WOMEN WITH EPILEPSY- AN UPDATE

Dr. Sunil Kumar Sharma

Senior Resident

Moderator

Dr. Bharat Bhushan(DM)

(Asso. Prof.)

Dept. of Neurology

GMC Kota

INTRODUCTION

Epilepsy is a highly prevalent neurological disorder

≈1% of the population.

Men > women.

About half of the women with epilepsy are in the

reproductive age group of 15–49 years.

- Forsgren L, Beghi E, Oun A, et al. The epidemiology of epilepsy in Europe—a systematic review. Eur J Neurol 2005;12:245–53.

-O’Brien MD, Gilmour-White SK. Management of epilepsy in women. Postgrad Med J 2005;81:278–85.

…

The possibility of pregnancy should be considered

in any woman of childbearing age with epilepsy.

The National Institute for Health and Care

Excellence (NICE) has also identified women in the

reproductive age group to have specific and unique

problems in managing their epilepsy

FACTORS AFFECTING CONTRACEPTION IN

WOMEN WITH EPILEPSY

Induction of hepatic cytochrome P450 enzyme

activity –Phenytoin ,Pheno.,CBZ etc.

Increases the rate of metabolism of both oestrogen

and progestogen.

None of the newer AEDs share the broad spectrum

enzyme-inducing activity of older generation

agents.

The failure rate of contraceptive pill with AEDs is

about twice that in the general population.

Other modalities of contraception may need to be

considered.

Morrell MJ. The new antiepileptic drugs and women: efficacy, reproductive health, pregnancy and fetal outcome. Epilepsia

1996;37(Suppl 6):S34–44.

Enzyme-inducing AEDs can affect the metabolism

of the progestogen only pill, progestogen implant

and the morning after pill thus requiring higher

doses or alternative forms of contraception.

Medroxyprogesterone acetate depot injection is

unaffected by enzyme-inducing AEDs.

Use of any oestrogen-based contraceptive can result in

a significant reduction of lamotrigine levels (by 40-

60%) and lead to loss of seizure control.

When a woman or girl starts or stops taking these

contraceptives, the dose of lamotrigine may need to be

adjusted. [NICE 2012]

Sabers A, Buchholt JM, Uldall P, et al. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res 2001;47:151–4.

CATAMENIAL EPILEPSY AND EFFECT OF

SEX HORMONES ON EPILEPSY

Catamenial epilepsy- Periodicity of the

exacerbation of the seizure is in association with

the menstrual cycle.

Oestradiol decreases seizure threshold

Progesterone has antiepileptic effects .

Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997;38:1082–8.

There are three commonly recognised seizure

Patterns:

Perimenstrual Day −3 to +3),

Periovulatory (day 10 to 3)

Entire luteal phase in anovulatory cycles (day 10

to 3)

Herzog AG. Catamenial epilepsy: update on prevalence, pathophysiology and treatment from the findings of the NIH Progesterone

Treatment Trial. Seizure 2015;28:18–25.

Sometimes intermittent Rx in addition to regular

drug Rx.

Eg. Clobazam and progesterone

EPILEPSY AND PREGNANCY

Managing epilepsy during pregnancy is often

challenging.

AEDs-higher doses –risk of fetal malformation

AEDs-lower doses - uncontrolled seizures

WOMEN WITH EPILEPSY

Effect of epi. On pregnancy

-15% fewer children

-Blunt trauma

-Does not affect the course of

pregnancy

- Risk of-

severe pre-eclampsia,

early pregnancy bleeding,

pregnancy induction,

cesarean section

-Teratogenesis

Effect of pregnancy on epi.

-↓ in ≈ one-fourth

-↑ in ≈ one-fourth

-Half-no change

-Consensus state.-insufficient

evidence

-CPS worsened

-Hormonal changes

-Vol. of distribution

-↓ level of unbound drug

-Alt. metabolism

EFFECT OF EPILEPSY ON PREGNANCY

In pregnant women, a diagnosis of epilepsy is

associated with a small but significant increase in

adverse pregnancy outcomes-

- Spontaneous miscarriage

- Antepartum haemorrhage

- Postpartum haemorrhage

- Hypertensive disorders

- Induction of labour

- Caesarean section

- Any preterm birth before 37 weeks of gestation

- Fetal growth restriction

Viale L, Allotey J, Cheong-See F, et al. Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis.

