Penovich PE. The effects of epilepsy and its treatment on sexual and reproductive function. Epilepsia 2000; 41(Suppl. 2): S53–S61.

5 Rättyä J, Turkka J, Pakarinen AJ, et al. Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy. Neurology 2001; 56: 31–36.

6 Herzog AG. Disorders of reproduction in patients with epilepsy: primary neurological mechanisms. Seizure 2008; 17: 101–110.

7 Bauer J, Stoffel-Wagner B, Flugel D, et al. Serum androgens return to normal after temporal lobe epilepsy surgery in men. Neurology 2000; 55: 820–824.

8 Isojärvi JIT, Taboll E, Herzog AG. Effect of antiepileptic drugs on repro-ductive endocrine function in individuals with epilepsy. CNS Drugs 2005; 19: 207–223.

9 Isojärvi JIT, Löfgren E, Juntunen KST, et al. Effect of epilepsy and anti-epileptic drugs on male reproductive health. Neurology 2004; 62: 247–253.

10 Bauer J, Jarre A, Klingmuller D, Elger CE. Polycystic ovary syndrome in patients with focal epilepsy: a study in 93 women. Epilepsy Res 2000; 41: 163–167.

11 Luef G, Abraham I, Trinka E, et al. Hyperandrogenism, postprandial hyperinsulinism and the risk of PCOS in a cross sectional study of women with epilepsy treated with valproate. Epilepsy Res 2002; 48: 91–102.

12 Morrell M, Bhatt M, Özkara C, et al. Higher incidence of polycystic ovary syndrome in women with epilepsy treated with valproate versus lamotrigine. Neurology 2005; 64(Suppl. 1): 428.

13 Mikkonen K, Vainionpää LK, Pakarinen AJ, et al. Long-term reproduc-tive endocrine health in young women with epilepsy during puberty. Neurology 2004; 62: 445–450.

14 Lossius MI, Taubøll E, Mowinckel P, et al. Effects of antiepileptic drugs on reproductive endocrine function in men and women with epilepsy – a prospective randomized double-blind withdrawal study. Epilepsia 2007; 48: 1875–1882.

15 Rättyä J, Vainionpää L, Knip M, et al. The effects of valproate, carba-mazepine, and oxcarbazepine on growth and sexual maturation in girls with epilepsy. Pediatrics 1999; 103: 588–593.

16 Vainionpää L, Rättyä J, Knip M, et al. Valproate induced hyperan-drogenism during pubertal maturation in girls with epilepsy. Ann Neurol 1999; 45: 444–450.

17 Bauer J, Isojärvi JIT, Herzog AG, et al. Evaluation and management of reproductive endocrine abnormalities in women with epilepsy. J Neurol Neurosurg Psychiatry 2002; 73: 121–125.

18 O’Brien MD, Guillebaud J. Contraception for women with epilepsy. Epilepsia 2006; 47: 1419–1422.

19 Schwenkhagen AM, Stodieck SR. Which contraception for women with epilepsy? Seizure 2008; 17: 145–150.

20 Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-con-trolled trial. Epilepsia 2007; 48: 484–489.

21 Tomson T, Luef G, Sabers A, et al. Valproate effects on kinetics of lamotrigine in pregnancy and treatment with oral contraceptives. Neu-rology 2006; 67: 1297–1299.

22 Tomson T, Hiilesmaa V. Epilepsy in pregnancy. BMJ 2007; 335: 769–773.

23 Hiilesmaa VK, Bardy A, Teramo K. Obstetric outcome in women with epilepsy. Am J Obstet Gynecol 1985; 152: 499–504.

24 EURAP study group. Seizure control and treatment in pregnancy. Obser-vations from the EURAP epilepsy and pregnancy registry. Neurology 2006; 66: 354–360.

25 Adab N, Kini U, Vinten J, et al. The long term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psych 2004; 75: 1575–1583.

26 Schmidt D. The effect of pregnancy on the natural history of epilepsy. In: Janz D, Dam M, Bossi L, Helge H, Richens A, Schmidt D (eds). Epi-lepsy, Pregnancy, and the Child. New York: Raven Press, 1982: 3–14.

27 Vajda FJE, Hitchcock A, Graham J, et al. Seizure control in antiepileptic drug-treated pregnancy. Epilepsia 2008; 49: 172–176.

28 Tomson T, Battino D. Pharmacokinetics and therapeutic drug monitoring of newer antiepileptic drugs during pregnancy and the puerperium. Clin Pharmacokinet 2007; 46: 209–219.

29 Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in pregnancy. Clear-ance, therapeutic drug monitoring and seizure frequency. Neurology 2008; 70: 2130–2136.

30 Tomson T, Palm R, Källén K, et al. Pharmacokinetics of levetiracetam during pregnancy, delivery, in the neonatal period, and lactation. Epilep-sia 2007; 48: 1111–1116.

31 Richmond JR, Krishnamoorthy P, Andermann E, Benjamin A. Epilepsy and pregnancy: an obstetric perspective. Am J Obstet Gynecol 2004; 190: 371–379.

32 Katz O, Levy A, Wiznitzer A, Sheiner E. Pregnancy and perinatal outcome in epileptic women: a population-based study. J Matern Fetal Neonatal Med 2006; 19: 21–25.

33 Perucca E. Birth defects after prenatal exposure to antiepileptic drugs. Lancet Neurol 2005; 4: 781–786.

34 Tomson T, Battino D, French J, et al. Antiepileptic drug exposure and major congenital malformations: the role of pregnancy registries. Epi-lepsy Behav 2007; 11: 277–282.

