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This page intentionally left blank CHAPTER 13 Reproductive Aspects of Epilepsy Michael R. Johnson and John J. Craig Introduction men and women, as well as abnormalities of bone health. Female sexual hormones may also aff ect the seizure threshold in women resulting in a greater likelihood of seizures at certain times of the menstrual cycle (catamenial epilepsy). Although reproductive aspects should be important for both men and women with epilepsy almo st all attention has concentrated on women, in particular those of childbearing age. In thi s chapter we will cover the important reproductive issues that apply to both men and women with epilepsy. However, since it is the manage- ment of women with epilepsy of childbearing age, especially those who contemplate pregnancy, or who become pregnant, that causes most concern, the topics covered in this chapter will tend to focus on the issues relating to th e management of women with epilepsy. There are many important topics when considering the r epro- ductive aspects of epilepsy ( Table 13.1 ). In this chapter we will dis- cuss the int eractions between reproductive hormones and epilepsy, including the effects of epilepsy and antiepileptic drugs (AEDs) on reproductive hormones, the effects of reproductive hormones on epilepsy (catamenial epilepsy), and the interactions between AEDs and hormonal contracep tion. We will also consider teratogenicity and perinatal outcomes, concentrating on the ris ks for major con- genital malformations (MCMs) and the effects of AEDs on cogni- tive funct ion and behavior. Lastly, we will consider the relevant management issues in pregnancy and lactation, not forgetting the importance of optimal preconceptual counseling. Hormonal alterations that occur following seizures include changes in prolactin, luteinizin g hormone, and follicle stimulating hormone ( 1 ). These changes may occur as a consequence of both generalized and focal seizures and are thought to arise as a result of connections between the hypothalamic \200\223pituitary axis and areas of the brain involved in seizure s. The precise hormonal mechanisms remain somewhat unclear and are reviewed in detail elsew here ( 1 \200\2233 ). These hormonal changes may result in reproductive dys- function in wo men with epilepsy, with the most common disor- ders being polycystic ovarian syndrome (PCOS ) and hypothalamic amenorrhea ( 1 , 4 ). PCOS is de \201 ned as the presence of: ( 1 ) multiple follicular cysts, ( 2 ) ovulatory d ysfunction (oligo-ovulation and anovulation), and ( 3 ) clinical or serological evidence of hyperandrogenism ( 3 ). PCOS is associated with secondary health consequences including in sulin resistance and obesity. It is estimated that PCOS occurs in about 5 % of women withou t epilepsy but in up to 20 % of women with epilepsy. The relationship between PCOS and epil epsy is compli- cated by the potentially confounding effects of antiepileptic medi- cation on female sexual hormones. Since the original observation by Isojarvi and colleagues ( 5 ) that sodium valproate may be associ- ated with an increased incidence of PCOS, cross sectio nal studies have produced con \202 icting results, demonstrating both a signi \201 cant a ssociation between valproate and PCOS or reporting no signi \201 - cant association ( 3 ). In contrast to valproate, data relating to car- bamazepine and lamotrigine have failed to show an increased prevalence of PCOS in women taking these AEDs ( 3 ). To date, there is li ttle evidence relating to the risks of PCOS with long-term treatment with levetiracetam ( 6 ). To address the con \202 icting results of cross sectional studies of valproate, Morrel l and colleagues ( 7 ) conducted an important prospective, randomized, longitudinal evaluat ion of the impact of valproate on the development of PCOS. In this study, women with epilep sy and regular menstrual cycles were randomized to treatment with valproate or lamotrigine and followed for 12 months. Women initiating valproate were signi \201 - cantly more likel y to develop PCOS than those taking lamotrigine (9 % vs. 2 % respectively, p = 0.007). Thes e observations together Epilepsy and antiepileptic drugs and their relationship to reproductive hormones Epilepsy a nd AEDs are associated with changes in hormones that may contribute to reproductive and sex ual dysfunction in both Table 13.1 Reproductive topics in epilepsy to be considered The effects of AEDs on appearance The effect of hormones on seizure control The effects of epilepsy and AEDs on fertility The effects of AEDs on contraception and vise versa The effects of pregnancy on AEDs and seizure control The effects of epilepsy and AEDs on pregnancy including fetal