Epilepsy Pregnancy Kandeel

8/14/2019 Epilepsy Pregnancy Kandeel

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Epilepsy in PregnancyEpilepsy in Pregnancy

BYBY

Mohamed A.S. KandeelMohamed A.S. Kandeel

(M.B.B.CH., M.Sc.(Ob/Gyn), M.D.(Ob/Gyn)(M.B.B.CH., M.Sc.(Ob/Gyn), M.D.(Ob/Gyn)

Professor of Obstetrics and GynecologyProfessor of Obstetrics and Gynecology

Menofyia UniversityMenofyia UniversityEgyptEgypt


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Learning ObjectivesLearnin

g Objectives

At the end of this presentation, you should:

1-Understand the effects of pregnancy on epilepsy and thecomplications that epilepsy may have on pregnancy,lactation and neonate.

2-Be able to outline a management plan for an epilepticpregnant woman.

3-Be aware of the different AEDs, their toxic effects and thesafest drug that can be used in pregnancy.


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Definition and IncidenceDefinition and Incidence

Epilepsy is recurring spontaneous seizures due tosudden excessive and disordered electrical discharge

from the neurones of the Cerebral cortex. It is estimated

that 7% of epileptic women become pregnant andepilepsy affects about 0.5-1% of pregnant women.

Epilepsy can be partial or generalized.


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Classification Of EpilepsyClassification Of E

pilepsy

A- Partial Seizures (Focal Seizures): This is the commonest type andis subcategorized as :

1-Simple Partial Seizures (Jacksonian epilepsy): The affectedwoman does not lose consciousness but may experience confusion,

tingling, or odd mental and emotional events. Such events mayinclude dj vu phenomenon, mild hallucinations, or extremeresponses to smell and taste.

After the seizure, the patient usually has temporary weakness in

certain muscles.


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pilepsy

2- Complex Partial Seizures (>50% in adults):

They can result in loss of judgment, involuntary uncontrolledbehavior & loss of consciousness. Prior to the actual seizure, somepeople may experience a warning aura, which can be an odd odor,a feeling of warmth, or a visual or auditory hallucination. They thenmay lose consciousness briefly and appear to others as motionlesswith a vacant stare. After a few seconds, some may begin toperform 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 intosecondarily generalized seizures. The progress may be so rapidthat the partial stage is not even noticed.


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pilepsy

B- Generalized Seizures

They occur in more diffuse areas of the brain and they have more seriouseffect 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 falland 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 musclesbegin 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 thepatient remains unconscious for a while and then awakens to confusion andextreme fatigue.


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Classification Of EpilepsyClassification 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. Suchseizures may pass unnoticed by others. About 25% of

patients with petit mal develop grand mal seizures


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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 ofthe body so that, for instance, the jaw slackens and the head drops.At other times, the whole body may lose muscle tone, and theperson can suddenly fall.

2- Simply Tonic or Clonic Seizures. Seizures can also be simply tonicor clonic. In tonic seizures, the muscles contract and consciousnessis altered for about 10 seconds, but the seizures do not progress tothe clonic phase. Clonic seizures, which are very rare, occurprimarily in young children, who experience spasms of the muscles

but not their tonic rigidity.

3- Myoclonic. Myoclonic seizures are a series of brief jerkycontractions of specific muscle groups, such as the face or trunk.


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4-Gestational epilepsy: Some patients experience their first seizuresduring 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 singleor multiple seizures in one or more of their pregnancies. It can alsobe a manifestation of epilepsy that may extend beyond the

pregnancy.

The workup of these patients should involve a neurologicexamination, consultation with a neurologist, CBC count, chemistrypanel (particularly for electrolytes), head MRI versus CT scan, andEEG. The differential diagnosis should include eclampsia and any

possible etiology considered in the nonpregnant patient, includingstroke, electrolyte abnormalities, tumor, trauma, drugs/withdrawal,and epilepsy


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Effects Of Pregnancy On EpilepsyEffects 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 lowerthreshold for seizures.

-Nausea and vomiting.


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Effects Of Pregnancy On Epilepsy (Cont.)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.


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Effect Of Epilepsy On PregnancyEffect Of Epilepsy On Pregnancy

Data on 1st trimester losses, PROM, ante-partumhemorrhage, operative vaginal delivery and CS areinconclusive.

Increased incidence of IUGR, cognitivedysfunction, microcephaly and perinatalmortality (1.2 - 3 times normal).

Increased incidence of congenital malformations.


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Effect Of Epilepsy On LactationEffect 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.


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Effects Of Epilepsy On Fetus And NeonateEffects 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.


