Second-generation antiepileptic drugs and pregnancy: a guide for clinicians

Abstract

When treating pregnant women with antiepileptic drugs (AEDs), clinicians have to balance potential fetal adverse effects against the risks of uncontrolled maternal disease. Only recently have emerging scientic data provided a rational basis for treatment decisions considering both aspects. The focus of research is currently moving from the first to the second AED generation. Lamotrigine is relatively well studied, and data on other novel AEDs, such as levetiracetam, oxcarbazepine, topiramate, zonisamide, gabapentin and pregabalin, are in progress. Safety issues appear to be favorable for lamotrigine, and preliminary results are also promising for levetiracetam and oxcarbazepine. Drugs metabolized by uridine-diphospate glucuronosyl transferase or excreted unchanged by the kidneys are particularly susceptible to increased body clearance during pregnancy. Lamotrigine is subject to both mechanisms, and therapeutic serum levels may sometimes be difficult to maintain. The authors review the recommendations and clinical research on modern AED treatment during pregnancy, highlighting current experience with second-generation drugs.

Keywords::

• breast feeding
• gabapentin
• lamotrigine
• levetiracetam
• oxcarbazepine
• pharmacokinetics
• pregabalin
• pregnancy
• teratogenicity
• topiramate
• zonisamide

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/expertendo; (4) view/print certificate.

Release date: 31 May 2012; Expiration date: 31 May 2013

Learning objectives

Upon completion of this activity, participants will be able to:

• • Describe altered pharmacokinetics and other issues affecting treatment with AEDs during pregnancy, based on a review

• • Describe issues specific to treatment with LTG during pregnancy, based on a review

• • Describe practical recommendations for use of AEDs during pregnancy, based on a review

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Laurie Barclay

Freelance writer and reviewer, Medscape, LLC

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Arne Reimers, MD, PhD

Department of Clinical Pharmacology, St. Olavs University Hospital, Trondheim, Norway; Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway Disclosure: Arne Reimers, MD, PhD, has disclosed no relevant financial relationships.

Eylert Brodtkorb, MD, PhD

Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Neurology and Clinical Neurophysiology, St. Olavs University Hospital, Trondheim, Norway

Disclosure: Eylert Brodtkorb, MD, PhD, has received honoraria and/or financial support for conference attendance from the following manufacturers of antiepileptic drugs: Eisai, Desitin, GlaxoSmithKline, Janssen-Cilag, Novartis, and UCB.

Epilepsy is one of the most frequent neurological disorders, with an overall estimated prevalence of 0.5–0.7% in western countries [1]. The prevalence in pregnant women has been estimated to be 0.3–0.5% [2]. At least 25% of people with epilepsy are women of child-bearing age; the majority of them are seizure free with one or more antiepileptic drugs (AEDs) [3]. AEDs are also used for the treatment of other conditions, such as bipolar disorder, neuropathic pain, generalized anxiety disorder and migraine [4]. Thus, AEDs are widely used by a large number of young women.

Seizure type and epilepsy syndrome are the fundamental determinants for the treatment choice in seizure disorders. However, different AEDs are characterized by different side effect and interaction potentials, and individual patients may have different tolerance and pharmacokinetic profiles. Sex, age, genetic profile and comorbidity are important factors [5–7]; pregnancy represents a unique situation in these respects. All of these elements need to be considered when selecting an AED for the individual patient.

The era of the second AED generation started in the 1990s when several new drugs were launched in rapid succession (Table 1) [8,9]. This marked the end of a 20-year long hiatus after the introduction of valproate (VPA), the last of the first-generation AEDs. The second-generation AEDs did not generally prove to be more effective than the first generation, but many of them are better tolerated, less prone to drug interactions and have more predictable pharmacokinetics [10,11].

During the last two decades, much attention has been directed towards problems with the use of first-generation AEDs in women: hormonal and metabolic disturbances, pharmacokinetic interactions with contraceptives and pregnancy-related problems, including adverse reactions in the offspring. VPA, which for many years was a first-choice drug in generalized epilepsy of both sexes, has demonstrated the highest teratogenic potential among the first-generation AEDs [12]. The desire to avoid VPA has led to a wider use of second-generation AEDs in fertile women, particularly the novel broad spectrum drugs in women with generalized epilepsies. New drugs devoid of interactions with hormonal contraceptives are also preferred in fertile women. This trend is confirmed by a recent survey of AED prescription patterns in Norwegian patients with epilepsy. Lamotrigine (LTG), gabapentin (GBP) and topiramate (TPM) were used to a larger extent in female than in male patients, whereas carbamazepine (CBZ), VPA, phenytoin and oxcarbazepine (OXC) were more frequently used in male patients [13].

