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. The North American AED Pregnancy Registry published data on 146 women who had used phenobar bital as monotherapy during the \201 rst trimester of pregnancy. The MCM rate among 77 ex posed pregnancies was 6.5 % (95 % con \201 dence interval (CI) 2.1 % \200\22314.5 % ), si gni \201 cantly more than the background risk of 1.62 % (relative risk 4.2, 95 % CI 1.5 \200\2239.4 % , 1-sided P = 0.001) ( 46 ). In contrast to many other potential teratogens, which may be given for short periods or can be stopped when the woman becomes pregnant, AEDs usually have to be taken throughout the p regnancy and so the embryo/fetus is chronically exposed. The timing of exposure is also imp ortant with MCMs resulting from exposure in the \201 rst trimester. In contrast any effec t on cognitive functioning and growth extends throughout the pregnancy and possibly even be yond birth. The risk of MCM for phenytoin has been reported to be 3.4 % and 3.7 % in 87 ( 37 ) and 82 ( 41 ) pregnancies respectively. In a systematic Table 13.2 Epilepsy and pregnancy registers \200\224 advantages and disadvantages The effects of seizures The fetus seems relatively resistant to the effects of seizures alt hough anecdotal evidence suggests that tonic \200\223clonic seizures may cause fetal bradyc ardia or miscarriage. There is no evidence that simple partial, complex partial, absence, o r myoclonic seizures are harm- ful to the fetus. Prospective studies have not found an asso ciation between tonic \200\223clonic seizures and malformations, ( 29 , 30 ), although one study reported a reduced verbal intelligent quotient in infants exposed to more than \201 ve tonic \200\223clonic seizures in preg- nancy ( 31 ). Nevertheless the risk of seizure r ecurrence, injury, \227\206 Pharmaceutical company (e.g. GSK, UCB-Pharma) \227\206 National (USA, UK & Irela nd, Australia, India) \227\206 Multinational (EURAP) Potential disadvantages Potential advantages \227\206 Not randomized \227\206 No control population \227\206 Selective reporting \227\206 Heterogeneous populations \227\206 Incomplete confounding variables studied \227\206 Prospective/observational \227\206 Re \202 ect current practice \227\206 Broad based \227\206 Adequate numbers recruited \227\206 Homogeneous population CHAPTER 13 reproductive aspects of epilepsy 149 review of 1198 pregnancies exposed to phenytoin a higher MCM rate of 7.4 % (95 % CI 3.6 \200\22311.1) was reported ( 47 ). Phenobarbital, primidone, and phenytoin have been associ ated with congenital heart defects and facial clefts ( 48 ). A few studies have found a pos i- tive dose-response with barbiturates. Phenytoin has also been impli- cated as causing ur ogenital defects, and dysmorphic facial and other features such as distal phalangeal hypopl asia ( 49 ). valproate in addition to lamotrigine (n = 150) the rate of major birth defects was 10.7 % ( 95 % CI 6.4 \200\22317.0 % ). This compared with a rate of 2.8 % (95 % CI 1.5 \200\2235.0 % ) for polytherapy combinations which included lamotrigine but not sodium valproate (n = 43 0). No distinctive pattern of malformations was reported in this study. Data from the UK Ep ilepsy and Pregnancy Register revealed a simi- lar malformation rate for pregnancies expose d to lamotrigine alone, with 21 of 647 (3.2 % ) infants having a MCM. A positive dose-respo nse was seen, with 5.4 % of pregnancies exposed to more than 200 mg a day of lamotrigine ha ving a major congenital mal- formation ( 41 ). This rate was not that different for that ob served by the same investigators for pregnancies exposed to less than 1000 mg a day of valp roate ( 41 ). A positive dose response for lamotrig- ine has not however been reported by t he International Lamotrigine Registry ( 45 , 63 ) or the North American Pregnancy Register, who found a MCM rate of 2.3 % among 684 infants exposed to lamot- rigine in monotherapy ( 64 ). A 10.4-fold (95 % CI 4.3 \200\22324.9) increase in the rate of clefting abnormalities was noted in the North American Pregnancy Registry ( 64 ). In contrast the UK Epilepsy and Pregnancy Register ( 65 ) and the European Surveillance of Congenital Anomalies found no e vidence of increased isolated orofacial clefts relative to other MCMs for lamotrigine ( 66 ). The risks for MCMs with carbamazepine are less clear. In one case \200\223control study the MCM rate for infants exposed to car- bamazepine was found to be approximately twice that o f control group (relative risk 2.24; 95 % CI 1.1 \200\2234.56) ( 50 ). In contrast, an incr eased risk was not found by the UK Epilepsy