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Pregnancy and epilepsy; meeting the challenges over the last 25 years: The rise of the pregnancy registries

  • M.O. Kinney
    Affiliations
    Department of Neurology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Grosvenor Road, Belfast, Northern Ireland BT12 6BA, United Kingdom
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  • J.J. Craig
    Correspondence
    Corresponding author.
    Affiliations
    Department of Neurology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Grosvenor Road, Belfast, Northern Ireland BT12 6BA, United Kingdom
    Search for articles by this author
Open ArchivePublished:October 14, 2016DOI:https://doi.org/10.1016/j.seizure.2016.10.004

      Abstract

      Purpose

      Women with epilepsy (WWE), of all ages, have much to consider if their care is to be optimised and they are not to be denied the choices open to those without epilepsy. At no time is this more critical than during their child-bearing years when treatment decisions are complex.

      Methods

      In this article we will provide a personal commentary and review of the pertinent literature on how the management of WWE of childbearing years has changed over the last 25 years. As well as reflecting on the state of knowledge at the start of the 1990s and the approach to managing WWE at this time, we will demonstrate that in addition to much more information now being available that there has also been an attempt to standardise how WWE should be managed.

      Results

      As a means of achieving this increase in knowledge and standardisation of care, we argue that the various pregnancy registries have played a significant part in these positive developments. As vehicles for collecting clinically relevant data, they have provided information that has helped empower women and their health care providers to make sound clinical decisions, as well as highlighting the difficulties and unknowns.

      Conclusions

      Still being active the pregnancy registries maintain a continued focus on the relevant issues relating to WWE.

      Keywords

      1. Introduction

      Women with epilepsy (WWE), of all ages, have much to consider if their care is to be optimised and they are not to be denied the choices open to those without epilepsy. At no time is this more critical than during their child-bearing years when treatment decisions are complex [
      • Kinney M.O.
      • Morrow J.I.
      Epilepsy in pregnancy.
      ].
      Bearing in mind WWE, of child-bearing age, account for approximately one quarter of all patients with active epilepsy and despite the awareness of potential teratogenic signals with some anti-epilepsy drugs (AEDs) [
      • Robert E.
      • Guibaud P.
      Maternal valproic acid and congenital neural-tube defects.
      ], it is somewhat surprising, that it is only in the last 25 years that the complexities of managing WWE have started to be considered and systematically studied in their entirety and as importantly the results disseminated and incorporated into regular clinical practice.
      In this article we will attempt to provide a personal commentary on how the management of WWE of childbearing years has changed over the last 25 years. As well as reflecting on the state of knowledge at the start of the 1990s and the approach to managing WWE at this time, we will demonstrate that in addition to much more information now being available that there has also been an attempt to standardise how WWE should be managed. As a means of achieving this we will argue that the various pregnancy registries have played a significant part in these positive developments. As vehicles for collecting clinically relevant data, they have provided information that has helped empower women and their health care providers to make sound clinical decisions, as well as highlighting the difficulties and unknowns. Still being active they also maintain a continued focus on the relevant issues.

      1.1 Historical context

      At the beginning of the 1990s there was understanding that WWE were at increased risk for adverse outcomes in pregnancy [

      Devinsky O, Feldmann E, Hainline B. Advances in neurology. Vol 64: neurological complications of pregnancy. Chapter 5. Epilepsy and pregnancy. Raven Press; 1994.

      ]. Studies had demonstrated WWE taking an AED in monotherapy had an increased risk over background of having an infant with a major congenital malformation (MCM), from 2–3% to 4–7% [

      Devinsky O, Feldmann E, Hainline B. Advances in neurology. Vol 64: neurological complications of pregnancy. Chapter 5. Epilepsy and pregnancy. Raven Press; 1994.

      ,
      • Delgado-Escuta A.V.
      • Janz D.
      Consensus guidelines: preconception counselling, management, and care of the pregnant woman with epilepsy.
      ] with the risks being greater for those taking AEDs in combination [
      • Lindhout D.
      • Rene J.E.
      • Hoppener A.
      • Meinardi H.
      Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation of carbamazepine.
      ] and the more AEDs were taken. It was suspected that some AEDs had a higher risk for MCMs and for particular types of malformations, such as neural tube defects (NTDs) with valproate [
      • Robert E.
      • Guibaud P.
      Maternal valproic acid and congenital neural-tube defects.
      ]. Looking back it seems that any perceived differences in MCM risk did not substantially impact on prescribing practices. Furthermore, the studies on which any conclusions had been drawn were often small, retrospective and from single centres and did not take account of confounding variables [

      Devinsky O, Feldmann E, Hainline B. Advances in neurology. Vol 64: neurological complications of pregnancy. Chapter 5. Epilepsy and pregnancy. Raven Press; 1994.

      ]. They also tended to focus on AEDs that were becoming less frequently used with the advent of the ‘newer’ AEDs.
      A focus of early research was specific AED-related foetal syndromes [
      • DiLiberti J.H.
      • Farndon P.A.
      • Dennis N.R.
      • Curry C.J.R.
      The fetal valproate syndrome.
      ,
      • Jones K.L.
      • Lacro R.V.
      • Johnson K.A.
      • Adams J.
      Pattern of malformations in the children of women treated with carbamazepine during pregnancy.
      ]. These were defined by the presence of combinations of minor anomalies and were reported for most of the available AEDs. The significance of these alterations, other than on appearance was not well studied, albeit some specific concerns had been raised for valproate.
      The long term effects of in-utero exposure to AEDs on cognitive functioning and neurodevelopment were also largely unknown, although small early uncontrolled studies had shown that mean intelligence quotient (IQ) was significantly lower in children born to WWE. Certain AEDs had also been implicated in causing problems resulting in additional educational needs [
      • Scolnik D.
      • Nulman I.
      • Rovet J.
      • Gladstone D.
      • Czuchta D.
      • Gardner H.A.
      • et al.
      Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy.
      ].
      In regards to the effects of pregnancy on epilepsy, while there was an understanding of the differing pharmacokinetics of many AEDs in pregnancy, how to best manage these changes had largely not been considered. For seizure control, early studies had consistently suggested roughly equivalent proportions showing no change, an improvement, or a deterioration in seizure control, with some studies suggesting ranges of increased risk of seizures of between 4–75% [

      Devinsky O, Feldmann E, Hainline B. Advances in neurology. Vol 64: neurological complications of pregnancy. Chapter 5. Epilepsy and pregnancy. Raven Press; 1994.

