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