UK Epilepsy Research Articles

The effect of socioeconomic status on treatment and pregnancy outcomes in women with epilepsy in Scotland

Compared to the background population, people with epilepsy tend to have lower rates of education and employment, lower rates of marriage and childbearing, and lower overall socioeconomic status (SES). Disparities in epilepsy care based on sociodemographic factors have been observed in the literature, but it is not known whether any such disparities exist in the UK.The UK Epilepsy and Pregnancy Register is a prospective, observational, registration and follow-up study that was set up to determine the relative safety of all AEDs taken in pregnancy. Here, we report outcomes of registered pregnancies to women with epilepsy living in Scotland from December 1996 to June 2012, based on the degree of socioeconomic deprivation of their postcode area. The Scottish Index of Multiple Deprivation (SIMD) quintile scores from 2006 were used to determine degree of socioeconomic deprivation, and group 1 (most deprived) and group 5 (least deprived) were compared.There were 1526 pregnancies with complete outcome data to women living in Scotland. Of these, 1453 (95.1%) resulted in a live birth and 68 (4.7%) had a major congenital malformation (MCM). Postcodes could not be reliably identified or verified for an additional three women, who have been excluded from SIMD group analysis. Of all women included in this study, 32.4% were in group 1 and 13.2% in group 5. No difference in MCM rate was observed between the two groups (4.4% in group 1 compared to 4.7% in group 5, p=0.84). Women in group 5 were more likely to take preconceptual folic acid (56.8% compared to 14.0%, relative risk: 4.1; 95% CI: 3.1–5.2) and less likely to have generalized tonic–clonic seizures in pregnancy (13.0% compared to 29.2%, relative risk: 0.4; 95% CI: 0.3–0.7) than those in group 1. Women in group 5 were more likely to be on monotherapy regimens (80.2% compared to 65.9%, relative risk: 1.2; 95% CI: 1.1–1.3), less likely to be on valproate (19.5% compared to 28.0%, p=0.05), and more likely to be on lower doses of the drug (825.9mg/day compared to 1012.0mg/day, p=0.05) compared to those in group 1.Although no change in MCM rate was seen based on SES, differences in treatment between socioeconomic groups do exist, particularly for preconceptual folic acid consumption, AED regimen, and seizure frequency. Greater emphasis on the importance of preconceptual counseling, both to discuss AED choice and folic acid intake, would be of benefit, particularly to those living in areas of high socioeconomic deprivation, to improve equity of healthcare delivery for women with epilepsy in Scotland.

Fall in UK epilepsy cases due to better diagnosis and reduced exposure to risk

Fall in UK epilepsy cases due to better diagnosis and reduced exposure to risk

Levetiracetam in pregnancy: Results from the UK and Ireland epilepsy and pregnancy registers

In the article “Levetiracetam in pregnancy: Results from the UK and Ireland epilepsy and pregnancy registers” by E. Mawhinney et al. ( Neurology® 2013;80:400–405), there is an error in the body of the abstract and in table 1. The polytherapy major congenital malformations (MCM) rate should read 5.56% (3.54%–8.56%) rather than 6.47% (4.31%–9.60%). The authors regret the errors.

Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study

Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age. In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, at 25 epilepsy centres in the UK and the USA. Our primary outcome was intelligence quotient (IQ) at 6 years of age (age-6 IQ) in all children, assessed with linear regression adjusted for maternal IQ, antiepileptic drug type, standardised dose, gestational birth age, and use of periconceptional folate. We also assessed multiple cognitive domains and compared findings with outcomes at younger ages. This study is registered with ClinicalTrials.gov, number NCT00021866. We included 305 mothers and 311 children (six twin pairs) in the primary analysis. 224 children completed 6 years of follow-up (6-year-completer sample). Multivariate analysis of all children showed that age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94-101) than to carbamazepine (105, 102-108; p=0·0015), lamotrigine (108, 105-110; p=0·0003), or phenytoin (108, 104-112; p=0·0006). Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs and on non-verbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ (r=-0·56, p<0·0001), verbal ability (r=-0·40, p=0·0045), non-verbal ability (r=-0·42, p=0·0028), memory (r=-0·30, p=0·0434), and executive function (r=-0·42, p=0·0004), but other antiepileptic drugs were not. Age-6 IQ correlated with IQs at younger ages, and IQ improved with age for infants exposed to any antiepileptic drug. Compared with a normative sample (173 [93%] of 187 children), right-handedness was less frequent in children in our study overall (185 [86%] of 215; p=0·0404) and in the lamotrigine (59 [83%] of 71; p=0·0287) and valproate (38 [79%] of 40; p=0·0089) groups. Verbal abilities were worse than non-verbal abilities in children in our study overall and in the lamotrigine and valproate groups. Mean IQs were higher in children exposed to periconceptional folate (108, 95% CI 106-111) than they were in unexposed children (101, 98-104; p=0·0009). Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. Reduced right-handedness and verbal (vs non-verbal) abilities might be attributable to changes in cerebral lateralisation induced by exposure to antiepileptic drugs. The positive association of periconceptional folate with IQ is consistent with other recent studies.

Levetiracetam in pregnancy

Levetiracetam is a broad-spectrum antiepileptic drug (AED) which is currently licensed in the United States and the United Kingdom and Ireland for use as adjunctive treatment of focal-onset seizures and myoclonic seizures or generalized tonic-clonic seizures, occurring as part of generalized epilepsy syndromes. In the United Kingdom and Ireland, it is also licensed as monotherapy treatment for focal-onset seizures. Previous small studies have suggested a low risk for major congenital malformations (MCM) with levetiracetam use in pregnancy. The UK and Ireland Epilepsy and Pregnancy Registers are prospective, observational registration and follow-up studies that were set up to determine the relative safety of all AEDs taken in pregnancy. Here we report our combined results for first-trimester exposures to levetiracetam from October 2000 to August 2011. Outcome data were available for 671 pregnancies. Of these, 304 had been exposed to levetiracetam in monotherapy, and 367 had been exposed to levetiracetam in combination with at least one other AED. There were 2 MCM in the monotherapy group (0.70%; 95% confidence interval [CI] 0.19%-2.51%) and 19 in the polytherapy group 5.56% (3.54%–8.56%) [corrected]. The MCM rate in the polytherapy group varied by AED regimen, with lower rates when levetiracetam was given with lamotrigine (1.77%; 95% CI 0.49%-6.22%) than when given with valproate (6.90%; 95% CI 1.91%-21.96%) or carbamazepine (9.38%; 95% CI 4.37%-18.98%). This study, in a meaningful number of exposed pregnancies, confirms a low risk for MCM with levetiracetam monotherapy use in pregnancy. MCM risk is higher when levetiracetam is taken as part of a polytherapy regimen, although further work is required to determine the risks of particular combinations. With respect to MCM, levetiracetam taken in monotherapy can be considered a safer alternative to valproate for women with epilepsy of childbearing age.

Fetal Antiepileptic Drug and Folate Exposure: Cognitive Outcomes at Age 6 Years (IN5-2.003)

