Antiepileptic drugs and Pregnancy..

1.. •What is the epilepsy??

2.. •Antiepileptic drugs and association with pregnancy..

3.. •risk associated with epilepsy and pregnancy ..

4.. •Management of epilepsy before , during and after conception ..

5.. •Recommendation..

What is the epilepsy? Epilepsy is a brain disorder in which clusters of nerve

cells, or neurons, in the brain sometimes signal abnormally. Neurons normally generate

electrochemical impulses that act on other neurons, glands, and muscles to produce human thoughts,

feelings, and actions. In epilepsy, the normal pattern of neuronal activity becomes disturbed, causing strange sensations, emotions, and behavior, or

sometimes convulsions, muscle spasms, and loss of consciousness..

Risk associated

with epilepsy and

pregnancy..

OBSTETRICAL COMPLICATIONS A number of obstetrical complications are reported to be more common in women with epilepsy; these range from mild to severe, and

include -: low birth weight ,lower Apgar scores ,preeclampsia ,bleeding ,placental abruption, and prematurity..

Perinatal mortality and miscarriage 

The rates of stillbirth, neonatal death, and perinatal death vary widely and have been reported to be as high as two to three times greater in infants born to women with

epilepsy.. Absolute values are in general low but vary considerably among populations studied (1.3 to 14 percent for women with epilepsy compared with baseline values of 0.4 to 8 percent).

The risk of fetal malformations is strongly influenced by AED therapy, in particular valproate exposure .. Phenytoin, carbamazepine, phenobarbital, and topiramate have also been associated with higher baseline rates of fetal malformations

Polytherapy with more than one AED is a risk factor for fetal malformation as identified in a number of prospective, registry studies, with a risk of major malformation increasing to 6 to 8.6 percent

A family history of birth defects, low folate levels, and a low maternal level of education have been identified as additional risk factors for fetal malformations, at least in some studies

Some groups may be at higher risk than others..

EFFECT OF PREGNANCY ON SEIZURES

The frequency of seizures does not increase during pregnancy in the majority of women with epilepsy

Seizures, particularly convulsive seizures, are believed to be harmful to the fetus. Fetal bradycardia has been documented during maternal seizures

A two- to three-fold risk of perinatal mortality has been reported in infants

born to women with epilepsy compared with controls.

Most women will have no alteration of their seizure pattern during pregnancy, especially if noncompliance and sleep

deprivation are minimized. Altered pharmacokinetics of AEDs during pregnancy may also contribute to

increased seizure frequency in a small number of women

PRECONCEPTION MANAGEMENT

!! Epilepsy is not a contraindication for pregnancy.

!!Over 90 % of women with epilepsy will have good outcomes .

!!Preconception counseling is important for all women of child bearing years because many pregnancies are unplanned and the risks of complications can be minimized by interventions before

and early on in pregnancy..

Counseling should include information regarding risks

associated with epilepsy and pregnancy, potential interactions with oral contraceptive therapy,

and recommended folate supplementation

Contraception — Women with epilepsy should be

aware that hormonal contraceptive failure may occur with antiepileptic drugs (AEDs) which are inducers of

the hepatic cytochrome P-450 system..

Folic acid supplementation

Low serum folate levels in women with epilepsy are independently associated with an increased

risk of major fetal malformations. It has not yet been conclusively determined if

folic acid supplementation prevents neural tube defects in women receiving AEDs. However, animal studies have shown that valproate and phenytoin

decrease the concentration of certain forms of folate and are associated with neural tube defects

Folic acid supplementation (5mg daily) is recommended for all women of child bearing potential to minimize the risk of neural tube defects ..Published clinical guidelines regarding the dose of folate supplementation in women with epilepsy vary and are not definitive ..In contrast, the American College of Obstetricians and Gynecologists recommend 4.0 mg of folic acid daily for women at risk of having offspring with neural tube defects

(including women taking AEDs)..

Maternal supplementation with multivitamins containing folic acid

has not been associated with a reduction in the risk of congenital anomalies (cardiovascular defects, oral clefts, urinary tract defects) in

women taking AEDs during pregnancy

 There are two issues that must be considered concerning the administration of antiepileptic drugs (AEDs) in any woman with a seizure disorder who wants to

become pregnant..

Is the diagnosis of epilepsy well established? In some patients,

routine EEG recordings or continuous video/EEG monitoring may be warranted to confirm the

diagnosis

Does the patient require AEDs and if so, is she on the most

appropriate medication(s) and at the minimum dose to maintain

seizure control?

Other recommendations concerning the use of AEDs include

•The AED shoul

d be ad

mi

nistered at the l

owest dose and l

owest pl

as

ma l

evel that protects agai

nst tonic-

clonic and/or co

mpl

ex parti

al seizures

•The plasma drug level should be monitored regularly during pregnancy including, if available, the physiologically important free or unbound drug concentration

•The use of

multi

pl

e agents shoul

d be avoi

ded,

if pos

sibl

e,

especially co

mbi

nations i

nvol

vi

ng

valproate

, carbamazepine

, and

phenobarbital

•If there is a fa

mily history of neural tube defect

s, both

valproate

and

carbamazepine

shoul

d be avoi

ded,

unl

ess a patient's seizures cannot other

wise be controlled

IN ESTABLISHED PREGNANCY, CHANGES TO ALTERNATE AED THERAPY SHOULD NOT BE

UNDERTAKEN SOLELY TO REDUCE TERATOGENIC RISK FOR SEVERAL REASONS-:

•Changing AEDs may precipitate seizures1..

