1. Planning pregnancy in woman with epilepsy
Cristina Panea
Elias University Emergency Hospital
Bucharest

2. Disclosure
Sanofi
Novartis
UCB-Pharma

3. Three to five births per thousand will be to women with epilepsy
The majority of people with epilepsy are otherwise healthy and, if they have well-controlled seizures, they are entitled to enjoy a family and children
BUT
Three to five births per thousand will be to women with epilepsy
Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society, 2009

4. Doctors discourage the patients
Close monnitoring
Teratogenic risks
Patients are afraid
risk of disease transmission
seizure and treatment influence on child.

5. And yet… 1500-2000 in Australia and over 5000 in USA
epileptic women on AED become pregnant each year
95% give birth to healthy babies
Australian Family Physician Vol. 43, No. 3,2014
North American Pregnancy Registry

6. At least 1 year before conception
Pregnancy planning
Genetic counseling
Epilepsy management
Lowest seizure risk
Lowest malformation risk
At least 1 year before conception
All female patients of yo with epilepsy should be provided with the following information from the point of diagnosis onwards, even if not immediately planning pregnancy, and should receive the AED with no interactions with contraception and low teratogenic risk.

7. Avoid unplanned pregnancy
Effective contraception
Reduced hormonal contraception in patients on enzyme-inducing anticonvulsants: CBZ, PHT, PB
Use a non enzyme-inducing AED
contraceptive pill > 50 microgrammes of oestrogen/day
non- hormonal methods

8. Genetic counseling
Both potential parents’ family histories should be reviewed
The risk of epilepsy:
among people with epileptic parents or siblings: 4-8%
in the general population: 1-2%
depending on the type of epilepsy:
higher in the relatives of a person with generalized epilepsy
lower in the relatives of a person with focal epilepsy.

9. The risk may be modified by de novo mutations
Infantile spasms and Lennox-Gastaut syndrome
Combination of inherited mutations and random mutations that occur after birth: de novo mutations
people with a family risk of the disease never develop it, while others do
certain medications are more effective in some patients than others.
”The study analysis revealed de novo (random) mutations on nine specific genes with four mutations being completely new ones never before associated with epilepsy”
Andrew S Allen et al.  De novo mutations in epileptic encephalopathies. Nature, 2013

10. The decision is of patient and her family
Genetic risk
The chance is less than 1 in 10 that a child of a person with epilepsy will also develop epilepsy
Evaluate and advice
The decision is of patient and her family

11. The management of epilepsy
- Are the seizures dangerous for the child?
- Yes, and for mother also !
- Is the treatment dangerous for the child?
- Yes

12. The consequences of tonic-clonic seizures on…
The fetus
The mother
Traumatic injury
Hypoxic injury
Fetal acidosis
fetal heart rate decelerations
fetal death
Traumatic injury
ruptured fetal membranes
Infections
miscarriages
stillbirths
premature labor
Maternal death
30% increase seizure frequency
EURAP

13. Anticonvulsant treatment during pregnancy should be chosen so as to minimise the occurrence of convulsions

14. The pathogenesis of fetal malformations
Multifactorial:
direct effect of AEDs
toxic AED metabolites
reduced folate availability
hypoxic injury
associated with seizures and genetic predisposition

15. How do we manage?
Purpose: at least 9 month free of seizures before conception
If seizure-free for at least two years -> supervised withdrawal of anticonvulsant medication over a period of 3-6 months.

16. Adjust the treatment If the lowest dose that protects against seizures
not seizure - free
specific epilepsy syndrome which require continual drug treatment
unacceptable risk of seizure recurrence
the lowest dose that protects against seizures
monotherapy

17. AED teratogenity
The reported MCM rates in the general population: %
Women with a history of epilepsy on no AEDs show similar MCM rates.
The average MCM rates among all AED exposures vary between 3.1% - 9%, or approximately 2-3 folds higher than the general population

18. Do we change the AED ?
Adapt AAN 2016

19. Risk of major congenital malformation
North American Pregnancy Registry
Hernandez-Diaz, et al., Neurology 2012 (8).

20. Do we change ? Change AED with another one with lower teratogenic risk
1 y before
If we expect seizures control 
If sodium valproate is the single agent of choice:
Dosage < mg
Divided daily dose to avoid high plasma levels
NHS Guideline

21. Teratogenic risk
VPA monotherapy during the first trimester possibly increases the risk of malformations ( class II evidence)
Politherapy with VPA probably - compared cu polytherapy that not included VPA (class I evidence).
CBZ probably does not substantlly increase the risk (class I evidence) if < 400 mg
LTG < 300 mg – best option
UK Epilepsy and Pregnancy Register
Australian Registre of Antiepileptic Drugs in Preganancy 

22. Folic acid supplementation
Possibly effective in preventing or reduction the rate of neural tube defects (level C)
Positive effect on mean IQ in infants exposed to AED in utero (DEAD study group) for all AEDs studied (VPA, CBZ, LTG, PHT)
Insufficient published data for dosing: least 0.4mg (0.5-5mg) per day
Before and during pregnancy   
Holmes et al, 2000; Gaily et al, 2004; NEAD Study Group; Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society, 2009

23. Conclusions
In pregnant women with epilepsy the risk of increased seizure frequency and the risk of AEDs must considered and weight carefully
Team of providers (neurologist, obstreticians, perinatalogist)
Informed decision (preconceptual preferably)
Early genetic counseling
Discuss the relative risk and benefits for adjusting medication
Withdrawal of theraphy (no seizure for 2-5 years)
Attempt to decrease to monotheraphy
Taper dosages of AEDs to the lowest therapeutic dose
Folate supplementation

24. Epilepsy is not a contraindication for pregnancy