Recent clinical research has demonstrated that physiological changes during different stages of gestation may change the pharmacokinetics of AEDs significantly and with great interindividual variation [14]. Some second-generation AEDs are more prone to these changes than others. Nevertheless, most of these difficulties can be dealt with, although close, time-consuming clinical and laboratory monitoring may be required. Treatment with AEDs may indeed be complex in females who are, or wish to become, pregnant. The balance between maternal and fetal health risks can be very demanding. Profound knowledge of these issues is necessary, not only to create a rational treatment strategy, but also to provide appropriate information to the woman wishing to conceive while being treated with AEDs.

This article reviews recommendations and clinical research on modern AED treatment during pregnancy, with particular reference to current experience with second-generation drugs.

Fetal adverse reactions

Major congenital malformations

It has been known for decades that prenatal exposure to AEDs is associated with an elevated risk for minor and major birth defects [15]. In different studies, the prevalence of major congenital malformations in the offspring of women taking AEDs has ranged from 4–10%, corresponding to a two- to four-fold increase from the expected rates in the general population [2]. There is increasing evidence for differential effects on the fetus by various AEDs, both in regard to frequency and pattern of malformations. Worldwide, large multicenter observational studies have now been collecting data for many years. The largest number of pregnancies has been enrolled in the European and International Registry of Antiepileptic drugs in Pregnancy (EURAP), in which the offspring is followed up until the age of 1 year [12]. Data from almost 5000 eligible monotherapy exposures were recently released, permitting a comparison between the most used second-generation drug, LTG, and first-generation drugs. Irrespective of dose, the frequencies of malformations were as following: LTG 2.9% (n = 1280), CBZ 5.6% (n = 1402), phenobarbital 7.4% (n = 217) and VPA as high as 9.7% (n = 1010). These findings are largely in harmony with data from other pregnancy registries [16]. However, owing to differences in methodology, all data from the various registries are not directly comparable [17]. The EURAP study also found an increased rate of malformations with increasing dose at time of conception. The lowest malformation rates were found for LTG monotherapy at daily doses below 300 mg (2%; n = 836) [12].

So far, outcome data on monotherapy with newer AEDs other than LTG are scarce. Second-generation drugs were used only in 37% of the eligible monotherapy pregnancies (n = 4540) in the 2011 EURAP report [12], and LTG was used in as many as 75% of them. Separate preliminary experience on TPM has been reported from the UK Epilepsy and Pregnancy Register [18]. Of 178 live births, there were three (4.8%) major congenital malformations in 70 monotherapy cases. A detailed review of the teratogenic potential of newer AEDs has recently been performed by Hill et al. [19]. While LTG and levetiracetam (LEV) appeared to have the lowest risk, TPM showed a significantly increased rate of major congenital malformations. This is supported by recent EURAP data on less commonly used second-generation AEDs [12], which are shown in Table 2. Although the available data are based on too small numbers for reliable assessments of risks, apart from the LTG results, the preliminary findings raise concerns for TPM and appear promising for LEV and OXC. The findings from a population-based study from Demark are similar [20]. Polytherapy data are still few. For LTG, it has been found that the malformation risk is not higher in combination with CBZ, compared with monotherapy with either of the drugs, whereas it is higher in combination with VPA [21].

Neurodevelopmental effects

In utero exposure to VPA has been identified as a risk factor for cognitive impairment in children. Cognitive functions in the offspring have recently been compared for VPA, CBZ, phenytoin and LTG in an ongoing prospective, observational multicenter study. Exposure to VPA during pregnancy was associated with the poorest cognitive results at 3 years of age, compared with the global IQs of their mothers, whereas offspring and maternal IQs correlated well for the other drugs [22]. However, verbal performance was lower than nonverbal for each drug, suggesting that all of these compounds may have some neurodevelopmental effects. LTG came out best for both verbal and nonverbal abilities [23]. This study raises the suspicion that AEDs as a class may be associated with a skewed cognitive profile with a particular vulnerability for verbal skills in the offspring of treated mothers. However, confounding factors are ample, and controls were not studied; the findings were only compared with population-based reference values. In two recent studies of young children exposed to monotherapy with LTG and LEV in utero, the results were compared with unexposed controls. Detrimental effects on neurodevelopment were not found with either drug. In the LTG study (n = 44), children were examined at the age of 9–60 months [24] and in the LEV study (n = 55) at an age below 2 years [25]. More studies of novel AEDs and in older children are needed.