and Pregnancy Register , where the MCM rate for 927 prospectively collected car- bamazepine monotherapy exposures pregnancies was 2.2 % ( 41 ) . Carbamazepine has been reported to be associated neural tube defects, at a rate of a nything from 0.2 \200\2231 % of exposed pregnancies as well as heart defects, inguinal hern ia, hypospadias, and hip dis- locations ( 51 ). There have also been reports of reduced hea d cir- cumference, weight, and length at birth. In a recent systematic review and case \200 \223control study the EUROCAT Antiepileptic Study Working Group reported that for carbamaze pine, teratogenicity appeared to be relatively speci \201 c to spina bi \201 da ( 52 ). Valproate has consistently been shown to be associated with the greatest risk for MCM. The North American Pregnancy Registry described 16 major malformations among 149 valproate-expo sed women (10.7 % ; 95 % CI 6.3 \200\22316.9 % ). Compared with a background prevalence of 1.62 % for major malformations, they calculated a relative risk for major malformations in valproate exposed preg- nancies of 7.3 (95 % CI 4.4 \200\22312.2 % ) ( 53 ). The Australian Pregnancy Registry for Women on Anti-epileptic Medication revealed an even higher malforma tion rate of 15.2 % % for pregnancies exposed to valproate in monotherapy (n = 224) ( 54 ). That valproate was asso- ciated with the highest MCM rate compared with other commonly use d AEDs alone was shown by the UK Epilepsy and Pregnancy Register: of 762 pregnancies expose d to valproate alone, 6.2 % had a major malformation ( 41 ). The risk of MCM is dose depend ent with valproate with total daily doses over 1000 mg being associated with a higher risk of MCMs ( 41 , 54 ). There is some evidence of a pharmacogenetic susceptibility to the tera togenic effects of val- proate both, from human reports ( 55 , 56 ) and preclinical studies ( 57 ). Preclinical studies have also suggested that for valproate high peak plasma concen trations are associated with an increased risk of malformations ( 58 ). Thus, it has been s uggested that a sustained- release preparation may be preferable, with the total daily dose being divided into two or three administrations per day. Reported data on the other new AEDs are sparse. A report of 55 exposures to oxcarbazepine ( 35 monotherapy and 20 polytherapy) noted only one major malformation ( 67 ). Six malformati ons from the outcomes of the 248 monotherapy exposures to oxcarbazepine (2.4 % ), either re ported in the literature or held by the Novartis Germany database have been reported ( 68 ) . In a post-marketing surveillance study of gabapentin as add-on therapy for 3100 patients in England no congenital abnormalities were seen in the 11 infants born to women who used g abapentin in the \201 rst-trimester of preg- nancy ( 69 ). In the tiagabine clinical tria ls 22 patients who received the drug became pregnant, of whom nine carried to term. In one of these a hip displacement was noted, though this was a breech deliv- ery ( 70 ). The UK E pilepsy and Pregnancy Register reported on 203 pregnancies exposed to topiramate. Of the 70 cases that had just received topiramate, three (4.8 % ) had a MCM, of which two were cleft ing abnormalities and one a case of hypospadias ( 71 ). In con- trast, in another study of 52 pregnancies exposed to topiramate, no concerns were raised ( 72 ). With regards to levet iracetam, published cases are limited. Three small reports of pregnancies exposed to leveti racetam have not raised any obvious concerns ( 73 \200\22375 ). The UK Epilepsy and Pregnan cy Register have reported on 362 preg- nancies exposed to levetiracetam. There were no MCMs among the 133 monotherapy exposures and nine among the 229 exposed to levetiracetam as par t of a polytherapy regimen ( 76 ). Exposure to valproate in early pregnancy is associated with sig- ni \201 cantly increased risks for spina bi \201 da, atrial septal defects, cleft palate, hypospadias, and craniosy nostosis ( 59 ). The risk of spina bi \201 da (1 \200\2232 % ) ( 41 , 60 , 61 ) is dose de pendent, with the greatest risk for those exposed to doses of greater than 1000 mg per day. Skeletal defects, including radial ray aplasia, rib and vertebral anomalies ( 62 ), and po lydactyly have also been reported. The North American AED Pregnancy Registry has published data in abstract form for 197 monot herapy exposures to both topiramate and levetiracetam in which eight and four MCMs were not ed respectively equating to rates of 4.1 % and 2.0 % . In keeping with results from the UK two of the eight MCMs with topiramate were cleft lip deformities ( 77 ). Considering the newer AEDs, most human data are available for lamotrigine. The Internationa l Lamotrigine Pregnancy Registry recently reported a MCM rate of 2.2 % (95 % CI 1.6 \200 \2233.1 % ) among 1558 \201 rst trimester lamotrigine-exposed pregnancies ( 45 ). For pol - ytherapy outcomes containing lamotrigine, the occurrence of birth defects varied accordin g to whether sodium valproate was included in the polytherapy regimen. For combinations con taining sodium For zonisamide, data for exposed pregnancies are even more limited. The only published repo rt includes 25 pregnancies ( 78 ). Considering some concerns were expressed in this small s tudy, not to have further information from many more pregnancies is clearly of concern in i tself. For all the newer AEDs, preclinical models are therefore of inter- est. In these studies to piramate was teratogenic in mice, rats, and oxford textbook of epilepsy and epileptic seizures 150 delay for infants exposed prenatally to carbamazepine of between 8 % and 20 % ( 86 , 91 , 9 2 ). rabbits at high doses, with limb and digital malformations, includ- ing right-sided ectroda ctyly being observed in rats and rib and ver- tebral malformations in rabbits. Vigabatrin w as also shown to be teratogenic in rabbits, inducing cleft defects. Gabapentin was asso- ci ated with skeletal malformations, including delayed ossi \201 cation of the calcaneus and hindlimb digits in mice, and incomplete fusion of skull bones and sternebrae in rats. Howev er, the type and incidence of these abnormalities were not felt to be indicative of develop mental toxicity. Tiagabine, oxcarbazepine, and levetira- cetam have not been shown to be te ratogenic. In a more thorough investigation of partly the same cohort of children Adab et al. found th at verbal IQ was signi \201 cantly lower in children exposed to valproate monotherapy (mea n 83.6, 95 % CI 78.2 \200\22389.0 % ; n = 41) than in unexposed children (90.9, CI 87.2 \200\223 94.6 % ; n = 80) or in children exposed to carbamazepine (94.1, CI 89.6 \200\22398 .5; n = 52) or phenytoin (98.5, CI 90.6 \200\223106.4; n = 21) ( 31 ). Doses of valproate a bove 800 mg/day were associated with lower verbal IQ than lower doses. Using multiple regre ssion analysis it was found that in addition to valproate exposure, \201 ve or more ton- ic \200\223clonic seizures in pregnancy and low maternal IQ were also associated with lower verbal IQ in the offspring. Interpreting MCM rates in pregnancies exposed to combination therapy is dif \201 cult. Cri tically, emerging data from the pregnancy registries mostly show that combinations containi ng valproate carry the highest risk ( 41 , 45 , 79 ). In a study from Finland among a small number of exposed infants, full scale IQ was low (<80 ) in four of 21 infants that had been exposed to valproate (19 % ) and exceptionally low (< 70) in two infants (10 % ). Of note, the mothers of the valproate exposed group performed s igni \201 cantly worse on IQ tests and also had signi \201 cantly lower educational level s ( 93 ). Antiepileptic drugs and minor abnormalities Children of women with epilepsy, whether or not they are taking AEDs, are at increased risk of minor anomalies ( 80 ). Speci \201 c AED-r elated fetal syndromes have been suggested for most of the older AEDs ( 49 , 81 , 82 ). The types of abnormalities have included minor craniofacial and digital anomalies and growth r etardation. Except for valproate ( 81 , 83 , and Table 13.4), there is no convinc- ing evid ence that a speci \201 c syndrome is associated with a speci \201 c AED, hence the term \200\230fetal-AED \200\231 syndrome may be more appro- priate for other AEDs. It is unclear what the in \202 uence is of other variables, such as maternal epilepsy and hereditary fa ctors. In any case minor abnormalities have mostly been felt in themselves to cause little disability. This opinion is however changing so that facial dysmorphism is increasingly fel t to predict cognitive and behavioral upset ( 31 , 84 ). Using an Indian adaptation of the Bayley Scale of Infant Development, motor and mental deve lopment were measured in 395 infants born to women with epilepsy ( 94 ). In addition to pae - diatricians being blinded to AED exposure, multiple confounders were taken into account. Unfortunately these did not include maternal IQ. Valproate was associated with signi \201 cantly lower mental and motor developmental scores compared with car- bamazepine, but not w ith other AEDs used in monotherapy. While maternal educational status was signi \201 cantl y correlated with motor development