Epilepsy is the most common neurological disease to be found during pregnancy, and has a significant risk of morbidity and mortality to the woman and the developing fetus (Borgelt et al, 2016; Knight et al, 2017). It is characterised by seizures, which cause a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain (Fisher et al, 2014). The subsequent effect of seizures and treatment prescribed to reduce these symptoms is likely to have a significant impact on health-related quality of life for those with epilepsy and their families (Michaelis et al, 2018). Personalised treatment and management is essential, and requires calculation of risks and benefits of diagnostic and therapeutic options, which are frequently readjusted throughout a person's life (Voinescu and Pennell, 2017). Prevention of seizures and optimisation of treatment therefore should be paramount in pre-conception and pregnancy planning for all women with epilepsy of childbearing potential. Despite this recommendation, maternity mortality reports in the UK have repeatedly identified a high rate of maternal death in women with epilepsy who did not receive pre-conception counselling and, subsequently, did not have the involvement of an epilepsy nurse or specialist in their pregnancy care (Kelso and Willis, 2014).
This article explores the complexities of care provision for women with epilepsy and includes recommendations to optimise maternity health outcomes. This includes the latest recommendations from the Medicines and Healthcare products Regulatory Agency (MHRA) for women taking valproate medicines (Table 1) (MHRA, 2018). Increasing understanding of the risks associated with epilepsy and its treatment will positively influence the contribution that midwives can make in risk awareness and reduction strategies.
| Valproate medicines (Epilim▾, Depakote▾ Convulex▾, Episenta▾, Epival▾, Kentlim▾, Orlept▾, Syonell▾, and Valpal▾) Valproate is licensed for epilepsy and bipolar disorder and prescribed off-license for migraine prophylaxis. Valproate medicines are contraindicated in women and girls of childbearing potential unless conditions of the pregnancy prevention programme are met (MHRA, 2018) |
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The Pregnancy Prevention Programme is a system of ensuring all female patients taking valproate medicines: |
| Babies born to mothers who take valproate medicines during pregnancy have a 30–40% risk of developmental disability and a 10% risk of birth defects |
| Birth defects seen when mothers take valproate during pregnancy include: spina bifida, facial and skull malformations (including cleft lip and palate) and malformations of the limbs, heart, kidney, urinary tract and sexual organs |
| In women who take valproate while pregnant, about 3–4 children in every 10 may have developmental problems. The long-term effects are not known. The effects on development can include: being late in learning to walk and talk; lower intelligence than other children of the same age; poor speech and language skills; and memory problems |
| Children exposed to valproate in utero are more likely to have autistic spectrum disorder or develop symptoms or attention deficit hyperactivity disorder (ADHD). |
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| The Medicines and Healthcare products Regulatory Agency (MHRA) actively encourages patients and healthcare professionals (including midwives) to report suspected adverse drug reactions including in the baby or child through the Yellow Card Scheme |
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| Midwives have a responsibility to obtain the latest valproate information as this is an iterative regulatory process |
Risk factors in women with epilepsy
UK prevalence data from population-based studies estimate that between 0.5-1% pregnancies occur in women with epilepsy (Edey et al, 2014; Kapoor and Wallace, 2014). Given that women with epilepsy were found to have a significantly lower fertility rate over the age of 25 than women without epilepsy (Farmen et al, 2016), they are over-represented in indirect maternal death rate statistics (Knight et al, 2017). It is estimated the risk of death in women with epilepsy is 10 times higher than in women without epilepsy (Edey et al, 2014). Where recorded, the highest risk of death appears to be in the third trimester or following birth, miscarriage or termination of pregnancy (Kapoor and Wallace, 2014; Kelso et al, 2017).
