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Journal of Pregnancy and Child Health
Priya and Singh, J Preg Child Health 2017, 4:4
DOI: 10.4172/2376-127X.1000342
ISSN: 2376-127X
Review
Article
Research
Article
OMICS
International
Open
Access
Pregnant Women with Epilepsy: Management Issues
Bhanu Priya1 and Nilanchali Singh2*
1
2
Department of Obstetrics and Gynaecology, University College of Medical Sciences, India
Department of Obstetrics and Gynaecology, Maulana Azad Medical College, India
Abstract
Epilepsy is one of the common neurological disorders complicating pregnancy with a prevalence of 0.5-1%.
Epilepsy seizures are characterized by paroxysmal cerebral dysrhythmias. Epilepsy in pregnancy (EIP) is challenging
to both obstetricians and to neurologist. Pregnancy alters the natural history of epilepsy and seizure episodes are
likely to worse. Obstetricians also face challenges of increased risk of teratogenicity while women on anti epilepsy
drugs (AED). Epilepsy in pregnancy in Indian scenario also has both social and gender related issues. This review has
been designed to address the management of women with epilepsy (WWE). Also, there will be particular stress on the
recommendation regarding issues of pregnancy including antenatal and intrapartum care, preconceptional counselling
and information regarding teratogenicity of AED and drug monitoring and its optimization.
Keywords: Epilepsy; pregnancy; Obstetricians; Drug monitoring
Pregnancy Care
WWE has multiple issues in the antenatal, intrapartum and
postpartum period. Epilepsy is likely to affect the seizure frequency,
risk of teratogenicity and obstetric outcome [1]. It is a special situation
of pregnancy as it can be confused with Non proteinuric hypertension
and there are also conflicting report of increased chances of abruptio
placentae and pre eclampsia and eclampsia in WWE [2].
Epilepsy behavior in pregnancy and vice versa
Pregnancy behaves unpredictably on seizure frequency. Classically
said, rise in estrogen and progesterone in pregnancy increase the
neuronal excitability, hence, lowers the seizure threshold. Majority of
women (66.6%) remained seizure free throughout the pregnancy and
Generalized tonic-clonic seizures (GTCS) occurred in 15.2% of the
pregnancies [3]. The EURAP registry reported, using first trimester as
reference, seizure control remained unchanged throughout pregnancy
in 63.6%, 92.7% of whom were seizure-free during the entire pregnancy.
For those with a change in seizure frequency, 17.3% had an increase
and 15.9% a decrease [4]. Seizure control prior to the pregnancy is a
good predictor of seizure control during pregnancy. A study done by
Vajda et al. in 2008 observed little impact on seizure frequency in WWE
on AED. A seizure free interval of one year cause 50-70% reduction in
seizure frequency [5].
Significant impact of epilepsy has been observed over the obstetric
outcome. A meta analysis done between a period of 1990-2015
observed increased odds of spontaneous miscarriage (OR 1·54, 95%
CI 1.02-2.32), antepartum haemorrhage (1.49, 1.01-2.20), post-partum
haemorrhage (1.29, 1.13-1.49), hypertensive disorders (1.37, 1.21-1.55),
induction of labour (1.67, 1.31-2.11), caesarean section (1.40, 1.231.58), any preterm birth (<37 weeks of gestation, 1.16, 1.01-1.34) and
fetal growth restriction (1.26, 1.20-1.33) when compared with women
without epilepsy. The odds of early preterm birth, gestational diabetes,
fetal death or stillbirth, perinatal death or admission to neonatal
intensive care unit did not differ between women with epilepsy and
those without the disorder [6].
Epilepsy related mortality is not so uncommon entity and the
subject is still under research. The risk of death is ten folds in WWE
than women without the condition [1]. A United Kingdom based
research observed, 0.6% or 13,978 were WWE out of 2,291,493
maternities. Fourteen deaths were epilepsy-related, of which 11
J Preg Child Health, an open access journal
ISSN: 2376-127X
(79%) were sudden and unexpected (SUDEP). Nine occurred during
pregnancy and five were postpartum [1]. Another retrospective study
conducted by Macdonald et al. in 2015 observed a risk of death in
WWE during delivery hospitalization was 80 per 1,00,000 pregnancies
and was statistically higher than 6 deaths per 1,00,000 pregnancies in
women without epilepsy (adjusted OR 11.46) [7].