Lancet 2015;386:1845–52.

Women with epilepsy have approximately 15% fewer

children than expected.

Reasons –

-Social effects of epilepsy,

-Menstrual irregularity-

-1 of 3 women with epilepsy,

-Oligo and polymenorrhea (1/3)

-Anovulatory MC(1/3) .

-Effect of some antiepileptic medications on the ovaries

-Effect of seizures/AED on reproductive hormones.

-Herzog AG. Menstrual disorders in women with epilepsy. Neurology. 2006 Mar 28. 66(6 Suppl 3):S238.[Medline].

- Murialdo G, Galimberti CA, Magri F, Sampaolo P, Copello F, Gianelli MV, et al. Menstrual cycleand ovary alterations in women with

epilepsy on antiepileptic therapy. J Endocrinol Invest. 1997 Oct. 20(9):51926. [Medline].

In an Indian registry-based study, 38.4% of women

with epilepsy were infertile.

Age, lower education, and polytherapy with

antiepileptic medications as risk factors

(Sukumaran et al., 2010)

The relative impacts of different seizure types are

difficult to determine.

SPS have minimal effect on the fetus.

CPS may leads to injuries due to L.O.C.

GTCS are feared the most-injury, alterations in

electrolytes, blood pressure and oxygenation.

INDICATIONS OF CAESAREAN

SECTION

If frequent seizures greatly impair cooperation in

forthcoming labour and delivery

Generalised seizure during labour

Refractory status epilepticus in the third trimester

-Sveberg L, Svalheim S, Taubøll E. The impact of seizures on pregnancy and delivery. Seizure 2015;28:35–8.

-Dubovický M. Neurobehavioral manifestations of developmental impairment of the brain. Interdiscip Toxicol 2010;3:59–67.

EFFECT OF PREGNANCY ON EPILEPSY

Many studies suggest-↑ in ≈ one-fourth

-↓ in ≈ one-fourth

A consensus statement and review of the evidence

available concluded that there is insufficient evidence

regarding change in the frequency of seizures or

status epilepticus during pregnancy (Harden et al.,

2009b)

TERATOGENIC EFFECTS OF AEDS

AED teratogenicity should be considered during drug

selection for all women of childbearing potential.

Frequency of major malformations =1.8% in normal

control population.

With one AED (phenytoin, carbamazepine, or

phenobarbital) this rate rose to 3.4% to 5.2%,

With two or more to 8.6%. (Holmes et al., 2001)

Valproic acid causes a higher rate of teratogenicity

than other commonly used AEDs. ≈ 9.1% for higher

valproic acid doses in one study (Morrow et al.,

2006).

Higher-dose lamotrigine (>200 mg/day) also

possibly increased teratogenicity up to 5.4%

(Brodie, 2006).

Most serious teratogenic effects occur during thefirst 2.5 months of gestation.

Changing medication before or during the firsttrimester is most useful.

The neural tube closes between 3 and 4 weeks.

Cleft lip and palate occur with exposure before 5and 10 weeks, respectively

Congenital heart disease occurs before 6 weeks.

Highest malformation rates were seen for valproate

(4.7%–10%) and the lowest for lamotrigine (2%–

3.4%) .

Valproate doses over 800 mg/day - highly

teratogenic.

Lamotrigine has been associated with low

teratogenic risks.

The major limitations of lamotrigine in pregnancy is

the problem of induction by sex hormones -higher

risks of seizures in up to 58% of pregnant women.

-Tomson T, Battino D, Perucca E. Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug. Lancet

Neurol 2015;15:210–8.

-Vajda FJ. Effect of anti-epileptic drug therapy on the unborn child. J Clin Neurosci2014;21:716–21.

-Reimers A. New antiepileptic drugs and women. Seizure 2014;23:585–91.

