Symposium review J R Coll Physicians Edinb 2013; 43:49–58

http://dx.doi.org/10.4997/JRCPE.2013.112
© 2013 Royal College of Physicians of Edinburgh

Neurological diseases in pregnancy

1
D Kevat, 2L Mackillop
Honorary Specialist Registrar, Oxford University Hospitals NHS Trust, Oxford, UK and PhD candidate, School of Public Health, Monash
1

University, Melbourne, Australia; 2Consultant Obstetric Physician, Oxford University Hospitals NHS Trust, Oxford, UK

This review is based in part on a presentation given by Dr Mackillop at the Neurology Symposium on 4 October 2012
at the Royal College of Physicians of Edinburgh

ABSTRACT Neurological diseases are a major cause of morbidity and mortality in Correspondence to L Mackillop
pregnancy. The management of multiple sclerosis, epilepsy, myasthenia gravis, certain Women’s Centre,
John Radcliffe Hospital
neuropathies and headache in pregnancy is described; the potentially life-threatening Headley Way,
conditions of stroke and eclampsia are also discussed. Management of most Oxford
neurological conditions is similar to outside of pregnancy, but special consideration OX3 9DU, UK
should be given to delivery plans and the safety of medications antenatally and during
tel. +44 (0)1865 55615
breastfeeding. Pre-pregnancy counselling, regular review and effective communication e-mail lucy.mackillop@ouh.nhs.uk
among a multi-disciplinary team are key to optimising management and outcomes.

Keywords Pregnancy, neurology, multiple sclerosis, epilepsy, headache

Declaration of Interests No conflicts of interest declared.

Physiological Changes in Pregnancy The decrease in albumin concentration, increase in total

body water and glomerular filtration rate (+50%) and
A brief summary of the physiological changes helps changes in hepatic P450 system activity can greatly affect

education
contextualise the pathogenesis, differential diagnosis and the pharmacokinetics of drugs,5 including anti-epileptic
management options for neurological conditions in and thromboprophylactic medications. Other factors
pregnant women. These changes are designed to optimise that can affect drug metabolism include nausea and
conditions for the feto-placental unit, and potentially vomiting (often worst in the first trimester) and longer
reduce risks for the mother at the time of delivery. gastrointestinal transit times.

Cardiac output rises by 25% to 50% in singleton Multiple Sclerosis

pregnancies through both increased heart rate and
stroke volume, peaking at the beginning of the third The peak incidence of multiple sclerosis (MS) occurs in
trimester. Even greater increases occur in multiple women aged 15 to 45, child-bearing age. Latitude-
pregnancies.1 As systemic vascular resistance decreases dependent,6 the disease has a relatively high prevalence in
during pregnancy, blood pressure is usually lower until the UK of 0.1–0.2%.7 It is not a ‘contraindication’ to
the third trimester when the increased circulating pregnancy, and in most cases, pregnancy has little or no
volume and cardiac output increases it to near pre- deleterious effect on the condition and vice versa. Indeed,
pregnancy levels.2 Such variations of blood pressure and overall relapse rates for MS are lower during pregnancy,
cardiac output are important when considering the particularly during the third trimester.This is likely related
threshold for treatment of hypertension, the risk of to decreases in cell-mediated immunity, though a variety
stroke and the diagnostic criteria for pre-eclampsia, as of immune system changes in pregnancy may also play a
well as the management of rarer conditions such as role, including an increased production of tolerance-
known arteriovenous malformations. promoting signalling molecules and CD4 interferon-γ.
However, in the first three months post-partum, risk of
In addition to the commonly found iron deficiency relapse is increased with approximately 30% of women
anaemia, the ‘anaemia of pregnancy’ consists of a marked experiencing recurrence.8 The risk normalises after ten
increase in total red blood cell mass and a proportionally months, with no strong evidence to suggest overall
greater increase in plasma volume. Total blood volume disease progression or prognosis is changed. Given the
increases by approximately 1.5 L. Driven by rises in high risk of relapse after delivery, (Figure 1) planning to
levels of factor VIII, IX, X and fibrinogen3 there is an maximise social supports in this period is worthwhile.
overall shift to a pro-coagulant state with an increasing
risk of thrombus formation and stroke. Evidence suggests The mode of delivery for women with MS should be based
that changes in cytokine levels and diminished cytotoxic on obstetric factors. Similarly, the full choice of anaesthetic
immune response contribute to fewer flare or relapses options for delivery should be available to almost all
of autoimmune diseases, such as rheumatoid arthritis or women with MS. It is important therefore to ensure
multiple sclerosis.4 anaesthetic assessment has taken place prior to onset of
labour so these options are fully discussed with the patient.