Folic acid supplementation

Folic acid supplementation before pregnancy and during the first trimester is recommended according to current guidelines for the management of epilepsy in pregnancy [26,27]. However, its beneficial effect is unclear [12]. The increased risk of AED-associated malformations are likely to occur through mechanisms other than that of folic acid metabolism [28,29]. Nevertheless, recent studies have suggested that folic acid may reduce the number of spontaneous abortions in women using AEDs [30] as well as protect against cognitive impairment in children exposed to AEDs in utero [23]. Further, larger and AED-specific studies on the effect of folate supplementation, including its dosing and duration, are needed.

Pregnancy changes the pharmacokinetics of AEDs

Recently, several pharmacokinetic studies have identified and characterized factors which may alter AED pharmacokinetics during pregnancy:

• • Renal blood flow and glomerular filtration rate increase by as much as 50–80% during pregnancy. Serum concentrations of AEDs and/or their metabolites that are predominantly eliminated via the kidneys may be reduced accordingly. This effect starts shortly after conception with persistence throughout the second trimester and with some reduction in the last few weeks of pregnancy [31–33];

• • Hormonal changes, that is, increased estrogen levels, lead to accelerated drug glucuronidation. This effect seems to increase gradually throughout the first and second trimester, with little change during the last trimester [34]. In addition, the activity of some CY P450 enzymes is increased [33];

• • Reduced serum albumin concentrations may affect AED protein binding and, thus, total plasma clearance;

• • Increased plasma volume and/or increased total body water may increase the volume of distribution, and thus lead to reduced AED serum concentrations.

From the above, pregnancy-induced changes of AED kinetics may to some extent be predicted by their respective pharmacological properties. However, other potential factors that may affect their serum concentrations, and the marked interindividual differences both in drug disposition and seizure control, make clinical reality anything other than simple. For example, frequent vomiting may impair intake and intestinal absorption of AEDs in an unpredictable manner. Medication noncompliance due to fear for harmful effects to the unborn child may be concealed by the mother. Comedication with enzyme-inducing or enzyme-inhibiting AEDs, which themselves may be subject to altered pharmacokinetics, is another factor [35]. Therefore, it is difficult to anticipate whether and how pregnancy-related changes in AED pharmacokinetics will become clinically relevant in individual patients or not.

Prepregnancy serum concentrations are of major importance as reference values for later use. Particular care is warranted in combined treatment with drugs known to be strongly affected by pregnancy-induced pharmacokinetic alterations. It should also be noted that for several of the AEDs, pregnancy-induced changes are reversed within few weeks postpartum [14]. This may also require close clinical and therapeutic drug monitoring in this period in order to avoid overdosing.

Generally accepted guidelines for the treatment of epilepsy in women wishing to become pregnant recommend monotherapy at the lowest effective dose [36]. Diligent adherence to this advice may leave some child-bearing women with weak seizure control. As serum concentrations of most second-generation AEDs decrease significantly during pregnancy, minimal effective treatment as a starting point may result in vulnerability to potential pregnancy-related seizure deterioration [14]. Close monitoring of the pregnant patient, both clinically and by measurement of AED serum concentrations, is generally advisable. A recent Danish study showed that women receiving follow-up at a specialized clinic had a lower risk for seizure deterioration compared with those first referred after conception [37].

Breast feeding

All second-generation AEDs pass into breast milk, although to variable degrees [38]. Passive transfer into milk is common in drugs with low protein binding. Breast-milk concentrations of LTG, GBP and TPM reach or nearly reach the mother's serum concentration and may possibly produce clinically relevant levels in the nursed infant [39–41]. This depends not only on the amount of AED in the breast milk, but also on the metabolic capacity of the child. Drugs that undergo glucuronidation, such as LTG, have longer half-lives in newborns. Renal function is also not fully developed during the first weeks after birth [42]. However, adverse effects in the breast-fed child are rarely reported and consist mainly of sedation, poor suckling and similar, unspecific symptoms [38]. Replacement of one or more breast-milk meals with formula milk meals may reduce the AED exposure of the infant [38]. Possible long-term consequences of breast feeding while taking second-generation AEDs have not been studied sufficiently [26], but in a study including the offspring of women receiving LTG, the cognitive outcomes at 3 years of age were the same in breastfed as in non-breastfed children [43]. Current guidelines generally encourage women taking AEDs to nurse their infants [36,44]. However, close clinical monitoring of the child is advisable [38].

