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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.
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.
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.
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-
134191
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