Objective: Determine if differential long-term neurodevelopmental effects exist across commonly used antiepileptic drugs (AEDs). Background The primary outcome (age 6 year IQ) of the NEAD study and other cognitive findings at this age are reported here. Preliminary findings at age 3 were previously reported (Meador et al. NEJM 2009). Design/Methods: Pregnant women with epilepsy on AED monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled in a prospective observational multicenter study in the USA and UK from 1999-2004. Multivariate analyses were conducted on intent-to-treat (n=310) and completer samples (n=224) with appropriate follow up analyses and secondary analyses of other cognitive measures. Results: Children exposed to valproate (adjusted mean IQ = 99) had significantly lower IQ scores than children in each of the other AED groups (carbamazepine = 105, lamotrigine = 108, phenytoin = 106). Children in the valproate group also performed more poorly vs. each of the other three AEDs on measures of verbal abilities and memory, and more poorly vs. lamotrigine on measures of non-verbal and executive functions. Valproate dose was negatively associated with IQ, verbal, non-verbal, memory, and executive functions, but the other AEDs did not demonstrate a dose relationship. Age 6 IQ correlated positively with IQ at earlier ages, and IQ scores improved with age across all AEDs. Verbal abilities were impaired compared to non-verbal abilities for all AEDs combined and for each individual AED except phenytoin. Children exposed to peirconception folate exhibited higher IQ (108 vs. 102 for those not receiving folate). Conclusions: Fetal valproate exposure is associated with lower IQ and reduced cognitive abilities across a range of cognitive domains at age 6 years. Verbal abilities may be impaired by several commonly used AEDs. Periconceptional folate may have positive effects on cognitive outcomes. Many unanswered questions remain, and additional research is needed. Supported by: NIH [NS038455 and NS050659] and UK Epilepsy Research Foundation [RB219738]. Disclosure: Dr. Meador has received research support from Cyberonics, Neuropace, Pfizer, and UCB Pharma. Dr. Baker has received personal compensation for activities with UCB as a speaker. Dr. Baker has received research support from UCB and Sanofi Aventis. Dr. Browning has nothing to disclose. Dr. Cohen has received personal compensation for activities with the Children9s Memory Scale. Dr. Brombley has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc. Dr. Brombley has received research support from Sanofi-Aventis Pharmaceuticals, Inc. Dr. Clayton-Smith has received personal compensation in an editorial capacity for Clinical Dysmophology. Dr. Kalayjian has received personal compensation for activites with GlaxoSmithKline as a speaker. Dr. Kanner has received research support from Pfizer Inc. Dr. Liporace has received personal compensation for activities with UCB Pharmaceuticals as a speaker. Dr. Pennell has nothing to disclose. Dr. Privitera has received personal compensation for activities with UCB Pharmaceuticals and GSK as a consultant and speaker.Dr. Privitera has received research support from UCB Pharmaceuticals and Eisai. Dr. Loring received personal compensation from NeuroPace as a consultant.

Valproate and the risk for congenital malformations: Is formulation and dosage regime important?

BackgroundUse of valproate in pregnancy, especially in doses over 1000mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs. We sought to investigate whether the increased risk could be minimised by using controlled release or divided daily doses of valproate. MethodsThe UK Epilepsy and Pregnancy Register is a prospective, observational and follow up study set up to determine the risks of major congenital malformations for infants exposed to antiepileptic drugs in utero. In this study we have extracted data for those pregnancies exposed to valproate in monotherapy. We have calculated malformation rates and relative risks as a function of valproate exposure. ResultsOutcome data were available for 1109 pregnancies exposed to valproate in monotherapy. Exposure to 1000mg a day or more of valproate was associated with almost double the risk of major congenital malformation compared with daily valproate doses below 1000mg daily (8.86% vs 4.88%, RR: 1.7; 95% CI: 1.1–2.9). There were no differences in the risks for malformations between standard release valproate and controlled release valproate preparations (RR: 1.11; 95% CI: 0.67–1.83) or for those exposed to single or multiple daily administrations (RR: 0.99, 95% CI: 0.58–1.70). ConclusionPrescribing controlled release valproate or multiple daily administrations in pregnancy did not reduce the risk for malformations. Higher malformation rates observed with in utero exposure to valproate are more likely related to total daily dose, rather than peak serum levels.

051 Valproate and the risk for congenital malformations; is formulation and dosage regime important?

BackgroundUse of valproate in pregnancy, especially in doses over 1000mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs....

A web-based survey of impact and experience of young people with epilepsy

AimsTo understand the opinions of young people with epilepsies regarding the impact of diagnosis and their experience of health services.MethodsBetween April and May 2010 an online questionnaire survey was coordinated...

Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine

ObjectiveTo establish the relative risks of in utero exposure to lamotrigine (LTG), sodium valproate (NaV) and carbamazepine (CBZ) monotherapy for neurodevelopment.DesignObservational cohort study.Patients and methodsThe study group consisted of children...

