The Management of Pregnant Women With Epilepsy A Multidisciplinary Collaborative Approach To Care
The Management of Pregnant Women With Epilepsy A Multidisciplinary Collaborative Approach To Care
The Management of Pregnant Women With Epilepsy A Multidisciplinary Collaborative Approach To Care
12413
The Obstetrician & Gynaecologist
Review
http://onlinetog.org
Key content To understand the risk factors associated with poor outcomes in
Epilepsy is the most common serious neurological problem pregnant women with epilepsy.
encountered in pregnancy; however, women with epilepsy are To understand the risks associated with specific types of AEDs:
often not referred to high-risk pregnancy services. mono- and polytherapy.
The 2015 Mothers and Babies: Reducing Risk through Audits and To understand the issues regarding the titration of AEDs during
Confidential Enquiries across the UK (MBRRACE-UK) report on pregnancy, postnatal and breastfeeding periods.
maternal mortality highlights that the care of pregnant women To understand the importance of a multidisciplinary antenatal,
with epilepsy requires urgent improvement. intrapartum and postnatal schedule of care and
The two most recently available guidelines (Scottish Intercollegiate special considerations.
Guidelines Network and Royal College of Obstetricians and
Ethical issues
Gynaecologists guidelines) require comparative critical appraisal.
Collaboration between general practitioners, specialist epilepsy
When should we advise women to avoid pregnancy?
When, how and by whom should AEDs be modified?
nurses/midwives, obstetricians, obstetric physicians, neurologists Are women with epilepsy aware of the risk of sudden unexpected
and anaesthetists is vital to ensure optimal
death in epilepsy in pregnancy?
standardised management.
Keywords: anti-epileptic drugs / epilepsy / sudden unexpected
Learning objectives
death in epilepsy in pregnancy
To understand the role of pre-conception counselling: to include
advice on seizure control, anti-epileptic drugs (AEDs) and
pre-conception folic acid.
Please cite this paper as: Bhatia M, Adcock JE, Mackillop L. The management of pregnant women with epilepsy: a multidisciplinary collaborative approach to care.
The Obstetrician & Gynaecologist 2017; DOI: 10.1111/tog.12413.
100 000 despite urgent calls to improve services and care for are more recently published. The authors assessed the quality
this group.8 It is suggested that the majority of poor of the recommendations by performing a comparative critical
outcomes associated with women with epilepsy could be appraisal between the two most recently published guidelines
prevented by identifying women with epilepsy as high risk (Table 1). In addition, the authors have identified differences
and offering more specialised care. in the recommendations between the two guidelines
The management of epilepsy during pregnancy may be (presented later in the article), which to the authors’
challenging, especially in those taking AEDs, as one balances knowledge is the first such comparative critical appraisal of
potential adverse effects of AEDs on the fetus with seizure these two guidelines. The AGREE II-Global Rating Scale tool
frequency in the mother.9 A number of clinical reviews detail was used, which is a reliable and widely accepted tool for
the maternal and fetal risks associated with pregnancy and rapid appraisal of guidelines and can be used by clinicians in
epilepsy; however, this review aims to outline an evidence- daily practice.12 This tool consists of five domains that assess
based multidisciplinary pathway of care for women with guideline reporting, and each domain is scored out of seven.
epilepsy to optimise outcomes based on the available
literature and guidelines, including the new Royal College
Why is pre-conception care important and
of Obstetricians and Gynaecologists (RCOG) guidelines.10,11
what elements should be included?
