Epilepsy in Pregnancy

Epilepsy has a prevalence of 0.5–1.0% and affects 50 million people globally, of whom 15 million are women of reproductive age. While most women with epilepsy will have uncomplicated pregnancies and healthy children, there is evidence for an increased risk of complications, including increased maternal mortality and adverse outcomes in their babies. Advice for women should be individualised and influenced by having identified and stratified the risks for each pregnancy (Craig, 2021). There is about a 4-fold increase in the risk of epilepsy in infants of women with epilepsy.

According to statistics from both the USA and Denmark, the risk of maternal mortality in women with epilepsy is probably 5–10 times higher than background. The MBRRACE-UK report showed a similar increase in mortality. During 2016–2018 in the UK and Ireland, 22 women died from causes related to epilepsy during or up to a year after the end of pregnancy (Craig, 2021). Six of nineteen of those women with available records were prescribed lamotrigine monotherapy and a recent case–control study from Norway found that lamotrigine was associated with an increased risk of sudden unexplained death in pregnancy (Craig, 2021).

Use of medication to control epilepsy ranges from 4 to 9 per 1,000 or about 0.5-1% of the population. In Australia, approximately 1,500 to 2,000 women on antiepileptic drugs become pregnant per year. Most women with epilepsy continue taking antiepileptic drugs in pregnancy to prevent the harmful effects of seizures. Most women who have epilepsy do not have a seizure during pregnancy and have healthy pregnancies and healthy babies. Although patients taking a higher drug load were more likely to have seizures in the first trimester (35%) than those taking monotherapy (15.3%), seizure freedom during pregnancy varies according to the antiepileptic drug used, with the lower rates seen with lamotrigine (58.2%) compared to 75% with valproate, 67.35% with carbamazepine, or 73.4% with phenobarbital (Craig, 2021). In this study, the lamotrigine cohort had significantly more convulsive seizures (21.1%) than those taking valproate (11.5%). These results have been challenged by smaller trials of women who were more closely scrutinised with anti-seizure medication serum concentrations and tighter control of their antiepileptic medication dose (Pennell, French, May et al, 2020).

Any woman who presents prenatally or antenatally with the history of a seizure in the previous year or who takes anti-seizure monotherapy should at the outset be referred to a neurologist, as their risk of a seizure during pregnancy is highest (Craig, 2021).

Pronounced alterations have been reported in the apparent clearance of lamotrigine, with an increase of > 300% from baseline in late pregnancy in some patients on monotherapy, most likely due to enhanced metabolism. The available data suggest that the corresponding decline in plasma concentrations can be associated with loss of seizure control. More limited data indicate that a similar decline in plasma concentrations of the active monohydroxy derivative of oxcarbazepine may occur in late pregnancy. Preliminary experience also suggests that a significant fall in plasma concentrations of levetiracetam may occur during pregnancy. No systematic information is available on the pharmacokinetics during pregnancy of other newer AEDs such as gabapentin, pregabalin, tiagabine, topiramate or zonisamide (Tomson, 2007). 

Lamotrigine changes in pregnancy and postpartum period

Author	Comparative measure	Preconception	Trimester 1	Trimester 2	Trimester 3	Post-partum (time of sample)
Pennell et al	Increase in clearance cf preconception		91% (±107%)	149% (±142%)	261% (±194%)	50%±69%
Fotopoulou et al	Median ratio lamotrigine dose: serum (1st and 3rd quartiles)	39 (39–41)	77 (68–154)	92 (76–167)	97 (74–110)	35 (35–36) (at 3 weeks)
Petrenaite et al	Mean ratio serum lamotrigine: dose	63.5±30.8	46.7±18.3	22.1±5.4	21.7±7.1	70±10 (at 6 weeks)
de Haan et al	Mean ratio serum lamotrigine concentration to dose (as percentage of preconception baseline)		82%±14%	51%±14%	97%±15%	48%±10%
Öhman et al	Mean ratio lamotrigine dose: plasma				227±74	66.5±17.9

The obstetric risks associated with epilepsy include pregnancy-induced hypertension, pre-eclampsia, antepartum and postpartum haemorrhage, induction of labour and instrumental deliveries.

