Epilepsy service

Consultants Epilepsy Nurse First fit Clinic Rapid review clinic Regular Clinic and

Ward consults EEG Service led by

Neurophysiologist Consultant

The future: Another Epilepsy

Nurse ( or 2? ) Video Telemetry

Unit? Another Consultant

with interest in epilepsy

EPILEPSY IN PREGNANCY

Zoltan Kaliszky MD.Consultant Neurologist

Cumbria Partnership NHS Trust

Goals

Preconception planning and counselling

Teratogenic risk of specific antiepileptic drugs/

antiepileptic drug choices

Management of epilepsy during pregnancy

Management after delivery

A. Preconception planning and counselling

The epilepsy itself is not a contraindication to pregnancy even if it requires AEDs.

Planned pregnancy- (changes 6-12 mo.) Over 90 % -remarkable event free/ good

outcome Assess seizure activity- controlled? Not? Any changes prior to pregnancy ( on VA? ?) Monotherapy ? / if not: lowest poss. dose There is 1.6-3.2 % risk of major congenital

malformation in the general population !

A/2. Preconception planning and counselling

D/C medication prior to pregnancy? Consider if: seizure free for min. 2 years normal neuro exam + I/Q single type of seizure + neg.

EEG and: if the patient is willing to take the risk ! Determine a good baseline level with the lowest effective dose:- Obtain serum level 2 times wks. apart ( before the am. dose ) – this will be the range of effective level.

A/3. Preconception planning

Review hx. of congenital malformations during prev. pregnancies

Discuss the increased risk Consider genetic consultation Change the drug used in previous

pregnancy AND: Start Folic acid 5 mg po./ day !

AEDs - effect on hepatic enzymes

STRONG INDUCERS WEAK INDUCERS:

Phenobarbital Phenytoin Carbamazepine Primidone Oxcarbazepine Clobazam

Topiramate Lamotrigine Felbamate

NON INDUCERS: Valproate, Levetiracetam,Ethosuximide, Gabapentin,Clonazepam,Zonisamide

Teratogenic risk of AEDs

The overall risk of major congenital malformation in the general population is

1.6-3.2 %. In general with the AED use it is 2-3x higher. 1. Valproate: first trimester exposure : 3 x

higher risk for malformation compare to the other AEDs; absolute risk: 6-9%.

Dose related risk: > 700 mg/d – 4%. ( = LTG <300 mg/d or CBZ 400 mg/d.)

VPA dose 1500mg – 20%.

Other congenital malformations with VPA

Atrial septal defect Cleft palate Hypospadias Polydactyly Craniosynostosis autism

Analysis of the NAAEDP Registry data

Not only the VPA but thee Phenobarbital has also highly increased risk – mainly cardiac malformations.

The VPA and PB has no overlap with the other AEDs.- the CBZ, LTG, PHT, LVT – cluster closely around 2-2.5%.

The risk ratio for malformation compared to Lamotrigine:

VPA: 5x, PB: 3x, TPM.: 2x.

Other AEDs.

Topiramate: 1st. Trimester exposure – facial clefts. NAAEDP Registry: 1.4 % ( 10 fold increase

compare to the local control ) UK AED Pregnancy Register: 2.2% -facial

clefts Carbamazepine: EUROCAT ( European Surveillance of

Congenital Anomalies Antiepileptic Study ( -Spina bifida ( OR: 2.6% _ - but: it is 80 % less

than in case of VPA.

The Levetiracetam ( Keppra )

UK Pregnancy Registry: 671 first trimester exposure/ 304

monotherapy Only 2 major congenital malformation

case: 1. inguinal hernia ( dose: 4000mg/d ) 2. reflux - requiring op. – ( dose;

2000mg/d ) NAAEDP Registry: risk: 2.4 % - with 450

exposures.

AED polytherapy

Lamotrigine and Carbamazepine – modest major congenital malformation risk change in any polytherapy combination which does not contain VPA.