Specialist pre-conception and pregnancy services for women with epilepsy are fragmented throughout the UK (Joint Epilepsy Council of the UK and Ireland, 2011). This is likely to be a reflection of inter-site NHS variability in epilepsy care covering the entire care pathway, including inadequate provision of pre-conception counselling (Dixon et al, 2015). Failure to receive pre-conception counselling is contrary to recommendations for women with epilepsy to be reviewed by specialist services before planning pregnancies, and may contribute to unplanned pregnancy (Scottish Intercollegicate Guidelines Network (SIGN), 2015). Despite a small qualitative UK study identifying that women with epilepsy experiencing unplanned pregnancies seemed to be more vulnerable to primary care deficiencies; social disadvantage and misunderstandings about epilepsy and pregnancy (Pashley and O'Donoghue, 2009), robust quantitative data regarding intention to conceive in women with epilepsy is lacking in the UK. This is concerning, as retrospective data collated from a USA web-based survey of 1144 women with epilepsy identified that the majority of women with epilepsy (78.9%) reported experiencing at least one unintended pregnancy and that 65% of all pregnancies reported were unintended (Herzog et al, 2017). This was more likely to occur in women with epilepsy who were younger, Hispanic or of an ethnic minority. Those using oral forms of hormonal contraception and taking enzyme inducing anti-epileptic drugs (AEDs) were significantly more likely to have a contraception failure than women with epilepsy using non-oral forms of contraception (Herzog et al, 2017). These findings are likely to reflect contraception failure due to enzyme-inducing AEDs causing sub-therapeutic oestrogen and progesterone levels (The Faculty of Sexual and Reproductive Healthcare, 2018).
There are multi-professional guidelines on care of pregnant women with epilepsy but no standardised management plan (Royal College of Obstetricians and Gynaecologists (RCOG), 2016a). This is because women with epilepsy are not a homogenous group: a proportion of women may be misdiagnosed; others will have a diagnosis but will not take AEDs; others will be taking an enzyme-inducing AED; a proportion will be taking non-enzyme-inducing AEDs; others will be having regular seizures and many will be seizure-free. Women with epilepsy are not always regarded as high-risk by obstetric and midwifery teams (Kelso and Willis, 2014). Without correct identification, women will not be alerted about risk-reducing strategies and there will be no emphasis for diligent medical and nursing support during hospital admissions. Midwives may face a gap in knowledge about caring for women with epilepsy, which may be a contributing factor to the substandard care provision identified in the MBRRACE-UK report (Knight et al, 2017).
Learning from MBRRACE-UK
Sudden unexpected death in epilepsy (SUDEP) (Box 1) continues to be the major cause of death in maternities, with seven out of eight women with epilepsy dying as a result of SUDEP and one woman drowning (Knight et al, 2017). Features of the women who died as identified within the MBRRACE-UK report (Kelso et al, 2017) included uncontrolled seizures, lack of effective pre-conception counselling, discontinuance of AEDs, poor access to specialist care during pregnancy, non-attendance of appointments, socially complex lives or those who were vulnerable. Socio-biological factors included poor English language skills, forensic issues, domestic abuse, contact with social services, other children in care, and learning disability (Kelso et al, 2017). The reviewers identified that improvements in care would have made a difference to 52% of women with epilepsy (Kelso et al, 2017). Risk reduction strategies are therefore an important part of epilepsy management (Watkins et al, 2018). Midwives may be integral in the identification of the risk of maternal mortality in vulnerable women with epilepsy. Through the provision of health education and holistic, flexible support, midwives can work with these women with epilepsy and their families to provide risk reduction strategies.
A lack professionals taking responsibility for caring for women with epilepsy, fragmented services and inefficient or poor communication with women and the wider multidisciplinary team were also main contributors to these deaths (Kelso et al, 2017). If a first seizure or a new presentation of seizures occurs during pregnancy, women should receive an emergency assessment by a neurologist and an obstetric physician/obstetrician to exclude other causes, including eclampsia. Reinforcement of safety advice, especially around water, sleeping and cooking, seizure first aid and care of the infant should be provided at each midwifery encounter (RCOG, 2016a).
Seizure freedom is the most important preventative measure for SUDEP (Mclean et al, 2017). The pregnancy continuum can be an unpredictable time for seizure control; therefore, it is important for midwives to include women in the risk assessment process and ask them to contact members of their multidisciplinary care team if there is a change in their seizure control. This proactive midwifery approach to risk assessment will increase maternal autonomy and empowerment. Encouraging women with epilepsy to download a SUDEP self-risk assessment and communication tool will assist with this process (Box 2).