      ]. The effects of status epilepticus in pregnancy were considered to be particularly severe.
      For pregnancy related complications accepted wisdom was that most, if not all, were increased in WWE, with haemorrhagic disease of the newborn, in those exposed to enzyme inducing AEDs, having been highlighted as being a particular concern [

      Devinsky O, Feldmann E, Hainline B. Advances in neurology. Vol 64: neurological complications of pregnancy. Chapter 5. Epilepsy and pregnancy. Raven Press; 1994.

      ]. Increased rates of foetal loss and reduced growth parameters had also been reported. It was also noted that WWE were up to four times more likely to have an induced labour and twice as likely to have a caesarean section, despite widespread knowledge that most could achieve a normal delivery [
      • Hiilesmaa V.K.
      • Bardy A.H.
      • Teramo K.
      Obstetrical outcome in women with epilepsy.
      ].
      In keeping with information available at the time, guidelines reflected the defects in knowledge and in particular were unable to differentiate between the risks for individual AEDs [
      • Crawford P.
      • Appleton R.
      • Betts T.
      • Duncan J.
      • Guthrie E.
      • Morrow J.
      • et al.
      Best practice guidelines for the management of women with epilepsy.
      ]. In clinical practice the need to provide greater focus on women with epilepsy had yet to be realised. In fact in some areas, including resource rich countries, dedicated epilepsy clinics within neurological services had just been established. Some of the early guidelines [
      • Crawford P.
      • Appleton R.
      • Betts T.
      • Duncan J.
      • Guthrie E.
      • Morrow J.
      • et al.
      Best practice guidelines for the management of women with epilepsy.
      ] did identify the importance of pre-conceptual counselling, the importance of proper preparation for pregnancy and close follow up during pregnancy into the postpartum period, with attention on seizure breakthrough, and correct foetal monitoring in conjunction with obstetric teams, however these standards were far from being the expected level of care.
      With an ever increasing number of AEDs being introduced in the early 1990s, some of which had better preclinical safety data than the established AEDs, there was a realisation that new mechanisms needed to be put in place to collect the requisite data to allow evidence based decisions on the safety of AEDs, and in particular to determine if any AED conferred a lower risk of teratogenicity in ‘real life’ practice.

