Epilepsy in Pregnancy BY

ABHISHEK JAGUESSAR

Learning Objectives
At the end of this presentation, you should: 1-Understand the effects of pregnancy on epilepsy and the complications that epilepsy may have on pregnancy, lactation and neonate. 2-Be able to outline a management plan for an epileptic pregnant woman. 3-Be aware of the different AEDs, their toxic effects and the safest drug that can be used in pregnancy.

Definition and Incidence

Epilepsy is recurring spontaneous seizures due to sudden excessive and disordered electrical discharge from the neurones of the Cerebral cortex. It is estimated that 7% of epileptic women become pregnant and epilepsy affects about 0.5-1% of pregnant women. Epilepsy can be partial or generalized.

Classification Of Epilepsy
A- Partial Seizures (Focal Seizures): This is the commonest type and is subcategorized as : 1-Simple Partial Seizures (Jacksonian epilepsy): The affected woman does not lose consciousness but may experience confusion, tingling, or odd mental and emotional events. Such events may include dj vu phenomenon, mild hallucinations, or extreme responses to smell and taste.

After the seizure, the patient usually has temporary weakness in certain muscles.

Classification Of Epilepsy
2- Complex Partial Seizures (>50% in adults): They can result in loss of judgment, involuntary uncontrolled behavior & loss of consciousness. Prior to the actual seizure, some people may experience a warning aura, which can be an odd odor, a feeling of warmth, or a visual or auditory hallucination. They then may lose consciousness briefly and appear to others as motionless with a vacant stare. After a few seconds, some may begin to perform repetitive movements, such as chewing or smacking of lips. Episodes usually last no more than two minutes. Ocassionally a simple or complex partial seizures evolve into secondarily generalized seizures. The progress may be so rapid that the partial stage is not even noticed.

Classification Of Epilepsy
B- Generalized Seizures They occur in more diffuse areas of the brain and they have more serious effect on the patient. They are further subcategorized as follows: 1-Tonic-Clonic (Grand Mal) Seizures: a-The tonic phase: muscles suddenly contract, causing the patient to fall and lie rigidly for about 10 to 30 seconds. Some people experience aura; most, lose consciousness without warning. If the throat or larynx is affected, stridor occurs when the patient inhales. b-The clonic phase: Seizure is said to enter this phase when the muscles begin to alternate between relaxation and rigidity. After this phase, the patient may lose bowel or urinary control. The seizure usually lasts a total of two to three minutes, after which the patient remains unconscious for a while and then awakens to confusion and extreme fatigue.

Classification Of Epilepsy
2- Absence (Petit Mal) Seizures: Petit mal or absence seizures are brief (three to 30 seconds) losses of consciousness and may consist of only a short cessation of physical movement and loss of attention. Such seizures may pass unnoticed by others. About 25% of patients with petit mal develop grand mal seizures

Classification Of Epilepsy
C- Other Seizures: 1- Atonic (Akinetic) Seizures. A person who has an atonic (or akinetic) seizure loses muscle tone. Sometimes it may affect only one part of the body so that, for instance, the jaw slackens and the head drops. At other times, the whole body may lose muscle tone, and the person can suddenly fall.

2- Simply Tonic or Clonic Seizures. Seizures can also be simply tonic or clonic. In tonic seizures, the muscles contract and consciousness is altered for about 10 seconds, but the seizures do not progress to the clonic phase. Clonic seizures, which are very rare, occur primarily in young children, who experience spasms of the muscles but not their tonic rigidity.
3- Myoclonic. Myoclonic seizures are a series of brief jerky contractions of specific muscle groups, such as the face or trunk.

Classification Of Epilepsy
4-Gestational epilepsy: Some patients experience their first seizures during pregnancy. This can be a result of true gestational epilepsy, a rare syndrome of seizures occurring only during pregnancy. Patients with this syndrome have a variable presentation with single or multiple seizures in one or more of their pregnancies. It can also be a manifestation of epilepsy that may extend beyond the pregnancy.

