Worldwide, epilepsy is thought to affect approximately 1% of people (Grant, 2016). Though subject to various methodological (definitions of disease) and clinical issues (diagnostic criteria) this statistic equates to around 600,000 people having the condition in the UK (Joint Epilepsy Council of the UK and Ireland (JEC), 2011). Current best estimates suggest that 23% (about 139,000) of people diagnosed with the condition and receiving anti-epileptic drugs (AEDs) are women of reproductive age (12–50 years old) (JEC, 2011). This statistic equates to around 2500 pregnancies per year across the UK for women with epilepsy (WWE) (JEC, 2011). Of particular concern for WWE and health professionals are the risks posed to infant health due to tonic-clonic epileptic seizures and the effects of AED regimes (Veiby et al, 2013; Bromley et al, 2014). This article explores maternal and neonatal effects of epilepsy, its management and the use of AEDs for this condition and others for positive pregnancy outcomes. Having a greater understanding of this topic will help midwives appreciate the need for multi-professional and multi-agency working and why the provision of specialist advice and support is important.
Epilepsy pathology and treatments
Epilepsy is a heterogeneous neurological disease caused by abnormal paroxysmal neurological activity originating in the brain (Fisher et al, 2014). People with the condition have a long-term disposition to have epileptic seizures (National Institute of Health Care and Excellence (NICE), 2012; Fisher et al, 2014). Seizures can be characterised by alterations in consciousness, abnormal body movements, and/or behaviours or feelings. Often signs of seizure may be overt or subtle and potentially missed by observers. Impaired consciousness poses a clear safety risk however; the exact symptomology varies depending upon the area of the brain affected. Epilepsy is not a single condition and various classifications exist reflecting a dynamic and complex debate; some suggest that there are more than 40 different seizure types (Berg et al, 2010). Technical descriptions of the epilepsies vary and relate to the type, frequency and duration of seizure, effects, and causes of the condition (Fisher, 2015). Causes are multiple and include traumatic brain injury and blood vessel abnormalities in the brain, but many with the condition have no known causation. Epilepsy has cognitive, psychological and social consequences for those people affected which can extend to their families (Campbell et al, 2014; Grant, 2016; NICE, 2016a). Historically the disease was subject to misunderstandings leading to social injustices. Though this situation improved, myths about epilepsy prevail in modern times and continue to pose upsetting challenges (Grant, 2016).
‘Midwives need to be aware of the nature of comorbidities for women associated with epilepsy and AED use as these can have significant effects on maternal and infant wellbeing. It is important that midwives are mindful of this fact when gathering information about medical history’
Anti-epileptic drugs
For most people, treatment involves careful selection of neuroactive drugs to control the severity of seizures using AEDs. These drugs should be administered at the lowest effective dose which balances symptom control and the severity of side effects. Treatment of seizures with AEDs is a specialist area based upon descriptions and history of seizure activity (ictal phenomenology) and responses to specific drugs or combinations. Explanations of the range of AED dosing regimens and drug combinations are beyond the scope of this article.
The pharmacology of individual and combinations of AEDs are complex and not wholly predictable. For example, branded and generic versions of the same active drug can have different effects in individuals (Joint Formulary Committee, 2017). Midwives need to be cognisant that considerable care should be taken when switching between variants of the same drug or changing prescribing regimes. The general rule in therapy is to begin with the first drug of choice and if this proves ineffective prescribe an alternate drug, and then use drugs in combination. This situation necessitates regular review and adjustment of therapy over time and through the life course reflecting developmental changes in life (e.g. puberty, aging, work–life balance). Compared to men, AED prescribing for women requires greater thought as their menstrual cycles and contraceptive choices can affect the efficacy of AEDs and some contraceptive methods (Zhao et al, 2014; NICE, 2016a; NICE, 2016b).
In pregnancy, additional priorities to minimise fetal exposure to AEDs also feature (Patel and Pennell, 2016). However, these concerns about the effects of AEDs on the developing fetus are not restricted to women with epilepsy alone. AEDs are also used to treat other long-term conditions. These conditions include psychiatric disorders (e.g. bipolar and anxiety disorders) as well as pain syndromes and migraine prophylaxis (Tomson and Battino, 2012). Pregnant women receiving AEDs for non-epileptic disorders carry similar risks for drug effects and harm and these might be compounded by comorbidities. It is important that midwives are mindful of this fact when gathering information about medical history.