Focus on individual second-generation AEDs

The following section discusses the most commonly used second-generation AEDs in relation to pregnancy. Key elements are highlighted in Table 3.

Lamotrigine

With respect to pregnancy, LTG is the best studied second-generation AED. Soon after its introduction, this drug was heavily marketed as an alternative to VPA in women of child-bearing age. LTG is extensively metabolized, mainly to LTG-N2-glucuronide by uridine-diphosphate glucuronosyl transferase (UGT) 1A4. Compared with baseline, its apparent clearance in pregnancy at least doubles, and the dose-normalized serum concentration may be reduced by 40–60%, while quickly returning to nonpregnant levels within 1–2 weeks after delivery [39,45]. The fall in LTG serum concentrations has been attributed to estrogen-induced glucuronidation [35]. However, a recent study suggests that increased renal blood flow accounts for about a half of the reduction of LTG serum concentration during pregnancy. Enhanced renal excretion of the unchanged drug appears to be responsible for the rapid decline of LTG concentrations during early pregnancy. Later, estradiol-induced glucuronidation seems to predominate, leading to a further fall, but with little further change during the last trimester [34]. Loss of seizure control due to reduced LTG serum concentrations has been reported [45]. Thus, close therapeutic drug monitoring and dose adjustment is recommendable. After delivery, the serum concentration may rapidly increase, and the dose may have to be adjusted to avoid toxicity in the mother as well as unnecessary exposure of the nursing infant [46]. Although LTG may be difficult to use during pregnancy due to its pharmacokinetic profile, it appears to be a relatively safe option with respect to teratogenicity, at least in the lower dose range, as daily doses below 300 mg do not seem to be associated with any increased risk of malformations [12].

Another issue that deserves attention is that the discontinuation of hormonal contraceptives containing ethinyl estradiol may double LTG serum concentrations [47,48], leaving the woman with undue high LTG levels at conception and the critical first weeks of pregnancy, if the dose is not reduced.

LTG passes over into breast milk and can produce infant/maternal plasma concentration ratios of 2.9–46.2% [49]. The accumulation of LTG in infants is probably due to low glucuronidation capacity up to the age of 20 months [50]. There is only one case report on serious adverse effects in the breastfed child, describing episodes of apnea at day 16 in a nursed infant [51]. The mother took 875 mg LTG daily and after delivery she developed CNS toxicity herself. Given the widespread use of this drug, this suggests that breast feeding can be regarded safe in most cases. However, caution is advised with high LTG doses.

Levetiracetam

Protein binding of LEV is very low, making it unlikely that changes in serum albumin may affect its serum concentrations. At least a quarter of an oral dose is metabolized in blood by hydrolysis, while two-thirds are usually found unchanged in the urine [52]. The apparent clearance of LEV increases significantly during pregnancy and case series have demonstrated reduced serum concentrations as low as 40% of baseline concentrations [53–55]. The underlying mechanism has not been explored, but it is reasonable to assume enhanced excretion due to increased renal blood flow. Increased peripheral hydrolysis may also occur, but this has not been investigated. Serum levels return to normal within the first week after pregnancy [54]. LEV is excreted into breast milk in considerable amounts and the mean milk/maternal serum concentration ratio has been determined to be around one [55]. However, measured serum concentrations in the breast-fed child do not seem to reach clinically relevant values as they mostly stay below 10–15 µmol/l [55,56]. Accordingly, no adverse reactions in breastfed children have so far been reported.

Oxcarbazepine

After oral intake, OXC is quickly and almost completely metabolized to the pharmacologically active monohydroxycarbazepine, which is then eliminated as a glucuronide [57]. The protein binding of monohydroxycarbazepine is about 40% [58]. Available studies on the pharmacokinetics of OXC during pregnancy report that the serum concentrations of monohydroxycarbazepine are at least 36% lower during pregnancy, compared with pre- or post-pregnancy values [59–61]. An increased rate of glucuronidation, induced by raised estrogen levels, may be the responsible mechanism, although increased renal excretion may also contribute. A trend toward a correlation between decreased plasma concentrations and deteriorated seizure control has been demonstrated [62]. After delivery, however, serum concentrations return to prepregnancy levels within a few weeks [62]. Concerning breast feeding, only two cases are reported. In both, serum concentrations in the child remained low despite a breast milk/maternal serum concentration ratio of about 0.5–1 [63,64]. No adverse effects in the nursing infants were observed in these cases.