in infants, mental development was not. The impor- tanc e of including parental variables was shown in a prior study from the same group where low maternal IQ and maternal educa- tion as well as AED exposure were found to be associated wi th signi \201 cant impairment of intellectual and language functions in children of mother s with epilepsy ( 89 ). In a study that recruited cases that had been identified prospectiv ely through the UK Epilepsy and Pregnancy Register exposure to valproate and to a lesser ex tent carbamazepine, but not lamotrigine, had a signi \201 cant detrimental effect on neuro development, when compared with a control population ( 95 ). Effects of antiepileptic drugs on cognitive functioning The effects of in utero exposure to AEDs on cognitive functioning and behavior have not been studied as comprehensively as stu dies on MCMs. An early Cochrane review concluded that the majority of studies in this area were of limited quality with little evidence implicating one drug over another with respect to a detrimental effect on development ( 85 ). However, more recent studies have begun to clarify the impact of AEDs on neurodevelopment. The prospective Neurodevelopmental Effects of Antiepileptic drugs (NEAD) study applied the Bayley Mental Developmental Scale at 3 years in 309 children born to mothers taking AEDs ( 96 ). In the NEAD study, the valproate group global IQ was reduced by 9 points compared wit h the lamotrigine group, 7 points compared with the phenytoin group and 6 points com- pared with the carbamazepine group. The association between valproate use and global IQ was dose dependent: children born to mothers taking a valproate dose of less than 1000 mg per day h ad a global IQ that was not signi \201 cantly different to that in children born to mother s taking carbamazepine, lamotrigine, or phenytoin. In a further study in the same cohort ( 97 ), dose- related effects of AED exposure on both verbal and non-verbal cognitive ability was assessed using a variety of measures. At the time of assessment (mean age 3 years), in fants exposed to val- proate scored worse on tests of verbal and non-verbal function- ing ( scores adjusted for maternal IQ, maternal age, dose, race, alcohol, and folic acid use duri ng pregnancy). In contrast, car- bamazepine was negatively associated with verbal performan ce (language abilities) only, and no signi \201 cant effects were observed Studies have shown mean intelligent quotient (IQ) to be signi \201 - cantly lower in the c hildren of women with epilepsy compared with controls ( 86 \200\22389 ). In one study, 24 % of AED exposed infants had a developmental disorder compared with 10.5 % of non- exposed s iblings ( 88 ). In another study from India, children of mothers with epilepsy had signi \201 cantly lower full-scale IQs and language development compared with children that had n ot been exposed to AEDs ( 89 ). While it has been suggested that these \201 nd- ings are independent of AED exposure, a growing body of evidence suggests AEDs do carry risks. Altho ugh valproate has been reported as having the most detrimental effect, other AEDs including car- bamazepine and phenytoin may also have an adverse effect ( 88 ). In a retrospective observational study, 16 % of 224 children who had been exposed to AEDs p renatally had additional educational needs compared with 11 % of 176 exposed to no drugs (o dds ratio 1.49, 95 % CI 0.83 \200\2232.67 % ) ( 90 ). A total of 30 % of those exposed to v alproate, and 20 % exposed to polytherapy containing valproate, had additional educational needs. This compared with 3.2 % and 6.5 % exposed to carbamazepine and other monotherapy re gimens, respectively. These results compare with rates for developmental CHAPTER 13 reproductive aspects of epilepsy 151 Folic acid The prescription of folic acid before conception and at least until the end of t he \201 rst trimester is recommended in patients taking antiepileptic medication, as it i s for all women. This followed the recognition that there is an increased risk of neural tu be defects in children born to mothers taking AEDs, in particular sodium val- proate and ca rbamazepine ( 60 , 61 , 103 ). Large community-based studies have demonstrated a reduction in the rate of neural tube defects in women taking folic acid preconceptually ( 104 , 105 ) . It has been inferred from this that folic acid will protect women with epilepsy who are a lso at increased risk of this complication. The optimum dosage of folic acid remains undete rmined. Community- based studies have used dosages ranging from 0.5 \200\2234.0 mg