49
 D Kevat, L Mackillop

Delivery

1.4

Pregnancy
1.2

1
Annual relapse rate

0.8

0.6

0.4

0.2

0 1 2 3 4 1 2 3 1 2 3 4 5 6 7 8
education

Trimesters before Trimesters during Trimesters after

pregnancy pregnancy pregnancy

figure 1 Risk of relapse of multiple sclerosis.8

There are concerns around the treatment of relapses Myasthenia Gravis

during pregnancy should they occur. None of the current
MS-specific drugs are approved for use during pregnancy Myasthenia gravis (MG) is twice as likely to affect women
in the US or the UK. However, no significant harm has and onset is usually between the ages of 20 and 45. The
been established. Glatiramer acetate has the most lifetime prevalence of the disease in the UK is 0.04%.13 It
reassuring data based on animal testing models (FDA is caused by polyclonal immunoglobulin G (IgG) antibodies
Category B) and a small case series.9 A recent systematic directed against the nicotinic acetylcholine receptor of
review (which included Canadian population database the skeletal muscles resulting in classic fatigable weakness,
information) did not show an increased risk of adverse ptosis, diplopia, dysphagia, dysarthria and, in severe cases,
outcomes with natalizumab. Interferon beta was associated respiratory muscle weakness. It is associated with thyroid
with premature birth.10 Glucocorticoids, usually in pulse disease and thymoma. Women requiring treatment may
dosing, can be prescribed, though use in the first trimester be taking anticholinesterases such as neostigmine and
(where organogenesis occurs) is best avoided. Intravenous pyridostigmine, which inhibit breakdown of the
immunoglobulin (IVIG) may be used throughout pregnancy, neurotransmitter. While placental transfer is likely, there
though the usual risks of using a pooled blood product has been no significant evidence of adverse fetal outcomes
apply. A higher loading dose of 60 g (over three days) among pregnant women taking these medications. Many
provides no extra benefit compared to 10 g; subsequent women with MG will require management aimed at broad
infusions can be four-weekly and reduce the risk of post- immune system dampening including IVIg, steroids,
partum relapse.11 Progestin and estradiol are currently steroid-sparing agents (e.g. azathioprine, methotrexate,
being trialled for the same purpose.12 Breastfeeding has mycophenylate), plasmapheresis and/or thymectomy.
not been consistently shown to be protective of a relapse Methotrexate is absolutely contraindicated in pregnancy
of MS in the postnatal period. As there are no definitive and mycophenolate is teratogenic and should be avoided.
data on whether disease-modifying drugs such as More than 40% of women experience exacerbations of
glatiramer, used to treat MS, enter breast milk, breastfeeding MG during pregnancy or in the post-partum period,
is considered a contraindication to treatment with these where symptoms can be particularly sudden and severe.
agents. In cases of relapse, steroids or disease-modifying The risk of exacerbation is lower in women who have
IVIG can be used, or breastfeeding ceased and disease- undergone a thymectomy.  Approximately 30% of women
modifying drugs (re-)commenced. will experience no change in symptomatology, with the

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 Neurological diseases in pregnancy

remainder experiencing improvement, particularly in the headache are tension and migraine and evidence suggests
third trimester.14 The course of the disease can vary in they tend to improve during pregnancy, although the
different pregnancies for the same individual. course can be unpredictable. Given the prevalence of
these conditions, approximately one-third of all women
Myasthenia gravis can cause a number of adverse effects will suffer symptom(s) during pregnancy, some for the first
on delivery; it has been associated with preterm delivery, time. Knowledge of management techniques, including
protracted and complicated labour and increased rates medication options in the context of the developing fetus
of caesarean section.15,16 Women with MG may tire in and lactation, is thus useful for all doctors caring for
particular in the second stage of labour, which requires pregnant women.
repeated striated muscle contraction, and may need an
Migraine
instrumental delivery and sometimes a caesarean section.
Epidural anaesthesia is permissible, but expert anaesthetic The classic features of a migraine include visual or
input is advised in planning and drug selection given the sensory symptoms prior to headache, nausea and/or
atypical pharmacokinetics and potential risk of a drug- vomiting and photophobia. ‘Hard’ neurological signs such
induced MG crisis. Beta blockers, aminoglycosides (such as aphasia and hemianopia can also accompany migraine.
as gentamicin), and opioids may increase weakness. Atypical migraines also exist, where there is minimal or
Depolarising and non-depolarising muscle relaxants can no headache. An expectant woman who suffers from
be administered in MG but at smaller doses – non- migraines is at a greater risk of hypertensive diseases
depolarising muscle relaxant (e.g. atracunium, vecuronium) associated with pregnancy.24,25 Migraine is considered to
dosing starts at a tenth of usual dose. Patients should be be a neurovascular disorder with mechanisms resulting
warned of the possible need for prolonged ventilation, in vasodilation, serotonin release, activation of n-methyl-
and kept in a high dependency unit in case of post- D-aspartate (NMDA) receptors and stimulation of the
partum worsening.17,18 peripheral and central nervous system. There is some
evidence of hormonal influences on the process – the

