1. MANORI WIJAYATH STAFF SPECIALIST- NEUROLOGY
WOMEN WITH EPILEPSY
MANORI WIJAYATH
STAFF SPECIALIST- NEUROLOGY

2. PREVALENCE OF EPILEPSY IN WOMEN
Commonest medical condition in pregnant female
USA- Year 2000, 3-5 /1000 births are for WWE
Australia –2000 women on AEDs become pregnant each year

3. 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

4. Sz free: 66.6% continuing:33.4%
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%

5. DO WWE HAVE AN INCREASED RISK OF PREGNANCY-RELATED COMPLICATIONS?
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

6. Perinatal foetal outcome with intrauterine AED exposure

7. Worsening of sz in 2nd than 1st T
LTG- (19.9%) than in those exposed to CBZ (14.6%, p < 0.001), PB (11.7%, p < 0.01), or
during delivery in 2.6% of pregnancies exposed to CBZ and to LTG, in 1.9% of those exposed to PB, and in 1.4% of those exposed to VPAVPA (13.2%, p < ).
The mean dose increase from the first to the third trimester was 5% for CBZ, 26% for LTG, 11% for PB, and 6% for VPA. Adding a second AED was more common among LTG pregnancies (58/1, %, p < )

8. *Adverse effects of AEDs on the foetus are dose-dependent
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)

9. Recurrent GTCS>4/SE Foetal loss malformations
Epilepsy
Seizures AEDs
Recurrent GTCS>4/SE
Foetal loss malformations
Poor cognitive development neurocognitive
(Adab et al., 2004; Meador et al., 2009b) effects

10. free concentrations may be preferable in such situations- PHT, VPA
(Johannessen & Tomson, 2006; Patsalos et al., 2008)
pH, gastric emptying, intestinal motility
No Rx failures
LTG, OXC, Variable, cannot predict
(Tomson & Battino, 2007;
Patsalos et al., 2008

11. TREND Utilization of antiepileptic drugs during pregnancy: the EURAP registry -1999-2005

12. 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

14. AED Metabolism Protein binding Change to [serum] monitoring
Carbamazepine
Phenytoin
 Phenobarbital
Valproate
Topiramate
Levetiracetam
Oxcarbazepine
 MHD- mono-hydroxycarbazepine
Hepatic, CYP
 Hepatic, CYP
Hepatic, glucuronidation
Kidney
75%
90%
50%
>90%
15% -
40%
Total-9–12%
Unbound- minimal change
Total-55%
Unbound- 25%   
55% T3
Total-40%
30% to 40% T3
Variable
40%-60% - T3(VARIABLE)
30-40%
Corrected 7-8days PP
Advisable 
Advisable  
Needed
Insufficient evidence NA
If available

15. AEDs whose pharmacokinetic properties are affected, the extent variable between individuals.
Polytherapy makes it even more difficult to predict

16. What should we monitor?
AAN/AES guidelines

17. 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)

18. 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

19. 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

21. Behavioural terratogenesis
WWE on RX
neuronal 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 RX
No difference to normal controls

22. Doses during pregnancy ? Sz freq in unRx WWE?
Exposure to antiepileptic drugs in utero and child development: 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?

23. 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)

24. 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

25. 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%

26. Australian Pregnancy Registry
THANK YOU
Australian Pregnancy Registry