Epilepsy risks in pregnancy
Maternal effects
Though most WWE can be reassured that this is an unlikely scenario (NICE, 2016b), for a small number of women there is a risk of worsening seizure control resulting in increased frequency and/or severity during pregnancy or shortly after. This might be due to pathological mechanisms or inadequate AED therapy (Zhao et al, 2014). It could also reflect concordance and prescribing behaviours based on socioeconomic factors (e.g. Campbell et al, 2013; Tomson and Klein, 2015) or the precautionary advice given to health professionals prescribing for women (Medicines and Healthcare products Regulatory Agency (MHRA) Sanofi, 2016). Patel and Pennell (2016) advocate that therapeutic drug levels should be routinely monitored during pregnancy to ensure optimal seizure control. In contrast several expert panels (NICE, 2016b; RCOG, 2016) conclude that this stance is not justified by the current evidence though the circumstances of individual women should be accommodated.
Midwives need to be aware of the nature of comorbidities for women associated with epilepsy and AED use as these can have significant effects on maternal and infant wellbeing. For example, research data has shown associations between having epilepsy and having other psychological illness such as increased suicide risk, depression, and other mood disorders (Fiest et al, 2013). It is unclear what the biochemical mechanisms underlying these associations are, but some data points to familial and genetic components (Chentouf, 2016). However, these associations could also be influenced by the social consequences of having epilepsy (Campbell et al, 2013).
Fiest et al (2013) reported significant increases in the presence of depression in people with epilepsy during their lifetime in a systematic review of 23 articles representing 14 separate studies involving 1.2 million people. This finding was evident regardless of age, medication, or diagnostic criteria of depression. Bjørk (2016) in a Norwegian study of WWE and other long-term conditions (n=106,511) reported that having epilepsy was predictive of having peripartum depression or anxiety. Some of this increase might be attributable to observations that pregnant WWE who had depression were less likely to be prescribed antidepressant drugs than women without the condition during pregnancy (particular those on poly-use AED) (Bjørk et al, 2016). Why this is the case is uncertain, but might reflect more general concern about potential concomitant drug use interactions and the desire to limit fetal drug exposure. For example, Boukhris et al (2015) drew attention to the association between using antidepressant drugs (particularly selective serotonin inhibitors) during the second and third trimesters and autistic spectrum disorders (ASD) in the children who resulted from these pregnancies. Though ASD has heritable traits and some epilepsy syndromes have associations with some ASDs (Wood et al, 2015), evidence about high-dose valproate and poly-drug exposure during pregnancy is also associative with the presence of this diagnosis in children (Christensen et al, 2013).
In the UK and Ireland, maternal death affects 8.5 in 100,000 pregnancies (Knight et al, 2016). Precise data is limited, but it is evident that WWE experience greater mortality during pregnancy than other women (Nair et al, 2016). Edey et al (2014) in an analysis of UK maternal death data observed that 1 in 1000 pregnant WWE died due to sudden unexpected death in epilepsy (SUDEP) during pregnancy or in the early postpartum period/shortly after. This is an important and worrying figure, and it is sure to cause anxiety for women if this fact is not conveyed in an appropriate manner.
Neonatal effects
AEDs have been known to have adverse effects on the developing fetus for over half a century (Inoyam and Meador, 2015). This situation is unsurprising given the intended neurological effects of these medications and the sensitivity of the developing brain to perturbations caused by chemical imbalances of neuroactive substances. However, interpretation of studies into these effects is challenging because many of the outcome measures could be influenced by confounding factors and the studies themselves have used a mixture of methodologies (Inoyam and Meador, 2015). Nevertheless, recent data from a number of large studies confirms that fetal and neonatal teratogenic effects (anatomical-structural, functional and cosmetic, behavioural and cognitive) of maternal AEDs is related to specific drug dose and exposure in utero (Patel and Pennell, 2016). Several studies (Meador et al, 2013; Baker et al, 2015; Bromley et al, 2016) and a Cochrane systematic review (Bromley et al, 2014) have concluded that sodium valproate, particularly in high dose regimes or used in poly-therapy, is the most harmful. This led influential guidance (NICE, 2016b) to conclude that the risks this drug poses are best avoided in women of reproductive age if at all possible. However, this advice leaves health professionals and women in a quandary about the best choice of drug, as no drug is without risk.
