Pregnancy in women with epilepsy : preliminary results of Kerala registry of epilepsy and pregnancy.

SV Thomas, L Indrani, GC Devi, S Jacob, J Beegum, P Jacob, K Kesavadas, K Radhakrishnan, PS Sarma 
 Department of Neurology, Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum - 695011, India., India

Correspondence Address:
S V Thomas
Department of Neurology, Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum - 695011, India.
India

Full Text

::   Introduction

Epilepsy is one of the commonest neurological

disorders in our country. Some 30% of the 75,000

women with epilepsy (WWE) in Kerala come under

the reproductive age group. The social stigma and

negative attitude prevalent in the society make it hard

for WWE to integrate well into normal social life.

There is considerable concern regarding the safety of

pregnancy and health of the baby among these

couples. Most of the previous studies indicate that

WWE may have a slightly reduced fertility, when

compared to others.[1] However, a recent community

based study revealed that fertility is not reduced

among WWE.[2] They may also face increased risk of

complications of pregnancy such as hyperemesis

gravidarum, spontaneous abortions, premature labour

and assisted delivery or cesarean section.[3] The risk of

congenital malformations is increased among the

infants born to WWE by two to three times (4%-6%).[4]

Most of the data on epilepsy and pregnancy had been

compiled through the registries operating in the

developed countries. The special situations prevailing

in India and other developing countries are not

adequately addressed in these studies. The outcome of

pregnancy among WWE in developing countries

further depends on these factors also. The preliminary

results of the registry are presented here.

::   Material and methods

This study was carried out in the Kerala registry of

epilepsy and pregnancy. The protocol of registry is

described in Annexure I. Patients got enrolled in the

registry at the preconception period or during

pregnancy. Terminology according to International

League Against Epilepsy (ILAE) was followed in

classifying seizures and epileptic syndromes.[5],[6]

Patients were followed up according to the consensus

protocol developed by a team of doctors consisting of

neurologists, gynaecologists, imageologists and

experts from genetics and biochemistry departments

during a workshop held for this purpose.[7] Clinical and

laboratory investigations were carried out at

predetermined intervals as laid down in the protocol.

85 WWE were enrolled in the registry between June

1998 and November 1998. Twenty of them (23.5%)

reported in the preconception period and 65 (76.5%)

during pregnancy. 14 patients were in the first

trimester, 16 were in the second trimester and 35 in

the third trimester. Follow up was incomplete in four

of them and they were excluded from the analysis.

The results pertain to the 32 patients, who had

completed their current pregnancy. As per the policy

of the registry, obstetrical follow up and delivery are

conducted at a centre chosen by the patient. We

compiled data on deliveries conducted elsewhere.

Student's 't' test was performed to ascertain

significance of group means. Odds ratio was

calculated to estimate the risk of malformation with

different AEDs.

::   Results

Patient characteristics and AED therapy : Thirty-two

women had completed their pregnancy under this

protocol. Their age ranged from 19-38 years (mean 26

years), and parity ranged from 1-4 (mean 1.6).

Nineteen (59.38%) of them had generalized epilepsy,

11 (34.37%) had localisation related epilepsy and 2

(6.26%) had other types. The seizure frequency during

current pregnancy ranged from 0-8 (mean 0.7). Only

23 (71.9%) of them were taking AED, whereas nine

(28.1%) were not on any AED. Nineteen were on

monotherapy and 4 (12.5%) were on polytherapy.

Nine patients were on phenobarbitone, seven on

carbamazepine, six on sodium valproate and five on

phenytoin. Regular consumption of folic acid was

documented in only 40% patients although majority

of them were recommended nutritional supplements

including folic acid. None of them had any

preconception evaluation or counseling.

Pregnancy outcome : There was an increase in seizure

frequency in only 4 women (12.5%) whereas there

was no change in the seizure frequency in 25 (78.1%).

Seizure frequency had decreased among 3 (9.4%)

women. Over a quarter of these patients experienced

pregnancy induced hypertension (PIH) or preeclampsia.

Other complications observed during

pregnancy were intrauterine growth retardation

(IUGR), post term, placenta previa and hydramnios

[Table I]. There was one case of spontaneous abortion.

Nineteen (59.4%) women had normal vaginal

delivery. Nearly one-third (10) required cesarean

section [Table II]. The indication for cesarean section

was foetal distress, uterine inertia and failure of

induction. There was no episode of postpartum

hemorrhage.

Foetal outcome : There were 28 (87.5%) term babies,

2 (6%) were post term and 1 (3%) was pre-term. The

mean head circumference of the babies was 34.9 cm

(range 32-44 cm) and mean birth weight 2.84 kg

(range 1.8-4 kg). 6 (21.4%) of the term babies were of

low birth weight(<2.5 kg) and 3 (10.7%) had birth

asphyxia (apgar 1 mt/5 mts = 2-6/3-7).

Congenital malformations : Congenital malformations

were detected in 4 babies [Table III]. The

anomalies included hydrocephalus, meningomyelocele,

spina bifida, Arnold-Chiarri malformation,

intracerebral haemorrhage, talipes equinovarus and

minor anomalies like asymmetric ears, pectus

excavatus. Two of these babies were exposed to

sodium valproate, while others to carbamazepine and

phenobarbitone respectively. Two babies with

malformations died in the immediate neonatal period.

The baby with minor malformation Case 4, [Table III]

was delivered in a peripheral hospital. The baby was

transferred to neurology care when it developed

neonatal seizures. An ultrasound examination through

anterior fontenella showed intracerebral haemorrhage

that was confirmed by CT Scan. This baby was

managed with vitamin K injections, anti-convulsants

and cerebral anti-oedema measures but died on 30th

day.