      1.2 Rise of the registries

      Since it would be unethical to perform randomised controlled trials on pregnant women, the collection and analysis of observational data has been the means of informing practice in the management of WWE. Given that only one in two hundred pregnancies occurs to a WWE [
      • Olafsson E.
      • Hallgrimsson J.T.
      • Hauser W.A.
      • Ludvigsson P.
      • Gudmundsson G.
      Pregnancies of women with epilepsy: a population-based study in Iceland.
      ], and most of these are normal pregnancies, no single centre, no matter how big, could ever have enough pregnancies to collect sufficient outcomes. Against this background, it was apparent to a number of like-minded researchers that information would need to be collected at a national or international level. While post-marketing surveillance programmes did exist, and continue to provide important signals of potential harmful effects from any drug exposure, they generally concentrate on adverse outcomes and so cannot provide information on the relative risks between treatments. As a result of these considerations a number of pregnancy registries, collecting prospective data, on pregnancies exposed to AEDs were established from the mid-1990s [
      • Campbell E.
      • Kennedy F.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Morrison ​ P.J.
      • et al.
      Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.
      ,
      • Hernández-Díaz S.
      • Smith C.R.
      • Shen A.
      • Mittendorf R.
      • Hauser W.A.
      • Yerby M.
      • et al.
      Comparative safety of antiepileptic drugs during pregnancy.
      ,
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Sabers A.
      • et al.
      Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
      ]. The registries were either sponsored by an individual pharmaceutical company, in which case the focus was on a single AED, with the Lamotrigine International Pregnancy Registry [
      • Cunnington M.C.
      • Weil J.G.
      • Messenheimer J.A.
      • Ferber S.
      • Yerby M.
      • Tennis P.
      Final results from 18 years of the International Lamotrigine Pregnancy Registry.
      ] being a particularly successful example, or represented the endeavours of independent researchers, based either within a region of a single country or being national or international in their remit.
      While the methodologies of the independent national and international pregnancy registries vary somewhat [
      • Tomson T.
      • Battino D.
      • Craig J.
      • Hernandez-Diaz S.
      • Holmes L.B.
      • Lindhout D.
      • et al.
      Pregnancy registries: differences, similarities, and possible harmonization.
      ] (Table 1), they all have a similar aim, that of collecting information on the risks of MCMs in infants born to WWE, for all AED exposures. In addition to collecting information on AED exposure before and during pregnancy, demographic details and other confounding variables are collected, to include folate exposure, exposure to other teratogens, family history of MCMs and past pregnancy details. Details on epilepsy and seizure control before and during pregnancy are also generally collected. At various pre-determined time points post-partum information is then collected on pregnancy outcomes.
      Table 1Comparison of the attributes of the major national and international AED and pregnancy registries.
      RegistryUK and Ireland Epilepsy and Pregnancy Register
      • Campbell E.
      • Kennedy F.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Morrison ​ P.J.
      • et al.
      Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.
      North American Epilepsy and Pregnancy Registry
      • Hernández-Díaz S.
      • Smith C.R.
      • Shen A.
      • Mittendorf R.
      • Hauser W.A.
      • Yerby M.
      • et al.
      Comparative safety of antiepileptic drugs during pregnancy.
      EURAP
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Sabers A.
      • et al.
      Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
      MethodologyNational, prospective based in the United Kingdom. Ascertainment is approximately 33% of the population of WWE in pregnancyNational prospective based in United states of America, and Canada.International (>40 countries) prospective/retrospective (includes Australian data)
      Participation50% self-enrollment WWE, and rest through physicians, nurses, midwives.Self-enrollment by WWEThrough a network of physicians who report cases. No self-enrollment.
      Inclusion criteriaWomen with epilepsy, treated on AEDs or untreated in 1st trimesterWomen taking AED for any reason in pregnancyPregnancies with AED exposure at conception.
      Exclusion criteriaPre-enrollment knowledge of malformation, or change in 1st trimester AED, or commencing the AED after conception.If AEDs are switched in first trimesterChange in 1st trimester AED, or outcome not classifiable.
      Data collection methods, and follow upAt enrollment and at 3 months after birth, the patient’s general practitioner provides follow up on the case.Telephone interview with patient at 7 months gestation, and then 8–12 weeks after pregnancy further interview, and in 60% of cases data extracted from patient/infants medical records.Within 12 months of birth, and also followed up during pregnancy at end of each trimester.
      Type and level of exposureDrug and dose (including dose changes recorded). Highest dose recorded taken as dose exposure.Drug dose and brandDrug regime and dose
      Drug levelsNot systematically recordedNot systematically recordedNot systematically recorded
      Diagnosis of epilepsyPhysician reported diagnosis of epilepsy, and clinical geneticist reviews medical record to determine if malformation presentSelf reported diagnosis. Medical teratologist blinded review of medical record.Made by patient’s physician. Central classification of outcomes based on teratologists assessment of medical reports.
      While the information collected from registries do not involve randomly assigned treatments, confounding variables are not always well recorded, reporting can be very selective and there is often no adequate control population, they have proven an effective means of providing outcome data on large numbers of pregnancies in WWE. The results produced, in particular the observed trends for risks of MCMs by AED exposure, have also generally been similar, providing some reassurance as to the validity of the results. Differences have however been noted on occasions. These could be due to a number of factors to include differing methodologies and true differences between the populations studied. This has led to concerns in regards to the ability to pool data for statistical analysis.
      Apart from the three largest registries [
      • Campbell E.
      • Kennedy F.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Morrison ​ P.J.
      • et al.
      Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.
      ,
      • Hernández-Díaz S.
      • Smith C.R.
      • Shen A.
      • Mittendorf R.
      • Hauser W.A.
      • Yerby M.
      • et al.
      Comparative safety of antiepileptic drugs during pregnancy.
      ,
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Sabers A.
      • et al.
      Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
      ] (see Table 1) several other groups have established effective means of collecting useful information. These include the various Scandinavian national birth registries [
      • King P.B.
      • Lie R.T.
      • Irgens L.M.
      Spina bifida and cleft lip among newborns of Norwegian women with epilepsy: changes related to the use of anticonvulsants.
      ,
      • Kilic D.
      • Pedersen H.
      • Kjaersgaard M.
      • Parner E.T.
      • Vestergaard M.
      • Sørensen M.J.
      • et al.
      Birth outcomes after prenatal exposure to antiepileptic drugs—a population-based study.
      ], the Kerala Registry of Epilepsy and Pregnancy (KREP) [
      • Thomas S.V.
      • Indrani L.
      • Devi G.C.
      • Jacob S.
      • Beegum J.
      • Jacob P.P.
      • et al.
      Pregnancy in women with epilepsy: preliminary results of Kerala registry of epilepsy and pregnancy.
      ] and the Australian registry of AEDs [
      • Vajda F.J.E.
      • O’Brien T.J.
      • Lander C.M.
      • Graham J.
      • Eadie M.J.
      The teratogenicity of the newer antiepileptic drugs – an update.
      ] in pregnancy. Some of these also contribute substantially to EURAP. There are also non-disease/drug specific registries such as EUROCAT [

      Eurocat. European surveillance of congenital anomalies. Available on: www.eurocat-network.eu [last accessed 27.08.16].

      ] (European Concerted Action on Congenital Anomalies and Twins).