Diagnostic uncertainty
Women with epilepsy should be provided with a diagnostic reassessment and treatment review before planning pregnancy, as part of the pre-conception support continuum (RCOG, 2016a). A systematic review determined the frequency of a false positive diagnosis of epilepsy was between 2% and 71% (Xu et al, 2016). The frequent causes of misdiagnosis of epilepsy were syncope (a temporary loss of consciousness usually related to insufficient blood flow to the brain) and non-epileptic seizures (events that resemble epileptic seizures but are not due to abnormal electrical brain discharges; causation is physiological or psychological). In addition to the possible impact on legal driving status, employment and health-related quality of life; this has serious implications if misdiagnosis predisposes a developing fetus to unnecessary AED exposure. With the potential of syncopal and non-epileptic seizures increasing in pregnancy, there needs to be a prompt reassessment of the diagnosis to prevent unnecessary escalation of AEDs. If there is diagnostic or treatment uncertainty, women should be fast-tracked for epilepsy specialist assessment (Morley, 2016a).
Improving antenatal care provision
Epilepsy is an unpredictable condition necessitating a multidisciplinary, joined-up approach to care provision (Morley, 2016a; 2016b; Bhatia, 2017). Although adverse outcomes of pregnancy are sometimes unavoidable, research suggests more can be done to improve pregnancy care provision (Kelso et al, 2017).
Bhatia et al (2017) recommend that a thorough epilepsy history should be taken at the first antenatal appointment and that women should be fast-tracked for timely planning of their pregnancy. As most antenatal booking forms are standardised checklists, midwives may not have the knowledge or prompts to instigate this vital conversation. Consequently, the use of the author's peer-reviewed maternity epilepsy toolkit (Morley, 2018a) will enable the midwife to collate a concise clinical history and allows sharing of risk minimisation information from a range of epilepsy patient support groups (Table 2). Many NHS Trusts have adopted its use, and Hugill and Meredith (2017) support its amalgamation of guidance and information from community, maternity and epilepsy services to embrace multi-professional working. However, without investigating its effectiveness, the intended influence on improving maternal and fetal outcome in women with epilepsy will be unknown. Current qualitative research into its use at the booking appointment will help determine midwives' experience in clinical practice; these data will contribute to its continued development.
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| Advise urgent medical review if vomiting is affecting AED ingestion |
| Discuss adherence with AEDs at every midwifery contact; further information can be obtained from Epilepsy Action (2017) |
| Advise women to avoid sleeping alone, where possible, due to increased risk of SUDEP |
| Advise women to maintain a seizure diary |
RCOG: Royal College of Obstetricians and Gynaecologists; AED: anti-epileptic drugs; SUDEP: sudden unexpected death in epilepsy
Prioritising referrals
The majority of women with epilepsy will be treated as high-risk. However, the RCOG Green-top Guideline (RCOG, 2016a) recommends that women with epilepsy can be managed as low-risk (providing there are no other maternal/fetal factors which would put them in a high-risk category), if they have a history of a childhood syndrome and reached adulthood, or have been seizure-free for at least 10 years and off AEDs for at least 5 years (RCOG, 2016a). A midwife conducting the booking assessment would not be expected to determine risk category; instead it is recommended this assessment is personalised and made by a medical practitioner specialising in epilepsy (RCOG, 2016a). This specialist could then identify the symptoms indicative of ongoing untreated seizures, or risk factors that are due to a symptomatic cause or epilepsy syndrome, that could predispose the women to seizure recurrence. All women with epilepsy, or women with a history of seizures (the cause of which is undetermined), should therefore be referred for neurological and obstetric assessment to enable a multidisciplinary approach to this review.
The MBRRACE report recommends that antenatal services identify an epilepsy nurse to integrate into routine antenatal service (Kelso and Willis, 2014); however, they are unlikely to be present for the booking appointment. RCOG recommends that an evaluation should be made at subsequent visits of the mother's wellbeing and ability to cope; memory, concentration and sleep; AED adherence, behaviour and management; and seizure frequency and type (RCOG, 2016a). Without incorporating these assessments into the booking appointment, it could be challenging for the midwife to determine if the woman needed urgent support from the multidisciplinary team. With this in mind, the maternity epilepsy toolkit (Morley, 2018a) can be used to guide the user through a checklist, with the aim of identifying women with epilepsy most at risk of a poor maternal or fetal outcome (Box 3). Following completion of the toolkit, midwives are encouraged to fast-track referrals appropriately and make early contact with interpreters or professionals from substance misuse, mental health, learning disability or social service teams where indicated.