Adjusted OR of maternal complications in patients with epilepsy

	Adjusted OR	95% CI
Maternal death	11.46	8.64 to 15.19
Induction of labour	1.14	1.12 to 1.16
Pregnancy-related hypertension	1.30	1.27 to 1.33
Pre-eclampsia	1.59	1.54 to 1.63
Seizures with pre-eclampsia	5.18	4.65 to 5.77
Antepartum haemorrhage	1.38	1.31 to 1.45
Severe postpartum haemorrhage	1.76	1.61 to 1.93
Gestational diabetes	1.11	1.07 to 1.15
Preterm labour	1.54	1.50 to 1.57
Chorioamnionitis	1.17	1.11 to 1.23
Poor fetal growth	1.68	1.61 to 1.750
Fetal distress	1.04	1.02 to 1.06
Stillbirth	1.27	1.17 to 1.38

An awareness by women of the potential for harm resulting from prenatal exposure to antiseizure medications may lead to reduced adherence and account for some loss of efficacy in pregnancy. Around 40% of women with epilepsy have low adherence to antiseizure medications during pregnancy, which is worse than for treatments prescribed to pregnant women with other chronic conditions. The extent of this pregnancy-related drop in adherence is variable and unpredictable (Craig, 2021).

For most women with epilepsy, the frequency of seizures does not increase during pregnancy. The International Registry of Antiepileptic Drugs and Pregnancy (EURAP) reported in 2006 on 1882 women with epilepsy whose seizure control and treatment were prospectively recorded: 58% of participants were seizure-free during pregnancy; and seizure frequency and AED treatment remained unchanged in 62–64%. The APR also found that pregnancy had little impact on seizure frequency among treated women. A 12-month seizure-free period before pregnancy was associated with a 50–70% reduction in seizure risk during pregnancy (compared to matched controls). Many women who experience increased seizure frequency are sleep-deprived or non-compliant because of concerns about the effects of the medication on the developing fetus. Altered AED pharmacokinetics may also contribute to change in seizure frequency during pregnancy.

Pregnancy also induces significant physiological and metabolic changes. Further, absorption of AED medications can be reduced by changes in intestinal motility or sustained vomiting, while changes in volume of distribution and protein binding could in theory reduce antiseizure medication concentrations and in some cases necessitate measurement of free serum concentrations. (Craig, 2021) Antiseizure medication metabolism may increase, particularly of those metabolised through glucuronidation (e.g., lamotrigine, oxcarbazepine and valproate), although the extent of this change during pregnancy varies considerably between individuals and is difficult to predict (Craig, 2021). Increases in renal blood flow and glomerular filtration rate are most prominent in the first two trimesters. This can lead to reduced concentrations of those antiseizure medications that are mainly excreted renally (e.g., gabapentin, levetiracetam and pregabalin) and may partly explain the pronounced increase in clearance of lamotrigine and its N2-glucuronide metabolite (Craig, 2021).

Effect of pregnancy on individual antiseizure medications (Craig, 2021):

	Elimination	Decrease in serum concentration during pregnancy
Carbamazepine (Tegretol)	Hepatic	0-42%
Gabapentin	Renal—unchanged	Insufficient data
Lamotrigine (Lamictal)	Hepatic glucuronidation
Levetiracetam (Keppra)	Renal > hydrolysis	40-60%
Oxcarbazepine monohydroxy Derivative	Hepatic glucuronidation of active metabolite	28-36%
Phenytoin (Dilantin)	Hepatic	56-61%
Phenobarbital	Hepatic	50-55%
Primidone	Derived from phenobarbital	70%
Topiramate (Topamax)	Mainly renal – unchanged	13-40%
Valproate (Epilim)	Hepatic glucuronidation	0-28%
Zonisamide (Zonegran)	Mainly hepatic, 15-30% renal unchanged	40-50%

Retrospective studies report a 2 to 3-fold increase in adverse pregnancy outcomes for women on antiepileptic drugs. These include:

• miscarriage
• major congenital malformations – neural tube defects, orofacial defects, congenital heart abnormalities, and hypospadias
• minor congenital anomalies – hypertelorism, epicanthic folds, and digital hypoplasia
• microcephaly
• intrauterine growth restriction

Pregnant women with untreated epilepsy are not at increased risk of having a baby with a birth defect.

