Epilepsy is a neurological disorder characterised by recurrent unprovoked seizures (Krumholz et al, 2015). It is one of the most common chronic medical disorders, affecting up to 50 million people worldwide, and may require daily treatment with a known teratogen during pregnancy (Putta and Pennell, 2015). In epilepsy, seizures occur in the absence of electrolyte imbalances, temperature abnormalities, hypoglycaemia, alcohol withdrawal or toxins. Seizures are caused by abnormal discharges of cerebral neurons, and result in the alteration or impairment of consciousness, sensation or motor function (Devinsky et al, 2013). The presentation of seizures is dependent on the location and the number of dysfunctional neurons. Seizures are categorised as either simple focal seizures or complex focal seizures.
Simple focal seizure symptoms relate to the area of the brain encompassing visual, auditory, olfactory, sensory or motor symptoms, while consciousness is preserved. Therefore, olfactory, auditory and visual hallucinations are symptoms of simple focal seizures, as are paraesthesia and motor symptoms (weakness or twitching) (Tiwari et al, 2012; Scheffer et al, 2014). These usually precede complex focal seizures. Complex focal seizure presentation is characterised as impaired consciousness, automatisms and altered behaviour, and a decreased responsiveness (Power et al, 2015).
Generalised seizures are bilateral hemispheric dysfunctional neuronal discharges, resulting in loss of consciousness from the seizure onset, and are further classified as absent, myoclonic, atonic or generalised tonic-clonic seizures (Engel and Engel Jr, 2014). Generalised tonic-clonic seizures present as sudden loss of consciousness and initial stiffening of limbs, progressing to jerking movements. A post-ictal phase occurs following a seizure, characterised by the person regaining consciousness with a period of impaired consciousness such as confusion, drowsiness, irritability or aggressiveness (Barnett and Gay, 2015). There are varying degrees of consciousness associated with complex focal seizure, including a blank stare, appearing dazed or confused or in a trance-like state, being unresponsive or giving confused responses to questions, and being unaware of surroundings (Spray, 2015). Status epilepticus is defined as continuous seizure for longer than 5 minutes, or repetitive seizures without full recovery of conscious state between seizures (Glauser et al, 2016); this is a medical emergency that requires treatment to prevent serious morbidity and mortality.
Epilepsy in pregnancy
The majority of pregnant women with epilepsy have an uneventful pregnancy, labour and birth. The UK Epilepsy and Pregnancy Register reports that 96% of women who use anti epileptic medication in pregnancy have a child born without a major congenital malformation (Campbell et al, 2014). Research on the effect on seizure frequency in pregnancy is unclear, though progesterone and oestrogen have been shown to influence seizure activity (Ruth and Barnett, 2013). The presence of generalised tonic-clonic seizures is associated with maternal and fetal morbidity and mortality.
During a generalised tonic-clonic seizure, the lack of respiration and oxygenation leads to anaerobic metabolism and respiratory acidosis, with high-intensity muscle movements experienced both during the tonic and clonic periods, leading to an increase in lactic acid (Harden et al, 2013). Apnoea occurs during the post-ictal phase that contributes to the acidosis. Uterine contractions may increase and the uterus may become hypertonic, reducing blood flow to the placental bed. As a result of all these above mentioned changes, the fetus is deprived of oxygen. Cardiotocograph (CTG) monitoring will demonstrate fetal bradycardia, reduce short-term and long-term variability, late decelerations and a period of compensatory fetal tachycardia (Pirie et al, 2014). Continuation of a deoxygenated state, such as in status epilepticus, can lead to fetal and maternal death. Additionally, uterine trauma can occur due to the abrupt nature of the loss of consciousness causing the women to fall.
The main indicator of seizure occurrence in pregnancy is the frequency of seizures prior to conception (National Institute for Health and Care Excellence (NICE), 2016). Women who are seizure-free prior to conception have a reduced risk of seizure occurrence in pregnancy; however, labour, birth and the immediate postpartum period have a high risk of seizure, with a risk of a generalised tonic-clonic seizure at 1–2% (Ozdemir et al, 2015).