Anti-epileptic drug adherence
Urgent action is recommended when pregnant women with epilepsy have discontinued AEDs without specialist advice (Knight et al, 2017). Poor adherence to AEDs is a recurring feature associated with increased mortality, morbidity and healthcare costs (Al-Aqeel, 2017). A UK observational study demonstrated that women with epilepsy were twice as likely to stop receiving AEDs compared to non-pregnant women (Man et al, 2012). Non adherence with AEDs is frequently due to the misconception that all AEDs are more harmful to the fetus than seizures (Voinescu and Pennell, 2017). The upgrading of warnings about sodium valproate pregnancy exposure may be a further contributory factor to this behaviour (MHRA, 2018) (Table 1). Women with epilepsy have died because they were not taking AEDs during pregnancy; this includes women who formerly took sodium valproate (Kelso et al, 2017).
Midwives therefore need to be proactive in making sensitive inquiries into women's AED adherence behaviour at each midwifery encounter. If negative adherence with AEDs is disclosed, immediate referral should be made to a neurologist/epilepsy specialist nurse or specialist epilepsy midwife to review the woman's epilepsy and seizure control. A specialist epilepsy midwife with additional qualifications in non-medical prescribing can provide appropriate treatment recommendations. Behavioural interventions such as intensive reminders appear to provide more favourable effects on adherence than simplified dose regimen; patient instruction and counselling; close monitoring; rewards for success; family or psychological therapy or telephone follow-up (Al-Aqeel, 2017). Health professionals caring for women with epilepsy should be prepared to discuss and sensitively challenge a woman's decision to be non-adherent with AEDs, while maintaining trust and respect. If adherence with AEDs is compromised due to nausea and vomiting, women should be seen urgently by an obstetrician for assessment. Guidelines to determine management of first trimester nausea and vomiting do not mention the dilemmas for women with epilepsy with ingestion of AEDs affecting adherence (RCOG, 2016c). In contrast, the epilepsy in pregnancy guidance advises that nausea and vomiting occurring either during labour or the postnatal period should be treated and considerations be given for parenteral administration of AEDs if there is no oral intake (RCOG, 2016a). If women with epilepsy are admitted to hospital at any stage of pregnancy, or readmitted postnatally, single rooms should be avoided unless there is continuous observation by a partner, carer or nursing staff (RCOG, 2016a).
Midwives need to be mindful that, in addition to perceived harm to the unborn baby, non-adherence with AEDs has been found to be associated with depression or anxiety, poor medication management strategies, recent seizures, frequent medication dosing times and poor doctor-patient relationship (O'Rourke and O'Brien, 2017). As well as having a negative effect on quality of life, poor AED adherence places the woman at an increased risk of seizures and will compromise her eligibility to drive (Driver and Vehicle Licensing Agency, 2018).
Teratogenic risks of anti-epileptic drugs
Despite being the mainstay of epilepsy treatment, AEDs are known teratogens. The most common conditions associated with exposure are congenital heart disease, cleft lip and palate, urogenital abnormalities and neural tube defects (Bromley et al, 2017; Güveli et al, 2017; Petersen et al, 2017). Petersen et al (2017) obtained data from 240 071 women using the Health Improvement Network and found that sodium valproate was associated with the highest risks for major congenital malformations. Bromley et al (2017) identified lamotrigine and levetiracetam to be the lowest risk AEDs; however, in this study sodium valproate was associated with an even higher risk of major congenital malformations (Table 3). Sodium valproate exposure in pregnancy is associated with reduced IQ levels in children, reduced verbal abilities and an increased risk of autistic spectrum disorder, compared to other AEDs and control groups (Bromley, 2016). Midwives should therefore be vigilant about accessing the latest toolkits for women taking sodium valproate medicines from MHRA (2018) and British National Formulary (BNF) (Joint Formulary Committee, 2018a).
