September 30, 2023


Epilepsy is a gaggle of neurological ailments characterised by susceptibility to recurrent seizures. Antiseizure medicines (ASMs) are the mainstay of remedy, however many antiseizure medicines with variable security profiles have been accredited to be used. For ladies with epilepsy of their childbearing years, the security profile is essential for them and their unborn youngsters, as a result of remedy is usually required to guard them from seizures throughout being pregnant and lactation. Since no massive randomized managed trials have investigated security on this subgroup of individuals with epilepsy, being pregnant registries, cohort and case-control research from inhabitants registries, and some massive potential cohort research have performed an essential position. Valproate, in monotherapy and polytherapy, has been related to elevated threat of main congenital malformations and neurodevelopmental problems in youngsters born to moms who took it. Topiramate and phenobarbital are additionally related to elevated dangers of congenital malformations and neurodevelopmental problems, although the dangers are decrease than these of valproate. Lamotrigine and levetiracetam are comparatively secure. Inadequate information exist to succeed in robust conclusions concerning the latest antiseizure medicines corresponding to eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. Moreover antiseizure medicines, different therapies corresponding to vagal nerve stimulation, responsive neurostimulation, and deep mind stimulation are doubtless secure. Typically, breastfeeding doesn’t seem so as to add any further long run dangers to the kid. Inventive methods of optimizing registry enrollment and information assortment are wanted to boost affected person security.


Girls with epilepsy comprise nearly half of the inhabitants with normal epilepsy.1 Many remedy choices will not be influenced by intercourse; nonetheless, the potential of being pregnant and lactation are distinctive to girls of their childbearing years. Antiseizure medicines (ASMs) are sometimes continued all through being pregnant and lactation to mitigate the dangers of seizures, making them vital instances, owing to considerations for ladies with epilepsy, the fetus, and the kid.

The early information on elevated teratogenicity as a consequence of antiseizure medicines raised sufficient considerations that a number of potential being pregnant registries (table 1) had been created to assist decipher these dangers with extra accuracy.345678 Within the ensuing years, the event of latest antiseizure medicines has additionally been prolific (fig 1).910 As a result of nature of this area (randomizing girls to placebo could be unethical), no randomized managed trials have answered the safety issues and teratogenicity. Due to this fact, potential cohort research, together with registries, present the best high quality proof from which to make remedy choices. The big variety of present antiseizure medicines makes it troublesome to shortly accumulate applicable pattern sizes of exposures for particular person drug therapies. Moreover, the Meals and Drug Administration applied a brand new being pregnant labeling system in 2015, often called the being pregnant and lactation labeling rule (PLLR),11 which changed the previous being pregnant threat classes (A, B, C, D, or X) with narrative primarily based labeling necessities. The PLLR arguably offers with the overly simplistic nature of the previous being pregnant threat classes, however it additionally places the onus on healthcare professionals to investigate the dangers and advantages of a drug for a particular affected person. Whereas aiming to supply extra proof primarily based suggestions, the PLLR may need launched some complexity that has affected uptake and normal use.

Desk 1

Worldwide potential being pregnant registries for antiseizure medicines

Fig 1
Fig 1

Timeline of main antiseizure medicine introductions within the US.

This proof primarily based assessment will assist clinicians as they encounter these difficulties whereas treating girls with epilepsy. As we glance to the way forward for remedy of different persistent ailments in girls of childbearing age (HIV, despair, migraines), this assessment will inform and encourage information scientists, epidemiologists, and well being coverage makers to design extra environment friendly information assortment instruments, analytics, and different artistic research designs that may enhance scientific care.


About 50 million folks have epilepsy globally.12 Center earnings and low earnings international locations have a better incidence of epilepsy (80% of lively epilepsy circumstances) than excessive earnings international locations.

In america, about three million adults have epilepsy.13 The prevalence in girls and women is 46.2 per 100 000, in contrast with 50.7 per 100 000 for males and boys.14 The variety of girls of childbearing age with epilepsy is estimated to be at the least half 1,000,000,15 with about 24 000 giving beginning yearly.16 Fetal publicity to antiseizure medicines happens in about one out of each 50 pregnancies.17


Each authors searched PubMed and Medline-Ovid, limiting the dates from 1990 by way of September 2022. Trying to find “epilepsy and being pregnant” recognized >10 000 articles. This was restricted by “scientific trials”, giving 546 articles, of which 31 had been discovered to be straight related. Different search phrases included “fertility” AND “girls with epilepsy”, “first era antiepileptic medicine” AND “teratogenicity”, “second era antiepileptic medicine” AND “teratogenicity”, “third era antiepileptic medicine” AND “teratogenicity”, “Depakote” AND “neurodevelopmental problems”, “neurodevelopmental results of antiepileptic medicine”, “lactation” AND “antiepileptic medicine”, “vagus nerve stimulation” AND “being pregnant”, “responsive neurostimulation” AND “being pregnant”, “deep mind stimulation” AND “being pregnant”, “neuromodulation” AND “being pregnant”. A listing of being pregnant registries was compiled, and every registry web site was reviewed. The Maternal Outcomes and Neurodevelopment Results of Antiepileptic Medication (MONEAD) web site was additionally reviewed.18 Earlier assessment articles on these topics had been examined to establish articles earlier than 1990 for context and historic perspective. Included literature was restricted to randomized managed trials, registry analyses, case-control research from inhabitants degree databases, cohort research, and enormous hospital or single establishment case sequence or case experiences when the above weren’t accessible.