The workup of these patients should involve a neurologic examination, consultation with a neurologist, CBC count, chemistry panel (particularly for electrolytes), head MRI versus CT scan, and EEG. The differential diagnosis should include eclampsia and any possible etiology considered in the nonpregnant patient, including stroke, electrolyte abnormalities, tumor, trauma, drugs/withdrawal, and epilepsy

Effects Of Pregnancy On Epilepsy

Unpredictable
1-Seizure frequency may increase: due to: -Enhanced metabolism & increased drug clearance associated with pregnancy can result in decreased serum drug concentration. -Increased volume of distribution of the AED. -Increased serum binding proteins. -Decreased or non-compliance with medication. -Sleep deprivation, hormonal changes of pregnancy (high E), and associated psychological and emotional stress of pregnancy: all lower threshold for seizures. -Nausea and vomiting.

Effects Of Pregnancy On Epilepsy (Cont.)

2-Seizure frequency may decrease: Due to improved compliance with drug regimen in some patients. 3-Seizure frequency may remain unchanged.

Effect Of Epilepsy On Pregnancy

Data on 1st trimester losses, PROM, ante-partum hemorrhage, operative vaginal delivery and CS are inconclusive.

Increased incidence of IUGR, dysfunction, microcephaly and mortality (1.2 - 3 times normal).

cognitive perinatal

Increased incidence of congenital malformations.

Effect Of Epilepsy On Lactation

No studies on the effects of AED on either quantity or quality of breast milk.

Breast feeding should be stopped if obvious sedation develops in an infant and is likely to relate to the presence of AED in breast milk.

Effects Of Epilepsy On Fetus And Neonate

1-There is increased risk for infants of epileptic mothers to have epilepsy. The risk of neonatal susceptibility depends on: Nature of the mothers seizure disorder. Genetic factors. Seizures arises during pregnancy. Metabolic & toxic consequences of seizures and AEDs.

2-Increase perinatal morbidity.

Table 1. Antiepileptic Drug Exposure Through Breast Milk

Pennell PB, 2004

___________________________________
AED Breast milk/maternal conc Adult half-life NN half-life ______________________________________________________________________ Carbamazepine 0.40.6 825 828

Phenytoin Phenobarbital Ethosuximide Primidone Valproic acid Lamotrigine Topiramate Zonisamide Levetiracetam

0.180.4 0.360.6 0.80.9 0.70.9 0.010.10 0.6 0.690.86 0.410.93 3.09

1250 75126 3260 412 618 63

15105 45500 3240 760 3060 ___ ___ 61109 ___

Management I-Preconceptional Care:

A-Re-assessment: may show that the patient does not have epilepsy or may reveal a treatable cause before pregnancy (e.g. blood vessel abnormality in the brain).
B-Counseling: explain to the patient that: There is a chance of 90% of having normal child. Increased chance of having epileptic child (2-5%). Increased pregnancy complications. Increased unfortunate outcome if seizures arises during pregnancy. Increased risk of congenital malformations.

Management I-Preconceptional Care:

C-Measurement of the free unbound anti-epileptic drug level in maternal serum. D- Preconceptional folate supplementation: 5 mg daily. E- No trial to stop AED unless the patient is seizure free at least for 2 years. The AED dose should be tapered till stopped completely at least 6 months prior to any planned pregnancy to provide some reassurance that seizures are not going to recur.

II-Antenatal Care
A-Investigations: Metabolic: serum glucose, urea, electrolytes, Ca & Mg EEK MRI/CT scan of the head.

B-Drugs: Monotherapy at the lowest effective dose should be employed. If large daily doses are needed, use frequent smaller doses or extended-release formula to avoid high peak levels. Monitoring of serum AEDs level is mandatory.
Usually, women don't suspect they are pregnant until their fourth to sixth week of pregnancy. By that time, if there are any harmful effects from their AEDs, most of these effects would have already occurred.

II-Antenatal Care
C-Selenium supplementation: in a dose of 200 /day may be important to minimize the free radical mediated damage. D-Folic acid supplements. E-Morning sickness: If hyperemesis gravidarum, consider giving alternative route if vomiting is severe or prolonged. F-Antenatal diagnosis: of congenital malformations (screening should be done by detailed ultrasound and measurement of fetoprotein at 18 weeks).