development oxford textbook of epilepsy and epileptic seizures 146 gabapentin ( 21 ) may also be associated with an increased fracture risk. There is limited data on other commonly used AEDs, although drugs such as topiramate, zonisamide, and acetaz olamide that inhibit carbonic anhydrase may theoretically affect bone health by inducing a metabolic acidosis ( 18 ). There are no clinical studies on levetiracetam although animal d ata suggest levetiracetam may reduce bone strength without altering bone mass density ( 22 ). Unfortunately, as with concerns regarding AEDs and reproductive health, in respect of bo ne health, there are insuf \201 cient data to make \201 rm recommendations for the scree ning, prevention, or treatment of patients taking AEDs. One might reasonably conclude, howe ver, that all people taking enzyme-inducing AEDs should be counseled about the risks for bo ne disease and encouraged to adopt a lifestyle that maximizes bone health (regular exercise , avoidance of smok- ing, adequate dietary calcium and vitamin D intake, etc.). Screening f or osteoporosis or vitamin D de \201 ciency can be justi \201 ed if patients taking enzym e-inducing AEDs have additional risk factors for osteoporosis (e.g. older age, postmenopaus al, previous fracture, smoking history, low body mass index, or sedentary lifestyle) ( 18 ) , and the UK Medicines and Healthcare products Regulatory Agency advises that vitamin D sup plementation should be considered for such at-risk patients on long-term enzyme-inducing AE Ds or sodium valproate ( http://www.mhra.gov.uk/Publications/ Safetyguidance/index.htm ). with other data showing that valproate-associated changes are reversible when valproate is discontinued ( 8 , 9 ) suggest that a rea- sonable treatment option in women who develop PC OS and/or ovulatory dysfunction whilst taking valproate is to consider alter- native AED th erapy, bearing in mind the importance of seizure control in epilepsy and the suitability of a particular AED to an individual \200\231s epilepsy. As well as seizures having effects on neuroendocrine function, exacerbation of epilepsy its elf may occur as a result of menstrual cycle-related changes in reproductive hormones (cata menial epi- lepsy). There is no agreement on the degree of seizure exacerbation required to meet a de \201 nition of catamenial epilepsy and therefore reliable epidemiological estim ates on prevalence are lacking. Using a de \201 nition for catamenial epilepsy that 75 % o r more of seizures had to occur within 4 days before and within 6 days of the onset of mens truation, it was shown that only \201 ve of 40 (12.5 % ) women met this criterion ( 10 ). In contrast, 31 of 40 (78 % ) claimed that most of their seizures occurred around the time of menstruation. Physiological changes to gamma-aminobutyric acid A (GABA A ) receptor fun ction as a result of withdrawal of progesterone and its active metabolite allopregnanolone at the time of menstruation provide one possible mechanism for menstrual exacerbation of se i- zures ( 11 ), although other mechanisms are postulated ( 4 ). Regardless of the cause of catamenial epilepsy, the primary thera- peutic aim where catamenial exacerbation of seizur es is present remains control of epilepsy with standard chronic AED therapy. Clobazam or ac etazolamide given intermittently around the time of menstruation have been tried, but good evidence for the bene \201 t of this approach is lacking. Seven out of 11 women with uncon - trolled seizures given intramuscular medroxyprogesterone reported fewer seizures ( 12 ), but larger well-controlled studies on the bene- \201 ts of hormonal manipulation in catam enial epilepsy are lacking (and would be well worth doing). Hormonal contraception in epilepsy Contraception in women with epilepsy is a topic of great practical importance. Plenty of guidelines exist to assist the clinician includ- ing those of the UK National Institute for Health and Clinical Excellence (NICE) epilepsy guidelines ( http://guidance.nice.org. uk ), the Scottish Intercollegiate Guidelines Network (SIGN) g uide- lines on the diagnosis and management of adults with epilepsy ( http://www.sign.ac.uk /guidelines/fulltext/70/index.html ), pri- mary care guidelines on the management of epilep sy in women from the Royal Society of Medicine (http:// http://www.rsm.ac.uk/ media/pr160.p hp), Guidelines from the Royal College of Obstetricians and Gynecologists Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit, as well as sev- eral excellent jo urnal articles to which the reader is referred (e.g. 23, 24). Therefore, within this sectio n we seek only to highlight the key points that guide choice of hormonal contraception in w omen of childbearing potential with epilepsy, and