The clinical characteristics of pregnancies with and

without malformations in the babies are compared

[Table IV], even though the number of pregnancies with

foetal anomalie was too small, due to small sample.

There was no statistically significant difference in the

maternal age, between those who had babies with

malformations and those without malformations.

There was a statistically significant (p <0.05) increase

in frequency of major anomalies among babies

exposed to AEDs in general, when compared to those

not exposed to AEDs. The odds ratio for occurrence of

malformations with various AEDs was as follows:

sodium valproate (6), carbamazepine (1.2) and

phenobarbitone (0.8). There was no anomaly in

patients exposed to phenytoin.

::   Discussion

The gender issues and medical aspects of epilepsy and

pregnancy are gaining more focussed attention.

Majority of WWE had normal outcome of pregnancy

in our study. Only one patient (3%) had a spontaneous

abortion which is less than that in the community. This

is much less than that observed in our earlier

retrospective analysis.[8] Another cohort of WWE,

followed under a registry, had 9.4% rate of

spontaneous abortion.[9] One of the reasons for this low

estimate of spontaneous abortion in our series may be

that nearly half of the patients were enrolled in the

registry only in the third trimester.

The complications of pregnancy, observed in our

series is similar to that reported earlier.9,10 However,

the frequency of pregnancy induced hypertension and

pre-eclampsia is much higher in our series which

could partly be due to the geographical

preponderance. PIH and PET are multifactorial

complications of pregnancy that show much

geographical variation in frequency and severity. It is

commoner among lower socio-economic group.

The head circumferences of the newborns were within

normal limits for the community. One fifth of the term

babies had low birth weight (<2.5 kg), which indicates

some degree of intrauterine growth retardation.

The most important finding in this study is the

occurrence of major malformations in a relatively

high proportion (12.5%) of pregnancies. This

frequency is comparable to that described in other

prospective studies.[11],[12],[13] It is generally accepted that

the incidence of congenital malformations in

pregnancies among WWE is higher than that in

general population. The incidence of malformations is

comparatively higher in prospective studies (10 -

12%) than in retrospective studies were incidence of

2-6% has been reported.14 A retrospective study from

our center also had shown a lower (4%) frequency of

birth defects.[8] It appears that risk of malformations in

WWE is more than what was previously estimated.

We had examined several maternal clinical

characteristics for possible association with foetal

anomalies. There was no statistically significant

difference in the maternal age between those who had

babies with malformations and those without

malformations. Other maternal characteristics such as

age, parity and frequency of seizures during

pregnancy did not have any significant correlation

with congenital anomalies in our cohort. This is in

contrast to the observation from Italian registry where

the mothers who had babies with malformations had

higher age.[9] Frequent seizures during pregnancy had

been associated with adverse foetal outcome in earlier

studies. However, we could not establish any such

relationship. This may be because our patients had

very few seizures during pregnancy (mean seizure

frequency was 0.7) [Table IV]. In our study, the only

clinical factors associated with birth anomalies were

the type of maternal epilepsy and use of AED. There

was statistically significant increased in incidence of

malformations associated with generalized epilepsy.

statistically significant. Reports from Berlin also have

shown increased incidence of birth defects associated

with generalized epilepsy in mothers.[16] In our study

there was a clear correlation between the risk of neural

tube defects and the exposure to sodium valproate or

carbamazepine. Two of the six (33.3%) infants

exposed to sodium valproate and one of the seven

(14.3%) exposed to carbamazepine showed neural

tube defects. The odds ratio was maximum (6) for

sodium valproate. These observations are in

agreement with other studies from elsewhere.[17],[18],[19],[20],[21]

Polytherapy had been identified as one of the risk

factors for malformations in earlier studies.22,23 We

did not find such a correlation. This could be because

there were very few patients (12.5%) on polytherapy.

Another major observation in this study is the

inconsistency in the prescription and use of folic acid

during pregnancy. There was very poor compliance in

this aspect as only 40% patients were found to be

taking folic acid on a regular basis. The situation in

developed countries is better (64%-78%) although it

falls short of ideal situation.[24] Medical Research

Council study in UK has shown that folic acid

supplementation of 4 mg before conception prevented

nearly thee quarters of neural tube defects in nonepileptic

women.[25] There appears to be no uniform

prescription policy regarding folic acid during

pregnancy among WWE.

One of these babies with minor anomalies developed

intracerebral bleed and died on 30th day. This baby

was delivered in a peripheral center and was not

protected by vitamin K. There is much debate as to the

usefulness of administering vitamin K to the mother in

the immediate pre parturition period to prevent

hemorrhagic disease of newborn.[23] The American

Academy of Neurology in its practice parameters have

recently recommended Vitamin K (10 mg per day) in

the last month of pregnancy or parenteral Vitamin K1

as soon as labor sets in.[26]

The study has brought out many of the lacunae in the

care of WWE during pregnancy. Special situations

prevailing in India and other developing countries do

have a bearing on their outcome as observed in this

study. The consumption of folic acid during

pregnancy was less among WWE in our cohort. They

had increased frequency of PIH/PET, and low birth

weight babies. The frequency of cesarean sections was

more in our cohort. These preliminary results indicate

that major malformations occur in about 10% of cases

and the risk appears to be higher with sodium

valproate. The medical care of WWE in pregnancy

need an integrated multidisciplinary approach. In fact

the planning should begin much ahead of conception.

A detailed preconception counseling should address

all aspects of pharmacotherapy and obstetrical issues.

The AED therapy need to be carefully evaluated and

folic acid should be administered regularly. Pregnancy

should be followed up with regular review and

screening for serious congenital anomalies.

::   Acknowledgement

The authors gratefully acknowledge the financial

support from the Department of Science, Technology

and Environment, Government of Kerala to the Kerala

registry of epilepsy and pregnancy.

References