•Overlapping AEDs during the change exposes the fetus to effects of an additional AED2..

•There is limited advantage to changing AEDs if pregnancy has already been established for several weeks3..

MANAGEMENT DURING PREGNANCY AND DELIVERY

Management during pregnancy consists of folic acid supplementation, screening for major malformations, monitoring plasma AED levels,

and the administration of vitamin K late in pregnancy..

Preconception counseling may play a role in minimizing this risk ..

It is important to emphasize the importance of adequate sleep, medical compliance, and minimizing stress and other factors known to precipitate seizures.

In a study that included 95 women with epilepsy followed at a single tertiary care epilepsy clinic, 38 percent of pregnancies were associated with increased seizure frequency

compared with the pre-pregnancy baseline..

Continued folic acid supplementation—  Once a woman with epilepsy who is taking AEDs

becomes pregnant, serum and red cell folate levels can be monitored (goal is concentration above 4 mg/mL) . It is particularly important to maintain normal folate levels during the period

of organogenesis in the first trimester..

Vitamin K supplementation—  Most physicians recommend administration of

prophylactic vitamin K1 (10 to 20 mg/day) during the last month of pregnancy to women treated with AEDs to protect the child against severe postnatal bleeding due

to a deficiency in vitamin K-dependent clotting factors.. Enzyme-inducing AEDs, such as phenobarbital, phenytoin, and carbamazepine, cross the placenta and may increase the rate of oxidative degradation of vitamin K in the fetus, an effect that can be overcome by large doses of vitamin K.

All newborns receive 1 mg of vitamin K intramuscularly at birth. Fresh frozen plasma can be given if bleeding

occurs..

At delivery Most women have a normal vaginal delivery However,

elective cesarean section may be justified in women with frequent seizures during the third trimester or a

history of status epilepticus during severe stress.. A tonic-clonic seizure occurs during labor in 1 to 2 percent of women with epilepsy, and in another 1 to 2 percent 24 hours after delivery. It is therefore essential to maintain a plasma AED level known to protect against seizures during the third trimester and during delivery. Doses must not be missed during the period

of labor..

Convulsive seizures during labor and delivery should be treated promptly with intravenous benzodiazepines; lorazepam is considered

the drug of choice. Intravenous phenytoin is also highly effective

and has a longer duration of action . After delivery, phenobarbital, primidone, and benzodiazepines remain in neonatal plasma for several days. This can cause sedation and possibly a neonatal withdrawal syndrome

MANAGEMENT IN THE POSTPARTUM PERIOD

There are several basic principles of management of women with a history of seizures during the

postpartum period…-:

1..If the AED dose has been altered during pregnancy, a return to prepregnancy levels should be considered during the first few weeks after delivery. Lamotrigine clearance decreases quickly in the first week postpartum, and dose adjustments should be made sooner., The dose was incrementally reduced at postpartum days 3, 7, and 10, with return to preconception dose or preconception dose plus 50 mg to help counteract the

effects of sleep deprivation.. 2 ..The mother needs to be advised of the importance of

adequate rest, sleep and compliance with drug therapy..3..Precautions need to be taken to protect the infant if the mother

has a seizure. It is prudent, for example, to have another person present when the mother bathes the child. In addition, the baby should be changed on the floor or an alternative safe position

Breast feeding  The reported percentage of maternal plasma levels in breast milk

varies from 5 to 10 % with valproate to 90 % with ethosuximide. There is no evidence to determine whether this form of AED exposure has clinical effects on the newborn . Most experts believe that taking AEDs does not generally contraindicate breast feeding, as probable benefits outweigh risks.

Clinical experience generally suggests that problems tend to occur only with the sedative drugs, such as phenobarbital, primidone, or benzodiazepines. Exposure to these drugs may cause the child to become irritable, fall asleep shortly after beginning to nurse, or fail to thrive. If this occurs, breast feeding may need to

be discontinued but can be retried one week later..

P atien ts who h ave been se izu re free fo r two o r mo re ye ars shou ld be con side red fo r A ED withd rawal six mon th s o r mo re p rio r to p lanned con cep tion .

For

wo

men

taki

ng

carbamazepine

or

valproate

,

or

with

a

previ

ously

affected

chil

d,

we

suggest

higher

dose

f

ol

ate

suppl

ementati

on,

4

mg

per

day,

pri

or

to

concepti

on ..