to discuss some of the more recent or con tentious issues of practical importance. In addition to the effects of epilepsy on reproductive hormones, AED exposure may affect re productive hormones in both men and women. In a study of 85 men with focal epilepsy, the en zyme- inducing AEDs carbamazepine and phenytoin were associated with reduced bioavailable t estosterone and reduced levels of sexual function ( 13 ). Similarly, enzyme-inducing AEDs a re associated with reduced levels of oestrogens and androgens and an increased incidence of sexual dysfunction in women ( 14 , 15 ). In contrast, valproate is associated with increas ed androgen concentrations ( 16 ). Other factors contributing to an increased incidence of sexual dysfunction in men and women with epilepsy include the stress of living with a chron ic illness and the persisting social stigma associ- ated with epilepsy. Despite awareness o f hormonal issues occurring as a result of treatment with AEDs ( 17 ), there is no consensu s regarding their management. Although several studies suggest the adverse effects of AEDs on reproductive hormones may be revers- ible on AED withdrawal, any potential bene \201 ts in reproductive and sexual health from AED withdrawal (or switch to alternative AED) must be very carefully weighed against the increased risk of harm from uncontrolled seizures. Of prime importance are considerations relating to the pre- scription of oral contraceptive s in women taking hepatic enzyme (particularly the cytochrome P450 CYP3A4 isoenzyme) induci ng AEDs (phenytoin, carbamazepine, eslicarbazepine, oxcarbazepine, barbiturates). Topiramat e is a CYP3A4 inducer but warrants spe- cial mention and is discussed separately later in t he chapter. Women using hepatic enzyme-inducing AEDs who wish to use hormonal contraception should be advised against the use of low- er-dose progestogen-only methods (i.e. the proge stogen-only pill (POP) and the progestogen-only implant). Oral contraceptives that combine an estrogen and progestogen (combined oral contraceptive pills or COCPs) may be used, but s ince the clear- ance of oestradiol is increased by enzyme-inducing AEDs, a COCP containing a minimum 50 micrograms of oestradiol is recom- mended. The presence of breakthrough bleedi ng should be taken It is increasingly recognized that alterations of reproductive hormones by AEDs may have ad verse consequences for bone health ( 2 , 18 ). Whilst the negative impact on bone health ma y be a consequence of increased clearance of vitamin D by cyto- chrome P450 enzyme-inducing AEDs, it is clear that non-enzyme- inducing AEDs including valproate ( 19 , 20 ), clonazep am, and CHAPTER 13 reproductive aspects of epilepsy 147 as an indication of inadequate contraception even in the setting of an increased dose of oe stradiol. In the presence of breakthrough bleeding, higher doses of oestradiol can be used to achieve ade- quate contraceptive effect, but even in the absence of breakthrough bleedin g women on enzyme-inducing AEDs still need to be informed that there is a higher risk of co ntraceptive failure com- pared to the general population taking the COCP. Because of the po tentially serious consequences of unwanted pregnancy the addi- tional consistent use of con doms is recommended in women on enzyme-inducing AEDs choosing combined hormonal oral con- t raception. clinical judgment and/or referral to a specialist provider, since the use of the method is not usually recommended unless other meth- ods are not available or not acceptable \200\231 ( http://www.ffprhc.org. uk ). In contrast to the advice relating to the COCP, the United Kingdom Medical Eligibility Criteria for Contraceptive Use (UKMEC) categories for anticonvu lsant therapy and contracep- tion list lamotrigine therapy as a condition for which there i s no restriction on the use of either the POP or progestogen-only implant ( http://www.ffpr hc.org.uk ). Based on the results of the Siddhu study, however ( 26 ), there must be some d oubt over the effectiveness of progestogen-only methods of contraception in women taking la motrigine. Non-enzyme-inducing AEDs (clobazam, levetiracetam, gabap- entin, valproate, lacosamide, pre gabalin, vigabatrin, zonisamide) have no effect on contraceptive ef \201 cacy and so the s tandard COCP with 30 micrograms of oestradiol can be used, as well as standard low-dose pro gestogen methods such as the POP or progestogen- only implant. For enzyme-inducing AEDs, the ef \201 cacy of the progestogen-only injectable depot medrox yprogesterone acetate (DMPA) is not reduced. The rate limiting step for the clearance of me droxypro- gesterone (Depo-Provera ) is hepatic blood \202 ow, and so enzyme- inducing AEDs should have no effect. Re \202 ecting