      1.3 Results from the registries (Table 2)

      All of the pregnancy registries have confirmed that valproate is associated with the greatest risk for MCMs [
      • Campbell E.
      • Kennedy F.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Morrison ​ P.J.
      • et al.
      Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.
      ,
      • Hernández-Díaz S.
      • Smith C.R.
      • Shen A.
      • Mittendorf R.
      • Hauser W.A.
      • Yerby M.
      • et al.
      Comparative safety of antiepileptic drugs during pregnancy.
      ,
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Sabers A.
      • et al.
      Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
      ,
      • King P.B.
      • Lie R.T.
      • Irgens L.M.
      Spina bifida and cleft lip among newborns of Norwegian women with epilepsy: changes related to the use of anticonvulsants.
      ,
      • Kilic D.
      • Pedersen H.
      • Kjaersgaard M.
      • Parner E.T.
      • Vestergaard M.
      • Sørensen M.J.
      • et al.
      Birth outcomes after prenatal exposure to antiepileptic drugs—a population-based study.
      ,
      • Thomas S.V.
      • Indrani L.
      • Devi G.C.
      • Jacob S.
      • Beegum J.
      • Jacob P.P.
      • et al.
      Pregnancy in women with epilepsy: preliminary results of Kerala registry of epilepsy and pregnancy.
      ,
      • Vajda F.J.E.
      • O’Brien T.J.
      • Lander C.M.
      • Graham J.
      • Eadie M.J.
      The teratogenicity of the newer antiepileptic drugs – an update.
      ], with between approximately six and fourteen percent of exposure resulting in a child with a MCM. A clear dose response has also been demonstrated with total daily doses of less than 800 mg being associated with lower risks, with doses above 1500 mg per day being associated with much higher risks [
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Sabers A.
      • et al.
      Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
      ]. Two of the registries have suggested a pharmacogenetic susceptibility to the risks of MCMs for valproate [
      • Campbell E.
      • Devenney E.
      • Morrow J.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • et al.
      Recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero.
      ,
      • Vajda F.J.E.
      • O’Brien T.J.
      • Lander C.M.
      • Graham J.
      • Roten A.
      • Eadie M.J.
      Teratogenesis in prepeated pregnancies in antiepileptic drug-treated women.
      ]. EURAP [
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Sabers A.
      • et al.
      Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
      ] has also shown that a parental history of MCMs increased the risk of MCM by a factor of over four. The KREP, in which much lower doses of AEDs were taken, did not replicate the above; it has been postulated that this is indicative of an interaction between AED dose and the underlying pharmacogenetic susceptibility.
      Table 2Major congenital malformation data from major international, national, and drug company based registries.
      RegistryMCM rate following antiepileptic drug exposure
      ValproateCarbamazepineLamotrigineLevetiracetamTopiramate
      UK and Ireland Registry
      • Campbell E.
      • Kennedy F.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Morrison ​ P.J.
      • et al.
      Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.
      82/1220 (6.7% CI 5.5–8.3%)43/1657 (2.6% CI 1.9–3.5%)49/2098 (2.3% CI 1.8–3.1%)2/304 (0.7% CI 0.2–2.5%)3/70 (4.3% CI 1.7–13.3%)
      EURAP
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Sabers A.
      • et al.
      Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
      Dose <700 mgDose <400 mgDose <300 mgN/AN/A
      24/431 (5.6% CI 3.6–8.2%)5/148 (3.4% CI 1.1–7.7%)17/836 (2.0% CI 1.2–3.2%)
      Dose ≥700–<1500 mgDose ≥400–<1000 mgDose ≥300 mg
      50/480 (10.4% CI 7.8–13.5%)56/1047 (5.3% CI 4.1–6.9%)20/444 (4.5% CI 2.8–6.9%)
      Dose ≥1500 mgDose ≥1000 mg
      24/99 (24.2% CI 16.2–33.9%)18/207 (8.7% CI 5.2–13.4%)
      Australian registry of AEDs in pregnancy
      • Vajda F.J.E.
      • O’Brien T.J.
      • Lander C.M.
      • Graham J.
      • Eadie M.J.
      The teratogenicity of the newer antiepileptic drugs – an update.
      35/253 (13.8% CI 1.7–10.6%)19/346 (5.5% CI 0.6–4.4%)14/307 (4.6% CI 0.5–3.8%)2/82 (2.4% CI 0.2–3.8%)1/42 (2.4% CI 0.1–6.1%)
      International Lamotrigine Pregnancy Registry
      • Cunnington M.C.
      • Weil J.G.
      • Messenheimer J.A.
      • Ferber S.
      • Yerby M.
      • Tennis P.
      Final results from 18 years of the International Lamotrigine Pregnancy Registry.
      N/AN/A35/1558 (2.2% CI 1.6–3.1%)N/AN/A
      North American Antiepileptic Drug Pregnancy Registry
      • Hernández-Díaz S.
      • Smith C.R.
      • Shen A.
      • Mittendorf R.
      • Hauser W.A.
      • Yerby M.
      • et al.
      Comparative safety of antiepileptic drugs during pregnancy.
      30/323 (9.3% CI 6.4–13.0%)31/1033 (3.0% CI 2.1–4.2%)31/1562 (2.0% CI 1.4–2.8%)11/450 (2.4% CI 1.2–4.3%)15/359 (4.2% CI 2.4–6.8%)
      For valproate the types of MCMs have been well defined with an increased risk for neural tube defects, skeletal abnormalities, hypospadias and clefting abnormalities [
      • Campbell E.
      • Kennedy F.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Morrison ​ P.J.
      • et al.
      Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.
      ,
      • Jentink J.
      • Loane M.A.
      • Dolk H.
      • Barisic I.
      • Garne E.
      • Morris J.K.
      • et al.
      Valproic acid monotherapy in pregnancy and major congenital malformations.
      ],
      In contrast results for carbamazepine have been more reassuring [
      • Campbell E.
      • Kennedy F.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Morrison ​ P.J.
      • et al.
      Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.
      ,
      • Hernández-Díaz S.
      • Smith C.R.
      • Shen A.
      • Mittendorf R.
      • Hauser W.A.
      • Yerby M.
      • et al.
      Comparative safety of antiepileptic drugs during pregnancy.
      ], with MCM rates closer to background being reported. EURAP in contrast has reported a higher risk of approximately five percent [
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Sabers A.
      • et al.
      Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
      ]. This may reflect the longer period of follow-up, with outcome data reported one year after birth. For the other older AEDs results have been somewhat mixed with most information being reported for phenytoin, where the MCM rate was of the order of between 2.9 and 6.7%.