Topiramate

Only 20–30% of a TPM dose is metabolized; the remainder is found unchanged in the urine [65]. Thus, increased renal blood flow in pregnancy might lead to increased renal clearance of TPM and a decline in its serum concentrations. Indeed, serum concentrations of TPM have been found to be reduced by 30–40% during pregnancy, and close serum level monitoring is recommended [66,67]. Preliminary data indicate an increased risk for major congenital malformations, mainly oral cleft and hypospadia [12,18]. Moreover, TPM has been associated with decreased birthweight [68]. Breastfed infants had very low TPM concentrations, and no adverse effects were observed in them [69,70].

Gabapentin & pregabalin

GBP and pregabalin (PGB) are not metabolized, but are eliminated unchanged by the kidneys [71]. As renal blood flow increases by 50–80% during pregnancy, their serum concentrations may fall considerably. However, no systematic studies on the pharmacokinetics of GBP or PGB during the course of pregnancy have been published so far. Reports on the consequences of prenatal GBP exposure are limited and inconclusive [19]. In one study comprising 51 infants, no increased risk for fetal malformations was found [72]. However, it should be noted that a study in six women suggested an active transplacental transport of GBP with accumulation in the fetus. The mean umbilical cord/plasma concentration ratio was close to 2 [41]. In the newborn the half-life was 14 h, compared with 5–7 h in adults, in accordance with immature kidney function in the first weeks of life [42]. The mean milk–plasma ratio of GBP is around 1, and the relative infant dose has been calculated to be 1.3–3.8% of the mother's dose. The infant's plasma concentration was approximately 6–12% of the mother's. No adverse effects attributable to GBP were noted in the observed infants, and breast feeding has therefore been suggested as safe [40,41]. However, the above data are based on a total of only seven patients. Data on PGB and breast feeding are currently limited to one single case report. The passage into breast milk was extensive, but low concentrations were measured in the infant [73].

Zonisamide

Zonisamide (ZNS) is only 40–50% protein-bound and undergoes hepatic biotransformation by several pathways [74]. An oral dose of 15–30% appears unchanged in the urine. Decreased serum albumin concentrations would therefore not be expected to significantly affect the kinetics of ZNS. However, other pregnancy-related changes such as increased renal blood flow may affect ZNS serum concentrations. No systematic studies on the pharmacokinetics of ZNS during pregnancy have been published, but one case report indeed suggests an increased clearance of ZNS. In the reported case, the daily dose had to be increased from 200 to 300 mg to maintain seizure control [75]. Another report on two cases describes a modest increase of the ZNS serum concentration from 17.5 and 18.9 µg/ml at delivery to 23.3 and 25.5 µg/ml at 9 days postpartum [76]. The teratogenic effects of ZNS were assessed in one study with 26 children exposed to ZNS in utero. Malformations were found in two cases where ZNS was combined with first-generation AEDs, but not in the four monotherapy cases [77]. ZNS passes over into breast milk in concentrations similar to maternal blood concentrations, but in the few cases reported so far no adverse effects were observed [76,78].

Other newer AEDs

Eslicarbazepine (ESL) is rapidly converted to the S-enantiomer of monohydroxycarbazepine. It has recently been launched as a drug of its own and is by some authors considered a third-generation AED (Table 1) [8], in spite of the fact that the racemate of monohydroxycarbazepine is the active metabolite of OXC. Only a very small fraction of ESL is biotransformed to OXC [79]. Furthermore, lower serum concentrations of the S-enantiomer seem to be needed compared with the monohydroxycarbazepine racemate, which may represent an advantage during pregnancy. Possible changes of the kinetics of ESL during gestation have so far not been studied separately. However, it is likely that, similar to the racemate (see paragraph on OXC), serum concentrations will decline. No reports on ESL and breast feeding have been published so far.