education
One case report suggests that ergometrine can unmask ratio of migraine incidence skews further towards
MG; another indicates that betamethasone, given to women after puberty; some migraines are triggered by
mature the fetus’ lungs, can precipitate a crisis. Magnesium menstruation and exogenous estrogen has been used to
sulphate, which is used in the treatment of pre-eclampsia successfully treat this group in research settings.26,27
and eclampsia, has also been noted to precipitate crisis.19–21 Prospective studies indicate that for between 50% and
85% of migraine sufferers, symptoms will improve during
Women with MG should be counselled about the possible pregnancy.28 Migraine without aura and menstrual migraine
effects of the disease on the fetus. Passage of antibodies are more likely to improve than migraine with aura.
from mother to fetus in utero can cause inhibition of
skeletal muscle, leading to contractures, pulmonary Migraine may be associated with the risk of pre-term
hypoplasia and polyhydramnios.  Women with high antibody delivery through co-morbid conditions (e.g. mood
titres or who have had complications due to the condition disorders) in a subgroup of patients.29 Importantly, a
in a previous pregnancy should be observed closely with number of studies have established that migraine is
regular ultrasound monitoring of total and diaphragmatic associated with approximately double the risk of
fetal movement. Persistently high titres may be lowered by developing pregnancy-induced hypertension and pre-
plasmapheresis or other methods to reduce the likelihood eclampsia; with obesity an additional risk factor. In
of arthrogryposis multiplex congenita (AMC) and the addition, research supports a strong association with
considerable risk of perinatal mortality. The same venous thrombosis, pulmonary embolism and stroke.30
mechanism can affect up to 20% of neonates. Diagnosis of There is also a well-known association between migraine
neonatal MG is usually made within 48 hours, prompted by with aura, cryptogenic (unexplained) stroke, and the
clinical suspicion of a ‘floppy baby’, poor feeding and, in presence of a patent foramen ovale.31 While the closure
severe cases, respiratory compromise. The condition can of the latter seems a ‘biologically plausible’ way of
be managed expectantly or treated with anticholinergics, reducing the risk of stroke by abolishing the risk of
and usually resolves by eight weeks and often sooner.  The paradoxical embolism, there is currently insufficient
risk of neonatal MG is higher in babies born to women evidence to recommend this practice for primary or
with high antibody titres, and is probably lower in women secondary prevention; randomised trials are underway.
who have undergone a thymectomy.22
Tension headaches

Headache Tension type headaches are characterised by mild to

moderate pressing pain that is usually bilateral. The
Headaches are a common cause of complaint for women. discomfort is often described as a ‘tightening’ and can last
With the exception of cluster headaches, women are anywhere from minutes to days. Evidence exists for a
more affected by this condition than men (migraine 3:1, variety of pathogenic mechanisms including sensitisation
tension headache 1.25:1).23 The most common types of of central nociceptors, the involvement of serotonin and

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nitrous oxide, and a precipitant role for involuntary pregnant cases, including medications such as acetalozamide
movement of muscles (including teeth clenching). and thiazide diuretics. Repeated cerebrospinal fluid (CSF)
Comparatively little data is available on the course of drainage via lumbar punctures can be tried but there is
tension headaches during pregnancy. Existing research little evidence to support this practice.
supports the view that women are more likely to
experience improvement (20–80%) rather than Non-pharmacologic therapies for headache management
deterioration and some will experience complete are worth trying, particularly in the pregnant population.
remission. Other women will experience no change, and Identification and elimination of triggers (caffeine,
a small minority will find symptoms worsen.28,32 chocolate, smoking, dehydration, sleep patterns, insufficient
exercise, psychological and physical stress) should be the
Diagnosis and management
starting point. Evidence supports the efficacy of
A thorough history and examination of the patient is biofeedback (particularly electromyography [EMG]), and
essential for diagnosis and classification of headache in acupuncture for the treatment of tension type
pregnancy and the post-partum period. The pattern of headaches.33,34 Acupuncture has also been shown to be
any associated symptoms should be carefully considered effective for the treatment of migraine.35
and investigated, as headache can be a secondary
symptom of a number of dangerous conditions in The aim of pharmacotherapy in the treatment of
pregnancy (Tables 1 and 2). primary headache in pregnancy is to reduce the severity,
duration and/or the frequency of attacks and their
table 1 Key examinations and investigations for associated symptoms.
headache in pregnancy Management of the acute attack
• Full neurological examination (including eye Paracetamol should be tried as a first-line analgesic for
examination) headache. Codeine phosphate can be used as an adjunct
education