Pharmacodynamics of antiepileptic drugs in pregnancy
Antiepileptic drugs aim to prevent seizure activity by acting on the sodium ion voltage gates on the cell membrane by blocking repetitive electrical discharges, or by altering the excitatory or inhibitory synaptic function (Alarcón and Valentín, 2012).
Sodium valproate is an older-generation antiepileptic drug, of which exact mechanisms of action are unclear, but it is thought to increase the level of the inhibitory neurotransmitter GABA and act on the sodium channel voltage gates to increase the cells' recovery time between firing (Alarcón and Valentín, 2012). Sodium valproate is a pregnancy category D medication that is indicated for the management of primary generalised epilepsy and partial epilepsy (Schmidt, 2015). Usual dose of sodium valproate ranges from 600 mg to a maximum of 2.5 g per day; it is rapidly absorbed in the gastrointestinal tract as it is highly plasma protein bound and is then metabolised in the liver (Wlodarczyk et al, 2012; NICE, 2016).
‘ The majority of pregnant women with epilepsy have an uneventful pregnancy, labour and birth ’
Lamotrigine is a newer-generation antiepileptic drug, which acts on inhibiting the release of the excitatory neurotransmitter glutamate, preventing sodium channel voltage gates from opening and depolarisation of the neuron (Alarcón and Valentín, 2012). Lamotrigine is also a pregnancy category D medication, indicated for partial and generalised seizures. It should be commenced at 25 mg per day, with a maximum dose not exceeding 200 mg per day (Wlodarczyk et al, 2012). Lamotrigine is rapidly and completely absorbed in the gastrointestinal tract as it is approximately 55% protein bound, and metabolised by the liver.
Benzodiazepines can also be utilised in the management of active seizures and treatment of status epilepticus. The mechanism of action of benzodiazepines is to potentiate the effect of the inhibitory neurotransmitter GABA at the receptor sites on the dendrite terminal, resulting in a decrease in neuronal firing and sedation (Alarcón and Valentín, 2012).
Pharmacokinetics of antiepileptic drugs in pregnancy
Physiological changes that occur in normal pregnancy affect the effectiveness of prescribed medications. Decreases in antiepileptic drug concentrations occur owing to increased extra-cellular fluid, reduced intestinal absorption, decreased absorption binding, increased elimination and increased hepatic metabolism (Wlodarczyk et al, 2012). Decreased serum concentrations of anti epileptic medications may lead to a rise in seizure activity, and dosages will need to be increased accordingly.
Metabolism of lamotrigine in pregnancy is increased owing to elevated concentrations of oestradiol affecting liver function and increased renal excretion. A decrease in concentration of lamotrigine during pregnancy to 65% of pre-conception lamotrigine levels is a significant predictor of seizure occurrence (Reisinger et al, 2013). Serum concentration levels should be completed during each trimester or on occurrence of seizure activity. With the return of a normal physiological state in the postpartum period, antiepileptic doses should be titrated to pre-conception levels.
Antiepileptic drug therapy outcomes
The presence, incidence, and risk for adverse maternal and fetal outcomes remains unclear. Studies on antiepileptic drug use in pregnancy tend to be small, retrospective and observational (Wen et al, 2015; Martinez Ferri et al, 2016). Strong associations have identified an increased risk of congenital malformations, obstetrical complications, neo natal complications and impaired neurodevelopment and cognition of the child that is exposed to antiepileptic drugs in utero (Gedzelman and Meador, 2012). Antiepileptic drugs are expected to be prescribed when the harm of uncontrolled seizures outweighs the risk of treatment (NICE, 2016). The risks of antiepileptic polytherapy management of epilepsy in pregnancy are associated with poorer fetal outcomes and an increased risk of congenital malformations. The American Academy of Neurology recommends using the lowest effective dose of a single anti epileptic agent, particularly avoiding polytherapy with the first trimester, including avoiding sodium valproate during pregnancy and decreasing postpartum antiepileptic dosages to avoid medication toxicity (Ruth and Barnett, 2013). Slow-release preparations or divided drug doses will assist in avoiding peaks in maternal levels, further reducing the teratogenic effects of the medication. Maternal outcomes of antiepileptic drug use in pregnancy are poorly documented, with the majority of research conducted aimed at fetal and neonatal outcomes (Artama et al, 2013; Hernández-Díaz et al, 2014; Veiby et al, 2014).