The use of the other second-generation drugs such as tiagabine, vigabatrin, felbamate, stiripentol and rufinamide, as well as the third-generation drugs retigabine and lacosamide (Table 1), is at present mainly restricted to add-on treatment of difficult-to-control epilepsy or in specific syndromes (vigabatrin: West syndrome; stiripentol: Dravet syndrome; rufinamide: Lennox–Gastaut syndrome). Data on their pharmacokinetics in pregnancy, their teratogenic potential, passage into breast milk and neurodevelopmental effects in the offspring are very limited or nonexistent [80,81]. Thus, their use in pregnant women is not recommended until more is known about their potential to induce fetal adverse effects. Lacosamide is for a great part excreted unchanged in the urine [82], whereas retigabine is cleared from the body via multiple pathways, N-acetylation, renal clearance and glucuronidation (mainly by UGT1A4) [83]. An increased clearance during pregnancy can be expected for both drugs.

Practical recommendations

Prior to conception

• • Provide detailed information to the woman on risks and benefits of her specific AED treatment to ensure her ability to make informed decisions concerning pregnancy;

• • Reconsider AED regimen in women who wish to become pregnant in advance of intended conception: switch to drugs with low potential to fetal adverse effects when appropriate, and aim at lowest effective dose;

• • Assure treatment adherence and take AED serum concentrations as reference values;

• • In case of withdrawal of combined hormonal contraceptives in combination with LTG, consider reduction of the LTG dose in order to avoid an unintended increase in serum levels;

• • Start folic acid supplementation;

• • Instruct the woman to report her pregnancy to the AED-prescribing physician as soon as it is confirmed.

During pregnancy

• • Monitor AED serum concentrations as soon as pregnancy is established and refer to prenatal screening;

• • Monitor AED serum concentrations on a monthly basis and follow patients clinically;

• • Consider dose increments by 25% when serum concentrations fall below the patient's prepregnancy reference value, or according to clinical needs.

After delivery

• • As dose/serum concentration ratios of several of the second-generation AEDs return to prepregnancy levels within few weeks after delivery, gradually reduce the dose if it has been increased during pregnancy, to avoid overdosing;

• • Monitor maternal serum concentrations;

• • Observe mother and child clinically during breast feeding; particular attention is needed with high LTG doses;

• • When serum concentrations in the mother are high, also perform measurements in the nursing infant, particularly when LTG is used. Aim at serum concentrations below therapeutic levels in the infant; consider restricted nursing if necessary.

Conclusion

Second-generation AEDs are increasingly being used in pregnant patients, as most first-generation drugs have properties that make them unattractive to use in fertile women, such as fetal adverse effects or reduced efficacy of hormonal contraceptives. However, with the exception of LTG, systematic studies of second-generation AEDs in pregnancy are very limited.

Available safety data concerning fetal exposure to LTG are largely reassuring. Preliminary experience with LEV and OXC is also promising, but raises concerns for the use of TPM. Increased clearance of second-generation drugs during gestation is common, particularly for drugs that are metabolized by UGT and/or subject to direct renal excretion. LTG serum concentrations may decrease by more than 50%, LEV by 40%, and OXC and TPM by 30–40%. Recent data on LTG suggest that significantly increased renal excretion may take place already during the first trimester, whereas UGT activity becomes more gradually induced, particularly in the second trimester. There is a marked interindividual variability of these effects and frequent therapeutic drug monitoring is recommended. Dose adjustments may be necessary to maintain seizure control; this issue should receive attention in the first phase of pregnancy. Although the safety profile of LTG is favorable, its use in pregnancy is indeed complicated and demanding due to its pharmacokinetic vulnerability. The effects of breast feeding with second-generation AEDs are insufficiently studied, but nursing is generally considered as safe. Care should be taken with high doses of drugs metabolized by UGT, such as LTG, owing to low metabolizing capacity in infants. Continuous study efforts are needed to characterize fetal risks and the pregnancy-related pharmacokinetics of novel AEDs in order to optimize treatment outcome for both mother and child.

Expert commentary

Epilepsy is the most common neurological problem that requires pharmacological treatment throughout pregnancy. Fertile women constitute a considerable part of patients with epilepsy; feasibility in this patient group is of major importance for the marketing of AEDs. AEDs are also used for nonepilepsy indications; indeed the use of several second-generation AEDs in other disorders exceeds that in epilepsy. Generally, when treating pregnant women with AEDs, the risks associated with fetal drug exposure need to be weighed against the risks of uncontrolled maternal disease. When new AEDs are brought to the market, potential harmful effects on the development of the offspring are unknown. Although preclinical testing of new drugs involves teratogenic screening in animals, such effects are often species-specific and cannot be directly transferred to humans. Thus, observational studies in patients are the only way to assess human fetal drug adverse reactions. Because of the general low frequency of major malformations and the plethora of confounding factors, many hundreds or even thousands of pregnancies with monotherapy exposures are required in order to draw firm conclusions. This has led to the creation of prospective pregnancy registers, which are currently operational in several parts of the world. Although some answers concerning the most used second-generation drugs have started to emerge, continuing enrolments are imperative to gain systematic experience with the various novel AEDs. The cognitive outcome in the offspring as well as the presence of dysmorphic features needs more scientific attention.

