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Year : 2001  |  Volume : 49  |  Issue : 1  |  Page : 1-2

Pregnancy, epilepsy and antiepileptic drugs.






How to cite this article:
Satishchandra P, Sinha S. Pregnancy, epilepsy and antiepileptic drugs. Neurol India 2001;49:1-2


How to cite this URL:
Satishchandra P, Sinha S. Pregnancy, epilepsy and antiepileptic drugs. Neurol India [serial online] 2001 [cited 2023 Feb 3];49:1-2. Available from: https://www.neurologyindia.com/text.asp?2001/49/1/1/1310



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 Top

1.Kaneko S : Epilepsy, Pregnancy and the child. Epilepsia 2000; 41 (S9) : 8-13.  Back to cited text no. 1    
2.Epilepsy and reproduction in Clinical epilepsy. DuncanJS, Shorvon SD, Fish DR (eds), BI Churchill Livingstone Pvt Ltd, New Delhi, 1996; 267-282.  Back to cited text no. 2    
3.Thomas SV, Indrani G, Devi GC et al : Pregnancy in women with epilepsy : Preliminary results of Kerala registry of epilepsy and pregnancy. Neurology India 2001; 49 : 60-66.  Back to cited text no. 3    
4.Yerby MS : Teratogenic effects of AEDs: what do we advice patients? Epilepsia1997; 38(9) : 957-958.  Back to cited text no. 4    
5.Yerby MS : Quality of life, epilepsy advances, and the role of anticonvulsants in women with epilepsy. Neurology 2000;55(S1) : 21-31.  Back to cited text no. 5    
6.Kaneko S, Otani K, Kondo T et al : Malformations in infants of mother with epilepsy receiving AEDs. Neurology 1992; 42(S5): 68-74.  Back to cited text no. 6    
7.Lindhout D, Meinardi H, Meijer JWA et al : Antiepileptic drugs and teratogenesis in two consecutive cohorts: changes in prescription policy paralled by changes in pattern of teratogenesis. Neurology1992; 42 (S5): 94-110.  Back to cited text no. 7    
8.Rosa FW : Spina bifida in infants of women treated with CBZ during pregnancy. New Eng J Med 1991; 342 : 674-677.  Back to cited text no. 8    
9.Kondo T, Kaneko S, Ameno Y et al. Preliminary reports on teratogenic effects of Zonisamide in offspring from women with epilepsy. Epilepsia, 1996; 27:1242-1244.  Back to cited text no. 9    
10.Wegener C, Nau H : Alteration of embryonic folate metabolism by Valproate during organogenesis -  Back to cited text no. 10    
11.Implications for mechanism of teratogenesis. Neurology 1992; 42(S5): 17-24.  Back to cited text no. 11    
12.Delgado-escueta AV, Janz D : Consensus guidelines: preconception counseling, management and care of pregnant women with epilepsy. Neurology, 1992; 42(S5):149-160.  Back to cited text no. 12    

 

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