Pregnancy, epilepsy and antiepileptic drugs.

P Satishchandra, S Sinha 
 

Correspondence Address:
P Satishchandra

Full Text



P. Satishchandra, S. Sinha

Department of Neurology

National Institute of Mental Health and Neurosciences

Bangalore, India.

Women with epilepsy have some legitimate questions

and worries regarding the effect of epilepsy and use of

anti epileptic drugs (AEDs) upon their pregnancies

and their unborn babies. The concerns are : i)

increased seizure frequency during pregnancy, ii) risk

of birth defects, iii) risk associated with breastfeeding,

iv) psychomotor retardation in off springs

and v) foetal deaths. Due to better social adjustment

and awareness, more number of women with epilepsy

are getting married and bearing children.1,2 It is also

universally accepted that AEDs must be continued

through out pregnancy because uncontrolled seizures

during pregnancy may cause more harm if not treated

adequately. Therefore, it is important to put the

teratogenic potential of AEDs in proper perspective.

The article by Thomas et al in this issue attempts to

highlight some of the above problems of women with

epilepsy from Kerala registry. They have reported

follow up data of 32 women with epilepsy who

delivered babies. Among them, 23 were on treatment

with various AEDs.[3]

The report of 'foetal hydantoin syndrome' was first

published in 1960s. Since there many aspects of drug

toxicity in foetus have been reported[2],[4],[5] viz : a)

infants of mothers with epilepsy are at greater risk of

developing congenital malformations than general

population, b) foetal malformations among infants

born to mothers with epilepsy and AEDs during

pregnancy are higher than among infants of epileptic

mothers not exposed to AEDs in-utero, c) mean serum

AED level is higher in mothers of infants with

malformation, d) infants of mothers on polytherapy

have higher rates of malformations.

A prospective case control study is the best way to

determine the risks and factors responsible for

increased risks. The method used by Thomas et al

though prospective - unfortunately lacks control

group, has non-random use of AEDs and consists of

heterogeneous types of epilepsy. One must have

information segregated by seizure types along with

the proper number of subjects required to attain

adequate statistical power and control to determine the

potential influence of a specific type of seizure or

epilepsy syndrome that may itself pose risk of adverse

outcome independent of the AEDs administered.4

It is said that fertility of women with epilepsy is 85%

when compared to the general population. The

complications like pregnancy induced hypertension

(28.1%), intrauterine growth retardation (18.8%),

reported by Thomas et al mainly are in accordance

with that reported in literature.[2] Most women have a

normal vaginal delivery. A relatively lower incidence

(60%) of normal vaginal delivery in the study from

Kerala could be because of small sample. Regular and

periodic antenatal check up with a good ultra sound

examination for foetal well-being / malformations

and/or alpha feto protein (AFP) levels should be done

and the practitioner must choose a course that

prevents seizures and minimizes foetal exposure to

AEDs.[5]

The background risk of malformations is

approximately 1-3%, which increases to 7% with

monotherapy and to 15% with polytherapy.2 In a

study, it has been found that overall malformation risk

is 9.7% in infants of epileptic mothers compared to

4.8% in controls.1,6 It is believed that in prospective

studies the incidence of anomalies is more than that

reported in retrospective studies as the minor

anomalies are overlooked in the later. Thomas et al3 in

this issue report a rather high incidence of

teratogenecity of 12.5% (4/32). All the patients were

on monotherapy with different drugs. Surprisingly the

teratogenicity of sodium valproate i.e. neural tube

defects (NTD) is 33% (2/6) in this study which is

much higher than other reports in literature (1 to

1.5%). This, however, should not send a wrong

message to patients and physicians. The reasons could

be very small sample size in this preliminary report from Kerala and further studies with larger sample and comparison with controls may be required before

a final conclusion can be drawn.

All AEDs cross placenta and attain sufficient

pharmacological active levels in embryo. The

mechanisms of teratogenecity are still not clear but

may be because of formation of epoxide and/or oxide

metabolites and of cytotoxic free radicals. Though

there is no conclusive evidence for a differential

overall risk of teratogenicity of various AEDs, it is

generally believed that sodium valproate carries

probably a higher risk especially with regards to

neural tube defects.[7] Rosa et al reported that NTD is

slightly more with valproate (1.47%) than

carbamazepine (1.0%).[8] However, there are some

reports that valproate/carbamazepine along with other

AEDs in utero have decreased incidence of NTDs!

The reason however is not clearly understood.[1] There

is no conclusive evidence for or against the safety of

newer AEDs till now. Kondo et al from Japan have

reported that among 20 patients on zonisamide (18 on

polytherapy and 2 on monotherapy) used in

pregnancy, one had atrial septal defect.[9]

Valproate induced impaired embryonic folate

metabolism was studied by Wegener et al.[10] Serum

folate levels, less than 4 mg/dl have been found to be

associated with increased risk of anomalies.[10] An

MRC study from UK found that 4mg/day of folate

from pre-conception, to women who have given birth

to an infant with NTDs, was associated with 72%

protection. Thomas et al[3] found that only 40% of

women with risk were on folate supplement. It

appears that we should have some definitive

guidelines in India for prescribing folate during

pregnancy in order to prevent these anomalies. If

major anomalies are detected, medical termination

(MTP) should be recommended. A protocol, as

prepared by Keral registry, may be a good idea to

follow.

The problems addressed here are important to our

patients and us. The difficulties in mounting a

definitive prospective study are daunting. A detailed

preconception counseling of women with epilepsy

with a multidisciplinary approach and a good periodic

antenatal check up is required. Definitive steps for

folate supplementation are required.[5]

The suggested guidelines include - i) all women of

childbearing age with epilepsy, should be (during

preconception) counseled that the incidence of

malformation in infants of mothers with epilepsy who

are treated with AEDs is two or three times that of the

infants of mothers without epilepsy, ii) children of

mothers with epilepsy treated or untreated with AEDs

tend to have more minor anomalies than do children

of father with epilepsy or general population, iii) we

do not know which of four major AEDs

(phenobarbitone, phenytoin, car-bamazepine and

sodium valproate) is least teratogenic. Under

therapeutic conditions, valproate may be regarded as

considerably teratogenic while all other AEDs as

weakly teratogenic, iv) if AED therapy cannot be

avoided, the first drug of choice for the seizure type

and/or epilepsy syndrome should be used as

monotherapy in lowest minimal effective dose,

v) folate supplementation is a must, vi) intense search

for birth defects must be done during regular follow

up and interventions (if required) during pregnancy

and labour. Though there is small but significant risk,

more than 90% of women with epilepsy on AEDs

during pregnancy will deliver normal child without

any form of birth defects.[11]

References