| Study | Medication | Number pregnancies | MCM rate (%) |
|---|---|---|---|
| Petersen et al (2017) | Sodium valproate | 229 | 6.6 |
| Lamotrigine | 357 | 2.7 | |
| Carbamazepine | 334 | 3.3 | |
| No AEDs | 239 151 | 2.2 | |
| Bromley et al (2017) | Valproate | 2565 | 10.9 |
| Lamotrigine | 4195 | 2.3 | |
| Carbamazepine | 4549 | 3.7 | |
| Levetiracetam | 817 | 1.8 | |
| No AEDs | 2154 | 2.5 |
AEDs: anti-epileptic drugs; MCM: major congenital malformation
Reducing the fear of teratogenicity
To reduce maternal anxiety, midwives should reassure women that major congenital malformations are rare (RCOG, 2016a). The risk differs depending on the AED and the prescribed dose (Tomson et al, 2011). Unnecessary anxiety, inadequate treatment and needless termination of pregnancy can result in overestimation of risk by the woman and clinicians (Sanz et al, 2001; Widnes et al, 2012). Midwives are encouraged to advise women to register their pregnancy with the UK Epilepsy and Pregnancy Register (RCOG, 2016a). Women should also be assured of the anonymity of the data collection process and the value that this perspective research has in advising women about teratogenic risks associated with the different AED regimens (RCOG, 2016a).
Folic acid supplementation
RCOG advises that pre-pregnancy folic acid supplementation may be helpful in reducing major congenital malformations and AED-related cognitive deficits (RCOG, 2016a). It is recommended that women with epilepsy taking AEDs are prescribed folic acid 5mg once daily for 3 months pre-conception, which is then continued throughout the first trimester (RCOG, 2016a). There are significant interactions with some AEDs and high doses of folate (Asadi-Pooya, 2015); therefore, women with epilepsy who are taking AEDs should be provided with advice about folate dose by their prescribing doctor or epilepsy specialist.
Seizures during pregnancy
The risk of seizures occurring during pregnancy has been found to be three to four times greater in women whose seizures were active (i.e., not controlled) in the pre-pregnancy year and those who were non-adherent with AEDs in early pregnancy (Vajda et al, 2018). Women with focal epilepsy and those treated with AED polytherapy were found to be more likely to experience seizure occurrence during pregnancy (Vajda et al, 2018). Any women with epilepsy at risk of prolonged seizures or status epilepticus should have an emergency management plan in place—this includes women with epilepsy who are non-adherent with AEDs despite their seizure status.
Midwives are advised to refer women with epilepsy who experience an increased seizure frequency or seizure recurrence urgently to an epilepsy specialist. This change in symptoms may be due to the physiological effects of pregnancy, sleep deprivation, falling AED levels, non-adherence with AEDs and known individual triggers for seizures (RCOG, 2016a). Therefore, it is essential that midwives routinely ask women with epilepsy about seizure occurrence and frequency, and advise them to seek urgent advice from their epilepsy care team if seizures recur or risk factors increase.
Reducing risk factors associated with epilepsy in pregnancy and labour
Midwives are in an optimal position to offer support to women with epilepsy throughout the pregnancy continuum. It is imperative that they become an integral part of the care team to reduce the risk factors associated with this serious, often unpredictable condition. The maternity epilepsy toolkit (Morley, 2018a) signposts midwives to these risks and has been summarised in Table 4.
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AEDs: anti-epileptic drugs
To enable midwives to learn about epilepsy, its treatment and management, the Royal College of Midwives has created an i-module (Morley, 2018b) to improve midwives' confidence in supporting pregnant women and their relatives more effectively as part of a wider multidisciplinary team.
Postnatal advice
Midwives should support women with epilepsy with their choice of infant feeding. Precautions to be taken into account include safety, impact on sleep and AED ingestion by the infant through breast milk. Breastfeeding should be encouraged to optimise nutritional, immunological, developmental and psychological benefits (Meador et al, 2014; RCOG 2016a). In children exposed to lamotrigine, carbamazepine, phenytoin and valproate through breastfeeding, no adverse effects were observed at 3 and 6 years, and breastfed infants demonstrated higher IQ and increased verbal abilities in comparison to AED-exposed infants who were not breastfed (Meador et al, 2014). Based on evidence, mothers should be advised that the risk of adverse cognitive outcomes is not increased in children exposed to AEDs in breast milk (RCOG, 2016a).