35 Fried S, Kozer E, Nulman I, et al. Malformation rates in children of women with untreated epilepsy. A meta-analysis. Drug Saf 2004; 27: 197–202.

36 Wide K, Winbladh B, Kallen B. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Pae-diatr 2004; 93: 174–176.

37 Artama M, Auvinen A, Raudaskoski T, et al. Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neuro-logy 2005; 64: 1874–1878.

38 Morrow JI, Russell A, Gutherie E, et al. Malformation risks of anti-epileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006; 77: 193–198.

39 Cunnington M, Ferber S, Quarteny G, and the International Lamotrigine Pregnancy Registry Scientifi c Advisory Committee. Effect of dose on frequency of major birth defects following fetal exposure to lamotrigine monotherapy in an international observational study. Epilepsia 2007; 48: 1207–1210.

40 Holmes LB, Wyszynski DF, Lieberman ES. The AED (antiepileptic drug) Pregnancy Registry: a 6-year experience. Arch Neurol 2004; 61: 673–678.

41 Wyszynski DF, Nambisan M, Surve T, et al. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neu-rology 2005; 64: 961–965.

42 Holmes LB, Wyszynski DF, Baldwin EJ, et al. Risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy. Birth Def Res (Part A): Clin Mol Teratol 2006; 76: 318.

43 Hernandez-Diaz S, Smith CR, Wyszynski DF, Holmes LB. Risk of major malformations among infants exposed to carbamazepine during preg-nancy. Birth Def Res (Part A): Clin Mol Teratol 2007; 79: 357.

44 Kini U, Adab N, Vinten J, Fryer A, Clayton-Smith J; Liverpool and Manchester Neurodevelopmental Study Group. Dysmorphic fea-tures: an important clue to the diagnosis and severity of fetal anticon-vulsant syndromes. Arch Dis Child Fetal Neonatal Ed 2006; 91: F90–F95.


333

45 Perucca E, Tomson T. Prenatal exposure to antiepileptic drugs. Lancet 2006; 367: 1467–1469.

46 Gaily E. (1997) Minor anomalies and effects on psychomotor develop-ment associated with maternal use of antiepileptic drugs. In: Tomson T, Gram L, Sillanpää M, Johannessen SI (eds). Epilepsy and Pregnancy. Petersfi eld: Wrightson Biomedical Publishing Ltd, 1997: 63–70.

47 Hiilesmaa VK, Teramo K, Granstrom ML, Bardy AH. Fetal head growth retardation associated with maternal antiepileptic drugs. Lancet 1981; 2: 165–167.

48 Battino D, Kaneko S, Andermann E, et al. Intrauterine growth in the offspring of epileptic women: a prospective multicenter study. Epilepsy Res 1999; 36: 53–60.

49 Wide K, Winbladh B, Tomson T, Källen B. Body dimensions of infants exposed to antiepileptic drugs in utero: observations spanning 25 years. Epilepsia 2000; 41: 854–861.

50 Adab N, Tudur SC, Vinten J, et al. Common antiepileptic drugs in preg-nancy in women with epilepsy (Cochrane review). Cochrane Library, Chichester, UK. John Wiley & Sons Ltd, 2004: Issue 3.

51 Gaily E, Kantola-Sorsa E, Hiilesmaa V, et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology 2004; 62: 28–32.

52 Eriksson K, Viinikainen K, Monkkonen A, et al. Children exposed to valproate in utero – Population based evaluation of risks and confound-ing factors for long-term neurocognitive development. Epilepsy Res 2005; 65: 189–200.

53 Hägg S, Spigset O. Anticonvulsant use during lactation. Drug Saf 2000; 22: 425–440.

54 Tomson T. Gender aspects of pharmacokinetics of new and old AEDs. Pregnancy and breast-feeding. Ther Drug Monit 2005; 6: 718–721.

55 Czeizel AE, Dudas I. Prevention of the fi rst occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327: 1832–1835.

56 MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338: 131–137.

57 Berry RJ, Li Z, Erickson JD, et al. Prevention of neural-tube defects with folic acid in China. China–US Collaborative Project for Neural Tube Defect Prevention. N Engl J Med 1999; 341: 1485–1490.

58 Stokes T, Juarez-Garcia A, Camosso-Stefi novic J, Baker R. Clinical Guidelines and Evidence Review for the Epilepsies: Diagnosis and Man-agement in Adults and Children in Primary and Secondary Care. London: Royal College of General Practitioners, 2004.

59 Kjaer D, Horvath-Puhó E, Christensen J, et al. Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case-control study. BJOG 2008; 115: 98–103.

60 Hey E. Effect of maternal anticonvulsant treatment on neonatal blood coagulation. Arch Dis Child 1999; 81: F208–F210.

61 Choulika S, Grabowski E, Holmes LB. Is antenatal vitamin K prophy-laxis needed for pregnant women taking anticonvulsants? Am J Obstet Gynecol 2004; 190: 882–883.

62 Kaaja E, Kaaja R, Matila R, Hiilesmaa V. Enzyme-inducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate. Neurology 2002; 58: 549–553.

63 Kooper AJ, de Bruijn D, van Ravenwaaij-Arts CM, et al. Fetal anomaly scan potentially will replace routine AFAFP assays for the detection of neural tube defects. Prenat Diagn 2007; 27: 29–33.

the treatment of epilepsy || reproductive aspects of epilepsy treatment

Documents