Major CM rate increase in case of Lamotrigine and any other AED: 2.9 % but with VPA: 9.1 %

Also: In case of Carbamazepine and other AED

this increase is 2.5 % but with VA: 15.4 %

Repeated major congenital malformation risk

The risk is 35.7% if the first pregnancy ended up with major cong. malformation.

It is 57% if it happens with VPA.

The maternal genetic influence predisposes to teratogenicity and compounds the AED risk.

AED - teratogenic dose effect

EURAP Study ( International Registry of AEDs and Pregnancy )

4 drugs studied: CBZ, LTG, Pb, VPA The lowest major cong. malformation

rate: Lamotrigine less than 300 mg/d ( 1.7%) Carbamazepine less than 400 mg/d

( 2.0%) CBZ > 1000 mg/d- 7.7% LTG > 300 mg/d – 3.6% VPA and Pb – much higher with ALL

doses.

Stratification of risk for occurrence of major congenital malformation

Probably the safest AEDs: LTG,CBZ,LVT, PTHProbably have lower risk than Valproate:OXC, ZNS, GBPHave significant risk greater than other AED:Topiramate ( oral clefts)Phenobarbital ( cardiac defects)Valproate ( spina bifida, hypospadias )

Seizures during pregnancy Increased frequency: 20-33% During labour: 3.5 % ( EURAP study ) Causes : sex hormone concentration changes AED metabolism Sleep deprivation New stresses Non-compliance Note: Seizure during the month before

conception – 3.7x increase in the risk of seizure in the peripartum period.

Risk of seizure to the fetus:GTC – maternal and fetal hypoxia and acidosis - Fetal heart rate deceleration - Miscarriages - stillbirth Non-convulsive seizures: - trauma and its consequences ( ruptured fetal membranes, etc.)Obstetric risk in case of AED use:Mildly increased risk for :pre-eclampsia ( OR: 1.8 )Gestational HTN ( OR 1.5)Vaginal bleeding late in pregnancy ( OR: 1.9)Delivery before 34 wks of gestation (OR: 1.5)

Management of AED levels during pregnancy

The clearance of most AED increases during pregnancy leading to decreased serum concentration.

Causes: 1. hepatic enzymatic induction 2.increased volume distribution 3.increased renal blood flow 4. alterations in drug absorption 5. altered concentration of albumin and

alfa-1 glycoproteins

Lamotrigine level

May decrease remarkably because of the primary elimination happens via hepatic glucoronidation.

Needs close monitoring and correction Recommendation: Check the level 2 times prior to pregnancy Check the level every month during pregnancy Check the level at delivery and weekly later

until it is 25% higher only than the pre-pregnancy level – TOXICITY !!!

Needs fast dose decrease after delivery !

Other postconception follow up

Level in case of other AEDs: - before conception ( x 2 ) At the beginning of each trimester In the last month Post delivery ( Phenytoin + Valproate – needs free level ! ) High level U/S at 14-18 wks. Alfa – fetoprotein at 14-16 wks ( on VPA/ or

CBZ ) If abn.: amniocentesis ( AFP+ Ach-esterase –

97% sensitivity)

Supplementation

1. Vit-K.: in case of enzyme inducing AED. - increased risk of haemorrhagic dz. of the newborn

b/o.deficiency of vit.-K dependent clotting factors.- Suppl.: 20 mg. po./d from 36 wks of gestation +

1 mg. im to the baby at birth.

2. Folate: 5 mg from the time of the planning - decreases the risk for cong. malformations incl.

neural tube defects Decreases the risk of spontaneous abortion Improves the chance for better IQ.

Breast feeding

Ratios between the breast milk and the serum level:

VPA.: 0.1 PTH.: 0.19 Pb.: 0.36 CBZ.: 0.41 Be careful with Pb., Primidone, benzo –

sedation Safe breast feeding practice – sitting on

the floor, etc.

Thank you. Any question?