Pregnancy monitoring - the management of pregnant women with epilepsy - Doina Vanghelie, Ionela Codita, Cristina Panea Elias University Emergency Hospital Bucharest

Pregnancy and epilepsy Pregnancies in women with epilepsy are considered at high risk for adverse outcomes because can be complicated by various maternal and fetal issues careful management by both neurological and obstetrician specialist Asses risk and benefits with individual drugs Limited data about newest drugs

Pregnancy and epilepsy Objectives seizure control (the occurence of seizure / increasing of seizure frequency) monitor the development of the fetus (congenital abnormalities, cognitive and development delay) prevent birth complications for mother/child (miscarriage, premature labor, perinatal death, hemorrhage)

Increase in seizure frequency Mainly last quarter due to: lower plasma level of AEDs increase hepatic / renal clearance increase the volume distribution by fluid retention reduced protein binding an increased level of estrogen (epileptogenic by decreasing the seizure thresold) sleep deprivation stress, anxiety decreased compliance in taking AEDs ( due to nausea or concerns regarding the effect on their fetus)  Low risk for recurrence of seizures if the patient is seizure-free for 9 month prior to pregnancy (level B) (Gjerde et al, 1988, Tomson et al, 1994)

Changed AEDs plasma concentration Pregnancy cause an increase in the clearance and decrease in the concentrations of: lamotrigine phenitoine lesser for carbamazepine (9% in 2nd trim and 12% in 3rd trim) Decrease level of levetiracetam, oxicarbamazepine (active metabolite MHD) Recommendation: monitoring of total and free level of plasma AEDs monthly

Acute seizures during pregnancy As the result of: gestational epilepsy (idiopathic onset) symptomatic epilepsy: vascular malformations or meningioma with receptors for estrogen (exacerbated by pregnancy) cerebrovascular disease (cerebral thrombophlebitis, or paradoxical amniotic embolism) Eclampsia Hyponatremia - due to oxytocin which promotes water retention Syncope In response to the used anesthetic lidocaine Psychogenic seizure (especially peripartum)

Seizures related risks for foetus During pregnancy it is essential to continue the treatment to avoid the risks associated with seizures High: tonic-clonic seizures Injury miscarriage fetal bradycardia the level of risk depends also on seizure frequency (definitive data is lacking) Low: focal seizure, absence and myoclonic seizure

Seizures related risks for mother Discuss with those who plan to stop AED theraphy ! SUDEP Status epilepticus

Status epilepticus Exclude preeclamsia and eclampsia Check maternal vital signs Asses the fetal heart rate and fetal status Laboratory findings (AED levels, electrolytes, glucose, toxicology) Benzodiazepine iv, phenitoin with cardiac monitoring Monitor the fetus Emergency delivery if necessary

Seizures control must be balanced with the teratogenic risk

The AEDs cross the placenta in clinically important amounts: Phenobarbital, primidone, phenytoin , carbamazepine, levetiracetam and valproat potentialy clinically important amounts: Gabapentin, lamotrigine, oxcarbamazepine and topiramat inssufficient data for ethosuximide Symptomatic effects in newborns: lethargy, excessive somnolence, fussiness

Teratogenic risk Risk of major congenital malformations is 4-9% in women receiving AEDs Specific malformations: PHT: risk of cleft palate (class II) CBZ: posterior cleft palate (class II) VPA: neural tube defects, facial clefts (class I), hypospadias (class II); more than 800mg and polytherapy included VPA are associated with higher risk PB: cardiac malformations (class II) EURAP epilepsy and pregnancy register

BUT It is recommended that do not change the AED during pregnancy

The teratogenic risk must be evaluated before pregnancy ! CBZ probably does not substantlly increase the risk (class I evidence) LTG – best option Close monitoring of child development Fetal survey by ultrasonography at 19-20 week with careful attention to the face, central nervous system and heart Possibly amniocentesis UK Epilepsy and Pregnancy Register

Folic acid Folic acid supplementation is possibly effective in preventing or reduction the rate of neural tube defects (level C) Started before pregnancy At least 0.4mg (0.5-4mg) per day At least until the end of first trimester

Delivery Epilepsy and antiepileptic treatment increase the risk of maternal and fetal complications: preeclampsia hypertension Miscarriage prematurity neonatal asphyxia Cesarean delivery: moderately increased risk is possible (level C) compared with women with no epilepsy Insufficient evidence for preeclampsia, hypertension premature contractions or premature labor and delivery Increased risks for the smokers pregnant women with epilepsy Possibly an increased risk (level C) for bleeding complications and spontaneous abortion (lack of statical data) Viinikainen et al, 2006; Richmond et al, 2004

Labor and delivery Preparation and close monitoring Inform all care providers (obstreticians, neurologist, anesthesiologist, pediatricians, nurses) that the patient has epilepsy Check AEDs plasma level at admission Extra doses of AED if it is necessary or switch to i.v. benzodiasepine or phenytoin (seizure prophylaxis)

AEDs and newborns Newborns exposed to enzyme-inducing AED received vitamin K at delivery inadequate evidence to determine if the newborns have substantially increased risk of hemorrhagic complications.

AEDs and newborns Transfer into breast milk Possibly in clinically important amounts: primididone and levetiracetam; probably gabapentine, lamotrigine, topiramat Not in clinically important amounts: valproate, phenobarbital, phenitoin and carbamazepine  

Conclusions Monitor total and free level of AEDs monthly, EEG monitoring Manage acute seizure and status epilepticus Continue  folate supplementation Check maternal serum alpha fetoprotein levels Fetal survey by ultrasonography at 19-20 week It is not clear prophylactic effect of bleeding by administering vitamin K prepartum Prepare delivery Breastfeeding