• Blood pressure to paracetamol to increase its analgesic effect. Aspirin

• Full blood count (300 mg), acetaminophen, and non-steroidal anti-
• Electrolytes, liver and renal function tests inflammatories (NSAIDs) (e.g. ibuprofen, diclofenac)
• Clotting profile
should be avoided if possible particularly in the third
• Urinalysis and urine microscopy, culture and
sensitivity (MCS) trimester (NSAIDs in particular have been linked to
• Consider head computed tomography (CT)/magnetic fetotoxic effects on the fetal kidneys and premature
resonance imaging (MRI) scan closure of the ductus arteriosus). Stronger opioids
should only be used intermittently and avoided near full
table 2 Causes of secondary headache in pregnancy term because of the danger of maternal or fetal
dependence and neonatal withdrawal. Non-steroidal
• Infection anti-inflammatories are safe to take during breastfeeding,
• Pre-eclampsia and short-term opioid use during this period is also
• Ischaemic or haemorraghic stroke considered safe. Aspirin may also be used intermittently
• Subarachnoid haemorrhage during breastfeeding, though there is a theoretical risk of
• Idiopathic intracranial hypertension causing platelet dysfunction and Reye’s syndrome.
• Dural puncture (post-anaesthetic procedure)
• Cerebral vein thrombosis Sumatriptan is a member of a class of more selective
serotonin agonists with good efficacy for the treatment
of migraine attacks. However approximately 15% of the
Imaging may be required and should be undertaken if a drug passively crosses the placenta. There are registry
headache persists beyond 24 hours. The choice of data suggesting an association with lower birthweight,
modality of imaging depends on the indication and the but none with congenital malformations.36 It is suggested
availability in a particular institution. Although magnetic that the drug should be avoided if possible, but can be
resonance imaging (MRI) is an attractive choice due to used intermittently if the patient is having infrequent but
its lack of ionising radiation, a computed tomography severe attacks. Little data are available about pizotifen,
(CT) of the head confers negligible radiation to the fetus. another drug which should be avoided in the first
A CT is therefore usually the first-line investigation due trimester during fetal organogenesis, but may be tried in
to its availability, cost and speed compared to an MRI. the second and third trimester in those for whom other
therapies have failed. Unfortunately, most evidence of
Idiopathic intracranial hypertension is becoming an drug safety in this area is the accumulation of anecdotal
increasingly common condition due to the rise in obesity experience rather than trial data.Thus, while women can
in the obstetric population. Women with this condition be informed that these medications are often used in
should receive regular ophthalmic review during their pregnancy without adverse effects on the fetus, definitive
pregnancy. Management options are similar to non- reassurance is not possible.

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 Neurological diseases in pregnancy

Prophylaxis Epilepsy and pregnancy

Anti-emetics such as metoclopramide should be Two-thirds of women will have no change to the frequency
prescribed with analgesia if required, as nausea and of seizures during pregnancy, one in six will experience
vomiting can be as distressing as pain for patients. improvement, and one in six, deterioration.38 Those with
Prophylaxis treatment can be considered in patients poorly controlled epilepsy prior to pregnancy are more
who have frequent attacks.Although data are conflicting,37 likely to experience deterioration in their condition.
aspirin (75 mg) can be effective in some patients. Doses Epilepsy is associated with maternal deaths (0.5–1 per
of propranolol (the historic mainstay of preventative 100,000 pregnancies)39 via aspiration or the disorder itself.
treatment) should be kept to the lowest effective dose Unexplained death (sudden unexplained death in epilepsy
in order to minimise the risk of fetal growth restriction. [SUDEP]) can also occur, but rates have not been noted to
Noting the concomitant nature of depression and be different for non-pregnant women taking medications.
anxiety, medications targeted at these causes may also There is a 2–4% chance of having a seizure peri-delivery.40
be effective. Frequent headaches prior to pregnancy is This is likely due to a combination of factors, including an
strongly associated with poor health and coping increase in precipitants (tiredness, stress) and not taking or
difficulties during pregnancy and the postnatal period.29 vomiting medication during labour.