Comparing the General Practice Research Database and the UK Epilepsy and Pregnancy Register as Tools for Postmarketing Teratogen Surveillance

Use of pregnancy registries is a common method of postmarketing surveillance of pregnancy outcomes to identify potential teratogens. However, with the increase in electronic capture of healthcare data for administrative, audit and research purposes, data generated during routine clinical practice might be used to address questions similar to those explored using pregnancy registries. To establish how data from the UK General Practice Research Database (GPRD) compares with data from the UK Epilepsy and Pregnancy Register and to assess how it can contribute to postmarketing surveillance of pregnancy outcomes. Pregnancy outcomes were identified from the GPRD for women aged 14-49 years with a diagnosis of epilepsy and supporting evidence. Outcomes with a major congenital malformation (MCM) were identified and the relative risks (RRs) of an MCM following a range of first-trimester antiepileptic drug (AED) exposures were calculated and compared with those reported by the UK Epilepsy and Pregnancy Register. In addition, we also evaluated whether the known association between valproate and spina bifida could be identified using data from the GPRD. The study period ran from 1 January 1990 until 31 December 2006. A total of 1766 live mother-baby pairs were identified, as well as 551 pregnancy terminations, 13 stillbirths and 1 neonatal death. Including those that resulted in a termination, there were 62 unique pregnancy outcomes with an MCM. An increased risk of spina bifida was identified using the GPRD following first-trimester monotherapy exposure to valproate when compared with those with no AED exposure (RR 8.02; 95% CI 1.5, 43.5). More generally, comparing the GPRD with the UK register, the GPRD ascertained a lower number of first-trimester AED exposures: monotherapy 711 versus 2468; polytherapy 156 versus 718. We reproduced the UK register results of an increased MCM risk following first-trimester polytherapy AED exposure compared with no AED exposure (RR 2.89; 95% CI 1.43, 5.84). Using the GPRD, we identified similar point estimates to the UK register following monotherapy and polytherapy exposures (4.1% vs 3.7% and 7.1% vs 6.0%, respectively) but we were unable to reproduce the level of statistical significance. For individual AEDs, the MCM rate following valproate exposure was 4.9% (11/225) in the GPRD compared with 6.2% (44/715) in the UK register. The GPRD has potential for the identification of malformations and of a teratogenic association. For epilepsy, the GPRD does, however, identify fewer exposed pregnancies than a pregnancy registry. Therefore, in many circumstances pregnancy registries are likely to remain preferable as a method of surveillance. The GPRD may be better suited to monitoring medicines used in the treatment of more prevalent conditions, such as depression, or for monitoring medicines that have been on the market for a long time and for which no registry has been set up.

PATH39 Malformation risks of antiepileptic drugs in pregnancy: an update from the UK Epilepsy and Pregnancy Register

AimTo assess the relative risk of major congenital malformations (MCM) from exposure to anti-epileptic drugs (AEDs) during pregnancy.Methods15 year prospective observational study from 1996 until 2009. The outcome measure is...

Fetal valproate syndrome in a 2-month-old male infant

Fetal valproate syndrome (FVS) results from prenatal exposure to valproic acid. It is characterized by a distinctive facial appearance, a cluster of minor and major anomalies and central nervous system dysfunction. We describe a 2-month-old male infant with the typical dysmorphic features characteristic of FVS. He had a persistent left superior vena cava draining into a dilated coronary sinus and mild pulmonary hypertension. There was a history of maternal intake of sodium valproate during pregnancy.

Pregnancy registries: Differences, similarities, and possible harmonization

Epilepsy and pregnancy registries have been operational for more than 10 years, have accrued considerable experience, and collected an impressive amount of data. As findings have been published, it has become important to understand how observations from the different registries are comparable, especially since their methodologies differ somewhat. In September 2008, representatives of the UK Epilepsy and Pregnancy Register, the North American AED Pregnancy Registry (NAAPR), and the European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) met for a workshop. Their objectives were to exchange information on their methodologies and to discuss areas where harmonization might be possible. This report summarizes these discussions.