In general, evidence about the effects of newer AEDs on children's neurodevelopment is limited (Bromley et al, 2016) and some of this is conflicting (Vajda et al, 2014). For example, some are linked to increased likelihood of particular congenital malformations like cleft lip/palate and hypospadias (Vajda et al, 2014; de Jong et al, 2016) or fetal growth retardation (Veiby et al, 2014). In contrast, several drugs (lamotrigine, levetiracetam for example) appear to have lower teratogenic risks (Dolk et al, 2016; Meador and Lorring, 2016). This information could affect individual mothers' concordance with prescribing regimes. Further human study is required and this should be a research priority (Inoyam and Meador, 2015; de Jong et al, 2016), particularly as women are more likely to be prescribed these newer AEDs rather than men. This could be because of gender-based responsiveness to particular drugs (such as female hormone cycles) or that clinicians are avoiding prescribing valproate for women of reproductive age wherever possible.
‘Benefits of early engagement with midwives and specialist epilepsy services can ensure that women at risk of pregnancy-related complications receive appropriate care throughout’
Management and practice points
Antenatal care
The management of epilepsy during pregnancy is complex and challenging, requiring a multidisciplinary collaborative approach (Morley, 2016a). Pregnancy brings about a host of physiological changes in women's bodies which can affect the efficacy of previous treatments (Patel and Pennell, 2016). For example, increases in plasma volume, changes in drug absorption, hepatic function and renal clearance can all affect drug concentrations (Zhao et al, 2014). In addition, nausea and vomiting, fatigue, and exposure to increased emotional stress might affect drug ingestion or concordance (Patel and Pennell, 2016). These combined factors might help to account for the conflicting data concerning the effects of pregnancy on variations (both increases and decreases) in seizure activity and intensity. A situation which can leave women in a dilemma on how their epilepsy is best managed before and during their pregnancy.
Current consensus is that women should be encouraged to plan their pregnancy and engage with sources of specialist advice pre-conceptually. Despite limited evidence for benefit this advice will include advocating the taking of folate supplementation pre-conceptually (NICE, 2016b; RCOG, 2016) and for some AEDs taking vitamin K (Shahrook et al, 2014). Benefits of early engagement with midwives and specialist epilepsy services can ensure that women at risk of pregnancy-related complications receive appropriate care throughout. For example, information about the risks and benefits of taking different AEDs and dosing regimens for seizure control or other medical problems can be discussed with women pre-conceptually to minimise adverse effects for themselves and their fetus (Morley, 2016a).
Prenatal counselling of women should also ensure that information about the relative safety of particular drugs and its limited evidence base is conveyed to them during these conversations (NICE, 2016b; RCOG, 2016). Regardless, drug management requires a shared approach and specialist midwives have a role to play in supporting women during these decisions (Morley, 2016a). This will ensure that women feel in control of their own therapy and make informed decisions about whether to continue to take AEDs during pregnancy. WWE need access to consistent informed advice and support pre-conceptually, during pregnancy and after birth to reduce the effects of risk factors on pregnancy outcomes. In addition to specialist health professionals such as neurologists and epilepsy nurses/midwives, there are numerous supportive organisations that provide informed advice and support for people with epilepsy (seeBox 1). Professional and expert advice exists alongside more unregulated sources on the internet and on social media; this can be confusing for women as often the information is incorrect and misleading (Agricola et al, 2013).
Few midwives regularly encounter WWE during their everyday work, which can mean that their awareness of up-to-date knowledge can be lacking. To address this gap Morley (2016b), a specialist epilepsy midwife, has designed a tool to help women ensure they are provided with appropriate care during their pregnancy. This multi-professional tool brings together in one place guidance and information from community, maternity and epilepsy specialist services. It provides a concise summary of a woman's care in relation to her condition and can empower her to be the expert in her care. The tool is deigned to be readily appended to maternity hand-held notes; its use is commended to midwives caring for WWE. However, the evidence base about the effectiveness of pre-conceptual interventions is limited. This situation led Winterbottom et al (2014) to propose a systematic review to determine the effects of pre-conceptual counselling interactions on pregnancy outcomes and women's experiences; these results when available will be of interest to midwives.
Like many countries, the UK has established a voluntary pregnancy register for women with epilepsy (UK Epilepsy and Pregnancy Register), founded in 1996 to collate information on outcomes to identify optimal treatment and safety of AEDs (www.epilepsyandpregnancy.co.uk). Midwives should encourage women to register their pregnancy as they can collectively provide valuable epidemiological information to guide research priorities and share information with others planning a pregnancy.