Being pregnant success and fertility in girls with epilepsy

For ladies with epilepsy who need youngsters, one of many first questions is that if epilepsy or using antiseizure medicines impacts fertility. Outcomes from the PubMed search confirmed 10 research that investigated this query. One 1994 research, primarily based on interviewing 1558 folks with epilepsy and 316 siblings with out epilepsy, confirmed that ladies with epilepsy had been solely 37% as prone to have been pregnant as their feminine siblings with out epilepsy.19 One other research, primarily based on the Northern Finland beginning cohort, recognized 222 folks with epilepsy from a cohort of 12 058 sufferers with 39 years of follow-up, and confirmed that solely folks with lively epilepsy in maturity had fewer youngsters; individuals who went into remission earlier than maturity had the same variety of youngsters to these with out epilepsy.20 A Scandinavian beginning registry research recognized girls with lively epilepsy within the Kuopio College space of Finland, and confirmed that ladies with epilepsy had the same variety of youngsters (2.1, customary deviation 1.3) to wholesome girls (2.1, customary deviation 1.2).21 Extra not too long ago, retrospective analyses of registry information have proven lowered being pregnant charges and better charges of assisted reproductive providers in girls with epilepsy, suggesting that ladies with epilepsy have extra problem getting pregnant.2223 It has additionally been famous that lowered fecundity trended greater in these on antiseizure medicine polytherapy than these on no antiseizure medicine,23 however this development is also accounted for by extra poorly managed seizures that may necessitate antiseizure medicine polytherapy. Against this, one potential cohort research, designed particularly to reply questions on being pregnant in girls with epilepsy wanting being pregnant, confirmed that ladies with epilepsy develop into pregnant on the similar price as different girls.24 To particularly isolate the impact of the epilepsy prognosis, this research excluded girls with a historical past of infertility, which could clarify the distinction in contrast with earlier research.

Few research reply this query in decrease earnings international locations. One cross sectional research in Nairobi included 191 girls with lively epilepsy, and located that fertility charges had been two-thirds decrease than within the normal inhabitants.25 Whereas socioeconomic components, social stigma, and decrease marriage charges might contribute to this discovering, using first era antiseizure medicines might additionally affect the probabilities of profitable being pregnant. Within the Epilepsy Start Management registry within the US, reside birth-to-pregnancy ratios amongst sexually lively girls not utilizing contraception had been greater with using lamotrigine, a second era antiseizure medicine, in contrast with valproate, a primary era antiseizure medicine.23 Nevertheless, additional analysis is required to analyze this chance.

In abstract, top quality proof from a single potential cohort research with controls reveals that within the US, and possibly different prosperous international locations, girls with epilepsy have comparable charges of profitable pregnancies as girls with out epilepsy.

Being pregnant outcomes in girls with epilepsy

How effectively do the pregnancies proceed, and the way do infants do at beginning past the query of teratogenicity? About 100 research had been discovered that handled being pregnant and perinatal outcomes. Knowledge got here from inhabitants primarily based registries (eg, Iceland) and being pregnant registries (eg, Finland), potential cohort research such because the Fertility and Start Outcomes in Girls with Epilepsy Looking for Being pregnant research and the MONEAD, and some hospital primarily based retrospective cohort analyses.

An Icelandic research analyzed inhabitants degree information on 81 473 pregnancies between 1972 and 1990, and in contrast being pregnant outcomes within the 266 pregnancies in girls with epilepsy.26 Total, comparable charges of being pregnant associated outcomes had been noticed, besides that the speed of caesarean part was considerably greater in girls with epilepsy in contrast with management sufferers (13% v 8.8%, p=0.01). A Finnish research analyzed information from 179 girls with epilepsy in contrast with 24 778 controls, and located no distinction in charges of caesarean part.27 Most not too long ago, an evaluation of information from MONEAD additionally confirmed no distinction in charges of caesarean part in girls with epilepsy versus management sufferers.28 Charges of caesarean part in all probability rely extra on different components corresponding to native hospital tradition than on affected person variables; the best charges of caesarean part are present in greater earnings international locations.29

In girls with epilepsy, no distinction in perinatal mortality or beginning weight was discovered within the Icelandic research, however the price of infants small for his or her gestational age was greater; infants of ladies with epilepsy additionally had smaller head circumference within the Finnish research. A equally designed Danish research confirmed the danger of preterm beginning elevated as a operate of using antiseizure medicines.30 A research from Norwayrecommended that the danger of low beginning weight varies by drug.31 For instance, topiramate publicity has an elevated threat of microcephaly 11.4% versus 2.4% (odds ratio 4.8, 95% confidence interval 2.5 to 9.3) and small for gestational age 24.4% versus 8.9% (3.1, 1.9 to five.3). A assessment analyzed information from 38 research printed between 1990 and 2015 and confirmed small however vital elevated dangers of spontaneous miscarriage, antepartum hemorrhage, hypertensive problems, induction of labor, caesarean part, preterm beginning, and fetal progress restriction in girls with epilepsy in contrast with controls.32 Notably, no distinction was noticed in fetal or neonatal mortality. Concerning mortality of youngsters born to girls with epilepsy, one Danish research analyzing information from 1981 to 2016 recognized elevated mortality in youngsters born to girls with epilepsy, however solely within the years earlier than 2000.33 This means that different components had been doubtless chargeable for that mortality, corresponding to antenatal care or different well being system results, and never antiseizure medicines. A later assessment analyzed 11 research printed between 2000 and 2016, and confirmed that epilepsy was related to a small elevated threat of fetal progress restriction (odds ratio 1.28, 95% confidence interval 1.09 to 1.50, p<0.05), unaffected by antiseizure medicines.34 One other issue that appears to affect being pregnant outcomes is sweet antenatal care, together with routine neurological care and being pregnant planning. One research primarily based on a database prospectively collected between 2010 and 2018 in Chinain contrast being pregnant outcomes in unplanned and deliberate pregnancies in girls with epilepsy, and confirmed that deliberate pregnancies had fewer induced abortions and preterm births.35

Total, proof from cohort research persistently reveals that epilepsy and antiseizure medicine are related to an elevated threat of fetal progress restriction, and being pregnant related problems corresponding to preterm births; nonetheless, clear proof signifies that some antiseizure medicines have a stronger affect on fetal progress, corresponding to topiramate. Acceptable neurological routine care and pre-pregnancy planning can doubtless scale back these dangers (fig 2).