Epilepsy Long episodes of seizure activity (including status

epilepticus [SE]) can be harmful to both the fetus and
Epilepsy is a common condition, affecting 0.5% of the mother but it is relatively rare, affecting less than 2% of
population.13 Most women are aware of their condition, pregnancies.38 There is no association between epilepsy
providing an opportunity for pre-pregnancy counselling and early delivery or increased risk of obstetric
and drug optimisation in planned pregnancies. Epilepsy complications. Women who have significant seizures
may be diagnosed for the first time during pregnancy, but should deliver in a facility with on-site medical support
careful exclusion of other diagnoses and organic causes but a history of epilepsy is not an indication for induction

education
of seizures must occur (Table 3). of labour or a caesarean section.41

table 3 Possible causes of seizures in pregnancy A major and justifiable concern for women with epilepsy
is the risk that anti-epileptic drugs (AEDs) will cause fetal
• Eclampsia malformation. Rates of major congenital malformation
• Metabolic derangement (e.g. hypoglycaemia,
(MCM) are higher in women taking AEDs, with a greater
hyponatremia)
• Drug withdrawal risk of malformation for women taking sodium valproate
• Intracranical lesion or mass (e.g. arteriovenous alone (6%), or on polytherapy (6%), and particularly those
malformation becoming larger with increased on polytherapy regimes containing valproate (9%).42 Most
blood flow) studies indicate that the overall risk of MCM for women
• Ischaemic or haemorrhagic stroke on monotherapy (excluding valproate and topiramate) is
• Epilepsy approximately 3% (Table 5). Exposure to AEDs has been
• Cerebral vein thrombosis associated with orofacial clefts, congenital heart disease,
neural tube defects, dysmorphic facial features and
delayed cognitive development.
Diagnosis
Management
Given the broad and potentially life-threatening causes of
seizures in pregnancy, it is essential that a full patient Pre-pregnancy counselling is an important but sometimes
history is gathered, a complete examination performed neglected area of medical practice. Many women with
and any investigations are carried out as needed (Table 4). epilepsy will consider pregnancy at some point and thus
a proactive conversation (e.g. at time of an annual review,
table 4 Key examinations and investigations for seizures contraceptive prescription or cervical smear result)
in pregnancy asking patients to seek medical advice at the appropriate
time is warranted. Women may stop taking AEDs
• Neurological and cardiovascular examination
without seeking medical advice because of concerns
• Blood glucose
• Full blood count
about malformations. While the risk of MCM is a real
• Electrolytes, liver and renal function tests one, it must be weighed against the risks of increased
• Clotting profile seizure activity.
• Urinalysis
• Consider head computed tomography (CT)/ For most women, staying on the AEDs will be an
magnetic resonance imaging (MRI) and appropriate course of action.Those on sodium valproate
electroencephalogram (EEG) may consider changing to an AED with a lower MCM
rate, or have their dose split (to three times a day) and
ideally reduced to the minimum required for seizure

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table 5 Rates of major congenital malformation in six different studies42

Valproate Carba- Lamotrigine Pheno- Phenytoin

mazepine barbital
International Lamotrigine Pregnancy – 35/1,558 (2%)
Registry
Finnish Medical Birth Registry and drug 28/263 (11%) 22/805 (3%) – 1/38 (3%)
prescription databases
Swedish Medical Birth Registry* 29/619 (5%) 35/1,318 (3%) 26/867 (3%) 8/119 (7%)
UK Epilepsy and Pregnancy Registry 44/715 (6%) 20/900 (2%) 21/647 (3%) 3/82 (4%)
North American AED Pregnancy 30/323 (9%) 31/1,033 (3%) 31/1,562 (2%) 11/199 (6%) 12/416 (3%)
Registry
International Registry of Antiseptic 98/1,010 (10%) 79/1,402 (6%) 37/1,280 (3%) 16/217 (7%) 6/103 (6%)
Drugs and Pregnancy (EURAP)
Data are number with major congenital malformation/number exposed to antiepileptic drug monotherapy (%).
Källén K, University of Lund, Sweden. Personal communication.
*