Fetal outcomes
Fetal outcomes associated with antiepileptic drug exposure in utero include major congenital mal formations such as neural tube defects, orofacial clefts, congenital heart defects, hypospadias, skeletal abnormalities, and impaired neuro development in children (Dolk et al, 2016). Other associated risks of antiepileptic drug use in pregnancy include fetal loss, stillbirth, small for gestational age and intrauterine growth restrictions; however, the exact teratogenicity effects of antiepileptic drugs are unknown, and it is suggested that teratogenic effects are associated with folate deficiency, ischaemia, neuronal suppression and reactive intermediates (Gedzelman and Meador, 2012).
The use of sodium valproate in utero has the highest incidence rate of congenital malformations; it is not recommended for use in pregnancy unless alternative antiepileptic drugs are unable to provide adequate seizure control (Tomson et al, 2016). Fetal valproate syndrome was first defined in the 1980s, describing the dysmorphogenic features of neonates with sodium valproate exposure in utero (Arman et al, 2016). Dysmorphogenic features include: prominent melopic ridge; infraorbital grooves; broad and depressed nasal bridge; epicanthic folds; thin, arched eyebrows; short, upturned nose; smooth, long philtrum; and thin upper lip (Harden et al, 2013). In Australia, the incidence rate of fetal malformation for sodium valproate in pregnancy is reported to be 13.65% and a statistically significant association has been identified between sodium valproate and spina bifida, malformations of the heart, great vessels, digits, skull bones and brain (Vajda et al, 2013). In Finland, it has been reported that neonates born to epileptic women on sodium valproate have a twofold increase risk of low 5-minute Apgar scores, respiratory distress and admission to a neonatal care unit (Artama et al, 2013).
Fetal outcomes with the use of lamotrigine in pregnancy are less documented; studies tend to focus on the maternal psychiatric impact regarding lamotrigine use by pregnant women. Though limited data are available on lamotrigine use in pregnancy, data suggest that better fetal outcomes occur than with the use of sodium valproate in pregnancy. In Australia, the incidence of fetal malformations with the use of lamot rigine in pregnancy is 4.98% (Vajda et al, 2013). The incidence of fetal malformation in lamotrigine use in pregnancy in the UK and Ireland has been reported to be three times less than the incidence in sodium valproate exposure, with cardiac malformations, hypospadias and genitourinary tract malformations more likely to occur with sodium valproate exposure than lamotrigine exposure (Campbell et al, 2014).
Antiepileptic drugs and the postnatal period
Drug serum concentrations in the neonate depend on the amount of drug excreted in breast milk and the ability to absorb, distribute, metabolise and excrete the medication. Neonates have a lower risk of antiepileptic exposure from breast milk than the risk in utero, and the recommendation to advise against breastfeeding must be justified by evidence that a harmful effect cancels out the advantages of breastfeeding (Veiby et al, 2015). Women with epilepsy should be encouraged to breastfeed, with the decision being made in discussion with the medical provider regarding the potential risks of the drug's effects on the neonate. Breastfeeding a neonate who has been exposed in utero prevents abrupt withdrawal from the antiepileptic medication.
As lamotrigine is 55% protein bound, a large amount of the drug remains free within the plasma, and penetration into breast milk occurs in moderate amounts. Metabolism of lamotrigine by the neonate is limited, therefore neonatal serum concentration levels can be high (Veiby et al, 2015). Despite moderate amounts of penetration and impaired neonatal metabolism of lamotrigine, few adverse reactions are documented. Neonates, particularly preterm infants, should be monitored for signs of poor sucking, rash and drowsiness, which are all indicators of high serum levels.