Fig 2
Fig 2

Prompt remedy timeline for ladies with epilepsy planning being pregnant. ASM=antiseizure medicine; VPA=valproate; LEV=levetiracetam; LTG=lamotrigine.

Antiseizure medicines and dangers to the growing fetus and youngster

Congenital malformations

Main congenital malformations are structural abnormalities that carry medical, social, or beauty penalties requiring medical or surgical remedy.36 Within the US, main congenital malformations happen in about 3% of reside births.37 Main congenital malformations come up from genetic abnormalities or teratogenic exposures, or each. The information on main congenital malformations in girls with epilepsy might be examined on this assessment.

Valproate was accredited to be used in 1978, and case experiences within the Eighties confirmed that valproate preparations, and to a lesser extent phenytoin and phenobarbital, had been related to minor and main beginning defects.383940 Nevertheless, these dangers weren’t confirmed and in contrast amongst medicine till potential being pregnant registries started enrolling pregnant sufferers within the Nineteen Nineties. An essential case-control research inside the European Surveillance of Congenital Anomalies (EUROCAT) was printed in 2010, and confirmed an elevated threat of spina bifida, cleft palate, craniosynostosis, and polydactyly in youngsters born to moms who took valproate in contrast with these with no publicity to valproate preparations.41

Of the primary era antiseizure medicines, valproate and its preparations have the best threat of main congenital malformations,primarily based on research from all the foremost being pregnant registries;4243444546 the energy of affiliation was additional confirmed by a later Cochrane assessment (table 2).47 These information additionally help a dose-response impact, with greater dangers seen at doses round 1500 mg every day and decrease dangers with every day doses ˂800 mg.46 The Tomson research, primarily based on EURAP registry information, analyzed 7355 pregnancies between 1999 and 2016, and confirmed the prevalence of main congenital malformations in eight antiseizure medicines (fig 3).48 The primary era antiseizure medicines phenobarbital and phenytoin had a prevalence of main congenital malformations of 6.5% (19 of 294 pregnancies) and 6.4% (8 of 125), respectively. The prevalence of main congenital malformations with carbamazepine was much like phenobarbital and phenytoin at 5.5% (107 of 1957), and valproate had the best prevalence at 10.3% (142 of 1381). All registry analyses present the best threat of main congenital malformation in youngsters born to moms who took valproate.48495051525354 The Cochrane assessment47 examined 50 research, with 31 research included in a meta-analysis, with the next threat ratios in comparison with youngsters born to girls with out epilepsy:

Desk 2

Total main congenital malformation threat related to antiseizure medicine monotherapy

Fig 3
Fig 3

Danger of main congenital malformations related to perinatal antiseizure medicine publicity. An evaluation of information from the EURAP worldwide registry inspecting prevalence of main congenital malformations in offspring with perinatal antiseizure medicine publicity confirmed the prevalence to be 2.8% with levetiracetam, 2.9% with lamotrigine, 3.0% with oxcarbazepine, 3.9% with topiramate, 5.5% with carbamazepine, 6.4% with phenytoin, 6.5% with phenobarbital, and 10.3% with valproate. Knowledge from Tomson T, Battino D, Bonizzoni E, et al.48

  • Phenobarbital n=345 versus 1591 (threat ratio 2.84, 95% confidence interval 1.57 to five.13)

  • Phenytoin n=477 versus 987 (2.38, 1.12 to five.03)

  • Carbamazepine n=1367 versus 2146 (2.01, 1.20 to three.36)

  • Valproate n=467 versus 1936 (5.69, 3.33 to 9.73)

This meta-analysis additionally included information on second era antiseizure medicines: zonisamide, lamotrigine, oxcarbazepine, gabapentin, topiramate, and levetiracetam. Of those, topiramate was the one one to indicate an elevated threat of malformations: n=359 versus 442 (threat ratio 3.69, 95% confidence interval 1.36 to 10.07). This research confirmed a threat stratification with valproate having the best threat, adopted by modest improve with publicity to medicine corresponding to topiramate and phenobarbital, and the bottom threat in medicine corresponding to levetiracetam and lamotrigine. An examination of the North American Registry web site registry information reveals this stratification with present information (as of December 2022).55

Based mostly on these registry information, polytherapy with valproate clearly drives the danger, whereas information on polytherapy with out valproate means that the dangers are decrease.56 The MONEAD research, a potential observational research with controls, enrolled sufferers on polytherapy with out valproate. The most typical polytherapy mixture of levetiracetam and lacosamide (43% of the polytherapy group) confirmed no elevated threat of main congenital malformation, however the research won’t have been adequately powered.57 A Finnish research, evaluating charges of main congenital malformation in girls who continued antiseizure medicine with those that discontinued antiseizure medicine throughout being pregnant, additionally confirmed that polytherapy with out valproate was not related to elevated threat of main congenital malformation.58 Along with the info on valproate, the Kerala registry confirmed duotherapy with topiramate had the best threat of main congenital malformation (relative threat 14.62, 95% confidence interval 1.88 to 113.83).59 Registry information from Australia and China present equally elevated dangers associated to using topiramate, and in addition phenobarbital combos.6061