      Considering those AEDs launched in the 1990s, most information is available for lamotrigine. Among many thousands of reported monotherapy exposures, the MCM rate has not been found to be greatly increased above background [
      • Campbell E.
      • Kennedy F.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Morrison ​ P.J.
      • et al.
      Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.
      ,
      • Hernández-Díaz S.
      • Smith C.R.
      • Shen A.
      • Mittendorf R.
      • Hauser W.A.
      • Yerby M.
      • et al.
      Comparative safety of antiepileptic drugs during pregnancy.
      ,
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Sabers A.
      • et al.
      Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
      ], significantly less than for valproate and with only weak evidence for a dose response [
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Sabers A.
      • et al.
      Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
      ]. While an increased risk for clefting abnormalities was noted by one registry [
      • Holmes L.B.
      • Baldwin E.J.
      • Smith C.R.
      • Habecker E.
      • Glassman L.
      • Wong S.L.
      • et al.
      Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy.
      ] these findings have not been replicated, such that presently no specific pattern of abnormalities is considered for lamotrigine [
      • Dolk H.
      • Wang H.
      • Loane M.
      Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies.
      ].
      More recently data for levetiracetam [
      • Mawhinney E.
      • Craig J.
      • Morrow J.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • et al.
      Levetiracetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers.
      ] and topiramate [
      • Hunt S.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Robertson I.
      • Waddell R.
      • et al.
      Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register.
      ] and oxcarbazepine have been emerging. Results have generally been favourable compared with valproate, although concerns have been raised for topiramate and clefting abnormalities. Fewer data are available for the other more recently licensed AEDs, including zonisamide. This is disappointing bearing in mind its availability in some countries, since the inception of the pregnancy registries.
      Outcome data for pregnancies exposed to AED combinations have also been reported [
      • Holmes L.B.
      • Mittendorf R.
      • Shen A.
      • Smith C.R.
      • Hernandez-Diaz S.
      Fetal effects of anticonvulsant polytherapies: different risks from different drug combinations.
      ,
      • Vajda F.J.
      • Hitchcock A.A.
      • Graham J.
      • O’Brien T.J.
      • Lander C.M.
      • Eadie M.J.
      The teratogenic risk of antiepileptic drug polytherapy.
      ]. While the usual dogma of avoiding polytherapy, whenever possible, is still a reasonable starting point, results demonstrate that it is exposure to combinations containing valproate and possibly topiramate that carry the highest risks for MCMs. In contrast to the message to try and avoid valproate in pregnancy, whenever possible, for polytherapy combinations, some evidence has emerged, that low dose valproate in combination therapy carries a lesser risk for MCMs, than for valproate monotherapy, especially with higher doses [
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Perucca E.
      • et al.
      Dose-dependent teratogenicity of valproate in mono-and polytherapy.
      ]. Where valproate does need to be taken the registries have not demonstrated that the timing of administrations or the formulation of valproate reduces the risk for MCM [
      • Mawhinney E.
      • Campbell J.
      • Craig J.
      • Russell A.
      • Smithson W.
      • Parsons L.
      • et al.
      Valproate and the risk for congenital malformations: is formulation and dosage regime important?.
      ].
      Likewise peri-conceptual folate [
      • Morrow J.I.
      • Hunt S.J.
      • Russell A.J.
      • Smithson W.H.
      • Parsons L.
      • Robertson I.
      • et al.
      Folic acid use and major congenital malformations in offspring of women with epilepsy: a prospective study from the UK Epilepsy and Pregnancy Register.
      ] has not been shown to confer any additional protection against AED induced MCMs, although there are reports that pre-conceptual folate use is associated with higher verbal outcomes, especially for infants exposed to valproate [
      • Meador K.J.
      • Baker G.A.
      • Browning N.
      • Cohen M.J.
      • Bromley R.L.
      • Clayton-Smith J.
      • et al.
      Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study.
      ]. Whether folate use reduces foetal loss in WWE remains uncertain. In a recent EURAP report the main contributors towards foetal loss were a history of parental MCMs and use of AEDs in combination [
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.J.
      • Lindhout D.
      • Perucca E.
      • et al.
      Antiepileptic drugs and intrauterine death. A prospective observational study from EURAP.
      ].
      Possibly as a result of the above findings and their widespread dissemination, various published data now demonstrate shifts in prescribing habits [
      • The EURAP Study Group
      Utilization of antiepileptic drugs during pregnancy: comparative patterns in 38 countries based on data from the EURAP registry.
      ], with less teratogenic AEDs, such as lamotrigine and levetiracetam being favoured and more teratogenic agents such as valproate becoming less prescribed. Over time carbamazepine use has also fallen in WWE. This probably reflects a number of reasons to include more choice, issues with tolerability and because of issues related to short-term and long term use of enzyme inducing AEDs.
      Data have also shown much more reassuring results for seizure control during pregnancy. EURAP demonstrated in 3784 prospectively followed pregnancies that 67% were free from seizures during the entire pregnancy. Of those that had seizures, 16% had a worsening of control, 12% a reduction in seizures frequency as pregnancy progressed, with the remainder having an unchanged seizure frequency [
      • Battino D.
      • Tomson T.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Sabers A.
      • et al.
      Seizure control and treatment changes in pregnancy: observations from the EURAP epilepsy pregnancy registry.
      ]. Differences between AEDs were noted, with treatment with lamotrigine treatment being associated with more seizures and generalised seizures. For status epilepticus in pregnancy, EURAP reported its occurrence in 0.6% of 3806 pregnancies. In contrast to earlier reports there were no maternal deaths and only one adverse foetal outcome, not related to the timing of status epilepticus.

