WOMEN WITH EPILEPSY

MANORI WIJAYATH

STAFF SPECIALIST- NEUROLOGY

PREVALENCE OF EPILEPSY IN WOMEN

• Commonest medical condition in pregnant female

• USA- Year 2000, 3-5 /1000 births are for WWE

• Australia - 1500–2000 women on AEDs become pregnant each year

WOMEN WITH EPILEPSY(WWE)

• Pregnancy

Pregnancy complications

PIH, LSCS, premature labour, miscarriages, bleeding

Seizure frequency and seizure freedom

Management

Medications

medication related foetal complications

• Lactation• Contraception

Seizure control and treatment changes in pregnancy:Observations from the EURAP epilepsy pregnancy registry

Epilepsia, 54(9):1621–1627, 2013

• Prospective 3,806 pregnancies of 3,451 WWE on AEDs

(monotherapy with CBZ,LTG,PB,VPA)

Enrolment : 8.9/40 (SD 3.3)

IGE: 39.3%, Focal: 47.01%, undetermined: 13.6%

• Sz Frequency

Sz free: 66.6% continuing:33.4%

Sz freedom for at least 9 months prior to pregnancy - 84–92% chance of remaining sz free

1st vs 2/3 T Unchanged 70.5%

Reduction 12%

Increase 15.8%

DO WWE HAVE AN INCREASED RISK OF PREGNANCY-RELATEDCOMPLICATIONS?

• Class I study (Viinikainen et al., 2006)-n=179

Cesarean instrumental delivery

Preeclampsia/ PIH

No significantly increased risk of above BUT lack statistical precision to comment of an increased risk

Premature contractions and premature labour and delivery

Non smoking – no increase

Smoking- substantial increase

Spontaneous abortion- inadequate data

Perinatal foetal outcome with intrauterine AED exposure

Facts to remember in Rx

*Altered pharmacokinetics- eg- pronounced decline in serum concentrations for AEDs eliminated by glucuronidation (UGT)

*Adverse effects of AEDs on the foetus are dose-dependent (Meador et al., 2009a; Tomson et al.,2011; Hernandez-Diaz et al., 2012;)

*Aim at reducing GTCS- maternal and foetal morbidity and mortality

*Review and possibly revise treatment well before conception

*Titrate to the lowest effective dose before pregnancy (Harden et al., 2009, Tomson & Battino, 2012)

pH, gastric emptying, intestinal motility

No Rx failures

free concentrations may be preferable in such situations- PHT, VPA(Johannessen & Tomson, 2006; Patsalos et al., 2008)

LTG, OXC, Variable, cannot predict (Tomson & Battino, 2007;Patsalos et al., 2008

TRENDUtilization of antiepileptic drugs during pregnancy:

the EURAP registry -1999-2005

LAMOTRIGINE

• LTG clearance markedly increases in late pregnancy (Ohman et al., 2008; Pennell et al., 2008; Tomson et al., 2013)

  55% protein bound met by UGT

decline markedly (50-60%) Starts in T1 marked in mid

T3trimester

less pronounced when combined with VPA

• Rapid return to pre pregnant level post delivery

starts D1 and completed in 2 to 3/52 postpartum

AEDs whose pharmacokinetic properties are affected, the extent variable between individuals.

Polytherapy makes it even more difficult to predict

What should we monitor?

• AAN/AES guidelines

MAJOR CONGENITAL MALFORMATIONS

• heart malformations, (VSD)• orofacial defects, (cleft lip/cleft palate)• urologic defects, (hypospadias)• skeletal abnormalities, (radial ray defects, phalangeal hypoplasia, )• neural tube defects. (spina bifida)

(Meador et al. 2008a)

Mechanism?

• Uncertain

folate deficiency,

ischemia,

neuronal suppression,

reactive intermediates (e.g. free radicals or epoxides)

AED-induced neuronal apoptosis 

• T1exposure- highest risk of anatomical defects • T3exposure- highest risk of behavioural

Anatomical terratogenesis

• MCMs- 4.5% as opposed to 2.1% in controls• Increased risk for MCMs

only with VPA(5.6%, p = 0.005)

AED polytherapy (8.6%,p = 0.02) (Meador et al. 2008a)

• VPA as mono or in poly has the highest risk• dose-dependent esp VPA and LTG

0 6 12 18 24 30 36

LTG <= 75 (46)

LTG > 75 <= 275 (687)

LTG > 275 (394)

CBZ 350 (137)

CBZ > 350 <= 900 (978)

CBZ > 900 (194)

PB <= 80 (45)

PB > 80 <= 130 (107)

PB > 130 (48)

VPA <= 650 (394)

VPA > 650 <= 1400 (442)

VPA > 1400 (92)

malformation rate and 95% CI (%)

Behavioural terratogenesis

• WWE on RXneuronal apoptosis in neonatal rat brain -Clon, Diaz, PB, PHT,

synergistic effect of two AEDs, given at below threshold dosages

AEDs inherently not producing apoptosis in monotherapy, (CBZ, LTG and TPM) can enhance apoptosis induced by another

• WWE no RXNo difference to normal controls

Exposure to antiepileptic drugs in utero and childdevelopment: A prospective population-based study

*†Gyri Veiby, ‡§Anne K. Daltveit, ¶Synnve Schjølberg, ‡¶Camilla Stoltenberg, ¶#Anne-Siri Øyen,‡¶Stein E. Vollset, *†Bernt A. Engelsen, and *†Nils E. Gilhus

Doses during pregnancy ? Sz freq in unRx WWE?

FOLIC ACID

Insufficient data but 2x class II studies proved benefit

Recommend- 0.4mg, preceonception (AAN)

Vit K

Inadequate evidence

Practise- If enzyme-inducing AEDs used, routinely receive vitamin K at delivery (AAN)

AEDs and lactation

Safe

short t ½

>80% protein bound Contraindications

Long t ½- cumulative effect- sedation with BDZ

High milk to plasma ratio- ETX, ZNS

Most 1st G AEDs can be considered safe

VPA, CBZ, PB, PHT, Primidone

2nd G AEDs- not much known

clinically significant amounts in BM – LEV, LTG, OXC, TPM

but therotical infant dose < therapeutic dose for neonates

considered moderately safe

• ***remember to drop the LTG dose, PP

AED and contraception

• COCP, levenogestral implants- avoid with CBZ, PHT, PB, TPM, OXC

Start with oestradiol >50mcg/day• Preferred – intrauterine device/Depo- 10wkly• COCP can reduce the LTG level – 25-70%

THANK YOU

Australian Pregnancy Registry