Given the considerations about valproate dangers to the fetus, makes an attempt to wean valproate earlier than or throughout being pregnant are widespread. Nevertheless, warning is suggested when contemplating this technique, because it will increase threat to girls with epilepsy. An evaluation of EURAP observational worldwide registry of antiepileptic medicine and being pregnant information confirmed a twofold threat improve in generalized tonic clonic seizures amongst pregnant girls who had valproate withdrawn or switched to a different antiseizure medicine throughout the first trimester of being pregnant.62 In a Norwegian nested case-control research, lamotrigine, a generally chosen antiseizure medicine throughout being pregnant owing to its low threat of teratogenicity, was proven to have a better threat of sudden surprising demise in epilepsy sufferers (SUDEP) in contrast with different antiseizure medicines.63 Concern of teratogenicity and lack of affected person counseling can lead girls with epilepsy to abruptly cease or scale back antiseizure medicines with out doctor dialogue. In a single potential cross sectional research, 66 of 365 girls (18.1%) surveyed reported stopping or lowering antiseizure medicines with out enter from their doctor,64 a selection that may result in standing epilepticus and elevated threat of SUDEP. Administration choices ought to apply shared choice making between the girl with epilepsy and her doctor, after an intensive dialogue of dangers and advantages of all accessible choices from the angle of the girl’s security, in addition to that of the unborn youngster.

Total, proof from cohort research/inhabitants and particular beginning registry analyses persistently reveals that publicity to valproate carries an elevated (2-3 instances the baseline) threat of main congenital malformation. Lamotrigine and levetiracetam monotherapy have the bottom threat, and medicines corresponding to topiramate and phenobarbital carry intermediate threat. Moreover, polytherapy with valproate combos, topiramate combos, and phenobarbital combos additionally carry elevated threat of main congenital malformation, however polytherapy with out these drug therapies just isn’t related to an elevated threat of main congenital malformation. No robust conclusions can but be made on the danger of main congenital malformation with use of a lot of the third era antiseizure medicines. Administration choices must stability affected person selection and be made collectively between the girl with epilepsy and her doctor.

Neurodevelopmental problems

Case experiences within the Nineteen Nineties and early 2000s described decrease intelligence and elevated threat for developmental problems, corresponding to autism spectrum dysfunction, in youngsters born to moms who took valproate preparations,656667 however the research had been small and sometimes flawed. This propelled the launch of a big potential cohort research within the US referred to as the Neurodevelopmental Results of Antiepileptic Medication (NEAD), which enrolled pregnant girls between 1999 and 2004.68 The NEAD research is an observational research that not too long ago expanded to the MONEAD research, which has tracked not solely the ladies, however the youngsters born to moms taking antiseizure medicines. Evaluation of youngsters who had been uncovered to valproate, carbamazepine, lamotrigine, and phenytoin was carried out at 3 years and 6 years of age. Cognitive final result information from 309 youngsters aged 3 had been analyzed whereas controlling for maternal and different related traits, and valproate publicity was proven to be related to decrease IQ. This impact was additionally seen at age 6, with youngsters who had valproate publicity having IQ scores 6-10 factors decrease than youngsters uncovered to lamotrigine, carbamazepine, or phenytoin.69 Valproate appears to negatively affect verbal skills greater than non-verbal skills. In a later evaluation of information from the MONEAD cohort enrolled between 2012 and 2016, when most ladies took levetiracetam and lamotrigine, no vital distinction in cognitive outcomes was noticed in youngsters aged 2 born to girls with epilepsy, in contrast with controls.70

A latest evaluation of the Nordic register primarily based research of antiepileptic medicine in being pregnant (SCAN-AED) has spurred elevated warning within the prenatal use of topiramate, and triggered a security assessment within the UK.71 This massive observational cohort research assessed the cumulative incidence of autism spectrum dysfunction and mental incapacity at 8 years of age in these with prenatal publicity to 10 antiseizure medicine monotherapies and 5 duotherapies. On this research, each topiramate and valproate had been related to a higher threat of autism spectrum dysfunction (4.3% and a couple of.7%, respectively) and mental incapacity (3.1% and a couple of.4%, respectively) in a dose dependent trend, in comparison with unexposed youngsters (1.5% and 0.8%, respectively). Not surprisingly, the most secure duotherapy on this research was the levetiracetam-lamotrigine mixture. All different duotherapies confirmed a rise in neurodevelopmental problems, although pattern sizes had been smaller than the monotherapy teams. The elevated incidence of neurodevelopmental problems in youngsters uncovered to topiramate prenatally contradicts beforehand reported findings from different observational research.7273 The widespread apply of stopping topiramate early within the prenatal course owing to considerations for main congenital malformations might have additionally attenuated leads to earlier research.

In abstract, persuasive information from potential cohort research, in addition to evaluation of registry information, point out that valproate use throughout being pregnant is related to decrease IQs and extra developmental problems in youngsters with fetal valproate publicity. Topiramate may also be problematic, primarily based on a cumulative incidence evaluation from a inhabitants registry. Drug therapies like levetiracetam and lamotrigine haven’t any such affiliation.

Folic acid supplementation

Folic acid is crucial for nucleic acid and DNA synthesis. Folic acid deficiency throughout being pregnant has been linked to elevated threat of neural tube defects, in addition to different main congenital malformations, and proof helps using periconceptional folic acid supplementation to scale back these dangers within the normal inhabitants.747576 For pregnant girls with epilepsy, the query is whether or not they’re at further threat and whether or not greater doses of folic acid are wanted.

Girls with epilepsy have proven an elevated threat of main congenital malformations; whereas this elevated threat has been largely linked to particular antiseizure medicines,47 genetics might play a task in some circumstances. A number of antiseizure medicines have been proven to scale back serum folate ranges.77 One research additionally reported a low serum folate focus in pregnant girls with epilepsy as a big impartial threat issue for main congenital malformations (odds ratio 5.8, 95% confidence interval 1.3 to 27.0).78 It follows that folic acid supplementation may benefit these sufferers. One evaluation of Hungarian being pregnant registry information confirmed a discount of main congenital malformations in youngsters uncovered particularly to carbamazepine, phenobarbital, phenytoin, or primidone in utero, when their moms used periconceptional folic acid supplementation (1.27, 0.85 to 1.89), in contrast with these born to moms who didn’t use supplementation (1.47, 1.13 to 1.90),79 however this discovering didn’t attain statistical significance. A UK research discovered that no youngsters with main congenital malformations had been born to girls with epilepsy who took periconceptional folic acid.80 Notably, the UK being pregnant registry, in addition to these of different international locations, lacks conclusive information displaying that folic acid supplementation reduces the danger of main congenital malformations in youngsters born to girls with epilepsy.48 This means that the upper threat of main congenital malformations is attributable to an alternate mechanism, can’t be overcome with folic acid supplementation, or the info up to now lack the ability to detect an impact modification.