II-Antenatal Care (Cont.)

G-Vitamin K:

Oral 20mg daily is prescribed from 36 weeks until delivery to mothers taking hepatic enzyme-inducing drugs (phenytoin, phenobarbitone, primidone, carbamazepine and topiramate - Not necessary with sodium valproate).
Be aware of the nature of the AED you are using whether it is a hepatic enzyme inducing or not. Most of the newer AEDs are not enzyme inducers).

III-Labor and Delivery (Cont.)

The risk of developing a seizure during labor is 9 times that during the rest of pregnancy. Management of women with epilepsy upon labor and delivery: Check levels of AEDs. Inform all health care providers that the patient has epilepsy. Consider seizure prophylaxis with intravenous benzodiazepines or phenytoin.

III-Labor and Delivery (Cont.)

Manage seizures acutely with intravenous benzodiazepines (1-2 mg of diazepam), then load phenytoin (1 g loaded over 1 h). Labor management should be based on routine standards of care. Start administration of vitamin K1 for the infant, and send the cord blood for clotting studies.

III-Labor and Delivery (Cont.)

Management of a pregnant patient in status epilepticus: Establish the ABCs, and check vital signs. Assess the fetal heart rate. Rule out eclampsia. Administer a bolus of lorazepam (0.1 mg/kg, ie, 5-10 mg) at no faster than 2 mg/min.

III-Labor and Delivery (Cont.)

Load phenytoin (20 mg/kg, ie, 1-2 g) at no faster than 50 mg/min, with cardiac monitoring. If this is not successful, load phenobarbital (20 mg/kg, ie, 1-2 g) at no faster than 100 mg/min. Check laboratory findings, including electrolytes, AED levels, glucose, and toxicology screen. If fetal testing results are nonreassuring, move to emergent delivery.

III-Labor and Delivery

The majority of women who have epilepsy have a safe vaginal delivery without seizure occurrence; provided, the AED is taken before and throughout labor. Generalized tonic clonic Seizures GTCSs needs aggressive interference because of the high risk for the mother and fetus, especially if they progress to status epilepticus. Oxygen should be administered to the patient and she should be placed on her left side to increase uterine blood flow and decrease the risk for maternal aspiration.

III-Labor and Delivery (Cont.)

Emergency C.S. should be performed when repeated GTCSs cannot be controlled during labor or when the mother is unable to cooperate. Any lady having a seizure during labour must be observed closely for the next 72 hours. Obstetric analgesia may be used to allow for rest before delivery. Pethidine should never be used because it is metabolised to norpethidine, which is epileptogenic. Diamorphine is an option. Few cases of postpartum seizures were reported following epidural analgesia.

III-Labor and Delivery (Cont.)

During labor, oral absorption of AEDs may be inappropriate and any vomiting might complicate the situation. PB, PHT, and VPA can be given IV at the same maintenance dosage. Convulsive seizures and repeated seizures during labor should be treated promptly with parenteral lorazepam or diazepam.

Benzodiazepines, in large doses, can cause neonatal cardiac and respiratory depression; therefore, close monitoring for these neonates is mandatory.

IV-Postnatal Care
A-Infant: - Inspected for malformation. -Vitamin k 0.1mg/kg IM at birth reduces risks of hemorrhagic disease. B-Bathing: never should be performed alone, as a brief lapse in attention can result in a fatal drowning. Wet sponge not water bath. Changing diapers and clothes are performed best on the floor rather than on an elevated changing table. C-Breast Feeding: encouraged in suitable position. If excessive infant sedation is encountered, as may be seen with phenobarbital or primidone, the infant should be weaned slowly with monitoring for signs and symptoms of withdrawal and infant drug levels.

IV-Postnatal Care
D- The following safety issues must be taken into account: If the mother is likely to drop objects she is holding but remain upright, then she should use a harness when carrying the baby.

If she is likely to fall, then a stroller kept at home is a must.

IV-Postnatal Care
E- Sleep: If the mother is breastfeeding, sleep deprivation may be unavoidable. The mother should make up any missed sleep during the infant's daytime naps, whenever possible.