By contrast, the pharmacokinetics of second-generation AEDs during pregnancy is easier to study, not least because the basic physiological changes induced by pregnancy are well known. The large multicenter registries appear to have stimulated and facilitated clinical research in this field. Several of the pharmacokinetic studies of second-generation AEDs in pregnancy have been spin-off studies in enrolled patients. The vast majority of these studies have addressed LTG, the most widely used novel AED. Accordingly, studies on less commonly used second-generation AEDs such as GBP, TPM or ZNS are rare or missing. However, LTG studies in pregnancy have provided insight into the mechanisms behind the effects of pregnancy-related physiological changes on AED kinetics. Detailed knowledge of these interactions may now aid the clinician to anticipate pharmacokinetic changes in other less well studied AEDs, depending on their metabolism and excretion pathways.

Five-year view

Owing to the decreasing popularity of first-generation AEDs in women of child-bearing age, the use of second-generation AEDs is steadily growing. Valid reports from registry networks on fetal risks of second-generation AEDs in pregnancy have only started to emerge. More monotherapy data on common novel AEDs other than LTG are now urgently needed, particularly on LEV, which is developing into a first-line drug in the treatment of epilepsy. While the authors still are collecting data on second-generation drugs, the third generation has entered the scene (Table 1), and there are more new drugs in the pipeline [84]. Risk assessments of combined therapies are also important. Therefore, clinicians worldwide should be encouraged to feed their pregnant patients into prospective multicenter AED registries in a consecutive manner. Nevertheless, it will take a long time before the fetal risks of less frequently used second-generation AEDs are appropriately assessed.

Major congenital malformations are not the only focus of interest. Recently, much attention has been given to subtle neurodevelopmental disturbances in children exposed to AEDs in utero. Further studies are in progress. Moreover, detailed pharmacokinetic studies on the newer AEDs during pregnancy, puerperium and lactation will help clinicians to optimize treatment in these situations.

The ideal AED for fertile women is yet to be identified. Although the safety profile of LTG appears favorable, its use in young females is complicated by cumbersome pharmacokinetic interactions with endogenous as well as exogenous estrogens. The current position of LTG as the most used AED in women of child-bearing age may soon be ready for challenge.

Table 1. The three generations of antiepileptic drugs and the year of their introduction in Europe.

Generation of AED	AED	Year of introduction
First generation	Bromide	1857
	PB	1912
	PHT	1939
	PRM	1960
	STM^†	1960
	CBZ	1965
	VPA	1970
Second generation	VGB^†	1989
	OXC	1990
	LTG	1991
	GBP	1994
	FBM^†	1994
	TPM	1995
	TGB^†	1996
	LEV	2000
	PGB	2005
	ZNS	2007
	STP^†	2007
	RUF^†	2007
Third generation	ESL	2010
	LCM	2010
	RTG (ezogabine)	2011

^† Marketed at a low scale or for restricted use.

AED: Antiepileptic drug; CBZ: Carbamazepine; ESL: Eslicarbazepine; FBM: Felbamate; GBP: Gabapentin; LCM: Lacosamide; LEV: Levetiracetam; LTG: Lamotrigine; OXC: Oxcarbazepine; PB: Phenobarbital; PGB: Pregabaline; PHT: Phenytoin; PRM: Primidone; RTG: Retigabine; RUF: Rufinamide; STP: Stiripentol; STM: Sulthiame; TGB: Tiagabine; TPM: Topiramate; VPA: Valproate; VGB: Vigabatrin; ZNS: Zonisamide.

Data taken from [8,9].

Table 2. Data from the the European and international Registry of Antiepileptic drugs in Pregnancy on major congenital malformations after monotherapy exposure to commonly used second-generation antiepileptic drugs.

AED	Exposures (n)	Frequency of malformations (%)
LTG	1280	2.9
OXC	184	3.3
LEV	126	1.6
TPM	73	6.8

AED: Antiepileptic drug; LEV: Levetiracetam; LTG: Lamotrigine; OXC: Oxcarbazepine; TPM: Topiramate.

