WOMEN WITH EPILEPSY MANORI WIJAYATH STAFF SPECIALIST- NEUROLOGY.
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Transcript of WOMEN WITH EPILEPSY MANORI WIJAYATH STAFF SPECIALIST- NEUROLOGY.
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