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Table 1Table 1.. Antiepileptic Drug Exposure Through Breast MilkAntiepileptic Drug Exposure Through Breast MilkPennell PB, 2004Pennell PB, 2004

___________________________________AED Breast milk/maternal conc Adult half-life NN half-life

______________________________________________________________________

Carbamazepine 0.40.6 825 828

Phenytoin 0.180.4 1250 15105

Phenobarbital 0.360.6 75126 45500

Ethosuximide 0.80.9 3260 3240

Primidone 0.70.9 412 760

Valproic acid 0.010.10 618 3060

Lamotrigine 0.6 ___

Topiramate 0.690.86 ___

Zonisamide 0.410.93 63 61109

Levetiracetam 3.09 ___


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ManagementManagement

I-Preconceptional Care:

A-Re-assessment: may show that the patient does not have epilepsyor may reveal a treatable cause before pregnancy (e.g. blood vesselabnormality 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.


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ManagementManagement

I-Preconceptional Care:

C-Measurement of the free unbound anti-epileptic drug level inmaternal serum.

D- Preconceptional folate supplementation: 5 mg daily.

E- No trial to stop AED unless the patient is seizure free at least for 2years. The AED dose should be tapered till stopped completely atleast 6 months prior to any planned pregnancy to provide some

reassurance that seizures are not going to recur.


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II-II-Antenatal CareAntenatal 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 dailydoses are needed, use frequent smaller doses or extended-release formulato avoid high peak levels. Monitoring of serum AEDs level is mandatory.

Usually, women don't suspect they are pregnant until their fourth to sixthweek of pregnancy. By that time, if there are any harmful effects from their

AEDs, most of these effects would have already occurred.


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II-II-Antenatal CareAntenatal Care

C-Selenium supplementation: in a dose of 200 /day may beimportant to minimize the free radical mediated damage.

D-Folic acid supplements.

E-Morning sickness: If hyperemesis gravidarum, consider givingalternative route if vomiting is severe or prolonged.

F-Antenatal diagnosis: of congenital malformations (screening shouldbe done by detailed ultrasound and measurement of fetoprotein

at 18 weeks).


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II-II-Antenatal Care (Cont.)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 usingwhether it is a hepatic enzyme inducing or not. Most of

the newer AEDs are not enzyme inducers).


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III-III-Labor and Delivery (Cont.)Labor and Delivery (Cont.)

The risk of developing a seizure during labor is 9 timesthat 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 intravenousbenzodiazepines or phenytoin.


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Manage seizures acutely with intravenous benzodiazepines (1-2 mgof 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 cordblood for clotting studies.


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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) atno 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.


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III-III-Labor and DeliveryLabor 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 aggressiveinterference 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.


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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 thenext 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.


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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.


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IV-IV-Postnatal CarePostnatal 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 inattention can result in a fatal drowning. Wet sponge not water bath.Changing diapers and clothes are performed best on the floor ratherthan on an elevated changing table.

C-Breast Feeding: encouraged in suitable position. If excessive infantsedation is encountered, as may be seen with phenobarbital orprimidone, the infant should be weaned slowly with monitoring forsigns and symptoms of withdrawal and infant drug levels.


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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 whencarrying the baby.

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


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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.


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IV-IV-Postnatal Care (Cont.)Postnatal Care (Cont.)

F-Anticonvulsant: Any increase in drugs during pregnancy will needto 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.


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IV-IV-Postnatal Care (Cont.)Postnatal Care (Cont.)

In 1998, the American Academy of Neurology recommended theuse of an E2 dose of 50 g or its equivalent for 21 days of eachcycle when using OCPs with the enzyme-inducing AEDs. Morerecently, however, it is recognized that this still is inadequateprotection, 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 thatmidcycle bleeding indicates possible birth control failure, but itsabsence does not indicate adequate birth control efficacy. The

newer transdermal patch formulation have a higher failure rate withthese AEDs. IM medroxyprogesterone provides higher dosages ofprogestin but still may require dosing at 8- to 10-week intervalsrather than 12-week intervals.


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Table 2Table 2 .. Antiepileptic drug effects on hormonal contraceptivesAntiepileptic drug effects on hormonal contraceptives

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


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Anti-Epileptic DrugsAnti-Epileptic DrugsI-I-MonitoringMonitoring

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.


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Anti-Epileptic DrugsAnti-Epileptic DrugsI-I-MonitoringMonitoring

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 toeach situation, including increased monitoring for worsening seizure

control, adverse effects, and compliance issues.