The 2015 MBRRACE-UK report ascertained that 86% of
Clinical practice guidelines: a critical
women with epilepsy who died of sudden unexpected death
appraisal
in epilepsy (SUDEP) had not received prepregnancy
There are a number of guidelines on the management of counselling.6 Moreover, 25% of women with epilepsy who
pregnant women with epilepsy, including the National were members of the British Epilepsy Association said they
Institute for Health and Care Excellence (NICE) guidelines, had never discussed pregnancy with anyone, and only 38% of
the Scottish Intercollegiate Guidelines Network (SIGN) and a population-based study of women with epilepsy recalled
the recent RCOG guidance on epilepsy.10,11 The SIGN and any prepregnancy counselling.3,13 Preconception counselling
RCOG guidelines cover the subject of pregnancy in women for women with epilepsy is recommended as routine practice
with epilepsy more extensively than the NICE guidelines and and is associated with improved epilepsy- and non-epilepsy-
Table 1. Comparison of SIGN and RCOG guidelines and the quality of evidence supporting recommendations regarding pregnancy in women with
epilepsy (AGREE II-GRS Instrument)
GRS = Global Rating Scale; MHRA = Medicines and Healthcare Products Regulatory Agency; RCOG = Royal College of Obstetricians and
Gynaecologists; SIGN = Scottish Intercollegiate Guidelines Network.
related outcomes for both mother and baby.14 This should Effective counselling aims to allow for informed decisions
involve coordinated interdisciplinary communication to be made regarding pregnancy, and for pregnancy to be
between neurologists, physicians, general practitioners and planned at a time when maternal health is stable and
obstetricians; however, as up to half of all pregnancies are frequency of seizures is minimal to optimise pregnancy
unplanned, it is imperative that this discussion forms an outcomes (Table 2).14,15 Such counselling should involve
opportunistic part of the consultation for every woman with specific goals that include general health promotion.16
epilepsy of childbearing age.2,14 Women with epilepsy should be advised on optimisation of
Inform women Some may require dose adjustments during pregnancy to maintain seizure control
Most women with epilepsy can aim for a vaginal birth unless there are obstetric issues
Epilepsy alone is not an indication for induction of labour or caesarean section
Risk of developing childhood epilepsy Increased risk of epilepsy if first-degree relative has epilepsy
The risk is multifactorial and depends on the type of epilepsy syndrome
The individual genetic susceptibility should be discussed with the patient’s
neurologist/epileptologist
Medication 5 mg folic acid should be taken preconceptually and throughout pregnancy to reduce the risk of
congenital malformations and long-term cognitive deficits
Avoid any abrupt withdrawal of AEDs
Aim for monotherapy with the lowest effective AED dose, if possible
If taking sodium valproate consider weaning off or an alternative AED on the advice of a
neurologist or obstetric physician
If sodium valproate needs to be continued, change to the moderate release or increase the daily
frequency to reduce the risk of high peak levels of the drug. Doses >800 mg/day are associated
with greater risks of teratogenicity
Avoid using sodium valproate as first-line treatment in any women with epilepsy of childbearing
age unless other treatments are ineffective or not tolerated; lamotrigine, levetiracetam and
carbamazepine are suggested
Encourage all women To register their pregnancy on the national epilepsy and pregnancy database:
http://www.epilepsyandpregnancy.co.uk
AED = anti-epileptic drug; MCM = major congenital malformation; SUDEP = sudden unexpected death in epilepsy.