In addition to concerns about fetal exposure to AEDs, there are risks to the fetus from maternal seizures and maternal epilepsy. It is important to reassure women who do require AEDs that they are not at increased risk of having a baby with a birth defect. Although the fetus is relatively resistant to short hypoxic episodes, prolonged convulsive seizures may result in sustained fetal hypoxia. Protecting the fetus from the consequences of frequent or sustained seizures is a compelling argument for maintaining AED use during pregnancy. Additional risks of maternal seizures include injury to the fetus, abruption, or miscarriage due to maternal trauma sustained during a seizure.

The efficacy of lamotrigine during pregnancy has been particularly scrutinised of late. Pronounced alterations have been reported in the apparent clearance of lamotrigine, with an increase of > 300% from baseline in late pregnancy in some patients on monotherapy, most likely due to enhanced metabolism. This pharmacokinetic variability during pregnancy is of clinical significance. The available data suggest that the corresponding decline in plasma concentrations can be associated with loss of seizure control. More limited data indicate that a similar decline in plasma concentrations of the active monohydroxy derivative of oxcarbazepine may also occur in late pregnancy. Preliminary experience also suggests that a significant fall in plasma concentrations of levetiracetam may occur during pregnancy. No systematic information is however available on the pharmacokinetics during pregnancy of other newer AEDs, such as gabapentin, pregabalin, tiagabine, topiramate or zonisamide (Torbjorn and Baltino, 2007).

Lamotrigine changes in pregnancy and postpartum period

Author	Comparative measure	Preconception	Trimester 1	Trimester 2	Trimester 3	Post-partum (time of sample)
Pennell et al	Increase in clearance cf preconception		91% (±107%)	149% (±142%)	261% (±194%)	50%±69%
Fotopoulou et al	Median ratio lamotrigine dose: serum (1st and 3rd quartiles)	39 (39–41)	77 (68–154)	92 (76–167)	97 (74–110)	35 (35–36) (at 3 weeks)
Petrenaite et al	Mean ratio serum lamotrigine: dose	63.5±30.8	46.7±18.3	22.1±5.4	21.7±7.1	70±10 (at 6 weeks)
de Haan et al	Mean ratio serum lamotrigine concentration to dose (as percentage of preconception baseline)		82%±14%	51%±14%	97%±15%	48%±10%
Öhman et al	Mean ratio lamotrigine dose: plasma				227±74	66.5±17.9

The obstetric risks associated with epilepsy include pregnancy-induced hypertension, pre-eclampsia, antepartum and postpartum haemorrhage, induction of labour and instrumental deliveries.

Adjusted OR of maternal complications in patients with epilepsy

	Adjusted OR	95% CI
Maternal death	11.46	8.64 to 15.19
Induction of labour	1.14	1.12 to 1.16
Pregnancy-related hypertension	1.30	1.27 to 1.33
Pre-eclampsia	1.59	1.54 to 1.63
Seizures with pre-eclampsia	5.18	4.65 to 5.77
Antepartum haemorrhage	1.38	1.31 to 1.45
Severe postpartum haemorrhage	1.76	1.61 to 1.93
Gestational diabetes	1.11	1.07 to 1.15
Preterm labour	1.54	1.50 to 1.57
Chorioamnionitis	1.17	1.11 to 1.23
Poor fetal growth	1.68	1.61 to 1.750
Fetal distress	1.04	1.02 to 1.06
Stillbirth	1.27	1.17 to 1.38

The treatment goal in pregnancy is to maintain a balance between an effective but low dose of a single antiepileptic drug (AED) and the harmful effects of seizures. 