A Pregnant Pause to Consider Teratogenicity of Topiramate

Topiramate in Pregnancy: Preliminary Experience from the UK Epilepsy and Pregnancy Register. Hunt S, Russell A, Smithson WH, Parsons L, Robertson I, Waddell R, Irwin B, Morrison PJ, Morrow J, Craig J, UK Epilepsy and Pregnancy Register. Neurology 2008;71(4):272–276. Objectives Topiramate (Topamax®) is licensed to be used, either in monotherapy or as adjunctive treatment, for generalized tonic-clonic seizures or partial seizures with or without secondary generalization and for prevention of migraine. The safety of topiramate in human pregnancy is largely unknown. Here we report on our experience of pregnancies exposed to topiramate. Methods This study is part of a prospective, observational registration and follow-up study. Suitable cases are women with epilepsy who become pregnant while taking topiramate either singly or along with other antiepileptic drugs (AEDs), and who are referred before outcome of the pregnancy is known. The main outcome measure is the major congenital malformation (MCM) rate. Secondary outcomes include risk of specific MCM, minor malformation rate, birthweight, and gestational age at delivery. Results Full outcome data are available on 203 pregnancies. Of these, 178 resulted in live birth; 16 had an MCM (9.0%; 95% CI 5.6–14.1%). Three MCMs were observed in 70 monotherapy exposures (4.8%; 95% CI 1.7–13.3%) and 13 in cases exposed to topiramate as part of a polytherapy regimen (11.2%; 95% CI 6.7–18.2%). Four of the MCMs were oral clefts (2.2%; 95% CI 0.9–5.6%). Four cases of hypospadias were reported (5.1%; 95% CI 0.2–10.1%) among 78 known live male births, of which two were classified as major malformations. Conclusions The number of outcomes of human pregnancies exposed to topiramate is low, but the MCM rate for topiramate polytherapy raises some concerns. Overall, the rate of oral clefts observed was 11 times the background rate. Although the present data provide new information, they should be interpreted with caution due to the sample size and wide confidence intervals.

Serum concentration/dose ratio of topiramate during pregnancy

To study the impact of pregnancy on the serum concentration/dose ratio (C/D-ratio) of topiramate (TPM). Twelve women with epilepsy using TPM during pregnancy, and 15 pregnancies were studied. The main target variable was the C/D-ratio at baseline and during pregnancy. Additional variables were changes in TPM dose, concomitant use of other antiepileptic drugs, seizure frequency, and pregnancy outcome. Clinical and pharmacological data were obtained from the women's medical records. The average C/D-ratios in the second and third trimester were 30% (p = 0.002, n = 11) and 34% (p = 0.001, n = 8) lower than the baseline values, respectively. The interindividual variability was pronounced. Increased seizure frequency was common in pregnant women using TPM, but a correlation to the decline in TPM C/D-ratio could not be established from our data. Dose-corrected serum concentrations of TPM appear to decline gradually throughout pregnancy. The underlying mechanisms are not known. Increased glomerular filtration may play a major role. During pregnancy, therapeutic drug monitoring of TPM may be useful.

