dr jim morrow
TRANSCRIPT
Weighing up the risks of harm from AED
medication in pregnancy
Dr Jim Morrow
Major malformations with AED Monotherapy
(%)
2,3%
Incidence
general
population*
*EUROCAT
** Metaanalysis (Tomson 2008)
2,6% Incidence
in women with
epilepsy without
AED **
3
PB
PRM ETM
CBZ DZP
VPA, CZ
CLB VGB LTG GBP1 TPM2
OXC4, LEV5
TGB3
PB CLB = 9 AEDs = 70 years
VGB LCM = 10 AEDs = 18 years PGB6, ZNS7
LCM8
AED introduction in UK: 1912–20081,2
CBZ, carbamazepine; CLB, clobazam; CZ, clonazepam; DZP, diazepam; ETM, ethosuximide; GBP,
gabapentin; LCM, lacosamide; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PB,
phenobarbitone; PGB, pregabalin; PHT, phenytoin; PRM, primidone; TGB, tiagabine;
TPM, topiramate; VGB, vigabatrin; VPA, valproate; ZNS, zonisamide
Time 1920 1940 1960 1980 2000 2020
1. Patsalos, P. Seizure 1994; 3; 163-170; 2. SmPC, Topirmate
3. SmPC, Tiagabine; 4. SmPC, Oxcarbazepine
5. SmPC, Levetiracetam; 6. SmPC, Pregabalin
7. SmPC, Zonisamide; 8. SmPc, Lacosamide
Malformation risks of antiepileptic drugs in pregnancy:
The UK and Ireland Epilepsy and Pregnancy and Register (Est. 1996)
James Morrow, Belfast Neurology
Aline Russell, Glasgow, Neurophysiology
Henry Smithson, Sheffield General Practice
Linda Parsons, Luton Neurology
Ian Robertson, Preston Obstetrics & Gynaecology
Beth Irwin, Belfast Epilepsy Nurse Specialist
Normal Delanty, Dublin Neurology
Patrick Morrison, Belfast, Genetics
John Craig, Belfast Neurology
UKEPR . Data collected:
First trimester:
Information sheet
Informed consent
Pt details
Seizure history
AED treatment details
Folic acid
GP details / specialist
EDD
Three months post EDD: (GP) Longer term follow up
Pregnancy outcome: Neurocognitive delay
Gestional age Autistic spectrum disorder
Birth weight
Mode of delivery
Birth defect
Additional factors
Other Physician involved in care
Results of prenatal screening of infant
Previous pregnancy outcome(s) Family history of congenital malformation
Number of registrations – 10,625
Number with full outcome data – 8,952
Incomplete registrations – 1673
AED details (full outcome) Monotherapy = 6569 (73%)
Polytherapy = 1790 (20%)
No AED = 593 (6.7%)
Results – 28th August 2015
National/International prospective pregnancy registries.
Distribution of Verbal IQ (VIQ) According to Monotherapy Drug
Exposure In Utero Compared to the Expected Score in the General
Population
0
10
20
30
40
50
60
General population
Unexposed Carbamazepine
Valproate
Distribution of verbal IQ
Above average (>110)
Average (90–109)
Low average (80–89)
Low (70–79)
Exceptionally low (<69)
25
50
16
7
2
9
43
17
24
7
11
54
17
10 8 7
27 24
20 22
1. Adab N, Kini U, Vinten J et al. JNNP 2004;75:1575–1583
Guidelines
• ‘Pre-conception counselling for women with epilepsy
should be routinely delivered ‘ MBRAC 2014
• ‘Valproate should not be used to treat epilepsy or bipolar
disorder in girls and in women who are pregnant or who
can become pregnant unless other treatments are
ineffective or not tolerated.’
European Medicines Agency 2014
• ‘Where possible, valproate should be avoided in women of
childbearing potential.’
International League Against Epilepsy 2015
You have a woman on valproate expressing a
desire to get pregnant: Measuring risk.
Measuring the risk(s):
Reduce dose (with a view to stopping)
Introduce another drug to regime
Switch medication
Keep the status quo
Seek specialist advice
Valproate Carbamazepine Lamotrigine
0
2
4
6
8
10
12 M
CM
RA
TE (
%)
Valproate ≤600mg; Carbamazepine ≤500mg; Lamotrigine ≤200mg
Valproate >600-1000mg; Carbamazepine >500-1000mg; Lamotrigine >200-400mg.
Valproate >1000mg; Carbamazepine >1000mg; Lamotrigine >400mg
*** p=0.006
p=0.26
** p=0.03
Reducing dose: MCM Rate by AED dose:
Introduce another drug (with a view to
reducing SVP dose or switching):
i.e. Polytherapy
5.2
8.7
3.6 4.2
6.3
2.6
6.2
11.1
4.7
Total With SVP No SVP
0
2
4
6
8
10
12
Polytherapy
Comparative MCM rates (%)
Total / Including SVP/ Without SVP
5 4.6
13.4
1.39 1.27
7.93 8.61
7.93
18.87
less than 600mg
600-1000mg
Greater than
1000mg
0
2
4
6
8
10
12
14
16
18
20
Polytherapy including SVP
Comparative MCM rates (%): by dose
Switching to another drug:
which drug?
2000 2002 2004 2006 2008 2010
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
LTG
2000 2002 2004 2006 2008 2010
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
SVP
2000 2002 2004 2006 2008 2010
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
MISC
2000 2002 2004 2006 2008 2010
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
CBZ
-0.15 0.35 No AED 2… 2… 2… 2… 2… 2…
-0.15 0.35 P…
Distribution of treatment as a proportion of the total, over time.
Efficacy of AEDs during pregnancy EURAP data
EURAP Study Group Neurology 2006;66:354
Concentration to dose from before pregnancy and
throughout to postpartum Petrenaite et al. Epil Res 2005;65(3):185–188
Nr1
Nr2
Nr3
Nr4
Nr5
Nr6
Nr7
Nr8
Nr9
Nr10
Nr11
140
120
100
80
60
40
20
0 Pre TM1 TM2 TM3 PP
Time
Individual changes in ratio of
lamotrigine plasma levels
Keep the status quo
Confidential enquiry into maternal deaths
1985-2012 (UK).
Years of enquiry Maternities Direct and indirect deaths Ep Deaths
1985-87 2.27m 223 3 1988-90 2.36m 238 9 1991-93 2.32m 228 6 1994-96 2.19m 268 16 1997-99 2.12m 242 9 2000-02 2.00m 261 13 2003-05 2.11m 295 11 2006-08 2.29m 261 14 2009-12 2.37m 226 14 Total 20.06m 2269 95
Maternal death in Epilepsy 10 x background risk
Seek specialist advice:
N.I. where we are now.
UK Epilepsy and Pregnancy Register (UKEPR)
Pre-conceptual counselling
Regional Joint Epilepsy (Neurology) / Obsteteric
clinic RMJH
WORK IN PROGRESS