health before pregnancy (Table 3) and when to delay the general population (1–3%), indicating that epilepsy itself
pregnancy and continue contraception. does not significantly increase the risk of MCM.19 Children of
Women with unstable epilepsy or who are in poor health mothers taking AEDs have up to a 10% risk of MCMs
have a higher incidence of maternal mortality and perinatal compared with the general population.20,21 Potential
morbidity and mortality.6 Table 4 outlines when women fetotoxicity associated with AED use can occur in any
with epilepsy should be advised to delay or avoid pregnancy. trimester.20 Risk of fetal harm is highest during
organogenesis in the first trimester and the risk of cognitive
impairment typically occurs in the third trimester and is
Anti-epileptic drugs and pregnancy
associated with polytherapy.1 The extent of fetal risk is
Pregnant women with epilepsy taking AEDs will require influenced by type and dose of AED, maternal age and
input from both an obstetrician and a neurologist or parental history of malformation.22
obstetric physician about their recommended regimen The MCMs associated with AED use include oral clefts,
during pregnancy. They will be advised to continue on cardiovascular defects, urogenital defects and neural tube
their regimen until a medical review, and any women with defects.2 Minor malformations include fetal anticonvulsant
epilepsy who are on AEDs and have an unplanned pregnancy syndrome, which include dysmorphic features, hypertelorism,
should have an urgent review of their condition with a and hypoplasia of the nails, digits and midface.2
neurologist. Common concerns regarding AEDs in
pregnancy are the risk of major congenital malformation Small-for-gestational-age fetus and anti-epileptic
(MCM) and the risk of fetal growth restriction; these are drugs
outlined below (Table 5). In addition, there are concerns Offspring of women with epilepsy taking AEDs may have an
regarding the side-effect profile of certain AEDs, including increased risk of being small for gestational age (SGA).1
mood disturbance, poor concentration, irritability and There is evidence suggesting that there is a two-fold increased
tiredness in some women with epilepsy.17,18 risk of a baby being SGA in women with epilepsy taking
AEDs compared with women not taking AEDs.23 A recent
Risk of major congenital malformations due to anti- systematic review corroborates these findings.24 In addition,
epileptic drugs evidence has shown no increased risk in offspring being SGA
The majority of AEDs cross the placenta and are potentially in women with epilepsy who were not taking AEDs.25
teratogenic.2 The incidence of MCMs in women with Therefore, surveillance ultrasound scans for fetal growth may
epilepsy who are not exposed to AEDs is similar to that of be considered in women who are on moderate dose
polytherapy with AEDs, although the RCOG recommends
that serial scans should be performed from 28 weeks of
Table 3. How to optimise health pre-conceptually
gestation for all pregnant women with epilepsy taking AEDs.
Seizure Remain compliant with AED medication
frequency Close contact with neurology team to enable Other obstetric risks from anti-epileptic drugs
titration of medication
Avoid seizure triggers A recent systematic review on outcomes in pregnant women
with epilepsy demonstrated an increased risk of miscarriage,
AEDs Aim to manage seizures effectively with lowest
dose of AED
antepartum haemorrhage, hypertensive disorders, induction
Aim for low-dose monotherapy if appropriate of labour, caesarean section, preterm delivery and
Avoid changing medication if a women is seizure postpartum haemorrhage compared with the
free unless on the advice of a neurologist and after background population.24
close discussion with the patient
Consider changing to less teratogenic AEDs where
possible (lamotrigine, levetiracetam What is safe anti-epileptic drug practice in
and carbamazepine) pregnancy?
Avoid sodium valproate if other AEDs The choice of AEDs in women of childbearing age is
are appropriate
Note the optimal serum predominantly determined by the epilepsy type. However,
concentration preconceptually there is compelling evidence to recommend avoiding sodium
General Optimise health (optimise BMI, reduction of
valproate in all women with epilepsy of childbearing age, if
health alcohol consumption, regular exercise) possible. The developing fetus is at high risk (up to 10%) of
Stop smoking (smokers have a higher risk of MCMs, particularly neural tube defects, when exposed to
preterm labour) sodium valproate monotherapy and even more so with
Start 5 mg folic acid several months pre-conception
polytherapy.1,19,22,26,27 There is also evidence that children
AED = anti-epileptic drug; BMI = body mass index.