In women with epilepsy, especially those taking AEDs, an ultrasound examination at 11–13 weeks should be offered. If acrania (the precursor of anencephaly) or increased nuchal translucency (useful screen for cardiac and other structural defects) is found, an early referral should be made to the obstetrician. At mid-pregnancy, an expert morphological assessment should be performed. Notes on the history of the epilepsy and the medication regimen should be made on the referral so that a targeted assessment, particularly of the neural axis, heart and face, can be performed.

Recent evidence suggests no greater risk of major congenital malformations (MCMs) associated with lamotrigine when compared with untreated pregnancies in women with epilepsy. Although lamotrigine monotherapy was not associated with MCMs, in one study it was associated with the loss of two babies after status epilepticus or prolonged seizures after VPA withdrawal and replacement with lamotrigine. It is important to balance this lower risk of association with teratogenic outcomes against efficacy in controlling seizures. The aim should be to have seizure control for at least 6 months before conception and, if possible, cease or use the lowest effective dose of a single anticonvulsant according to the type of epilepsy. Medications should be taken in divided doses, avoiding high peak levels, and once pregnancy is established, medications should not be changed. Women with epilepsy who are contemplating pregnancy should also be advised to have 5 mg of folic acid/day for at least 1 month before conception and throughout the first trimester.

There has been increasing concern regarding the potential adverse effect of AEDs on fetal cognitive development. The risk of structural malformations is essentially confined to the first trimester, whereas effects of AEDs on cognitive development can occur throughout gestation. In a large-scale population-based study on early developmental outcomes in offspring of parents with epilepsy, exposure to AEDs during pregnancy was associated with adverse development (gross motor skills, sentence skills, autistic traits) at 18 and 36 months of age. The NEAD follow-up study at 6 years showed that fetal exposure to VPA has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. An investigation by Christensen et al provides the strongest evidence to date that fetal exposure to VPA is associated with increased risks of autism and autism spectrum disorder.

Advise all women with epilepsy of childbearing age that the risk of failure of oral contraceptive agents is increased several-fold if they are taking an enzyme-inducing antiepileptic drug (e.g., phenobarbital, phenytoin, carbamazepine, or primidone). The oral progestogen-only pill or progesterone implant (Implanon) is unreliable contraception for women on the enzyme-inducing anticonvulsants but acceptable for women on the others, with the exception of lamotrigine. Combined oral contraceptives may increase lamotrigine’s metabolism, decreasing its concentration and efficacy. Medroxyprogesterone acetate depot injection can be used, and most guidance suggests shortening the usual 12 weeks interval to 10 weeks for women taking enzyme-inducing AEDs. Levonorgestrel IUD (Mirena) is also a useful contraceptive in these circumstances. Sequential pills or combined pills containing less than 50 micrograms of oestrogen may be associated with an increased incidence of breakthrough bleeding, or contraceptive failure, and should be avoided. Women taking enzyme-inducing AEDs and the combined oral contraceptive should be advised: to take at least 50 micrograms of ethinyloestradiol (e.g., Microgynon 50) and to report any breakthrough bleeding. If breakthrough bleeding occurs the dose of ethinyloestradiol can be increased to 80 – 100 micrograms.

The enzyme-inducing antiepileptic drugs include:

• Carbamazepine
• Oxcarbazepine
• Phenobarbitone
• Phenytoin
• Primidone
• Topiramate

Enzyme inducing antiepileptic drugs are known to cross the placenta and promote oxidative degradation of vitamin K1 in the fetus. Consider antenatal prophylaxis with oral vitamin K1 20 mg per day in the last 4 weeks of pregnancy if enzyme-inducing drugs are used (Konakion MM ampoules 10 mg / 1 mL have Therapeutic Goods Administration [TGA] approval for oral use). If vitamin K1 has not been given antenatally, administer intravenous vitamin K1 10 mg by slow injection over 5 minutes in labour or threatened preterm labour. The findings of several case control studies challenging previous recommendation of vitamin K administration in late pregnancy have formed the basis of some consensus statements (e.g., NICE guidelines) that no longer recommend vitamin K supplementation for women with epilepsy receiving EIAEDs in late pregnancy, but rather administration of phytomenadione to the neonate.