AED ASSOCIATED CONG MALFORMATIONS

Cleft lip and cleft palate,

Heart (ASD,VSD,TOF, COA, PDA and PS)

Urogenital defects

NTD

FETAL HYDANTOIN SYNDROME (FETAL

ANTICONVULSANT SYNDROME)

Midfacial hypoplasia,

Long upper lip,

Low birth weight,

Cleft lip and palate,

Digital hypoplasia and nail dysplasia

Occurs with Phenytoin,Carbamazepine, Primidone,

and Valproic acid.

Some minor anomalies usually disappear during

the first years of life.

Levetiracetam having low teratogenesis and good

seizure control is a better choice .

Rates of all seizures in pregnant women taking

levetiracetam have been comparable to older AEDs.

NICE recommends a high-resolution USG scan of

pregnant women ,taking AEDs at 18–20 weeks’

gestation.

-Meador KJ. Epilepsy: Pregnancy in women with epilepsy—risks and management. Nat Rev Neurol 2014;10:614–16.

-Women and girls with epilepsy. Epilepsies: diagnosis and management. Published:11 January 2012.

http://www.nice.org.uk/guidance/cg137/resources/ epilepsies-diagnosis-and-management (accessed 2.3.2016).

NON-TERATOGENIC EFFECTS OF AEDS ON

CHILDREN EXPOSED , IN UTERO

There is a longer term risk to the cognitive and

behavioural development of the child exposed in

utero to sodium valproate.

Although less certain, there may also be risks

associated with phenobarbital and phenytoin

exposure.

Bromley RL, Baker GA, Meador KJ. Cognitive abilities and behaviour of children exposed to antiepileptic drugs in utero. Curr Opin

Neurol 2009;22:162–6.

PREGNANCY AND AED LEVELS IN

BLOOD

CYP enzyme induction-eg Phenytoin

,Phenobarbitone

Plasma concentration of AEDs metabolised through

glucuronidation such as lamotrigine and

oxcarbazepine can markedly decrease over the

course of the pregnancy.

Lamotrigine plasma concentrations can decline

during gestation to as much as 30% or less of

prepregnancy values.

-Parry E, Shields R, Turnbull AC. The effect of pregnancy on the colonic absorption of sodium, potassium and water. J Obstet Gynaecol Br Commonw

1970;77:616–19.

- Messmer K, Kemming G. Clinical hemodilution. In: Winslow RM, ed. Blood Substitutes 2006:178–87.

-Davison JM, Dunlop W. Renal hemodynamics and tubular function in normal human pregnancy. Kidney Int 1980;18:152–61.

…

Lower concentration of albumin -phenytoin and

valproic acid.

Increase of plasma volume

Increase of renal blood flow.

It has been found that when AEDs in the blood fell

>35% from preconception baseline, seizures

worsened significantly during the second trimester.

Eg. lamotrigine and levetiracetam.

Monitor AED serum concentrations with dose

adjustment in pregnant women with epilepsy.

ROLE OF FOLIC ACID IN TREATING

PREGNANT WOMEN WITH EPILEPSY

Folic acid supplements reduce the risk of NTD.

Valproate(1.5% )and carbamazepine(0.5%)

Folic acid 5 mg once daily is the widely recommended

dose for WWE on AED.

-MRC Vitamin Study Research Group. Prevention of neural tube defects; results of the Medical Research Council vitamin study. Lancet

1991;338:132–7.

- Biale Y, Lewenthal M. Effect of folic acid supplementation on congenital malformations due to anticonvulsive drugs. Eur J Obstet Gynecol

Reprod Biol 1984;18:211–16.

PLACE OF VITAMIN K IN PREGNANCY

All children born to mothers taking enzyme-inducing

AEDs should be given 1 mg of vitamin K

parenterally at delivery. [NICE]

WOMEN WITH EPILEPSY BREAST FEED

Breast feeding for most women and girls taking

AEDs is generally safe.

Thus, all women and girls with epilepsy should

have no concerns regarding breast feeding and be

encouraged to breast feed.