Folic acid supplementation, nonetheless, has been proven to have neurocognitive advantages in youngsters born to girls with epilepsy. A research in Norway discovered an elevated threat of autistic traits in youngsters uncovered to antiseizure medicines perinatally when their moms didn’t use periconceptional folic acid dietary supplements in contrast with these born to girls who did complement with folic acid (minimal of 0.4 mg/day).81 This elevated threat was famous in offspring at 18 months (adjusted odds ratio 5.9, 95% confidence interval, 2.2 to fifteen.8) and 36 months of age (7.9, 2.5 to 24.9). Knowledge from the NEAD research, a potential, observational, multicenter research of 311 youngsters born to girls with epilepsy on antiseizure medicine monotherapy, confirmed greater full scale IQ at 3 and 6 years of age in youngsters born to girls with epilepsy who took periconceptional folic acid dietary supplements of at the least 0.4 mg/day.82 No further safety was seen in those that took greater dose folic acid dietary supplements (>0.4-1 mg/day, >1-4 mg/day, and >4 mg/day). Different reported advantages of folic acid supplementation embody decreased threat of spontaneous abortion and preterm beginning.8384

Considerations have been raised concerning potential harms of excessive dose folic acid supplementation.8586 A latest Scandinavian observational cohort research analyzing registry information of over three million mother-child pairs collected over 20 years discovered an elevated threat of childhood most cancers in youngsters born to girls with epilepsy prescribed periconceptional excessive dose (≥1 mg every day, imply dose 4.3 mg) folic acid dietary supplements, in contrast with youngsters born to girls with epilepsy who weren’t prescribed excessive dose folic acid (adjusted hazard ratio 2.7, 95% confidence interval 1.2 to six.3),with an absolute threat if uncovered of 1.4% (95% confidence interval 0.5% to three.6%), and an absolute threat if unexposed of 0.6% (0.3% to 1.1%).87 This elevated threat was not seen in youngsters born to moms with out epilepsy who had been additionally uncovered to excessive dose folic acid (imply dose 2.9 mg), and it additionally couldn’t be accounted for by any particular antiseizure medicine publicity throughout being pregnant. One of many limitations of the research is the presumption that ladies who crammed folic acid prescriptions took the drug remedy as prescribed and that these not prescribed excessive dose folic acid weren’t taking over-the-counter folic acid dietary supplements. Dietary folate consumption can also be unaccounted for, and serum folate ranges weren’t accessible for evaluation. These components ought to be thought of in future research on the subject.

In brief, folic acid supplementation is advisable in pregnant girls with epilepsy. Registry information for pregnant girls with epilepsy has not but proven a discount of main congenital malformations with folic acid supplementation. Nevertheless, robust proof signifies neurocognitive advantages in youngsters born to girls with epilepsy who acquired periconceptional folic acid dietary supplements of at the least 0.4 mg/day. Additional analysis is required to determine optimum dosing suggestions, in addition to to analyze the security of excessive dose folic acid supplementation.

Vitamin Okay supplementation

The literature accommodates a number of case experiences of hemorrhagic illness in neonates born to moms taking enzyme inducing antiseizure medicines.8889 It has been hypothesized that enzyme inducing antiseizure medicines cross the placenta and result in an elevated price of oxidative degradation of vitamin Okay and resultant vitamin Okay deficiency within the fetus.90 This led to a suggestion for pregnant girls with epilepsy on enzyme inducing antiseizure medicines to take an oral vitamin Okay complement within the ultimate weeks of being pregnant.91 This suggestion was along with the usual 1 mg parenteral vitamin Okay supplementation given to all neonates on the time of beginning. Nevertheless, a big potential research of >600 pregnant girls with epilepsy taking enzyme inducing antiseizure medicines (carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine) discovered no vital distinction within the incidence of hemorrhagic illness of the new child in contrast with the management group.92 As a substitute, the incidence of neonatal bleeding was elevated when beginning occurred earlier than 32 weeks of gestation, or within the context of maternal alcohol abuse. No girls within the research acquired antenatal vitamin Okay, and all neonates acquired parenteral vitamin Okay after beginning.

Given these findings, proof is inadequate to advocate antenatal maternal vitamin Okay supplementation for all pregnant girls with epilepsy taking enzyme inducing antiseizure medicines. This conclusion is consistent with the present American Academy of Neurology pointers on the subject.93

Antiseizure medicine monitoring throughout being pregnant

Typically, antiseizure medicine ranges will not be ceaselessly measured in folks with epilepsy when seizures are managed and who’re with out scientific indicators of toxicity. Given the pharmacokinetic modifications that happen throughout being pregnant,94 an argument might be made to watch antiseizure medicine serum ranges carefully on this context, as tonic clonic seizures throughout being pregnant may cause decreased fetal coronary heart price, maternal and fetal hypoxia and acidosis, and probably contribute to miscarriage.95 The logical follow-up query is whether or not modifications in serum concentrations of antiseizure medicines result in a clinically vital affect on seizure frequency that may warrant monitoring of antiseizure medicine ranges. Two retrospective cohort research and two potential observational research have proven an elevated frequency of seizures in pregnant girls when antiseizure medicine concentrations decreased under 65% of preconception concentrations.96979899 The MONEAD research expands on these leads to a big potential cohort research (351 pregnant girls and 109 controls) that included antiseizure medicine serum monitoring for a number of antiseizure medicines.100 These within the being pregnant group taking lamotrigine, levetiracetam, oxcarbazepine, lacosamide, and zonisamide confirmed vital decreases in serum antiseizure medicine dose normalized concentrations, whereas vital modifications weren’t seen in dose normalized concentrations of topiramate, unbound carbamazepine, and carbamazepine-10,11-epoxide. The beforehand reported improve in seizure frequency accompanying decreased antiseizure medicine concentrations was not replicated on this research, however the antiseizure medicine doses had been additionally elevated all through the research primarily based on antiseizure medicine concentrations, which might account for this discrepancy.