IV-Postnatal Care (Cont.)

F-Anticonvulsant: Any increase in drugs during pregnancy will need to be decreased slowly to pre-pregnancy doses over 3-4 weeks to avoid toxicity. G-Contraceptions: Barriers and IUDs are recommended. Many AEDs induce the hepatic cytochrome P-450 system, which is the primary metabolic pathway of the sex steroid hormones. This leads to rapid clearance of steroid hormones and allow ovulation in women taking OCPs or other hormonal forms of birth control.

IV-Postnatal Care (Cont.)

In 1998, the American Academy of Neurology recommended the use of an E2 dose of 50 g or its equivalent for 21 days of each cycle when using OCPs with the enzyme-inducing AEDs. More recently, however, it is recognized that this still is inadequate protection, and a backup barrier method was recommended. Women on low dose pills or minipills and AED may get pregnant. Patients on hormonal contraception need to be warned that midcycle bleeding indicates possible birth control failure, but its absence does not indicate adequate birth control efficacy. The newer transdermal patch formulation have a higher failure rate with these AEDs. IM medroxyprogesterone provides higher dosages of progestin but still may require dosing at 8- to 10-week intervals rather than 12-week intervals.

Table 2 . Antiepileptic drug effects on hormonal contraceptives

Guberman 1999., Krauss et al 1996., Rosenfeld et al 1997

________________________________________
Lower hormone level No significant effect _______________________________________________ Phenobarbital Ethosuximide Phenytoin Valproate Carbamazepine Gabapentin Primidone Lamotrigine Topiramate Tiagabine Oxcarbazepine Levetiracetam Zonisamide

Anti-Epileptic Drugs
I-Monitoring
The ideal AED serum free level must be established for each patient before conception, and should be the level at which seizure control is the best possible for that patient without debilitating side effects. Levels should be repeated at the beginning of each trimester and again in the last 4 weeks of pregnancy. Monitoring should continue until the 6th to 8th week postpartum. In doing so, one may be able to avoid symptoms of toxicity that result from the changes in pharmacokinetics postpartum.

Anti-Epileptic Drugs
I-Monitoring
Some authors recommend monthly monitoring, given the possibility of rapid and unpredictable decreases in AED levels in an individual patient. The frequency with which levels are monitored must be tailored to each situation, including increased monitoring for worsening seizure control, adverse effects, and compliance issues.

Table 3: Therapeutic Levels of Anti-Epileptic Drugs (AEDs) Dichter MA, Brodie M.1996., Brodie M, Dichter MA 1996., Johannessen SI et al 2003., LaRoche SM et al 2004

Drug Carbamazepine

Common dose 600 mg

Doses qd-qid

Therapeutic levels 6-12 /ml

Gabapentin
Lamotrigine Levetiracetama Oxcarbazepine Phenobarbital

300 mg
25-30 mg 5001500 mg 300600 mg 120 mg

Qd
Qd bid bid qd-bid

70-120 mol/L
10-60 mol/L 35120 mol/L 50140 mol/L 1040 /mL

Phenytoin
Primidone Valproic acid

300 mg
500 mg 1000 mg

qd-bid
qd-bid qd-bid

1020 /mL
515 /mL 50100 /mL

Anti-Epileptic Drugs
II-Teratogenicity
Antiepileptic drugs (AEDs) have the potential to produce both anatomic and behavioral teratogenesis.

Mechanisms:
1-Direct drug toxicity: due to accumulation of the drug metabolites (reactive intermediates) which are embryotoxic. 2-Antifolate effect: Phyntoins, carbamazepine & barbiturates impair folic acid absorption. Valproic acid interferes with the production of folinic acid. 3-Genetically determined deficiency of the detoxifying enzyme epoxide hydroxylase. 4-Possible genetic link between maternal epilepsy and malformations.