exposed in utero to sodium valproate are at a higher risk of
learning difficulties and autistic spectrum disorders.28–30
No AED34,43,44 2.0–2.3%
Carbamazepine1,22,26,34,43,45 Cardiac defects 2–5% Pregnancy: Considered safest
Facial clefts Dose-dependent risk Breastfeeding: Safe
Lamotrigine1,5,22,34,43 Cardiac defects 2–5% Pregnancy: Considered safest; may need
Facial clefts Dose-dependent risk dose adjustment in third trimester (check
plasma levels)
Breastfeeding: Safe
Levetiracetam22,34,43 Cardiac defects 1–2% Pregnancy: Considered safest
Neural tube defects Breastfeeding: Safe
Further studies needed
Oxcarbazepine21,22,46 Cardiac defects 1–3% Pregnancy: Relatively safe
Facial clefts Breastfeeding: Safe
Phenobarbital1,22,45 Cardiac defects 2% Pregnancy: Relatively safe
Breastfeeding: Avoid (drowsiness)
1,5
Phenytoin Facial clefts 1–2% Pregnancy: Relatively safe
Poor cognition and Breastfeeding: Safe
neurodevelopment
Sodium Neural tube defects 6–10% Pregnancy: Avoid if possible
valproate1,19,22,26,27,47 Facial clefts Dose-dependent risk Breastfeeding: Safe
Hypospadias
Poor cognition and
neurodevelopment
Topiramate34 Cardiac defects 4–6% Pregnancy: Less safe, avoid if possible
Facial clefts Breastfeeding: Safe
Hypospadias
Monotherapy1,22 3–5%
Polytherapy1,22 6–8%
Polytherapy with Up to 10%
valproate1,25
Folic acid dose 400 micrograms: not on AEDs 5 mg prior to conception until at least end of first
5 mg: if on AEDs or if not on AEDs, but high risk (family trimester
history of neural tube defects or BMI >30 kg/m2)
AEDs Consider increasing dose of lamotrigine in pregnancy and Routine monitoring not recommended (individualise)
reducing postnatally
Consider dose adjustment of levetiracetam and other AEDs if
there is a change in seizure frequency or if suspecting toxicity
Antenatal corticosteroid Women with epilepsy on enzyme-inducing AEDs who require Routine doubling of the dose is not recommended
dose antenatal corticosteroids should receive double the dose of
betamethasone/dexamethasone (48 mg over 12–24 hours)
Oral maternal Consider 10 mg oral maternal vitamin K if there are additional There is insufficient evidence for routine maternal
vitamin K in the third risk factors for haemorrhagic disease of the newborn vitamin K to prevent haemorrhagic disease of the
trimester (maternal liver disease or anticipated preterm delivery) newborn or postpartum haemorrhage
Ultrasound scanning in There is insufficient evidence to support the use of routine Serial growth scans from 28 weeks in women with
third trimester to detect ultrasound scanning in the third trimester unless an SGA fetus epilepsy on AEDs as the odds ratio is 3.5
a SGA fetus is clinically suspected
Analgesia during labour Low threshold for epidural anaesthesia Pain relief options include: TENS, entonox, regional
anaesthesia
Avoid the use of pethidine during labour as it may be
epileptogenic
AED = anti-epileptic drug; RCOG = Royal College of Obstetricians and Gynaecologists; SGA = small for gestational age; SIGN = Scottish
Intercollegiate Guidelines Network; TENS = transcutaneous electrical nerve stimulation.
Involving Avoid seizure Ensure AED Assess seizure Consider AED levels Vitamin K
other specialties: triggers compliance frequency and titrate dose: (10 mg oral)
PAEDIATRICS if on lamotrigine or if on enzyme inducing
if on multiple AEDs levetiracetam or if AEDs if high risk for
or concerns about seizure frequency haemolytic disease of
congenital malformations increased (SIGN) the newborn (liver disease
or preterm delivery
anticipated) (SIGN)
ANAESTHETISTS
if on polytherapy
AEDs or concerns re.
interactions with
anaesthetic agents or
previous issues with
anaesthetics
NEUROPSYCHIATRISTS
if WWE may benefit from
their input
*Based on clinical experience
Figure 1. An evidenced-based multidisciplinary pathway of antenatal care for women with epilepsy
AED = anti-epileptic drug; GP = general practitioner; RCOG = Royal College of Obstetricians and Gynaecologists; SIGN = Scottish Intercollegiate
Guidelines Network; WWE = woman with epilepsy.
Recommendations for an antenatal pathway of care example, avoiding co-bedding and minimising excessive
Figure 1 depicts a suggested pathway for antenatal care for tiredness. Practical measures include: placing the baby in a
pregnant women with epilepsy based on the available cot or play pen if mother feels unwell; feeding the baby while
evidence and critical appraisal of the two national guidelines. sitting on the floor; changing and bathing the baby on the
floor; and not bathing the baby alone.