daily, t he higher dosage being suggested for women considered at higher risk. It is the higher dosa ge that is generally recommended in the UK for women with epilepsy (5 mg daily). for lamotrigine or phenytoin. A dose dependent relationship was present for lower verbal an d non-verbal abilities with valproate and for lower verbal abilities in children born to mo thers taking carbamazepine. Other groups have also reported that valproate is associated wi th worse cognitive outcomes, especially in regards to language skills and also that the eff ect is dose related ( 98 \200\223100 ). Further research is required on this important topic. As has been stated, and excepting the improvement in methodologies of recent studies, most studies have involved the analysis of relatively small, non-population based samples, have lacked randomization, have often lost enrolled subjects over time, have assessed children at a very young age and have not taken account of important con- founding variables ( 101 ). However, at this stage it might be r ea- sonable to conclude that valproate is associated with greater risks to cognitive abilit y (particularly verbal abilities) than either car- bamazepine, lamotrigine, or phenytoin. W hat it is unclear, though, is whether there is a \200\230safe \200\231 dose for valproate, below which the risk of cognitive impairment (as well MCMs) is equivalent to other AEDs. I n terms of clinical management therefore, it seems that valproate is a poor \201 rst choi ce for most women of childbearing potential ( 97 ), and for those women where the bene \201 ts of val- proate in terms of seizure control are judged to outweigh the risks the cor rect dose should be the lowest dose that adequately controls the seizures. Some concerns have been raised that folic acid may exacerbate seizures but these fears have been generally felt to be unfounded. There is no evidence that folic acid confers addition al protection against neural tube defects or other malformations seen in associa- tion with AEDs. There is some evidence that the neural tube defects which occur in association with sodium valproate are different from those seen in the general population. They tend to be l ow lumbar or sacral in site ( 106 ). Other abnormalities are less common and the defect may be the result of altered canalization rather than folding of the developing neural crest. It remains uncertain as to whether folic acid will protect against this form of neural tube defect ( 107 ) or other defects associated with AEDs ( 108 ). The potential effect of fola te supplementation was reported for 4680 cases from the UK Epilepsy and Pregnancy Register ( 109 ). While those women who received preconceptual folic acid, approximately three-quart ers of whom received 5 mg each day, appeared more likely to have a child with a MCM than th ose who did not (3.9 % vs. 2.2 % ; odds ratio 1.8 (95 % CI 1.2 \200\2232.5)), the rate of n eural tube defects for valproate-exposed pregnancies, while raised, was about half that in folate-exposed compared with those not exposed to folate (0.8 % vs. 1.6 % ). Since this is the very reason that high-dose folate is advocated in AED-exposed pregnancies, despite the lack of evidence for folate having additional protective effects, current guidelines should continue to be observed, at least for those pregnancies exposed to valproate. Furthermore, preconceptual folate use has been reported to be associated with higher verbal outcomes ( 97 ). Data for the other newer AEDs are restricted to Levetiracetam. In a study from the Liverpoo l and Manchester Neurodevelopmental Group and the UK and Epilepsy Pregnancy Register which com- pared cognitive development in children exposed to levetiracetam and valproate, childr en exposed to levetiracetam in utero were not at an increased risk of delayed early develop ment compared with control children. In contrast those exposed to valproate scored signi \201 cantly worse ( 102 ). Management of women with epilepsy before, during, and after pregnancy Preconception counsel ing should be available to all women with epilepsy contemplating pregnancy. This should sta rt at the time of diagnosis and at subsequent reviews. While it may not always be appropria te to discuss the many relevant issues (for example, in pediatric practice) it should certa inly be considered in female adolescents with epilepsy, including those whose care is being transferred from a pediatrician to an adult physician. The fact that the relevant issues h ave been discussed should always be clearly recorded in the notes. Monitoring pregnancy in women