MENOPAUSE & EPILEPSY

The hormonal changes in menopausal transition

seem to have an effect on seizure susceptibility in

certain women.

Women with catamenial epilepsy may experience

an increase in seizure frequency during the

perimenopause and a decrease after menopause.

…

There is some conflicting evidence with regard to

seizure frequency and severity in women during

menopause.

Studies suggested that the frequency and severity

of the seizures in premenopausal women were

similar with those in perimenopausal and

menopausal women.

-Rościzewska D. Menopause in women and its effects on epilepsy. Neurol Neurochir Pol 1978;12:315–19.

- Abbasi F, Krumholz A, Kittner SJ, et al. Effects of menopause on seizures in women with epilepsy. Epilepsia 1999;40:205–10.

HORMONE REPLACEMENT THERAPY & IT’S

EFFECT ON SEIZURE CONTROL

Combined oestrogen plus progesterone HRT inpostmenopausal women with epilepsy has beenassociated with an increase in seizure frequency.

AED use is an independent predictor of increased riskof osteoporosis and subsequent fractures inmenopausal women.

Due to the effect of enzyme-inducing AEDs on vitaminD.

Recommendation - vitamin D supplementation

-Harden CL, Herzog AG, Nikolov BG, et al. Hormone replacement therapy in women with epilepsy: a randomized, double-blind, placebo-controlled study. Epilepsia 2006;47:1447–51.

-Persson HB, Alberts KA, Farahmand BY, et al. Risk of extremity fractures in adult outpatients with epilepsy. Epilepsia 2002;43:768–72.

-Harden CL. Menopause and bone density issues for women with epilepsy. Neurology 2003;61(Suppl 2):S16–22.

- MHRA. Antiepileptics: adverse effects on bone. Drug Saf Update 2009;2:2–2.

NICE GUIDELINE RECOMMENDATIONS

Discuss with women and girls of childbearing potential(including young girls who are likely to need treatmentinto their childbearing years), and their parents and/orcarers if appropriate, the risk of AEDs causingmalformations and possible neurodevelopmentalimpairments in an unborn child.

Assess the risks and benefits of treatment withindividual drugs. There are limited data on risks to theunborn child associated with newer drugs. Specificallydiscuss the risk of continued use of sodium valproateto the unborn child, being aware that higher doses ofsodium valproate (more than 800 mg/day) andpolytherapy, particularly with sodium valproate, areassociated with greater risk. [new2012]

Be aware of the latest data on the risks to the

unborn child associated with AED therapy when

prescribing for women and girls of present and

future childbearing potential. [2012]

RECOMMENDATIONS FOR CONTRACEPTION

Alternative forms of contraception or higher doses

have to be considered in patients using hormonal

contraception and enzyme-inducing antiepileptic

drugs (AEDs) to prevent contraceptive failure

(NICE).

Medroxyprogesterone acetate depot injection is a

hormonal contraceptive option unaffected by

enzyme-inducing AEDs and is an option for women

on enzyme-inducing AEDs(new).

RECOMMENDATIONS FOR CONTRACEPTION

Review lamotrigine dosage as combined oral

contraceptive pill may reduce the blood

concentration of lamotrigine potentially leading to

breakthrough seizures (NICE).

RECOMMENDATION DURING PRECONCEPTION

Counsel regarding the need for good seizure

control with antiepileptic drugs (AEDs) during

pregnancy for women planning conception.

Valproate is not recommended for women of

childbearing age with focal epilepsies.

For generalised epilepsy, lamotrigine and

levetiracetam are preferred AEDs unless advised

differently by an epilepsy specialist for exceptional

circumstances.

Lamotrigine is a recommended AED during

pregnancy as it is associated with low teratogenic

risks.

However, this may have higher risks of seizures in

pregnancy due to lower plasma levels which may

require dose adjustment for optimal control (NICE).

…

Combination of low teratogenicity and good seizurecontrol during pregnancy makes levetiracetam analternative in place of lamotrigine.

Multiple AEDs is preferred less as this is associatedwith higher rates of major congenital malformations;thus, monotherapy at the lowest effective dosewhere possible is recommended (NICE).