For infants who are preterm, jaundiced, have a low birth weight, or if AEDs were commenced late in pregnancy or postnatally, there may be an increased risk of AED toxicity (SIGN, 2015). Parents are advised to report promptly if a breastfed infant appears excessively sleepy or shows potential signs of toxicity, including rash (SIGN, 2015). This is more likely when AEDs are prescribed in high doses or as part of polytherapy. Midwives can obtain evidence-based information about the effects on lactation and breast feeding from LactMed (US National Library of Medicine, 2018).
If the AED was increased during the pregnancy, multi-professional support from the obstetric and neurology team will be required following physiological haemoconcentration, to guide the woman on reducing her AED dosage if she or baby develops adverse effects. Having a care plan in place antenatally will facilitate this process and therefore is included in the maternity epilepsy toolkit (Morley, 2018a).
It is imperative that midwives learn from maternal mortality reports (Knight et al, 2017), as the midwife has a key role in the risk assessment process; is in a position to encourage maternal autonomy and empowerment; can facilitate multi-professional working; and can provide a continuum of holistic care and support to the women with epilepsy and her family.
Women with epilepsy remain at risk of adverse outcomes in the immediate postnatal period and up to one year following birth, miscarriage or termination of pregnancy (Kapoor and Wallace 2014; Kelso et al, 2017). Mindful of this, a postnatal checklist facilitates proactive risk prevention strategies to optimise health outcomes of both the woman and her child (Table 5).
| Obtain informed consent to administer vitamin K (1 mg) IM for baby following delivery if taking AEDs. |
| Babies exposed to AEDs: recommend expert neonatal examination post-birth |
| Advise breastfeeding mothers who take AEDs to alert health professional urgently if baby develops difficulty in feeding, jaundice, a rash or becomes increasingly drowsy |
| Advise women complete Epilepsy Society risk assessment to optimise their safety while in hospital care. Advise showers rather than baths |
| Provide information about reducing risks when caring for children (Epilepsy Action, 2016) |
| Refer to AED postnatal plan for medication advice and encourage woman to alert GP promptly if any changes to medication are made. Advise contacting epilepsy specialist if additional medication support is required. Remind women to take epilepsy medication at prescribed times |
| Where possible, provide postnatal home visits to reduce impact of tiredness on seizure control |
| There should be vigilant monitoring of physical and mental wellbeing. When considering discharging a woman from midwifery care, ensure that the woman knows who to contact in an emergency if there is any deterioration in her seizure control or mental wellbeing |
| Provide contraception advice before discharge from maternity care. Refer to the British National Formulary (Joint Formulary Committee, 2018b) for individual drug advice on interactions with AEDs with hormonal contraception. |
| Where possible, advise women not to sleep alone, due to risk of nocturnal seizures |
| RCOG (2016a) recommends GP prescribes folic acid 5 milligrams once daily if risk of pregnancy/at least 3 months before future planned pregnancy for women taking most AEDs. This is usually continued until 12 weeks' gestation. |
| Ensure women receive the opportunity of flexible support for their epilepsy in the year following birth and before future pregnancies. Arrange urgent postnatal review by neurologist/epilepsy specialist if: |
AEDs: anti-epileptic drugs; RCOG: Royal College of Obstetricians and Gynaecologists
Conclusions
Increasing midwifery knowledge about risk awareness and prevention strategies for women with epilepsy is likely to result in reduced inequalities in multi-professional healthcare provision. Knowledgeable midwives taking the correct actions from the booking appointment and throughout the pregnancy continuum have the potential to empower women with epilepsy, significantly improve their care, and reduce morbidity and mortality rates. Despite the suggested integration of toolkits designed to assist risk assessment and enhance multi-professional care provision, little is known about the influence that their use will have on clinical practice or maternal and neonatal outcomes. To address this gap in knowledge, research is being conducted into midwives' experiences of using a maternity epilepsy toolkit, data from which will inform future modifications of toolkits designed for this process.