      1.4 Extension of the registries

      While lagging behind the study of MCMs, the effects of AEDs on cognitive development and neurodevelopment have been improving over the last 25 years [
      • Bromley R.
      The treatment of epilepsy in pregnancy: the neurodevelopmental risks associated with exposure to antiepileptic drugs.
      ]. This has been made possible by co-operation between groups of researchers, usually working as part of large, widely disseminated teams often spanning national boundaries and occasionally working alongside those maintaining the pregnancy registries. Successful examples are the US and UK Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) group [
      • Baker G.A.
      • Bromley R.L.
      • Briggs M.
      • Cheyne C.P.
      • Cohen M.J.
      • García-Fiñana M.
      • et al.
      IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study.
      ], and the Liverpool and Manchester Neurodevelopmental Group working in collaboration with the United Kingdom and Ireland Epilepsy and Pregnancy Register (UKIEPR).
      Information suggests that cognitive development is impaired and neuro-developmental disorders, such as autistic spectrum disorders, to include autism and Asperger’s syndrome and attention deficit hyperactivity disorder, are more frequent in the offspring of WWE, especially those exposed to AEDs [
      • Baker G.A.
      • Bromley R.L.
      • Briggs M.
      • Cheyne C.P.
      • Cohen M.J.
      • García-Fiñana M.
      • et al.
      IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study.
      ,
      • Christensen J.
      • Grønborg T.K.
      • Sørensen M.J.
      • Schendel D.
      • Parner E.T.
      • Pedersen L.H.
      • et al.
      Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism.
      ,
      • Bromley R.
      • Weston J.
      • Adab N.
      • Greenhalgh J.
      • Sanniti A.
      • McKay A.J.
      • et al.
      Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child.
      ]. Like MCMs, the risks are greatest for valproate, for which it is estimated that potentially up to 20–30% of exposed infants will be adversely affected. While there would also appear to be a dose effect, this is much less clear, especially in terms of any cut off points and magnitude of effect [
      • Baker G.A.
      • Bromley R.L.
      • Briggs M.
      • Cheyne C.P.
      • Cohen M.J.
      • García-Fiñana M.
      • et al.
      IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study.
      ].
      For other AEDs such as carbamazepine, lamotrigine and levetiracetam, while outcome data are less concerning more information is needed before the effects of these AEDs can be confidently stated (see Table 3). Preliminary data would however indicate that these are likely safer alternatives than valproate.
      Table 3Summary of neurodevelopmental data following prenatal exposure to antiepileptic drugs
      • Meador K.J.
      • Baker G.A.
      • Browning N.
      • Cohen M.J.
      • Bromley R.L.
      • Clayton-Smith J.
      • et al.
      Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study.
      ,
      • Bromley R.
      The treatment of epilepsy in pregnancy: the neurodevelopmental risks associated with exposure to antiepileptic drugs.
      ,
      • Baker G.A.
      • Bromley R.L.
      • Briggs M.
      • Cheyne C.P.
      • Cohen M.J.
      • García-Fiñana M.
      • et al.
      IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study.
      ,
      • Christensen J.
      • Grønborg T.K.
      • Sørensen M.J.
      • Schendel D.
      • Parner E.T.
      • Pedersen L.H.
      • et al.
      Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism.
      ,
      • Bromley R.
      • Weston J.
      • Adab N.
      • Greenhalgh J.
      • Sanniti A.
      • McKay A.J.
      • et al.
      Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child.
      .
      Anti-epileptic drug prenatal exposureNeuro-developmental data available
      Sodium valproateValproate is the most consistent AED, across the studies, with an increased risk of adverse cognitive outcomes. The NEAD study has shown that after controlling for confounders the mean IQ at 6 years of age was 8–11 points lower in children exposed to prenatal valproate, compared to carbamazepine, lamotrigine or phenytoin. The adverse cognitive profile appears to be dose related. Less than 1000 mg/day had a similar outcome to other AED exposed children. Even in children exposed to <800 mg/day despite similar IQ scores, they had reduced verbal abilities, and required more educational interventions. A Cochrane review has determined that the reduction in IQ is enough to influence later life educational achievements and occupational potential.
      CarbamazepineCarbamazepine is one of the most well studied of the AEDs in pregnancy from a neurocognitive perspective. IQ appears to be comparable in school aged children to controls, as well as children exposed to lamotrigine. With regards to specific skills the NEAD study raised possibility of dose relationship with poorer verbal and motor skills.
      LamotrigineStudies of global neurodevelopment carried out to date are relatively limited, but all 4 studies show that lamotrigine exposed childred are comparable to controls in terms of global neurodevelopment and adaptive behaviour. It is still not clear if there is any specific effects on fine motor skills, and language. With regards language there are conflicting results from small studies, with a questionaire study suggesting some increased difficulty with sentence structure at 36 months. There are no published comparisons with levetiracetam. No dose effect on cognition has been demonstrated.
      LevetiracetamLimited provisional data exist. The longest data is from a series of 53 children having been followed up until 3–4 years of age. Levetiracetam was found to be similar to controls in terms of development and language, and other cognitive functions. No dose effect has been identified at this stage.
      TopiramateOne study detailing 9 children is available, and clearly is not sufficient to base any firm recommendations on. Further studies are required.
      After pregnancy, the infant can still be exposed to AEDs via breastmilk [
      • Meador K.J.
      • Baker G.A.
      • Browning N.
      • Cohen M.J.
      • Bromley R.L.
      • Clayton-Smith J.
      • et al.
      Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years.
      ]. Whilst this has been considered a low dose exposure and not significant enough to cause harm, reassuring prospective data have emerged to indicate no abnormal developmental consequences of breast feeding in children followed up to 6 years of age.
      A recent meta-analysis [
      • Viale L.
      • Allotey J.
      • Cheong-See F.
      • Arroyo-Manzano D.
      • Mccorry D.
      • Bagary M.
      • et al.
      Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis.
      ] has drawn attention to a small but significant association of epilepsy, AED use and adverse outcomes in pregnancy. With increased odds of spontaneous miscarriage, antepartum haemorrhage, hypertensive disorders, induction of labour, caesarean section, preterm birth, and fetal growth restriction, the authors concluded that the pregnancy registries should pay attention to the obstetrical outcomes with further work to study the effects of seizure control, individual AEDs and their doses on obstetrical outcomes.

      1.5 Changing focus

      The importance of establishing how epilepsy and pregnancy interact has been manifest in a number of areas. In regards to the amount of published research, a PUBMED search for the terms “epilepsy” and “pregnancy” revealed an increasing number of citations with 85 in 1991 and 156 in 2015. In addition the integration of sessions at scientific conferences dedicated to topics relating to issues surrounding epilepsy and pregnancy has become commonplace, with for example a special interest group for the pregnancy registries having been established as part of the American Epilepsy Society annual meeting.
      The clinical approach to women with epilepsy in pregnancy has also evolved. While it may have initially seemed that the focus was more on the foetus than the WWE there is generally now more balance between foetal and maternal considerations. One key element of this is the understanding of the over-representation of WWE in cases of maternal mortality. The recent MBRRACE-UK confidential enquiry report [

      Maternal, Newborn and Infant Clinical Outcome Review Programme. MBRRACE. Saving lives, improving mothers’ care lessons learned to inform future maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2009–2012. Available at: https://www.npeu.ox.ac.uk/downloads/files/mbrrace-uk/reports/Saving%20Lives%20Improving%20Mothers%20Care%20report%202014%20Full.pdf [last accessed 23.11.15].