Modified with permission from [12].

Table 3. Overview of elimination pathways, pharmacokinetic changes during pregnancy and teratogenic potentials of common second-generation antiepileptic drugs.

LTG	Mainly glucuronidation via UGT, 10% unchanged in urine	Decrease by 40–60%	Low
LEV	Mainly unchanged in urine, a third metabolized by peripheral hydrolysis	Decrease by approximately 40%	Promising
OXC	Glucuronidation via UGT	Decrease by 30–40%^†	Promising
TPM	Mainly unchanged in urine, 20–30% hepatic biotransformation	Decrease by 30–40%	Concerning
GBP	Unchanged in urine	Not studied	Insufficiently studied
PGB	Unchanged in urine	Not studied	Not studied
ZNS	Mainly hepatic biotransformation, 15–30% unchanged in urine	Not studied	Not studied

^† Monohydroxy metabolite.

AED: Antiepileptic drug; GBP: Gabapentin; LEV: Levetiracetam; LTG: Lamotrigine; OXC: Oxcarbazepine; PGB: Pregabalin; TPM: Topiramate; UGT: Uridine-diphosphate glucuronosyl transferase; ZNS: Zonisamide.

Data taken from [12,18,19,34,35,52,57,65,71,72,74,77].

Key issues

• • Second-generation antiepileptic drugs (AEDs) are increasingly being used in pregnant women, as first-generation drugs have pharmacological properties which make them unattractive in fertile women.

• • When treating pregnant women with AEDs, risks associated with fetal drug exposure need to be weighed against the risks of uncontrolled maternal disease.

• • Gestation-induced pharmacokinetic alterations are common with many second-generation AEDs; decreasing serum concentration may render treatment ineffective. Frequent drug concentration monitoring is recommended and dose adjustments are often needed.

• • Care is warranted with the use of drugs that are cleared both by uridine-diphosphate glucuronosyl transferase and renal excretion, and particularly in combined treatment with such drugs.

• • Although the safety profile of lamotrigine appears favorable during pregnancy, its use in young females is complicated by its pharmacokinetic interactions with endogenous end exogenous estrogens.

• • Continuous study efforts are needed in order to characterize fetal risks and pregnancy-related pharmacokinetic changes of novel AEDs in order to optimize treatment outcome for both mother and child.

• • Individual pre-pregnancy patient counseling concerning reproductive issues is an essential part of modern AED treatment.

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Second-generation antiepileptic drugs and pregnancy: a guide for clinicians

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1. Based on the review by Drs. Reimers and Brodtkorb, which of the following statements about altered pharmacokinetics and other issues affecting treatment with antiepileptic drugs (AEDs) during pregnancy is most likely correct?

• □ A Fetal adverse effects preclude the use of AEDs during pregnancy

• □ B Drugs metabolized by uridine-diphosphate glucuronosyltransferase (UGT) are likely to undergo reduced body clearance during pregnancy

• □ C Drugs excreted unchanged by the kidneys are likely to undergo reduced body clearance during pregnancy

• □ D Second-generation AEDs are increasingly being used in pregnant patients because most first-generation drugs have undesirable effects in fertile women, including fetal adverse effects or reduced efficacy of hormonal contraceptives

2. Your patient is a 26-year-old pregnant female with a history of seizure disorder. Based on the review by Drs. Reimers and Brodtkorb, which of the following statements about use of lamotrigine (LTG) during pregnancy is most likely correct?

• □ A More data exist for use of levetiracetam and oxcarbazepine than for use of LTG during pregnancy

• □ B Safety profiles during pregnancy appear to be better with use of trimethoprim than with LTG

• □ C LTG is metabolized by UGT and excreted unchanged by the kidneys, and therapeutic serum levels may be difficult to maintain during pregnancy

• □ D Renal excretion of LTG does not increase significantly until the third trimester

3. The patient described in question 2 is taking LTG. Based on the review by Drs. Reimers and Brodtkorb, which of the following statements about practical recommendations for AED treatment during pregnancy would most likely be correct?

• □ A She can continue the same dose of LTG she took before getting pregnant without the need for monitoring drug levels

• □ B Care is warranted with drugs such as LGT that are cleared both by UGT and renal excretion, particularly when more than 1 such drug is needed

• □ C If LTG level becomes subtherapeutic, the dose should be doubled

• □ D LTG is contraindicated during nursing