AED= Anti-epileptic drug

control and less than 1,200 mg total daily dose. If drugs should be easily accessible. Women with a very
possible, those on polytherapy should have the number of high risk of seizures at this time can be managed with
drugs they are on reduced, but this may depend on their additional clonazepam, clobezam or phenytoin around
seizure history. All women should have baseline drug the time of delivery.
levels taken, be prescribed high-dose folic acid (5 mg) pre-
education

conceptually and for at least the first trimester, and be After delivery, any AED drug dose increased over
advised to avoid having baths or swimming alone. pregnancy should be decreased over the next one to
Screening for congenital malformation should be offered four weeks. Although small amounts of most AEDs are
to all women on AEDs. expressed in breast milk, the overall benefits outweigh
risks and women should be encouraged to breastfeed.
Women taking AEDs with minimal protein binding such Lamotrigine is measured in expressed breast milk at
as lamotrigine and carbamazepine may need to have much higher levels and is not eliminated quickly in the
drug doses increased, the former usually by 25%43 to newborn. Rarely, some babies may become excessively
50% of the pre-pregnancy dose. This is to ensure drowsy as a drug effect – feeding prior to ingesting
therapeutic levels of free drug concentration in the medication should be tried as plasma drug levels will be
context of increased plasma volume and hepatic and at their lowest. Mothers and their partners should be
renal clearance. Other drugs may also need their doses informed of the risks and management techniques for
adjusted because of the altered pharmacokinetics of seizures at this time. Babies should be bathed when the
pregnancy. With the exception of lamotrigine, usual mother is accompanied by another person. Nappy and
practice is to be guided in dose increases by seizure clothes changes should be done on the floor, and
symptomatology rather than drug levels. Women should co-sleeping is discouraged. Sleep deprivation can trigger
be reassured that fetal exposure will remain at low seizures and thus family members should be informed of
levels despite dose increases. the importance of placing the mother in the recovery
position, preventing choking and be provided with
Although little evidence supports the practice, women on seizure termination drugs if needed.
enzyme-inducing drugs such as carbamazepine and
phenytoin are often given oral vitamin K during the last Eclampsia
month of pregnancy to reduce the risk of maternal
haemorrhage at the time of delivery and to increase fetal Pre-eclampsia is a dangerous disease confined to
levels of vitamin K-dependent clotting factors. pregnancy, which occurs after 20 weeks gestation and
Intramuscular vitamin K should be given to all neonates has a diverse range of manifestations. The historical triad
to reduce the risk of haemorraghic disease of the of hypertension, oedema and proteinuria are common,
newborn which can be caused by insufficient vitamin but modern diagnostic criteria are more sophisticated
K-depending clotting factors. and do not require all of these to be present.44

All AEDs should be taken up to and including during Eclampsia is a tonic-clonic seizure associated with pre-
delivery. Peri-delivery seizures that are longer than 30 eclampsia. Current research indicates that the seizure
seconds should be terminated with a benzodiazepine. may result from cerebral vasospasm and/or hypertensive
In delivery planning this should be documented, and encephalopathy. The middle cerebral artery may not

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 Neurological diseases in pregnancy

autoregulate a rising blood pressure affecting the table 6 Key factors contributing to an increased risk of
parietal regions. Sympathetic control of the basilar stroke during pregnancy
arterial symptoms is poor, resulting in the supplied
Haematologic A rise in the levels of factor VIII, IX, X
parietal and occipital areas being at risk of autoregulatory
and fibrinogen and a decrease in the
failure and being most affected by hypertension.45 levels of antithrombin and protein S
Cardiac A large rise in cardiac output, increased
Along with headache, visual disturbance is a common
blood vessel distension, compromised
premonitory symptom. Cortical blindness is a rare but venous return, risk of hypertension
established complication associated with eclampsia, but and vasospasm in hypertensive diseases
fortunately resolves in some cases. More than a third of pregnancy; a higher incidence of
of eclamptic seizures occur post-partum, necessitating arrhythmias
continued vigilance after delivery. While the risks of Endocrine An increase in estrogen-mediated
eclampsia are higher in cases of severe pre-eclampsia, cholesterol and the potential for
it is not the ‘final’ stage in a temporal sequence or the women in a diabetogenic state to
‘culmination’ of worsening symptoms and signs. Indeed, result in gestational diabetes
two-thirds of women in the UK do not have established Surgical A caesarean section or other surgery/
hypertension or proteinuria in the week prior to their procedures
first seizure. A fifth of women have a seizure outside of
hospital.46 A first seizure after 20 weeks gestation Most estimates of the number of strokes associated with
should prompt consideration of eclampsia/pre- pregnancy place the risk between 4 and 40 per 100,000
eclampsia as a diagnosis. pregnancies, with variation depending on country,
diagnostic certainty (clinical signs vs imaging),48–50 whether
Eclampsia constitutes an obstetric emergency. Women the post-partum period has been included, and potential
should be transferred to an area of the ward which has selection bias as suggested by hospital type. Recent US