      ] into maternal deaths identified 14 cases of maternal mortality in WWE between 2009 and 2012. Of these twelve deaths were considered due to Sudden Unexplained Death in Epilepsy (SUDEP) and two from drowning. Of concern and showing that there is still significant room for improvement, only two had apparently received pre-conceptual counselling, seven had been seen during their pregnancy by someone with knowledge of epilepsy, and only three had controlled epilepsy before pregnancy.
      The risk of SUDEP may be linked to drug choice in WWE, with lamotrigine appearing to be associated with an increased risk in a case-control study involving 26 cases of SUDEP [
      • Aurlien D.
      • Larsen J.P.
      • Gjerstad L.
      • Taubøll E.
      Increased risk of sudden unexpected death in epilepsy in females using lamotrigine: a nested, case-control study.
      ]. The incidence of SUDEP in those using lamotrigine was estimated 2.5 per 1000 patient years and was significantly higher than the women not using lamotrigine at 0.5 per 1000 patient years. For WWE, for whom lamotrigine is often a favoured AED, this raises concerns, especially since serum lamotrigine levels may fall significantly during pregnancy [
      • Pennell P.B.
      • Peng L.
      • Newport D.J.
      • Ritchie J.C.
      • Koganti A.
      • Holley D.K.
      • et al.
      Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency.
      ]. It is clear that certain monotherapies are associated with higher rates of breakthrough seizures, most notably for lamotrigine and oxcarbazepine. This may in part be related to the increased clearance of these AEDs in pregnancy. The optimal monitoring frequency, and dose escalation strategy to prevent seizures have yet to be fully determined. It is hoped that the EMPIRE study will answer these questions.

      1.6 Improving services

      As part of an increased focus on pregnancy related issues the need to be able to offer services that can provide pre-conceptual counselling at the time of diagnosis and at intervals over the course of treatment and especially before conception is now considered part of good epilepsy care. Joint obstetric and epilepsy clinics have also been integrated into routine care in many neurology units and are now considered to be a standard component of services provided to WWE. These have been shown to improve how information is disseminated to patients. They are also a useful focus for research. Such is there importance, not only for the health of the baby but for the mother that they are now widely promoted, for example in the MBRRACE-UK report 2015 [

      Maternal, Newborn and Infant Clinical Outcome Review Programme. MBRRACE. Saving lives, improving mothers’ care lessons learned to inform future maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2009–2012. Available at: https://www.npeu.ox.ac.uk/downloads/files/mbrrace-uk/reports/Saving%20Lives%20Improving%20Mothers%20Care%20report%202014%20Full.pdf [last accessed 23.11.15].

      ]. Performing detailed assessments of foetal anatomy at eighteen to twenty weeks gestation to detect MCMs has also been stressed, with targets having been set for how often particular MCMs should be detectable.
      In addition, information for WWE and those treating them is now much more readily available both directly from health care providers and organisations as well as through the third sector, to include international epilepsy organisations such as the ILAE [
      • Tomson T.
      • Marson A.
      • Boon P.
      • Canevini M.P.
      • Covanis A.
      • Gaily E.
      • et al.
      Valproate in the treatment of epilepsy in girls and women of childbearing potential.
      ] and local bodies such as the National Society for Epilepsy in the UK [

      National Society for Epilepsy. Pregnancy and parenting. Available at: https://www.epilepsysociety.org.uk/pregnancy-and-parenting#.V8HgZSMrLLY [last accessed 27.08.16].

      ]. Alongside all of the other developments, the environment in which WWE are now managed has changed significantly with ready access to accurate and accessible information. This is a far cry from the start of the 1990s and before the birth of the electronic information age. Information on how to manage AEDs in pregnancy, in particular for those women using lamotrigine is available as it is for how to manage the risks to the mother from seizures, and minimise the risk of SUDEP.

      1.7 Guidelines/directives

      Guidelines have been developed both at an international level through for example the ILAE and at a national and local level (Table 4) [
      • Crawford P.
      • Appleton R.
      • Betts T.
      • Duncan J.
      • Guthrie E.
      • Morrow J.
      • et al.
      Best practice guidelines for the management of women with epilepsy.
      ,
      • Tomson T.
      • Marson A.
      • Boon P.
      • Canevini M.P.
      • Covanis A.
      • Gaily E.
      • et al.
      Valproate in the treatment of epilepsy in girls and women of childbearing potential.
      ,

      National Institute for Health and Clinical Excellence. Epilepsies: diagnosis and management (clinical guideline 137). Available at: www.nice.org.uk/guidance/cg137; 2012 [last accessed 26.10.16].

      ,
      • Harden C.L.
      • Meador K.J.
      • Pennell P.B.
      • Hauser W.A.
      • Gronseth G.S.
      • French J.A.
      • et al.
      Management issues for women with epilepsy-focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
      ,
      • Harden C.L.
      • Pennell P.B.
      • Koppel B.S.
      • Hovinga C.A.
      • Gidal B.
      • Meador K.J.
      • et al.
      Management issues for women with epilepsy-focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
      ,
      • Harden C.L.
      • Hopp J.
      • Ting T.Y.
      • Pennell P.B.
      • French J.A.
      • Hauser W.A.
      • et al.
      Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.
      ,
      • Scottish Intercollegiate Guidelines Network
      Diagnosis and management of epilepsy in adults.
      ]. The guidance contained in these stands in stark contrast to the situation at the start of the 1990s were there was more of a tendency to leave decisions to individual clinicians. This is no more evident than for the use of valproate in WWE of childbearing years. Instructions from the European Medicines Agency (EMA) [

      European Medicines Agency. Assessment report. Procedure under article 31 of directive 2001/83/EC resulting from pharmacovigilance data. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Valproate_and_related_substances_31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500177352. pdf [last accessed 26.08.16].

      ] and in the UK from the Medicines & Healthcare products Regulatory Agency (MHRA) [

      Medicines and Healthcare Products Regulatory Agency. Medicines related to valproate: risk of abnormal pregnancy outcomes. Available at: https://www.cas.dh.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=102287 [last accessed 26.08.16].