this, the SPC for Depo-Provera recommends no dosing adjustment for Depo- Provera in patients receiving enzyme-inducing AEDs, yet the SIGN and NICE guidelines recommend a reduced dosing interval of 10 weeks instead of 12. Topiramate and lamotrigine require special discussion. Topiramate is a CYP3A4 inducer, but the contraceptive ef \201 cacy of the COCP is thought not to be affected at monotherapy do ses less than 200 mg/day ( 25 ). Even so, it is the practice of the authors of this chapter to recommend consistent additional use of condoms even at doses of topiramate less than 20 0 mg/day. Low-dose pro- gestogen methods (such as the progesterone-only oral contracep- tiv e) are not recommended when topiramate is being taken. The situation for lamotrigine is mor e complex. Lamotrigine is metabo- lized by the UDP-glucuronyl transferases and there is no evidence that lamotrigine induces cytochrome P450 enzymes. In a study of 16 female voluntee rs, co-administration of lamotrigine (up to 300 mg/day) had no effect on the pharmacokineti cs of the ethiny- loestradiol component of a COCP but a modest increase in the clearance of the levonorgestral component was observed (and some volunteers reported vaginal bleeding), but with no corre- sponding hormonal evidence that suppression of ovulation had not been m aintained ( 26 ). However, as a consequence of this data, the manufacturer of lamotrigine r eleased new guidance and the Summary of Product Characteristics (SPC) now comments that the \200\230possibility of reduced contraceptive effectiveness cannot be excluded \200\231. I t would seem sensible therefore for prescribers of the COCP with lamotrigine to warn their patients that reduced contra- ceptive effectiveness cannot be excluded and recommend the co n- sistent use of condoms in addition to the COCP. A second issue relating to co-administra tion of the COCP with lamotrigine and which also warrants specialist discussion is the impo rtant effect the COCP has on systemic lamotrigine levels. Thus, plasma lamotrig- ine levels are approximately halved by co-administration of the COCP ( 27 ). This may result in reduc ed seizure control after the addition of the COCP or conversely may result in lamotrigine t ox- icity following removal of the COCP. Therefore, substantial care should be taken when i ntroducing the COCP in someone who is seizure free on a stable dose of lamotrigine or withd rawal of the COCP in patients on lamotrigine. In conclusion, for women on long-term enzyme-inducing AEDs, methods such as DMPA or intraut erine methods such as levonorg- estrel-releasing intrauterine or copper-bearing intrauterin e sys- tems (which are not discussed in detail here but where, like DMPA, there are no rest rictions on use in conjunction with enzyme-induc- ing AEDs) may represent the most reliable contraceptive options. Teratogenicity and perinatal outcomes Role of the epilepsy pregnancy registry Bearing in mi nd the risks to the fetus from in utero exposure to AEDs it is important to have as much in formation as possible on the safety, or otherwise, of these drugs. Since it would generally be considered unethical to carry out randomized controlled drug trials on women who could become pregnant (indeed women with epilepsy of childbearing years are often actively exclud ed from many of the pharmaceutical drug trials), and current post-market- ing surveillance programs are not organized in such a fashion as to be able to provide information of fetal risks, it seems logical, given that women are already becoming pregnant on AEDs, either sin gly or in combination, to gather data by whatever means possible. In recent years this has been attempted with the establishment of prospective epilepsy and pregnancy registries. A number of regis- tries exist, all of which have the principal aim o f collecting as much information as possible on the outcomes of pregnancies exposed to AEDs . Some caveats about the information generated must be appreciated. Principally, the inform ation does not apply to ran- domly assigned treatments. Instead treatment will have been at the discretion of the treating physician who will have chosen particular regimens for spec i \201 c reasons. At its simplest level, like may not be being compared with like, with it being dif \201 cult if not impossible to account for the effects of confounding variables . Reporting is often selective, depending on the type of registry and its catchment area, a nd therefore the results may not be representative of the broader population with epilepsy. Most also do not include a con- trol population, although some gather information on women with epilepsy who are not taking AEDs during pregnancy. Taking all this into account the Faculty of Sexual and Reproductive