'Epilepsy in Pregnancy' - Dr Zoltan Kaliszky (Consultant Neurologist for Cumbria Partnership NHS Foundation Trust) from the Cumbria Neuroscience Conference

1.  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

2. Zoltan Kaliszky MD.
Consultant Neurologist
Cumbria Partnership NHS Trust

3.  Preconception planning and counselling
 Teratogenic risk of specific antiepileptic drugs/
antiepileptic drug choices
 Management of epilepsy during pregnancy
 Management after delivery

4.  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 !

5. 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.

6.  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 !

7. STRONG INDUCERS WEAK INDUCERS:
 Phenobarbital
 Phenytoin
 Carbamazepine
 Primidone
 Oxcarbazepine
 Clobazam
 Topiramate
 Lamotrigine
 Felbamate
NON INDUCERS:
Valproate, Levetiracetam,
Ethosuximide, Gabapentin,
Clonazepam,Zonisamide

8.  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%.

9.  Atrial septal defect
 Cleft palate
 Hypospadias
 Polydactyly
 Craniosynostosis
 autism

12.  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.

13.  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.

14.  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.

16.  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 %

17.  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.

18.  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.

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

20.  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.

21. 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)

22.  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

24.  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 !

25.  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)

26. 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.

28.  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.