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

Disclosure Sanofi Novartis UCB-Pharma

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

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

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

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 16-44 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.

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

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.

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

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

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

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

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

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

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.

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

AED teratogenity The reported MCM rates in the general population: 1.6 - 3.2 % 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

Do we change the AED ? Adapt AAN 2016

Risk of major congenital malformation North American Pregnancy Registry 1997 - 2011 Hernandez-Diaz, et al., Neurology 2012 (8).

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 < 800-1000 mg Divided daily dose to avoid high plasma levels NHS Guideline

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 

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

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

Epilepsy is not a contraindication for pregnancy