education
sufficient medical and nursing care. Together with blood registry data have been at the lower end of this range but
pressure control, intravenous magnesium sulphate trending upward from 13 to 29 per 100,000 deliveries
should be commenced without delay. A loading dose of between 1994 and 2007.51 Recent UK data, collected
4 g should be given followed by an infusion of 1 g per using a different methodology estimated a rate of 1.5
hour. If a further seizure occurs, a bolus of 2 g can be strokes per 100,000 deliveries, though the post-partum
given and serum magnesium levels should be checked period was excluded in this study, and there was an
regularly – the therapeutic range is 2–4 mg/L. The acknowledged risk of a degree of under-ascertainment.50
infusion is usually stopped 24 hours after delivery or
post-partum seizure. Clinical judgement should be used Stroke is a rare event in pregnancy but can have a
in cases of antepartum or post-partum cerebral irritation devastating impact on a woman’s life, and her ability to
– agitation, confusion, drowsiness, hyperreflexia and care for her child. Post-stroke mortality has been found
headache. Magnesium can be used for primary to be higher in pregnant compared to non-pregnant
prophylaxis. As pre-eclampsia only begins to resolve after women, with an overall case fatality rate of 20% (50% for
delivery of the placenta, plans to expedite this should be haemorrhagic stroke).52
made. This should occur only after the mother’s condition
Haemorrhagic stroke
is stabilised with adequate blood pressure control, seizure
prophylaxis and reversal of any coagulopathy. As in any Hypertension is the single most important treatable risk
high-risk situation, ongoing monitoring of the fetus and the factor for haemorrhagic stroke in pregnancy; progressively
mother’s vital signs is required until the situation resolves. higher blood pressures are associated with increasing
The mother should receive post-partum blood tests (full risk level. Blood pressure should be kept below 160/110
blood count, electrolytes, renal and liver function, clotting mm Hg; measurements above this are a medical
profile, electrolytes and urinalysis) to ensure results are emergency in the obstetric population. Low dose aspirin
trending towards improvement. Thromboprophylaxis is (<150 mg) as prescribed to reduce the risk of pre-
important for these high-risk patients. clampsia is not associated with a significant increase in
risk of haemorrhagic stroke. Women with known
Stroke arteriovenous malformations should discuss their
condition with a neurologist or neurosurgeon. Some
While ischaemic stroke is more common (5:1) outside studies suggest that the risk of rupture during pregnancy
pregnancy, haemorrhagic stroke is more likely during (approximately 3.5–5.8%) is higher than the background
pregnancy.30,47 In addition to the usual vascular risk factors, risk though one small recent study recorded a rate of
a number of changes during pregnancy (Table 6) contribute 8.1%.53,54 There is an increased risk of bleeding in
to increased risks of stroke.The third trimester and post- pregnancy with larger malformations and if there has
partum period are the times of highest risk. been bleeding before. If a pregnancy is being planned then
required procedures may be done before conception.

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Women who suffer a haemorrhagic stroke should be resonance imaging/venography (MRI/V). Management is
seen urgently by a neurologist and admitted to an acute by hydration and anticoagulation with heparin and
stroke unit for multi-disciplinary care. appropriate symptomatic control.
Ischaemic stroke
Neuropathies
Some women will be at a higher risk of thrombotic or
ischaemic stroke due to known factors such as previous There is a greater incidence of entrapment neuropathies
unprovoked thrombosis, thrombophilias (in particular during pregnancy. Carpal tunnel syndrome affects at
antiphospholipid antibody syndrome), or who have a least 2% of pregnant women57 and usually manifests as
mechanical heart valve. Comprehensive guidelines for pain, numbness or parasthesia of the index and long
assessing these risks as well as management fingers and adjacent surfaces of the thumb and ring
recommendations are available.55 Management can finger. A recent systematic review identified a wide and
include aspirin, prophylactic or therapeutic unfractionated higher incidence of the condition (up to 43%) depending
heparin or low molecular weight heparin or warfarin on diagnostic criteria.58 It is precipitated by compression
throughout the entirety of the pregnancy, or a mixed of the median nerve in the carpal tunnel of the wrist, and
regime to minimise the chance of warfarin embryopathy. is treated with simple analgesia and/or wrist splints.
Warfarin and heparin are considered safe for Local steroid injections should be reserved for severely
breastfeeding mothers. No significant data are available affected patients; most cases will resolve post-partum.
on the other antiplatelet agents such as clopidogrel for
stroke prevention in pregnancy. The management of Post-partum dysfunction of nerves of the lumbosacral
anticoagulation during delivery can be challenging and is plexus can manifest in altered sensation and motor
beyond the scope of this paper but may be planned by function in the legs – the most common lesion is of the
elective delivery. Caesarean sections should be reserved peroneal nerve, causing foot drop. Short primigravidas,
for obstetric indications. forceps delivery, narrow pelvis, large fetal head, and
education