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Table 3:Table 3: Therapeutic Levels of Anti-Epileptic Drugs (AEDs)Therapeutic Levels of Anti-Epileptic Drugs (AEDs)

Dichter MA, Brodie M.1996., Brodie M, Dichter MA 1996., Johannessen SI et al 2003.,Dichter MA, Brodie M.1996., Brodie M, Dichter MA 1996., Johannessen SI et al 2003.,

LaRoche SM et al 2004LaRoche SM et al 2004

Drug Common dose Doses Therapeutic levels

Carbamazepine 600 mg qd-qid 6-12 /ml

Gabapentin 300 mg Qd 70-120 mol/L

Lamotrigine 25-30 mg Qd 10-60 mol/L

Levetiracetama 5001500 mg bid 35120 mol/L

Oxcarbazepine 300600 mg bid 50140 mol/L

Phenobarbital 120 mg qd-bid 1040 /mL

Phenytoin 300 mg qd-bid 1020 /mL

Primidone 500 mg qd-bid 515 /mL

Valproic acid 1000 mg qd-bid 50100 /mL


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Anti-Epileptic DrugsAnti-Epileptic Drugs

II-Teratogenicity

Antiepileptic drugs (AEDs) have the potential to produce bothanatomic 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 acidabsorption. 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.


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Table 4:Table 4: Timing Of Embryonic OrganogenesisTiming Of Embryonic Organogenesis(Pennell PB 2003)(Pennell PB 2003)

Organ system Defect Postconception age

CNS NTD 28 days

Face Cleft lip & palate 36 and 70 days

CVS VSD 42 days

Urogenital

system

Hypospadius 56 days


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Prenatal Screening for Fetal MalformationsPrenatal 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 acetylcholine-

esterase.


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Anti-Epileptic Drugs (Cont.)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.


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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 SymptomsStarts 1 week after birth & includes restlessness, constant crying,

irritability, difficult sleeping & vasomotor instability.


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Behavioral Teratogenesis

In utero AED exposure can produce long-term behavioral changes:

In a retrospective Danish study, babies exposed in utero to phenobarbitalhad a 7-point decline in verbal IQ.

A prospective Finnish study found the mean verbal IQ score following inutero exposure to valproate was 82 compared with 96 for carbamazepineand 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 additionaleducational needs compared with 3.2% of children exposed tocarbamazepine monotherapy and 6.5% for other ani-epileptics.


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Anti-Epileptic DrugsAnti-Epileptic Drugs

III-Mono Versus Polytherapy

It is better to prescribe the lowest possible dose of a single drug toprevent and control fits.

Studies have shown higher incidence of malformations withpolytherapy compared to montherapy.

If large daily doses are needed, then frequent smaller doses orextended-release formula may be helpful to avoid high peak levels.

Dose should be divided into 3-4 doses/day. This is because highpeak plasma levels of the drug is more teratogenic.


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Table 5:Table 5: Comparison of Malformation Rates DuringComparison of Malformation Rates During

PregnancyPregnancy Monotherapy Versus PolytherapyMonotherapy Versus Polytherapy(Cont.)(Cont.)

Study design Findings

Lindhout et

al. 1992

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 were9.9% & 7.6% in 70s and

80s cohorts, respectively.

The difference did not

reach stat significance

Samrn et al.

1997

Pooled data from 5

prospective European studies

For the AED-exposed

children, the RR for a

major malformation was

2.3 (95% CI 1.2 to 4.7) vs

controls


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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 neonatalperiod, TTT is by the infusion of FFP or concentrates of deficient

factors in addition to the routine administration of vitamin K1.


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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.


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Anti-Epileptic Drugs (AEDs) (Cont.)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.


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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 bypsychiatric conditions (e.g., panic attack, personality disorders).


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Differential DiagnosisDifferential 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 painexpands gradually over minutes toward one side.


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Differential Diagnosis (Cont.)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 orflushes, and fear of losing control and fear of dying.

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

epilepsy.


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5-Local Anesthetic Toxicity: Occurs due to either injection of the localagent 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, seizuredisorder or anxiety attacks. Diagnosis is by 24 hrs VMA,metanephrines or unconjugated catecholamines. Adrenallocalization is usually successful with CT or MRI.


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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 oracute viral hepatitis.


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ConclusionsConclusions

1-Epileptic woman can get pregnant. They are notdifferent than other women population.

2-Epilepsy and its medications increases the incidenceof malformations 2-3 times normal. However; there is

90% chance of having a normal child.

3-The most common malformations are cleft lip, leftpalate and congenital heart diseases.


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Conclusions (Cont.)Conclusions (Cont.)

4-A woman should not stop AED unless she has nothad seizures for 2 years; gradual discontinuation

can then be attempted.

5-A pregnant should not stops her AED Since mostmalformations develop during the 1st trimester.

6-Current AEDs are considered to be a necessary evil

until newer drugs become available. However, thesafest are: Phenobarbital and phenytoins.


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Thank you

Epilepsy Pregnancy Kandeel

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