Two to four percent of women with epilepsy will have a tonic-clonic seizure during labour or in the first 24 hours after labour. For these women, the:

• Tonic clonic seizures may result in fetal hypoxia
• Birth should be arranged in a hospital with facilities for emergency caesarean section and maternal and neonatal resuscitation
• Continue oral anticonvulsants
• Ensure intravenous access
• Paediatrician / neonatologist present at the birth

Women who have missed their anticonvulsant doses for more than 12 hours may need a parenteral dose. Consult a physician or neurologist. Phenytoin and phenobarbitone are the only parenteral antiepileptics. If the woman is on a different anticonvulsant, she will require a phenytoin loading dose of 15–20 mg/kg followed by maintenance doses of 8 mg/kg/day; that is, approximately 300 mg twice daily intravenously or orally.

Parenteral antiepileptics are indicated for the emergency treatment of convulsive-status epilepticus. They are also used for women in labour who have missed their anticonvulsant dose for more than 12 hours or are vomiting and unable to take their usual oral anticonvulsant medication. In these cases, consult with physician or neurologist. Magnesium sulphate is the drug of choice for treating eclampsia and pre-eclampsia:

Phenytoin

Phenytoin is available in ampoules containing 50 mg per mL concentrations of phenytoin sodium (100 mg/2 mL and 250 mg/5 mL ampoules). Administer phenytoin undiluted and without any other medications or fluids.

Precautions in the use of phenytoin:

• patients with hypotension and severe myocardial insufficiency
• dose reduction may be required in hepatic impairment

Contraindications to phenytoin use include:

• Hypersensitivity syndrome with phenytoin, carbamazepine or phenobarbitone
• Porphyria
• Sinus bradycardia, sinoatrial block, second- and third-degree atrioventricular block, Stokes-Adams Syndrome

Single-dose administration:

• Women not currently taking phenytoin can be given a single high bolus (‘loading’) dose
• The single high-bolus dose for women not already on phenytoin is 15–20 mg/kg (Australian Medicines Handbook 2014)
• In patients already taking phenytoin orally, their total daily dose can be given intravenously (instead of oral) according to the following administration regimen (usually around 5–10 mg/kg)

For women taking sodium valproate pre-pregnancy, consideration should be given to a suitable alternative agent if appropriate. Most experts currently recommend high dose folic acid for women taking antiepileptic medication i.e., 5 mg/day (10 times the prophylactic dose) for 1 month before conception and continue during the first trimester. Genetic counselling is required if both parents have epilepsy or the disease is inherited. Aim for seizure control at least 6 months before conception and, if possible, cease or use the lowest effective dose of a single anticonvulsant according to the type of epilepsy.

Once pregnancy is conceived, arrange review by a neurologist or specialist physician:

• Obtain complete blood picture and serum folate levels
• Explain the importance of continuing anticonvulsant medication when this is necessary because of the maternal and fetal risks associated with convulsions
• Women should be re-assured that there is no evidence that simple partial, complex partial, absence and myoclonic seizures affect the pregnancy or developing fetus adversely unless they fall and sustain an injury
• Monitor plasma anticonvulsant levels (not useful for valproate) every 1 to 2 months. If there is deterioration in seizure control, adjust dose accordingly

Women should be seen by the neurologist to adjust the AED dose. Maternal plasma levels of AEDs may fluctuate up until the eighth postpartum week and monitoring of plasma AED levels may be required. AED requirement is likely to fall in the puerperium and toxicity may occur if the dose is not adjusted. Lamotrigine and oxcarbazepine doses in particular may need to be reduced postpartum.

All AEDs are secreted in the mother’s milk; the newer AEDs are found in higher concentrations than the older ones. The benefits of breastfeeding must be balanced against the possible adverse effects of AEDs in the baby. It may be preferable for mothers taking lamotrigine and levetiracetam to abstain from breastfeeding.