occipito-posterior position are risk factors.59 Prolonged

Recent evidence shows that only 20% of pregnant squatting should be avoided to minimise pressure from
women in the UK who suffer a stroke in pregnancy are the fibular head on the nerve. Management is with
seen urgently by a neurologist and admitted to an acute physiotherapy and orthotics/boots if needed.
stroke unit even though this has been demonstrated to
improve outcomes.50 There are a number of case reports Bell’s palsy, a unlilateral lower motor lower palsy, may be
of successful thrombolysis in acute stroke in pregnancy, more common in pregnancy, and affects between 0.02–
but no high quality studies. There have also been reports 0.05%. of women.60,61 Symptoms and prognosis are the
of a number of intracranial haemorrhages in this same as outside pregnancy. If steroids are being
population following lysis; the decision to thrombolyse considered, Ramsay Hunt syndrome should be excluded
or not is therefore extremely challenging.  Aspirin should by ear examination. Prednisolone (which can be safely
be prescribed to all pregnant women for secondary given in pregnancy) can speed recovery and reduce the
prevention of stroke. severity of symptoms if instituted within 48 hours; more
than 90% of cases will resolve spontaneously over a
Cerebral Vein and Sinus Thrombosis period of months.62

Cerebral vein thrombosis occurs more commonly in Conclusion

pregnancy (11.6 per 100,000 deliveries) and is associated
with high morbidity and mortality;56 in some developing Neurological conditions are a significant source of
countries the rate is reported to be more more than morbidity and mortality in pregnancy. Pregnancy does
ten times higher due to infection, dehydration, anaemia, constitute a ‘special circumstance’ partly due to altered
vegetarian diet and higher homocysteine levels. The physiology and the need to consider specific issues such
diagnosis should be considered in any pregnant patient as mode of delivery, anaesthesia, the second stage of
presenting with the signs or symptoms of stroke – labour and breastfeeding. However, most neurological
raised intracranial pressure, headache, photophobia, conditions are managed in a similar manner to outside of
vomiting and/or fever. Pathogenesis likely involves the pregnancy. Communication and planning, including pre-
interaction between the hypercoagulable state of pregnancy counselling, are key to successful management.
pregnancy and micro trauma to the endothelium of For this reason women should be managed by a multi-
cerebral veins and sinuses. It is important to distinguish disciplinary team consisting of a neurologist, obstetrician,
cases of pseudotumour cerebri where symptoms are anaesthetist, midwife and general practitioner, contributing
secondary to raised intercranial pressure of unknown to optimum outcomes for mother and baby.
aetiology, as steroids may be used with good clinical
effect in the latter condition. Suspected cerebral vein
thrombosis should ideally be investigated by magnetic

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 Neurological diseases in pregnancy

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Senior fellows’ club prize

The Senior Fellow's Club Prize for 2012 has been won by DM Wood and colleagues
for their paper on ‘Intravenous fluid use in the acutely unwell adult medical inpatient:
improving practice through a clinical audit process’. This can be read in issue 3 2012
at http://www.rcpe.ac.uk/journal/issue/journal_42_3/wood.pdf

A prize of £250 will be awarded to the first-named (or corresponding) author of

an original research paper on a clinical topic, deemed by a panel of judges to be the
best paper by a doctor-in-training (i.e. pre-consultant level) published in The Journal
of the Royal College of Physicians of Edinburgh in 2013. The best paper will be selected
by a panel of judges, including a senior Fellow, an active clinician and a member of the
editorial team.
Further details may be obtained from the Editorial Office, RCPE, 9 Queen Street, Edinburgh, EH2 1JQ,
tel 0131 247 3652 or email editorial@rcpe.ac.uk.

58 J R Coll Physicians Edinb 2013; 43:49–58

© 2013 RCPE