with epilepsy Ideally, pregnancies in women with epilepsy sho uld be supervised in an obstetric unit, with access to high-resolution ultrasound scanning and the full range of prenatal tests, which has access to a physician with specialist exper tise in epilepsy. Where the latter is not available an obstetrician who specializes in medi cally compli- cated pregnancies should be identi \201 ed. Where resources permit, an organized joint obstetric/neurology preconceptual service should be available to allow rapid assessment of women actively contemplating pregnancy and to co ordinate care during pregnancy. This may not always be possible. Nevertheless, a recon \201 guration of clinics and additional resources to allow for this service should be activ ely considered. During counseling a re-evaluation of the diagnosis and the need for continued antiepilepsy medication should take place. Consideration should be given to the AED and indeed the dosag e of any AED that is prescribed. The risks and bene \201 ts of reducing or changing medica tion should be fully discussed with each individ- ual patient. Other areas that need to be covered are contraception, fertility, and the use of folic acid. Effects of pregnancy on epilepsy It is generally held that women with well-controlled epile psy are unlikely to experience a signi \201 cant change in their seizure fre- quency durin g pregnancy. This was con \201 rmed by the EURAP study group, who reported the outcomes of 1956 prospectively studied pregnancies. Using \201 rst trimester as reference, seizure c ontrol oxford textbook of epilepsy and epileptic seizures 152 remained unchanged throughout pregnancy in 63.6 % , of whom 92.7 % were seizure free during the entire pregnancy ( 33 ). Loss of seizure control was associated with a history of loca lization-related epilepsy, being on more than one AED, and taking oxcarbazepine in pregnanc y. For lamotrigine, however, some are of the opinion that close mon- itoring is mandatory and that drug levels should be increased if serum levels fall, to prevent deterioration in seiz ure control ( 120 ). That close monitoring may be effective at minimizing seizure deteriora tion was shown in 42 women receiving lamotrigine where monthly monitoring and dose adjustme nt was associated with only 19 % having an increased seizure frequency ( 121 ). Whether suc h practices expose the fetus to additional risks has not been established. Reasons for loss of seizure control are varied. Poor compliance with AED treatment because of nausea or the fear of harm from AEDs to the fetus can result in loss of control. Measuri ng compli- ance is problematic and monitoring serum levels or self-reporting may not be rel iable. The ability to study longer-term compliance is therefore of interest. In one study t hat measured AED levels in hair samples it was shown that 15 % of pregnant women had little or no AED in their proximal compared with distal hair measure- ments of AEDs ( 110 ). Most women with epilepsy will have a normal uncomplicated vaginal delivery. However, in app roximately 2 \200\2234 % the stress of labor may result in an increased risk of seizures du ring labor or in the following 24 hours ( 33 ). Tonic \200\223clonic seizures may result in fetal hypoxia and it is therefore generally recommended that deliv- ery takes place in a u nit equipped with facilities for maternal and neonatal resuscitation. Factors that increase the risk of seizures such as sleep deprivation, pain, overbreathing, and emotional dis- tr ess should be reduced as much as possible and early considera- tion given for epidural anes thesia. The analgesic pethidine may have a proconvulsant effect and is best avoided if poss ible. During pregnancy total serum AED levels may fall with less marked reductions in non-protein bound (free) drug concentra- tions ( 111 , 112 ) ( Table 13.5 ). Many factors may contribu te to this fall including increased metabolism/excretion, increased plasma volume, and redu ced protein binding. Total AED concentrations do not predict response during pregnancy and therefore if serum assessments are to be made, measurement of the unbound fraction is the m ethod of choice ( 113 ). This is especially relevant for those AEDs, such as valproate and phenytoin, that are moderately or highly protein bound. AEDs should be continued throughout labor. If necessary, all AEDs can be given by nasogastr ic tube; phenytoin, sodium val- proate, phenobarbitone, levetiracetam, diazepam, and clonaz epam can be given parenterally and carbamazepine rectally. Several studies have demonstrated pronounced alterations