It stays to be seen whether or not serial monitoring of serum antiseizure medicine ranges throughout being pregnant results in higher outcomes than scientific monitoring alone. In a single double blind, randomized trial nested inside a cohort research, performed at 50 obstetric and epilepsy clinics within the UK, pregnant girls with epilepsy taking lamotrigine, levetiracetam, carbamazepine, or phenytoin, who additionally had serum antiseizure medicine ranges ≤75% of their baseline degree, had been randomized to both a gaggle through which antiseizure medicine dose changes had been decided by scientific options alone (n=130) or a gaggle through which antiseizure medicine dose changes had been decided by antiseizure medicine serum degree along with scientific options (n=127).101 The time to first seizure between these teams was not considerably completely different (hazard ratio 0.82, 95% confidence interval 0.55 to 1.2). This discovering might have been influenced by the brink serum antiseizure medicine degree used as a criterion for group randomization, or probably by variabilities in apply patterns of the clinicians throughout the research websites.

Collectively, proof signifies that antiseizure medicine concentrations of lamotrigine, levetiracetam, oxcarbazepine, lacosamide, and zonisamide lower throughout being pregnant, and a rise in seizure frequency is related to a serum antiseizure medicine focus of ≤65% in contrast with preconception concentrations for ladies taking lamotrigine and levetiracetam. This helps routine antiseizure medicine degree monitoring for pregnant girls with epilepsy taking these drug therapies and applicable dose changes. In conditions the place monitoring just isn’t attainable, consideration could possibly be given to empiric dose changes primarily based on the everyday pharmacokinetics of the drug remedy throughout being pregnant or using carbamazepine, which didn’t have the identical fluctuations in focus within the unbound type or metabolite within the MONEAD research. Whereas topiramate additionally didn’t present vital fluctuations in focus, it ought to be averted when attainable, owing to elevated threat of main congenital malformations and probably neurodevelopmental penalties. Further analysis is required to find out optimum frequency of antiseizure medicine degree monitoring, and whether or not it results in higher outcomes at a sensible degree.


The interval when a lady with epilepsy is lactating can also be distinctive, and traditionally, there was a priority that the dangers of publicity to antiseizure medicines could possibly be too excessive for the toddler. The NEAD and MONEAD research provide the best high quality proof up to now, and help the apply of lactation for most ladies.102103104

The NEAD research, a potential multicenter observational research, supplied information of cognitive outcomes of youngsters who had been breastfed by a mom on antiseizure medicine monotherapy with carbamazepine, lamotrigine, phenytoin, or valproate, with a median breastfeeding time of six months.102 Out of a pattern measurement of 199 youngsters born to girls with epilepsy within the US and UK, 42% had been breastfed, and had been discovered to haven’t any statistically vital distinction in IQ at age three years in comparison with the kids within the pattern who weren’t breastfed. The evaluation on this pattern was subsequently prolonged to 6 years of age (42.9% of 181 youngsters within the breastfed group, with imply breastfeeding length of seven.2 months), and nonetheless, no vital distinction in IQ was noticed between the breastfed group and the non-breastfed group.103 Further measures of verbal, non-verbal, reminiscence, and government operate had been carried out and confirmed superior verbal skills (adjusted verbal index 4 factors greater (95% confidence interval 0-7, P=0.03)) within the breastfed group. Equally, the potential Norwegian Mom and Baby Cohort Examine confirmed no antagonistic outcomes in social abilities, language, or habits at three years of age in youngsters breastfed by moms taking antiseizure medicines (monotherapy with carbamazepine, lamotrigine, valproate, or polytherapy) in contrast with the non-breastfed group.105

Furthermore, the MONEAD research confirmed that breastfed infants born to girls with epilepsy usually have a a lot decrease antiseizure medicine serum focus than their moms.104 Of the 138 breastfed infants of ladies with epilepsy within the research inhabitants, 49.3% had antiseizure medicine concentrations under even the decrease restrict of quantification. The exception to this was lamotrigine, a discovering that highlights the significance of lowering the lamotrigine dose expeditiously in postpartum girls who required dose will increase throughout being pregnant. Notably, this research solely included girls with epilepsy on monotherapy with carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, topiramate, valproate, or zonisamide. The decrease serum concentrations might present one rationalization for the shortage of deleterious results attributable to breastfeeding in youngsters born to girls with epilepsy. Nevertheless, many antiseizure medicines at the moment in use weren’t included in these research.

Some specialists have beneficial breastfeeding with warning for ladies with epilepsy taking phenobarbital, primidone, clobazam, and clonazepam, with shut monitoring of the toddler for lethargy, hypotonia, poor suck, or apneas.106 Breastfeeding for ladies with epilepsy taking felbamate is usually averted owing to lack of security proof for the toddler and recognized dangers of acute hepatic failure and aplastic anemia in adults.107108 One other notable characteristic of the NEAD and MONEAD research is that antiseizure medicine publicity in utero preceded publicity throughout breastfeeding. Future analysis together with girls who require the addition of latest antiseizure medicines publish partum would even be precious and permit for extra goal steerage within the remedy of postpartum girls with new onset seizures, or those that require an antiseizure medicine for one more indication exterior of epilepsy.