Intrapartum care
Advice about the mode and place of birth for WWE are subjective and invariably based on risk assessments of seizure history, AED therapy and the availability of local services (RCOG, 2016). Decisions should be taken on an individual basis but the consensus is that women taking AEDs should have consultant-led care which involves an epilepsy specialist. There is no evidence that absences or clonic seizures affect pregnancy outcomes (Royal College of Obstetricians and Gynaecologists (RCOG), 2016). It is estimated that seizures during labour and the 24 hours after birth affect around 1-4% of women with tonic-clonic epilepsy (NICE, 2016b). Midwives caring for WWE should ensure that they know about local protocols for managing seizures during labour. However, it is important that assumptions are not made about WWE presenting with seizures in the second half of pregnancy being due to epilepsy, it is essential to exclude pre-eclampsia. Poorly-controlled pain management during labour is known to be one of the risk factors for triggering seizures, others being insomnia, sleep deprivation, dehydration, stress, and failing to continue with routine AEDs as prescribed. Transcutaneous electrical nerve stimulation machines (TENS), epidural, and nitrous are all safe options (RCOG, 2016). However, current opinion is that pethidine is best avoided and replaced with diamorphine; pethidine, in high doses, can lower the threshold for seizures and be epileptogenic (NICE, 2016b; Patel and Pennell, 2016; RCOG, 2016).
Postnatal care
Post-birth seizure risk is often lessened as the woman's physiology returns to its pre-gravid state; however, AEDs might require review to prevent toxicity and ensure optimal seizure control (NICE, 2016b). For the infant, midwives should ensure that vitamin K is given as some AEDs are known to affect haemostatic mechanisms adversely. Also, infants whose mothers have taken benzodiazepines or phenobarbital should be observed for withdrawal post-birth due to placental transfer during gestation. Baker at al (2015) conclude that children with early signs of having been affected by AED exposure should be identified, closely monitored and supported with specific interventions designed to enhance their cognitive development.
After birth WWE need to be provided with guidance about simple safety precautions around infant care to avoid the risk associated with any alterations in consciousness due to seizure activity (Morley, 2016b). To supplement guidance from midwives, epilepsy support groups (Box 1) provide invaluable practical information and assistance in this important area. In addition, tailored contraceptive advice to prevent unplanned pregnancy should be offered (RCOG, 2016). Some contraceptive drug and AED interactions can affect the efficacy of contraception or plasma concentration of AEDs. For example, enzyme-inducing AEDs like carbamazepine, phenytoin and topiramate can cause contraceptive hormones to be excreted more quickly, making progesterone-only medications and devices less reliable. Oestrogen-based contraceptives used in combination with lamotrigine can lower plasma drug concentrations, potentially below therapeutic levels (NICE, 2016b; Joint Formulary Committee, 2017). Previous positive outcomes are no predictor for subsequent outcomes and mothers should be made aware that future pregnancies might feature congenital abnormalities even when they were absent in this child, as each pregnancy is unique (Campbell et al, 2014).
In the past, it was difficult to determine if AED exposure via breast milk was harmful. This led many health professionals to advocate a precautionary principle and made many women to decide not to breastfeed. Recent analysis of research data by Meador and colleagues (2014) from a prospective longitudinal study (n=181) of monotherapy AED exposure, breastfeeding and IQ at the age of 6 years reports no adverse effects of AED exposure via breast milk. Instead, Meador et al (2014) found that breastfed children at the age of 6 years had higher IQ and verbal ability compared to formula-fed infants exposed to AEDs. This information is important as it adds further credence to midwives who advocate breastfeeding to this group of mothers and reassures them they are doing the best for their children. Recent guidance (NICE, 2016b) endorses this view and reiterates that WWE should be encouraged to breastfeed, adding that the benefits of breastfeeding far outweigh any known risks of postnatal exposure to AEDs via breast milk (with a few caveats).
Conclusions
Epilepsy in pregnancy presents a small but measurable increase in obstetric risk and the likelihood of poor pregnancy outcome for infants exposed to AEDs. Confounding factors make interpretation of studies into the longer-term effects of fetal AED exposure on children's educational outcomes difficult. Nevertheless robust data has emerged to suggest that valproate is the most problematic medication when compared to other AEDs and should be avoided if at all possible in women of reproductive age.
Midwives can help to provide better care for WWE by learning about the features and presentations of the condition, the condition's effects and its management both in general and specifically for the women they care for. Furthermore, organisations should locally develop multi-professional, multi-agency individualised care plans for women with complex needs like epilepsy and AED use. Developing individualised plans of care that involve women in decisions are the best way to ensure that WWE receive optimal care during pregnancy.