Table 4: Timing Of Embryonic Organogenesis

(Pennell PB 2003)

Organ system CNS Face CVS Urogenital system

Defect NTD Cleft lip & palate VSD Hypospadius

Postconception age 28 days 36 and 70 days 42 days 56 days

Prenatal Screening for Fetal Malformations

Transvaginal U/S can be performed at 18-20 weeks to diagnose the most severe defets (face - heart). However, sensitivity is better, for cleft palate and lips, if U/S is repeated between 24-28 weeks.

Screening for NTD: by combination of Maternal serum fetoprotein at 15-22 weeks and Level II,structural Ultrasound, at 16-20 weeks.

If results are equivocal, proceed with amniocentesis with measurements of amniotic fluid -fetoprotein and acetylcholineesterase.

Anti-Epileptic Drugs (Cont.)

Specific Syndromes Of Malformations

1-Fetal Hydantoin Syndrome: 11% of infants exposed will have the syndrome. There is pre and postnatal growth deficiency, dysmorphic facies and mental retardation.

Anti-Epileptic Drugs (Cont.)

Specific Syndromes Of Malformations 2-Facial Valproate Syndrome: Brachycephaly with high forehead, shallow orbits, small nose, small mouth & low posterior ears. Long overlapping fingers & toes & hyperconvex nails. Cleft palate & congenital heart diseases. 3-Barbiturates Withdrawal Symptoms Starts 1 week after birth & includes restlessness, constant crying, irritability, difficult sleeping & vasomotor instability.

Anti-Epileptic Drugs (Cont.)

Behavioral Teratogenesis In utero AED exposure can produce long-term behavioral changes: In a retrospective Danish study, babies exposed in utero to phenobarbital had a 7-point decline in verbal IQ.

A prospective Finnish study found the mean verbal IQ score following in utero exposure to valproate was 82 compared with 96 for carbamazepine and 95 for healthy controls.
In a retrospective UK study of school-aged children exposed to in utero AEDs, 30% of children exposed to valproate monotherapy had additional educational needs compared with 3.2% of children exposed to carbamazepine monotherapy and 6.5% for other ani-epileptics.

Anti-Epileptic Drugs
III-Mono Versus Polytherapy
It is better to prescribe the lowest possible dose of a single drug to prevent and control fits. Studies have shown higher incidence of malformations with polytherapy compared to montherapy. If large daily doses are needed, then frequent smaller doses or extended-release formula may be helpful to avoid high peak levels. Dose should be divided into 3-4 doses/day. This is because high peak plasma levels of the drug is more teratogenic.

Table 5: Comparison of Malformation Rates During Pregnancy Monotherapy Versus Polytherapy

Study design
Kaneko et al. 1988 Prospective study

Findings
Malformation rates were 6.5% &15.6% for monotherapy & polytherapy (p = 0.01)

Oguni et al. 1992

Comparison of 2 Major malformations decreased prospectively from 24.1% to 8.8% (p < 0.01), followed cohorts paralleling an increased no. of patients receiving monotherapy. Prospective study Malformations was higher in of effects of AEDs infants exposed to poly (15%) compared to monoth. (5%) (p < 0.01)

Dravet et al. 1992

Table 5: Comparison of Malformation Rates During Pregnancy Monotherapy Versus Polytherapy (Cont.)

Study design
Holmes al. 2001 et Frequency of embryopathy in control infants not exposed to AEDs (n = 508) and in infants exposed to AED monotherapy (n = 223) and AED polytherapy (n = 93) were compared

Findings
Frequency of embryopathy was higher in infants exposed to AED monotherapy vs. nonexposed controls (20.6% vs. 8.5%; OR 2.8; 95% CI 1.1 to 9.7). The frequency was also higher in infants exposed to AED polytherapy vs. nonexposed controls (28.0% vs. 8.5%: OR 4.2; 95% CI 1.1 to 5.1)

Table 5: Comparison of Malformation Rates During Pregnancy Monotherapy Versus Polytherapy (Cont.)
Study design Findings

Lindhout al. 1992

et Influences of changes in prescribing practices analyzed by comparing 2 cohorts, 19721979 and 19801985, in the Netherlands

Mean no. of drugs used during pregnancy decreased from 2.2 in the 70s to 1.7 in the 80s. Rates of anomalies were 9.9% & 7.6% in 70s and 80s cohorts, respectively. The difference did not reach stat significance

Samrn et al. Pooled data from 5 For the AED-exposed 1997 prospective European studies children, the RR for a major malformation was 2.3 (95% CI 1.2 to 4.7) vs controls

Anti-Epileptic Drugs (Cont.)