We

suggest

oral

vita

mi

n

K

suppl

ementati

on,

10

to

20

mg/day,

in

the

l

ast

month

of

pregnancy

f

or

wo

men

taki

ng

enzy

me-i

nduci

ng

AEDs

Antiepileptic drugs.. 1.. Na Valproate,

Valproate( valproic acid, VPA ) - is a broad spectrum AED that is used alone and in combination for the treatment of generalized and focal seizures…

The Australian Pregnancy Register has reported the risk to be as high as 16% for first trimester fetal exposure to valproate at doses above 1400 mg/day, compared with 6% at doses below 1400 mg/day. Others have reported higher risk when plasma valproate concentrations are consistently high (more than 70 mg/L). Valproate should therefore be avoided in reproductive women wherever possible.

CON.. !!One to 2 percent of fetuses exposed to valproate in utero

develop neural-tube like defects (spina bifida aperta, open lumbosacral myelocele), a 10- to 20-fold increase over the

general population..

!!There also may be a pattern of major malformations consisting of meningomyelocele, cardiovascular, and urogenital

malformations with minor craniofacial ,skeletal, and genital anomalies..

!! Breastfeeding is considered compatible with valproate therapy.

Valproate concentrations in breastfed babies are low.

2. Lamotrigine The cellular mechanism of action of lamotrigine (LTG) is not completely understood, and it may have multiple effects. In rodent brain preparations, LTG blocks the repetitive firing of neurons by inactivating voltage-dependent sodium channelsThe North American Pregnancy Register has reported thatexposure to lamotrigine in the first trimester may cause anincreased risk of oral clefts (a rate of 8.9 per 1000, as compared to 0.37 per 1000 in the reference population).. Significant dose related teratogenesis with lamotrigine exceeding 200 mg/day has

been reported..Lamotrigine clearance increases steadily through to 32 weeksof pregnancy. Plasma concentrations of lamotrigine fall earlyin pregnancy so dose increases may be necessary to controlseizures.

CON..

Lamotrigine is excreted in considerable amounts into breast milk.

Early reports show that most full-term babies seem to have little problem with breastfeeding , but close monitoring fortoxicity, especially in small or preterm babies, is advised.

3. Carbamazepinehas broad use as an AED for the treatment of focal and generalized seizures. It is also effective for the treatment of affective illnesses such as bipolar disorder and chronic pain syndromes such as trigeminal neuralgia.

CBZ binds to voltage-dependent sodium channels, probably after they change from the activated to the inactivated state

For almost 20 years reports have associated carbamazepine with an increased risk of structural birth defects including

spina bifida .

However, no pregnancy register has yet shownany statistically significant increase in risk relative to thetotal population.Carbamazepine is compatible with breastfeeding in the full-term infant.

4. PhenytoinPhenytoin was introduced in the 1930’s for use in

epilepsy and is still widely prescribed for focal and generalized seizures. Similar to carbamazepine, it blocks voltage-dependent neuronal sodium channelsPhenytoin is now used less frequently in women with epilepsy.

It has been reported to produce an increase in major malformations.

A marked increase in the clearance of phenytoin in pregnancy is associated with a fall in plasma concentrations and possible lossof seizure control.

!!Orofacial clefts, cardiac malformations, and genitourinary defects are the major anomalies described with phenytoin ..

!!In utero exposure to phenytoin has been associated with the development of neuroblastoma in several case reports..

!!Breastfeeding is acceptable with phenytoin..

4. PhenobarbitonePhenobarbital is among the oldest AEDs still in use. It is

effective for the treatment of generalized and focal seizures. However, its clinical utility is limited by its sedating effects..

Phenobarbital binds to the GABA(A) receptor, improving the effect of GABA by extending the duration of GABA-mediated

chloride channel openings..

Phenobarbitone is rarely used now in reproductive women with epilepsy. The North American Pregnancy Register suggests that it may carry a significant teratogenic risk. A marked increase in plasma clearance occurs in pregnancy.

Malformations of the heart, orofacial, and urogenital structures occur with increased

frequency with phenobarbital..Findings from the North American AED Pregnancy Registry found a 5.5 percent incidence of major malformations among 199 pregnancies associated with phenobarbital use, a rate that was somewhat higher than for unexposed pregnancies and for those exposed to lamotrigine..

Phenobarbitone in breast milk may cause neonatal drowsiness and apathy.

5. Oxcarbazepine, topiramate, ethosuximide

 Oxcarbazepine is a compound with a similar chemical structure to carbamazepine and likely a

similar mechanism of action.. Ethosuximide — Ethosuximide diminishes T-type calcium currents in thalamic neurons, which are further reduced as membrane potentials become more hyperpolarized .. The metabolite of trimethadione, another AED for absence seizures, acts similarly.

Ethosuximide is effective for the treatment of absence seizures; it has no activity against generalized

tonic-clonic or focal seizures..

Only a few pregnancies have been documented, so theteratogenic risks of these drugs are unknown. Oxcarbazepineclearance seems to increase significantly in pregnancy, but theclinical importance of this is uncertain.

These drugs are excreted in breast milk, but the very limited data available suggest that neonatal drug concentrations are usually low.

Breastfeeding is probably acceptable with clinical monitoring..

Neural tube defect..

Myelomeningocele Anencephaly

Cleft lip and palate..

DR.WALAA AHMED