Folic acid 5 mg should be given to all women takingAEDs contemplating pregnancy to preventteratogenicity (NICE).

RECOMMENDATIONS DURING

PREGNANCY

Care of pregnant women and girls should be shared

between the obstetrician and the specialist. [2004].

Pregnant women and girls who are taking AEDs

should be offered a highresolution ultrasound scan to

screen for structural anomalies. This scan should be

performed at 18–20 weeks' gestation by an

appropriately trained ultrasonographer, but earlier

scanning may allow major malformations to be

detected sooner. [2004]

…

All children born to mothers taking enzyme-

inducing AEDs should be given 1 mg of vitamin K

parenterally at delivery. [2004]

…

AEDs could be restarted (if discontinued prior to

conception) or increased after 12 weeks of

pregnancy to gain good seizure control as

teratogenic effects of AEDs ends at this time.

Aim for seizure freedom before conception and

during pregnancy (particularly for women and girls

with generalised tonic–clonic seizures) but consider

the risk of adverse effects of AEDs and use the

lowest effective dose of each AED, avoiding

polytherapy if possible. [new 2012]

Do not routinely monitor AED levels during

pregnancy. If seizures increase or are likely to

increase, monitoring AED levels (particularly levels

of lamotrigine and phenytoin, which may be

particularly affected in pregnancy) may be useful

when making dose adjustments. [new 2012]

…

Lamotrigine, oxcarbazepine and levetiracetamdosage may have to be increased as maternalplasma concentrations can markedly decline aspregnancy progresses affecting seizure control.

Aim to achieve maximum control of generalisedseizures as generalised seizures compared withfocal seizures have a greater impact on the fetusand pregnancy (NICE).

Caesarean section is indicated if frequent seizuresimpair cooperation in forthcoming labour or in thecase of refractory status epilepticus in the thirdtrimester

INDIAN GUIDELINES FOR WWE

All WWE should be advised to plan their pregnancies.

They should be cautioned that some AEDs may makeOCPs ineffective.

Barrier contraception is an alternative that can beconsidered.

All WWE in the reproductive age group should bestarted on folic acid (5 mg/day) at the time of startingAED.

Seizures may remain unchanged in 50% WWE orimprove (25%) or even worsen (25%) during pregnancy.

…

If a woman had an offspring with malformation in theprevious pregnancy, the AED therapy need to becarefully reviewed and if necessary, the AED could bechanged prior to the next pregnancy.

Antiepileptic drugs should be continued in pregnancy.

All pregnant WWE should be advised screening for fetalmalformations by serum alpha fetoprotein at 16 weeksand by detailed ultrasound scanning by an experiencedultrasonologist at 18 weeks.

If preterm labor is threatened in women taking enzyme-inducing AEDs, 48 mg betamethasone (double thenormal dose) should be given over 48 hours.

…

All WWE should be given two doses of vitamin K 10

mg intramuscularly (IM) at 34 and 36 weeks of

pregnancy, unless there is a contraindication for the

same. All infants born to mothers taking AEDs

should be given vitamin K 1 mg IM at birth.

Seizures during labor should be terminated as soon

as possible using intravenous (IV) lorazepam (4 mg

IV) or diazepam.

…

If seizures persist, those should be managed as

done for SE.

If seizures recur during labor, particularly after

prolonged remission, other etiological possibilities

such as CVT, eclampsia and other causes should

also be considered and managed accordingly.

All WWE should be encouraged to breast-feed their

babies.

Thank you

REFERENCES-

Bradley’s Neurology in clinical practice, 7th edi.

Epilepsies: diagnosis and management Clinical

guideline:11 January 2012 nice.org.uk/guidance/cg137

Guidelines for Epilepsy Management in India (GEMIND);

API India ,medicine update 2013; chapter 116.

Update on management of epilepsy in women for the non-

neurologist ; Gooneratne IK, Wimalaratna S. Postgrad Med

J 2016;92:554–559. doi:10.1136/postgradmedj-2016-

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