Typically, girls with epilepsy ought to be inspired to breastfeed. The proof means that breastfeeding is secure when the mom is taking carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, topiramate, valproate, zonisamide, or phenytoin. Shut monitoring for the toddler could possibly be advisable when the breastfeeding mom is taking phenobarbital, primidone, clobazam, or clonazepam. Additional analysis is required for ladies with epilepsy utilizing newer antiseizure medicines, however breastfeeding could possibly be thought of in such circumstances with shut toddler monitoring following cautious dialogue between affected person and doctor.

Rising therapies

Neuromodulation security in being pregnant

Vagus nerve stimulation has been used as adjunctive remedy for intractable epilepsy for the reason that Nineteen Nineties. The biggest research up to now investigating the security of vagus nerve stimulation for ladies with epilepsy and fetal outcomes throughout being pregnant was a world observational cohort research utilizing primarily EURAP registry information, in addition to Australian and UK being pregnant registries.109 Twenty-six pregnancies had been assessed in 25 girls, with most ladies (70%) on antiseizure medicine polytherapy. One main congenital malformation was reported (3.9%, 95% confidence interval 0.1% to 19.6%), consistent with the foremost congenital malformation price seen in girls on antiseizure medicine with out vagus nerve stimulation. The authors additionally famous a better proportion of ladies requiring obstetrical interventions (53.9%, 33.4% to 73.4%) in contrast with the EURAP common (48.2%, 47.2% to 49.1%). Though vagus nerve stimulation might in idea have led to physiological modifications contributing to the necessity for obstetrical interventions, the upper variety of obstetrical interventions may also be accounted for by the inhabitants of ladies who obtain vagus nerve stimulation, these with intractable epilepsy. Over 90% of the ladies included within the research had seizures throughout being pregnant, which additionally might contribute to the necessity for obstetrical interventions. Total, no proof indicated teratogenicity from vagus nerve stimulation, and no clear causation for the elevated obstetrical interventions was reported. Although most ladies receiving vagus nerve stimulation throughout being pregnant had the machine implanted earlier than conception, in a single case report, a lady with intractable epilepsy safely underwent vagus nerve stimulation implantation and activation throughout the third trimester of being pregnant, leading to improved seizure management.110

Responsive neurostimulation is an alternative choice for adjunctive remedy and has been FDA accredited since 2014 for adults with intractable focal onset epilepsy with one to 2 foci. The biggest research up to now specializing in the maternal and fetal security and outcomes of ladies with epilepsy and responsive neurostimulation adjunctive remedy was a retrospective cohort research together with information from 9 US epilepsy facilities between 2014 and 2020, that described outcomes of 10 sufferers and 14 pregnancies.111 No main congenital malformations had been reported, and the speed of obstetrical problems was consistent with that anticipated for ladies with epilepsy.

In 2018, deep mind stimulation acquired FDA approval as an adjunctive remedy for folks with intractable focal onset epilepsy. As the most recent of the neuromodulatory remedy choices within the US for epilepsy, the info on pregnant girls, particularly for intractable epilepsy remedy, is sparse. One case report of two girls with epilepsy with deep mind stimulation discovered no teratogenicity considerations or modifications within the anticipated obstetrical complication price.112 Further information can be found for deep mind stimulation for different indications exterior of intractable epilepsy. A case sequence of 11 girls with deep mind stimulation for motion problems or psychiatric indications additionally supported the security of deep mind stimulation for each mom and child.113

Total, the neuromodulatory therapies for intractable epilepsy appear to be secure in being pregnant, although the pattern sizes of the case sequence/case experiences resulting in this conclusion are small. Further information for these units are being gathered by way of the being pregnant registries, and updates are sure to comply with, as using neuromodulatory units turns into extra commonplace in girls with epilepsy. Ought to the security proceed to be proven in pregnant girls with epilepsy, future consideration could possibly be given to utilizing these therapies to assist scale back the variety of antiseizure medicines required in girls with epilepsy who’re on polytherapy and contemplating being pregnant.

The latest antiseizure medicines and being pregnant

Using antiseizure medicines accredited by the FDA over the previous 10 years has develop into extra frequent, however antiseizure medicines corresponding to eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate will not be but included within the accessible being pregnant registry information.55 Customary apply encourages using antiseizure medicines recognized to be secure in being pregnant in girls of childbearing age, which might contribute to the dearth of information on the newer antiseizure medicines in pregnant girls. Those that require these newer brokers to regulate seizures ought to be inspired to enroll within the being pregnant registries, to doc outcomes and contribute to the accessible information on this space.

Registries face particular challenges; for instance, not all girls contribute their information. Consideration ought to be given to mandating information assortment for all girls who’re on persistent drug remedy, like mandated information assortment for hemoglobinopathies in all black girls within the US. Within the case of hemoglobinopathies, testing is accomplished by obstetricians; a case might be made to have hospitals and obstetrics and pediatric clinics accumulate essential variables with out relying on the specialist neurologist. Knowledge from center earnings and decrease earnings international locations are additionally sorely wanted. One instance describes a multicountry, group primarily based registry not restricted to 1 illness.114 We hope that registries will be capable to work extra collaboratively to extend pattern sizes.

In short, the security of a lot of the latest antiseizure medicines just isn’t but recognized. We have to enroll a higher proportion of ladies with epilepsy in being pregnant registries, and for registries to collaborate internationally.


The Worldwide League Towards Epilepsy (ILAE) not too long ago surveyed its members to establish using pointers on this matter, and concluded that pointers in lots of international locations had been outdated and too obscure concerning questions corresponding to neurodevelopmental outcomes, antiseizure medicine selection, drug monitoring throughout being pregnant, and breastfeeding.115 Many international locations (35% of those that accomplished the survey), subsequently, use pointers from the American Academy of Neurology (AAN), American Epilepsy Society (AES), or the UK’s Nationwide Institute for Well being and Care Excellence (NICE).