in the pharmacokinetics of lamotri gine during pregnancy ( 114 \200\223118 ). Apparent clearance increases steadily throughout pregnancy, peak- ing at about the 32nd week of gestation, when a 330 % increase from basel ine has been observed. The observed fall in lamotrigine levels during pregnancy has been re ported as being associated with a decline in seizure control. Seizures in labor should be terminated as soon as possible using intravenous lorazepam or d iazepam. For persisting seizures treat- ment should be for status epilepticus and delivery expedited. Where there is doubt about whether seizures are due to eclampsia or epilepsy a s low bolus of 4 mg of magnesium sulfate over 3 \200\2235 minutes, followed by 1 mg/hour for 24 hours is recommended in addition to intravenous lorazepam or diazepam ( http://www.sign. ac.uk/guidelines/fulltext/70/index.html ). There is currently no consensus on how best to monitor AED levels during pregnancy. It has previously been advocated that a baseline, preconception, unbound (free) AED level, repeate d at the beginning of each trimester and in the last 4 weeks of preg- nancy should be the m inimum level of monitoring ( 119 ). More frequent measurements will be necessary if seizure control deteri- orates, side effects ensue, or compliance is an issue. For most AEDs routi ne monitoring of serum levels is probably not necessary. AED levels revert to prepregnancy levels after birth at a variable rate ( 115 ). Hence, if the dose of an AED has been increased during pregnancy because of falling AED levels it may be useful to meas- ure serum levels repeatedly during the \201 rst 6 \200\2238 weeks aft er delivery to anticipate and manage the potential development of drug toxic- ity. However, the decision to reduce the AED dosage following delivery back to the preconception dosage, and the rate of dose reduction, should be made on an individual basis and with great care. In particular, if the increase in dose has resulted in a sustained improvement in seizure control with no evidence of toxicity the dose should not be changed. If the dose of AED has been increased during pregnancy and a decision is subsequently taken to reduce the dose ba ck to preconceptual levels postpartum, then substantial care should be taken as too rapid a dose reduction may result in uncontrolled seizures and maternal harm. Table 13.3 MCM rates for AEDs \200\224 comparing monotherapy and polytherapy exposures Reference % MCM Monotherapy Polytherapy Samren et al. 1997 8.0 9.8 The effects of epilepsy and antiepileptic drugs on pregnancy The over-representation of epi lepsy as one of the leading indirect causes of maternal mortality in pregnancy raises signi \201 cant con- cerns. The con \201 dential enquiries into maternal deaths in the UK, cov ering the period from 1985 \200\2231999 identi \201 ed that maternal mor- tality was over- represented among women with epilepsy, with over a 10-fold increased risk compared with wha t might be expected con- sidering the prevalence of epilepsy. While the reasons for the inc reased risk are not fully understood follow up reports have con- sistently reported that SU DEP accounts for most of the excess deaths. Olafsson et al. 1998 3.4 8.7 Canger et al. 1999 5.7 5.3 Kaneko et al. 1999 7.8 9.6 (2 AEDs), 11.5 (3 AEDs), 13.5 (4 AEDs), 15.4 (5 AEDs) Samren et al. 1999 3.3 4.7 (2 AEDs), 4.4 (3 AEDs), 8 (4 + AEDs) Holmes et al. 2001 4.5 8.6 Kaaja et al. 2003 3.2 5.8 (2 AEDs), 8.3 (3 + AEDs) Morrow et al. 2006 3.7 6.0 CHAPTER 13 reproductive aspects of epilepsy 153 Table 13.4 Features of fetal valproate syndrome For the period 2000 \200\2232002, of the 10 out of the 13 epilepsy-related deaths (of 256 d eaths) that had a postmortem examination, nine cases were felt either to have died, or prob ably to have died from SUDEP. In two out of the seven cases where blood levels of AEDs were measured there was no measurable trace of AEDs. In the most recent report spanning 2006 \200\2232008, 14 of the 261 maternal deaths were recorded as being due to epilepsy ( 122 ). Of the 14, nine were taking lamotrigine, none of whom had their AED level measured in preg nancy and 11 were felt to have died as a result of SUDEP. Of the \201 ve that had AED lev els measured at autopsy, three had a subthera- peutic level and two a low level. Of note, t he proportion of deaths felt to be due to epilepsy has not increased over the years studied . \227\206 Tall forehead \227\206 Medial eyebrow de \201 ciency \227\206 Flat nasal bridge \227\206 Broad nasal root \227\206 Shallow philtrum \227\206 Long upper lip \227\206 Thin vermillion border