VI-Clinical Or Subclinical Coagulopathy
Factors II,VII,IX & X are decreased. Factors V, VIII & fibrinogen are normal. PT & PTT should be determined at delivery. If values are low or clinical coagulopathy develops in the neonatal period, TTT is by the infusion of FFP or concentrates of deficient factors in addition to the routine administration of vitamin K1.

Anti-Epileptic Drugs (Cont.) IV-Failure of AEDs

An AED's failure to reduce seizures can be attributed to factors such as: 1-Wrong dosing. 2-Improper timing. 3-Rapid administration of the drug. 4-Ignoring conditions that precipitated the seizure.

Anti-Epileptic Drugs (AEDs) (Cont.) IV-Failure of AEDs

5-Instability of the drugs. Many drugs disintegrate easily with moisture. AEDs should be stored in a dry place and kept away from heat.

6-Toxicity. 40% of patients experience toxic effects from older AEDs which often causes them to withdraw. Among the most distressing are sleepiness, problems in coordination and weight gain.

Anti-Epileptic Drugs (Cont.) IV-Failure of AEDs

7-About a quarter of patients who do not respond to AEDs actually have nonepileptic seizures that in many cases are caused by psychiatric conditions (e.g., panic attack, personality disorders).

Differential Diagnosis
1-Eclamptic Seizures:
HTN & Ptnuria are always present. Urine output is diminished & anuria may develop. Hemoglobinuria is common. Fever of 39 C or more indicates impending CNS hemorrhage.

2-Migraine headaches, particularly migraine with auras, may sometimes be confused with epilepsy. With epileptic seizure, the preceding aura is often seen as multiple, brightly colored, circular spots, while migraine sufferers tend to see black, white, or colorless lined or zigzag flickering patterns. Typically the migraine pain expands gradually over minutes toward one side.

Differential Diagnosis (Cont.)

3-Panic Attacks: One study reported on patients with partial seizures that resembled panic disorder. Symptoms of panic disorder include palpitations, sweating, trembling, sensation of breathlessness, chest pain, feeling of choking, nausea, faintness, chills or flushes, and fear of losing control and fear of dying.

4-Narcolepsy: a sleep disorder that causes a sudden loss of muscle tone & excessive daytime sleepiness, can be confused with epilepsy.

Differential Diagnosis (Cont.)

5-Local Anesthetic Toxicity: Occurs due to either injection of the local agent into a bl. vessel or the administration of excessive amounts. Manifestations of systemic toxicity are those of C.N.S. & C.V.S.

6-Pheochromocytoma: Clinically, there is hypertensive crisis, seizure disorder or anxiety attacks. Diagnosis is by 24 hrs VMA, metanephrines or unconjugated catecholamines. Adrenal localization is usually successful with CT or MRI.

Differential Diagnosis (Cont.)

7-Tetany: Occurs as a part of maternal hypo-parathyroidism. Diagnosis is confirmed by low ionized calcium & parathormone levels & by measurement of urinary AMP excretion after administration of parathormone.

8-Metabolic: Hypoglycemia or hyponatremia.

9-Fulminant hepatic failure: Due to acute fatty liver of pregnancy or acute viral hepatitis.

Conclusions
1 Epileptic woman can get pregnant. They are not

different than other women population. 2-Epilepsy and its medications increases the incidence of malformations 2-3 times normal. However; there is 90% chance of having a normal child. 3-The most common malformations are cleft lip, left palate and congenital heart diseases.

Conclusions (Cont.)
4-A woman should not stop AED unless she has not had seizures for 2 years; gradual discontinuation can then be attempted. 5-A pregnant should not stops her AED Since most malformations develop during the 1st trimester. 6-Current AEDs are considered to be a necessary evil until newer drugs become available. However, the safest are: Phenobarbital and phenytoins.

Thank you