Each the AAN and NICE have pointers that pertain to girls with epilepsy throughout being pregnant and postpartum durations. The AAN pointers had been initially printed in 2009 and reaffirmed in 2013 and 2022, per the AAN web site.93116117118 They’re proof primarily based and canopy teratogenesis and perinatal outcomes, obstetrical problems, and alter in seizure frequency and administration throughout being pregnant together with blood ranges, folic acid supplementation, vitamin Okay, and breastfeeding. NICE pointers are additionally proof primarily based,119 and its web site contains hyperlinks to an antagonistic occasion reporting system (the yellow card app).120 Few research appear to cowl data of those particular pointers by treating obstetricians; nonetheless, the proof primarily based pointers by the Royal Faculty of Obstetricians and Gynaecologists for epilepsy in being pregnant provide steerage that’s largely per that given by the AAN.121 The largest level of divergence between these pointers appears to be an absence of a constant dose suggestion for folic acid supplementation in girls with epilepsy, with steerage starting from 0.4 to five.0 mg/day.93121 This wide selection isn’t a surprise, given the dearth of top quality proof concerning the optimum dosing of folic acid supplementation on this inhabitants as mentioned beforehand on this assessment. A 1996 research recommended that obstetricians in Scotland may benefit from elevated collaboration with neurologists when treating pregnant girls with epilepsy.122

Tips particular for center and low earnings international locations are wanted, contemplating the dramatically completely different healthcare panorama. In 2011, the World Well being Group launched proof primarily based epilepsy care pointers for use in low and center earnings international locations.123 With regard to girls with epilepsy, these pointers beneficial the avoidance of valproate and polytherapy (in contrast with safer medicine carbamazepine, phenytoin, and phenobarbital) and beneficial folic acid supplementation. This guideline has not been up to date as of December 2022, however the entry to second era antiseizure medicines corresponding to levetiracetam or lamotrigine might be restricted or unreliable. As well as, regardless that epidemiologic analysis and registries are few and much between,124 when they’re tried, services ought to accumulate information on all related ailments; for instance, drug therapies used for HIV and publicity to antimalarials ought to be documented. It may be simpler to feed these information into well-known registries that exist already, corresponding to by way of WHO, or even perhaps registries corresponding to EURAP. Enrollment shouldn’t be depending on excessive degree specialists who won’t be accessible; standards ought to be simplified to permit skilled non-technical workers members to assist with information assortment.


Charges of profitable being pregnant in girls with epilepsy are typically comparable with different girls, in the event that they receive prenatal care and keep away from excessive threat drug therapies corresponding to valproate and topiramate. Antiseizure medicines have completely different dangers of main congenital malformation, with valproate having the best threat. Phenobarbital and topiramate are additionally problematic, though decrease threat than valproate. Phenytoin and carbamazepine are even decrease threat, and levetiracetam and lamotrigine have the bottom dangers, approaching the danger ranges of wholesome controls. With regard to cognitive outcomes, fetal valproate publicity is related to decrease intelligence in youngsters in comparison with carbamazepine, phenytoin, and lamotrigine. Fetal valproate and topiramate publicity are related to elevated threat of developmental problems corresponding to autism spectrum dysfunction. Using valproate (and doubtlessly topiramate and phenobarbital) ought to be averted in girls of childbearing age, until the prescriber and the affected person have an specific settlement.

Too few research have been completed on one of the best method for antiseizure medicine serum degree monitoring throughout being pregnant, however it appears affordable to test and alter the degrees of these drug therapies which are recognized to lower considerably.

Although many antiseizure medicines are current in breast milk, lactation doesn’t seem to confer any measurable long run dangers for the kid, and so ought to be inspired.

Knowledge on the most recent antiseizure medicines are restricted, so that they can’t be confidently beneficial for being pregnant right now.

Ongoing being pregnant registries have been essential on this inhabitants and could possibly be optimized by improved worldwide collaborations and elevated emphasis on enrollment.

Questions for future analysis

  • Does animal information on teratogenicity correlate with security in people?

  • What are the dangers of antiseizure medicine in folks with out epilepsy? (Many antiseizure medicines are used for ache and psychiatric problems.)

  • What number of exposures are wanted to know whether or not a typical antiseizure medicine is secure for being pregnant? Can predictive modeling and different massive information rules be used to outline easy timeframes for when a drug is deemed to be secure?

  • How can extra girls be enrolled in being pregnant registries within the US, the place enrollment is voluntary? Ought to neurologists be bypassed?

Questions to assist promote equitable care world wide

  • Can low earnings and center earnings international locations afford to persistently have safer medicine on their nationwide formularies?

  • How can low price being pregnant surveillance programs be designed in low earnings international locations to assist collect information to tell well being dangers related to persistent remedy in girls of childbearing age (malaria, epilepsy, HIV, and many others)?

  • Can low earnings and center earnings international locations depend upon the info collected from greater earnings international locations to tell their nationwide well being insurance policies?


  • State of the Artwork Evaluations are commissioned on the premise of their relevance to teachers and specialists within the US and internationally. For that reason they’re written predominantly by US authors.

  • Sufferers weren’t straight concerned within the creation of this text.

  • Competing pursuits: Now we have learn and understood the BMJ coverage on declaration of pursuits and declare the next pursuits: none.

  • Contributorship assertion and guarantor: Each authors participated within the literature search, reviewing the literature, in addition to conception, drafting, and revising the manuscript. Each authors settle for full duty for the work, had entry to the info, and managed the choice to publish. Each authors act as guarantors.

  • Funding: No funding was given to this research.

  • Provenance and peer assessment: commissioned; externally peer reviewed.


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