      ] now provide clear details not only on how valproate should be prescribed but who should be doing so. In January 2015 the MHRA published advice that in view of the risks for MCMs and neurodevelopmental delay that valproate should not be used in WWE of childbearing years unless other alternatives have been ineffective or not tolerated [

      Medicines and Healthcare Products Regulatory Agency. Medicines related to valproate: risk of abnormal pregnancy outcomes. Available at: https://www.cas.dh.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=102287 [last accessed 26.08.16].

      ]. For those for whom valproate was to be commenced it was advised that this should only be done by a clinician with experience in treating epilepsy and that the risks and benefit of treatment should be considered not only when it was being started but at subsequent reviews, especially when a girl reaches puberty or when pregnancy was being planned. As part of this guidance, clear information has been produced for WWE and those caring for them, including written consent documentation to be used with women about to commence valproate. Further to the recent publication of SIGN guidelines [
      • Scottish Intercollegiate Guidelines Network
      Diagnosis and management of epilepsy in adults.
      ], the UK now has a Greentop guideline [

      Green-top guideline no. 68. Epilepsy in pregnancy. Available at: https://www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg68_epilepsy.pdf; 2016 [last accessed 26.08.16].

      ] endorsed and developed by the Royal College of Obstetrics and Gynaecology to allow uniform high standard care amongst relevant practitioners.
      Table 4Examples of clinical guidelines making reference to WWE.
      Clinical practice guidelines with emphasis on women with epilepsy
      Crawford et al.
      • Crawford P.
      • Appleton R.
      • Betts T.
      • Duncan J.
      • Guthrie E.
      • Morrow J.
      • et al.
      Best practice guidelines for the management of women with epilepsy.
      NICE

      National Institute for Health and Clinical Excellence. Epilepsies: diagnosis and management (clinical guideline 137). Available at: www.nice.org.uk/guidance/cg137; 2012 [last accessed 26.10.16].

      AES/AAN
      • Harden C.L.
      • Meador K.J.
      • Pennell P.B.
      • Hauser W.A.
      • Gronseth G.S.
      • French J.A.
      • et al.
      Management issues for women with epilepsy-focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
      ,
      • Harden C.L.
      • Pennell P.B.
      • Koppel B.S.
      • Hovinga C.A.
      • Gidal B.
      • Meador K.J.
      • et al.
      Management issues for women with epilepsy-focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
      ,
      • Harden C.L.
      • Hopp J.
      • Ting T.Y.
      • Pennell P.B.
      • French J.A.
      • Hauser W.A.
      • et al.
      Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.
      SIGN
      • Scottish Intercollegiate Guidelines Network
      Diagnosis and management of epilepsy in adults.
      Greentop guidelines

      Green-top guideline no. 68. Epilepsy in pregnancy. Available at: https://www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg68_epilepsy.pdf; 2016 [last accessed 26.08.16].

      1.8 Future directions

      In spite of significant advances in knowledge surrounding all aspects of the management of WWE, of childbearing years, there is still much to be learned. Data for the risks of MCMs for most of the newer AEDs are still for the most part unavailable. The risks of the more common polytherapy combinations, while starting to be explored, also require further study. Likewise the long term effects on cognitive development and the neurobehavioural impact of AEDs of in utero exposure need to be elucidated.
      Guidance on how to best manage WWE before, during and after pregnancy also needs to be periodically agreed, based on best current knowledge. It is however clear that improving the management of WWE, during their childbearing years and improving outcomes in women and their offspring is likely to continue to be one of the most considered aspects of epilepsy care. In time it is hoped that there will be more answers to most of the on-going questions and debates. How to speed this process up does need to be the focus of concerted efforts. As a starting point in resource rich nations, especially those with already well-developed methods for collecting the relevant information, mandatory registration to pregnancy registries should be considered, with appropriate funding secured to allow the successful running of these and the completion of related studies [
      • Meador K.J.
      • Loring D.W.
      Developmental effects of antiepileptic drugs and the need for improved regulations.
      ]. There is still far too long a lag from the introduction of all drugs, AEDs included, to an understanding of the risks of exposure, before and during pregnancy. How to standardise studies of cognitive development and neurodevelopment and make studies possible that identify signals of concern, which measure clinically relevant differences between AEDs are also needed. Bearing in mind how laborious and costly these studies are, having studies that are achievable and generalizable is crucial. Further exploration of how to identify those women at risk for adverse outcomes, to include the discovery of biomarkers associated with pharmacogenetic influences on teratogenicity would be useful as would information on how to minimise any risks. If realised not only could any at risk AED be avoided, but equally as important its use could continue, where there were no other alternatives.

      2. Conclusions

      Except for the impact of imaging in epilepsy, it might be argued that over the last 25 years that it is the management of WWE of childbearing years that has undergone the biggest transformation. From a position where the research which had been done, while important, had for the most part had little impact on how most WWE were managed in clinical practice, to a position where the issues relevant for WWE now form a fundamental part of clinical practice it seems clear that the environment has changed utterly. There is now an expectation that everyone from trainees through to the most senior member of the treating team are up to date with the relevant information and guidelines and the results of contemporaneous research and that this information is presented to WWE, so that they can make informed choices.
      For many WWE it is concern about future pregnancies that is their prime consideration in determining treatment choices. It could however be argued that the decision making process has become even more difficult. From a position, where little information was being shared we now have a situation where WWE may seem that they are being bombarded with information, which may be difficult to fully appreciate, especially presented alongside the many unknowns, which we are obliged to divulge. This has the potential to make seemingly straightforward therapeutic decisions difficult. It is unlikely however that there are too many voices who would argue that the position at the start of the 1990s was preferable to that which currently prevails. It is also likely the case that without the rise of the registries and the endeavours of individual groups of researchers that the current position and push for ever more answers would have been possible.

      Conflict of interest statement

      Dr J. Craig is principal investigator of the United Kingdom and Ireland Epilepsy and Pregnancy Register and a member of the Central Project Commission of EURAP—An International Epilepsy and Pregnancy Registry. Dr M. Kinney has no declared conflicts of interest, financial or personal.

      Author’s contributions

      John Craig: Article conception and writing of the manuscript.
      Michael Kinney: Article conception and writing of manuscript.

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