Healthcare (FSRH) Clini cal Effectiveness Unit of the Royal College of Obstetricians and Gynecologists recently upd ated their guidance on AEDs and contraception to include lamotrigine as a \200\230conditio n \200\231 where the \200\230theoretical or proven risks of the COCP generally outweigh th e advantages \200\231 stating (in the context of lamo- trigine therapy) that the \200\230p rovision of the COCP requires expert oxford textbook of epilepsy and epileptic seizures 148 status epilepticus, or even death needs to be considered. Status epi- lepticus in pregnancy has been felt to be particularly dangerous to both mother and baby. Among 29 cases of stat us epilepticus occur- ring during pregnancy nine of the mothers and 14 of the fetuses died ( 32 ). In contrast, in a prospective study where there were 36 cases (1.8 % ) of status ep ilepticus, (one-third were convulsive in type) occurring in 1956 pregnancies, there was one still-birth which occurred around the time of status epilepticus, one spontaneous abortion occurring long after the period of status epilepticus, and no cases of maternal mortality ( 33 ). Nevertheless, despite these provisos, prospective pregnancy regis- tries probably offer the only hope of providing any useful informa- tion, in an acceptable time frame, to guide wom en with epilepsy and those looking after them of the risks of MCMs for particular AEDs or c ombinations (Table 13.2). Existing pregnancy registries are either sponsored by individual pharmaceutical companies a nd therefore focus on a single AED or represent the efforts of independent researchers base d in one or multiple countries who collect outcome data on all available AEDs. Their method ologies ( 28 ), while varying somewhat, are broadly similar in that they aim to collect inf ormation on pregnancies that have been exposed to AEDs, or not, in any combination and whic h have been identi \201 ed before the outcome of the pregnancy is known. In addition to co llecting demographic details, information is col- lected on drug exposure, including folate , history of exposure to other teratogens, epilepsy history and seizure control during preg - nancy, past pregnancy details, and family history of adverse preg- nancy outcomes. At a p rede \201 ned time period, or time periods, information is then collected on pregnancy out come. Antiepilepsy drugs and major congenital malformations There is good evidence from human pre gnancies that AEDs have an effect on fetal and embryonic development. It is a consistent \201 nding that women with epilepsy who are not taking AEDs have a lower risk of having chi ldren with MCMs than those who are ( 34 ). It has consistently been reported that women who take polytherapy are more at risk than those who take monotherapy ( 35 \200\22337 ). Anima l studies have also demonstrated teratogenicity with all of the older AEDs and some of the more recently introduced ones ( 38 ). The effects of antiepilepsy drugs on the developing fetus/embryo When considering the risks to the fetus these are usually taken to be the risk of: Overall, women with epilepsy who are taking an AED in mono- therapy have at least a 2 \210 \222 3 times increased risk over the back- ground population of having an infant with a MCM . This is equivalent to a 4 \200\2239 % chance of a major congenital malformation for each pregnancy ( 34 , 35 , 39 , 40 , 41 ). The risk of MCMs is higher for pregnancies exposed to polytherapy and increases the more AEDs are taken ( 34 , 37 , 39 , 40 \200\22344 ) ( Table 13.3 ). 1. MCMs, in other words malformations of such signi \201 cance that they require medical or surgical intervention. 2. Minor abnormalities, which while occasionally dis \201 guring, do not require intervention. With regard the safety of individual AEDs taken in monotherapy, there is evidence from mult iple sources of differences between AEDs, with the greatest risks being found for valproate . Data are now also available for the newer AEDs, with most outcomes being reported for lam otrigine ( 45 ). 3. Cognitive and behavioral delay/upset. 4. Intra-uterine growth retardation. Most research has concentrated on the risk of MCM, although increasing data are emerging on the cognitive and behavioral impact of in utero AED exposure. While it is clearly dif \201 cult to compare the impact of adverse pregnancy outcomes, as serious as MCMs can be, t hey can often be detected in utero presenting preg- nant women with choices. Occasionally t hey can also be recti \201 ed at birth or thereafter. Neither can yet be claimed for any e ffects on cognitive development or behavior. When considering the risk for MCM with AED exposure it is important not only to consider th e total risk but also the types of MCM that occur.