Midwifery role in the management of epilepsy in childbearing women
It is strongly recommended that women with underlying medical disorders receive pre-conceptual advice in the hope of optimising positive pregnancy outcomes (MBRRACE-UK, 2015; NICE, 2016). Further recommendations from the MBRRACE-UK (2015) report into maternal death highlight the importance of pre-conceptual counselling in relation to encouragement of compliance with antiepileptic medication and the importance of risk assessment regarding women's medical condition on the first antenatal visit. Evidence suggests that pregnant women should receive education from midwives regarding the risk of seizure and the possible risk of teratogenity to the fetus (Al Wattar et al, 2015). In view of this, it is recommended that women should ensure a planned pregnancy with the assistance of contraception, thereby optimising the appropriate timing of conception (NICE, 2016). It is suggested 5 mg of folic acid be taken pre-conceptually and should continue for the duration of the pregnancy as antiepileptic medication drugs impair folic acid absorption which, in turn, leads to an increased risk of neural tube defect development (Krishnamurthy and Morris, 2016).
Antenatal care should involve a multi-disciplinary team approach, with the involvement of an obstetrician who specialises in epilepsy, a midwife and a neurologist (Barnes et al, 2012). Midwifery management would include the overseeing of monthly serum blood measurements (Hart and Sibai, 2013), and ensuring ultrasound scanning is recommended before 20 weeks' gestation to assist in detecting con - genital malformations associated with maternal epilepsy (Jackson et al, 2015). Ultrasound is advised throughout the pregnancy to continually assess fetal growth and development, and the midwife can observe for signs of normal fetal growth when undertaking abdominal palpation. The midwife should monitor the woman for signs of depression, as the risk of depression is increased in women with epilepsy (Bjørk et al, 2015). Evidence suggests that vitamin K prophylaxis is recommended at 38 weeks' gestation as certain antiepileptic medications can cause vitamin K deficiency and, in turn, cause bleeding disorders (Shahrook et al, 2014).
The midwife should be aware that antiepileptic medication is recommended to be continued during labour, as non-compliance increases the risk of seizure (MacDonald et al, 2015). It is paramount that the midwife is involved in helping the woman with her options of reducing pain experienced in labour, as this can exacerbate seizure onset (Royal College of Obstetricians and Gynaecologists (RCOG), 2016). While the risk of seizure during labour is low, the midwife may be required to observe that continuous fetal monitoring is in place for women at high risk of a seizure to reduce adverse outcomes for the fetus.
The incidence of seizure activity is increased in the postpartum period, and in view of this, midwives should closely monitor the woman, particularly given that most women during the postnatal period are exposed to sleep deprivation and stress (Kinney and Morrow, 2016). The midwife should offer information and advice regarding any fear or anxiety the woman may have about harm occurring to the infant in the event of the woman having a seizure. Education about the introduction of safety precautions—such as breastfeeding the infant on the floor or on a large bed with one side near a wall, and using shallow water when bathing the infant—can usefully assist in alleviating anxiety levels and minimise accidents in the event of a seizure (Saramma and Thomas, 2007; RCOG, 2016).
Conclusion
Maternal and fetal outcomes of the aetiology and treatment of epilepsy in pregnancy remain unclear. Generalised tonic-clonic seizures are associated with maternal and fetal morbidity and mortality, and management of epilepsy in pregnancy is aimed at preventing seizures through the use of antiepileptic drugs. Antiepileptic drugs, particularly sodium valproate, have been linked to fetal malformations. Current recom mendations in the management of epilepsy in pregnancy include prescription of a single anti epileptic drug at the lowest possible dose, avoid ance of sodium valproate in pregnancy, slow-release drugs or staggered doses, prescription of antenatal folate and neonatal vitamin K supple-mentation, and the possible increase of medication doses during pregnancy and consequential titration of medication in the postnatal period. The midwife has an important role in assessing, managing and educating women regarding their epilepsy and their childbirth journey.