Appropriate counselling for contraception and advice regarding minimising the risk of seizures at home should be given to the woman and her family. This involves reinforcing the importance of medication compliance and adequate sleep. Offer advice to women at risk of further seizure activity to minimise any injury risk to baby. Tell them that they can minimise any risk of injury to the baby can be accomplished by:

• mother to feed baby while she is seated low or on floor
• bath baby with another person present whenever possible
• minimise carrying the baby
• use a pram with an automatic brake

Classification of epileptic seizures according to clinical type

Partial (focal, local) seizures
Simple partial seizures (SPS)
Temporal lobe SPS are the most common type of SPS	Symptoms can include: An ‘epigastric rising sensation,’ Dèjá vu (the feeling of “having been here before”) or jamais vu (where familiar things seem new); a flashback of memory; a sudden, intense feeling of fear or joy; a funny taste or smell
Frontal lobe SPS can be harder to describe	Some people experience: strange movements; a feeling of a wave going through the head or body; stiffness or jerking of part of the body that might start in one place, for example the face, and spread to other parts of the body
Parietal lobe SPS	Often include strange sensations such as: Numbness or tingling; burning sensations or a feeling of heat; a feeling that part of the body, an arm or leg, is bigger or smaller than they really are
Occipital lobe SPS	Involve visual sensations, such as: Distortion or loss of vision; seeing flashing lights or coloured shapes; seeing people or objects that are not there (hallucinations)
Complex partial seizures (CPS)
Temporal lobe CPS	Most common CPS Automatisms such as lip-smacking or chewing movements, or rubbing, stroking or fiddling with their hands;Or looking from one side to another in a confused way
Frontal lobe CPS	Often much shorter than temporal lobe CPS, usually lasting about 15-30 seconds: Make strange postures with their arms or legs; orMake juddering movements
Generalised seizures (convulsive or non convulsive)
Tonic-clonic seizures	Tonic–clonic seizures involve a tonic phase, in which the muscles suddenly contract, causing the person to fall and lie rigid. Up to a minute later, the seizure enters the clonic phase, when the muscles begin to alternate between relaxation and rigidity. The person may lose bowel or bladder control. The seizure usually lasts for 2–3 minutes, after which the person remains unconscious for a while. On waking, the person is likely to have a headache and to be confused and tired
Clonic seizures	A series of myoclonic contractions that regularly recur at a rate of 0.2 – 5/second
Atonic seizures	Cause a loss of postural tone. The result is loss of posture (head drops, falls) and are often preceded by a short myoclonic seizure
Myoclonic seizures	Short muscle contractions, usually lasting < 400 milliseconds
Absence seizures	Impairment of consciousness alone or with: mild clonic, atonic or tonic components, automatisms and/or autoimmune symptoms or signs
Secondarily generalized seizures
Partial seizures evolving to secondary generalized seizures (may be generalized tonic-clonic, tonic or clonic)	SPS evolving to generalized seizures
	CPS evolving to generalized seizures
	SPS evolving to CPS and then evolving to generalized seizures
Unclassified seizures

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References

Ahmed, Rehena; Apen, Kenneth and Endean, Coralie. “Epilepsy in pregnancy: A collaborative team effort of obstetricians, neurologists and primary care physicians for a successful outcome.” Australian Family Physician 43(3); Mar 2014.

South Australian Maternal & Neonatal Clinical Network. “South Australian: Perinatal Practice Guidelines intravenous phenytoin.” Version 4.0. Government of South Australia. Dec 19, 2014.

South Australian Perinatal Practice Guidelines workgroup. “South Australian Perinatal Practice Guidelines: Epilepsy and pregnancy management.” Version 6.0. Department of Health, Government of South Australia. Dec 19, 2014.

Craig, John J., Shona Scott, and John Paul Leach. “Epilepsy and Pregnancy: Identifying Risks.” Practical neurology 22, no. 2 (2021): 98-106. https://doi.org/10.1136/practneurol-2019-002304.

Tomson, Torbjorn, and Dina Battino. “Pharmacokinetics and Therapeutic Drug Monitoring of Newer Antiepileptic Drugs During Pregnancy and the Puerperium.” Clinical Pharmacokinetics 46, no. 3 (2007): 209-19. https://doi.org/10.2165/00003088-200746030-00002.