Teratogenicity and hyperprolactinemia

Byline: Chittaranjan. Andrade CME Questions A) Drugs should be prescribed with caution to women of childbearing age because of the risk of teratogenicity, should conception occur during treatment; this concern is particularly important when prescribing drugs that will be required for long periods, such as in the maintenance therapy of epilepsy, bipolar disorders, neuropathic pain, and migraine. Topiramate and valproate are sometimes prescribed as maintenance medications for certain or all of these indications. With this background, mark True or False against each of the following statements: *Topiramate monotherapy is safe during pregnancy. *The use of topiramate along with other antiepileptic drugs is associated with an unacceptably high teratogenic risk. *Valproate is one of the most teratogenic medications used in psychiatry. *The teratogenicity of valproate is substantially higher when the drug is used in combination with other antiepileptic medications. *The teratogenic risk of valproate is dose-dependent. *Valproate is teratogenic only during weeks 6-12 of gestation. *Exposure to valproate during pregnancy can be associated with low IQ in the offspring. B) Hyperprolactinemia is a common problem with different antipsychotic drugs. Hyperprolactinemia may lead to many adverse consequences, and may thereby jeopardize drug compliance. With this background, mark True or False against each of the following statements: *The normal prolactin level is 25 ng/ml and above. *Hyperprolactinemia may result in increased libido. *Hyperprolactinemia may result in osteoporosis. *Hyperprolactinemia is uncommon with paliperidone. *Aripiprazole augmentation reverses antipsychotic-induced hyperprolactinemia. View Answer CME Answers A) Teratogenicity Answers: 1. False; 2. True; 3. True; 4. True; 5. True; 6. False; 7. True. 1. Topiramate monotherapy during pregnancy Topiramate is a well-established teratogen in animals such as mice, rats, and rabbits. One study[sup] [1] examined the effects of first-trimester topiramate exposure in 52 pregnancies with 41 liveborn infants. Topiramate was observed to reduce birth weight without decreasing gestational age at delivery; there was no increase in the risk of structural birth defects. However, another larger and methodologically superior study[sup] [2] documented substantial teratogenicity with the drug. This study used data from the UK Epilepsy and Pregnancy Register. The subjects were 203 women with epilepsy who had been exposed to topiramate as monotherapy ( n =70) or as part of polytherapy ( n =133) during the first trimester of pregnancy, and who had been referred before the outcome of pregnancy was known. There were 178 live births; the risk of major congenital malformations with topiramate was 9% (95% CI, 5.6%-14.1%) in the entire sample, and 4.8% with topiramate monotherapy. In this context, studies suggest that the risk of major malformations is 2.7-3.5% in epileptic women who do not use antiepileptic drugs during pregnancy, and those who use antiepileptic drugs in monotherapy.[sup] [3],[4] 2. Teratogenicity of topiramate combined with other antiepileptic drugs In the UK Epilepsy and Pregnancy Register study[sup] [2] referred to above, major congenital malformations were more common in women exposed to topiramate combined with other antiepileptic agents (11.2%) than in those exposed to topiramate monotherapy (4.8%) during the first trimester of pregnancy. The highest risk of major malformations was when topiramate was used along with valproate (36%), or along with two or more other antiepileptic drugs (24%). Also, in women receiving topiramate in polytherapy, smallness for gestational age was associated with a higher dose of the drug. 3. Teratogenicity of valproate in monotherapy Data from the North American Antiepileptic Drug Pregnancy Registry,[sup] [4] the UK Epilepsy and Pregnancy Register,[sup] [3] and the Israeli Teratology Information Service database[sup] [5] suggest that the risk of major congenital malformations is 6-11% after first trimester exposure to valproate monotherapy. …

Folic acid use and major congenital malformations in offspring of women with epilepsy: a prospective study from the UK Epilepsy and Pregnancy Register

Folic acid use and major congenital malformations in offspring of women with epilepsy: a prospective study from the UK Epilepsy and Pregnancy Register

Folic acid use and major congenital malformations in offspring of women with epilepsy: a prospective study from the UK Epilepsy and Pregnancy Register

Objective: In the general population, folic acid supplementation during pregnancy has been demonstrated to reduce the frequency of neural tube defects (NTDs) and other major congenital malformations (MCMs). It is...

Importance of monotherapy in women across the reproductive cycle

Special treatment considerations are warranted in women with epilepsy, particularly those of childbearing age. Treatment guidelines generally recommend the use of antiepileptic drug (AED) monotherapy at the lowest dose possible during pregnancy. The UK Epilepsy and Pregnancy Register reported that the risk for major congenital malformations is higher with AED polytherapy than with monotherapy (6.0% vs 3.7%, respectively) and that valproate carries the highest individual risk. The AEDs that induce hepatic cytochrome CYP450 enzymes carry particular concern both before and after pregnancy. Hepatic enzyme inducers alter steroid metabolism in women receiving oral contraceptives, increase the risk for contraceptive failure, and interfere with calcium absorption and vitamin D metabolism, thus increasing the risk for osteoporosis and fractures. Vitamin K deficiency is another potential consequence of treatment with a hepatic enzyme-inducing AED, increasing the risk for coagulopathy and neonatal intraparenchymal and intracerebral hemorrhage during the first 24 hours of life. Supplemental vitamin K therapy during the last month of pregnancy is warranted. Preconceptional and gestational folate supplementation may also be warranted to prevent neural tube malformation related to AED treatment. Because AED pharmacokinetics may be altered during pregnancy, plasma AED concentrations should be measured before conception and monthly during pregnancy to prevent seizure breakthrough.