All women with epilepsy should be counselled about
Intrapartum care contraception and avoiding unplanned pregnancies in the
Women with epilepsy can be reassured that the risk of future. The recommended contraceptive preparations are
intrapartum seizures is low (3.5%); however, for all women on levonorgestrel-releasing intrauterine systems, copper
the high-risk care pathway, delivery in a consultant-led unit is intrauterine devices and medroxyprogesterone injections,
advised.10,11 Women with epilepsy should be admitted in early as these are not affected by enzyme-inducing AEDs.11
stages of labour and will require intravenous access and one-to- Those women on non-enzyme-inducing AEDs (lamotrigine
one midwifery care. It is important to have adequate analgesia, and levetiracetam) can consider estrogen-based preparations.
be well hydrated, be compliant with AEDs, and avoid stress,
hyperventilation and sleep deprivation, so as to reduce the risk Sudden unexpected death in epilepsy in
of seizures. In women with epilepsy, the use of pethidine during pregnancy
labour should be avoided due to the increased risk of seizures
associated with its use. An epidural is considered safe in women SUDEP is death that is unrelated to trauma, drowning or
with epilepsy. Seizures in labour should be treated promptly to status epilepticus. Unfortunately, it remains the
reduce the risk of maternal and fetal hypoxia and fetal acidosis. predominant cause of death in women with epilepsy.6 The
A seizure in labour should be treated with benzodiazepines MBRRACE-UK report highlights that the risk of SUDEP is
(intravenous lorazepam 2–4 mg bolus doses repeated every higher than expected in women with epilepsy. Modifying
10–20 minutes, or intravenous diazepam 5–10 mg in slow risk factors such as AED compliance, first aid training of
bolus dose if lorazepam is unavailable), and a left lateral tilt (or family members and avoiding sleeping alone may reduce the
manual displacement of the uterus), oxygenation and risk.6 There are concerns regarding the use of lamotrigine,
continuous electronic fetal monitoring should commence.11 as the incidence of SUDEP in women with epilepsy taking
In refractory cases, intravenous phenytoin can be used; a lamotrigine is higher (2.5 per 1000 patient years) than in
loading dose of 18 mg/kg can be increased by 5 mg/kg to a those taking other AEDS (0.5–1.0 per 1000 patient years).41
maximum rate of 50 mg/minute. Explanations for this higher risk include the relative
common usage of lamotrigine and the reduced serum
drug levels with advancing gestations potentially resulting in
Postnatal care and breastfeeding an increased seizure frequency.
The absolute risk of postnatal seizures in women with epilepsy
is low, but higher than the risk of seizures during pregnancy.
Conclusion
The risk is associated with increased stress, sleep deprivation
and reduced AED compliance. If the AED dose was modified There is scope to improve the general care provided to all
during pregnancy it will require a review to ensure it is effective women with epilepsy. Pregnancy is an excellent opportunity
postnatally. Ideally, any woman taking AEDs should have an to promote seizure control and good health in women with
epilepsy review within the first month of delivery. There may epilepsy, the effects of which may confer long-term benefits
be a need for a dose reduction to avoid AED toxicity, as the both at a patient level and from a global health perspective.
pregnancy-related physiological changes will now be reversed. There is sufficient evidence to suggest that the reorganisation
The alteration of AED dose should be planned by neurology of care and services should be a multidisciplinary priority in
and communicated effectively to the obstetric team for action the immediate future to prevent further avoidable mortality
in the immediate postnatal period. and morbidity.
Breastfeeding is actively encouraged in the term infant of
women with epilepsy, as the concentration of most AEDs in Disclosure of interests
breast milk is minimal (see Table 4 for the AED-specific The authors report no conflicts of interest.
safety profile in breastfeeding). Caution is advised in women
who are taking polytherapy, phenobarbitone or benzo- Author contributions
diazepines, or in preterm infants, who should be closely MB instigated, researched and drafted the article. LM and
monitored. Women with epilepsy and their families should JEA made critical revisions to the manuscript and all authors
be advised about safety measures for mother and baby, for approved the final version for publication.
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