On the contrary, fetus is relatively resistant to small degree of
hypoxia occurring while seizures episode but prolonged hypoxia
occurring during status epilepticus can result in sustained fetal hypoxia.
EURAP registry 2013 reported status epilepticus in 0.6% (2/3806) of all
pregnancies and observed only one perinatal death which eliminates
the prior belief of having poor outcome with status epilepticus. This
improved outcome suggests better maternal care and lower threshold
for delivery.
AED levels and dose optimization
Pharmacokinetics is significantly altered in pregnancy as changes
occur in body weight, drug absorption, protein binding, metabolism
and excretion of drug, hence, the levels of most of the drugs. As the
serum protein level fall, serum concentration of AED that is total
drug concentration falls, but the unbound concentration remains
stable. The relatively newer AEDs like lamotrigine, oxcarbazepine as
well as levetiracetam noted clinically significant reduction in plasma
concentration [8-10]. Lamotrigine levels can fall as low as 70% in
pregnancy [11]. There is a controversy whether the AED levels should
be measured or clinical monitoring should be done. There are no set
guidelines as no direct comparisons have been done between regular
therapeutic monitoring or clinical monitoring.
In WWE, the aim of therapy is to maintain seizure control with
*Corresponding author: Nilanchali Singh, Assistant Professor, Department of
Obstetrics and Gynaecology, Maulana Azad Medical College, Delhi, India, Tel:
+919811343168; E-mail: nilanchalisingh@gmail.com
Received: July 05, 2017; Accepted: July 29, 2017; Published: August 05, 2017
Citation: Priya B, Singh N (2017) Pregnant Women with Epilepsy: Management
Issues. J Preg Child Health 4: 342. doi:10.4172/2376-127X.1000342
Copyright: © 2017 Priya B, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Volume 4 • Issue 4 •1000342
Citation: Priya B, Singh N (2017) Pregnant Women with Epilepsy: Management Issues. J Preg Child Health 4: 342. doi:10.4172/2376-127X.1000342
Page 2 of 5
lowest AED dosage. So, clinicians should decide for therapeutic
drug monitoring if there is suspicion of non adherence, toxicity and
uncontrolled seizures.
Monitoring of birth defects
WWE on AED have relatively higher chances of congenital
malformations (CM) than general population (2-3%) [12,13]. The
WWE not on AED have same risk as of general population. Screening
of birth defects should be offered to the couple at 11-13 weeks by
early anomaly scan to detect acrania (early stage of anencephaly)
and increased nuchal translucency for ruling out cardiac and other
defects [14]. At mid trimester (18-20 weeks) detailed targeted scan
for CM should be done with special emphasis on heart, neural tube
and face. Biochemical screening by maternal serum alfa feto protein
(MSAFP) along with ultrasound increases detection rate of neural tube
defects to 94-100%. No study has separately recommended for fetal
echocardiography apart from the 20 week detailed scan.
Monitoring of WWE in pregnancy
Antenatal period should be regularly assessed for women’s
wellness, ability to cope, memory, concentration and sleep, tiredness
and dizziness. The AED being taken or missed, dosing schedule, dose,
seizure type, frequency and auras should be inquired about. Any
precipitating factor like fasting, stress, sleep deprivation should be
identified and treated. In WWE with active seizures, minimal time
the women should left unattended and unobserved. Individual with
unwitnessed seizures are at likely of SUDEP. Early discussion should be
done with neurologist if there is poor seizure control and any required
dose adjustment should be done.
Vitamin K supplementation
Prenatal vitamin K supplementation in late third trimester has
been an issue of controversy. It was proposed enzyme inducing AED
(EIAED) competitively inhibits precursor of clotting factors and affect
fetal microsomal enzymes that degrade Vit K thereby increasing the
risk of Early hemorrhagic disease of newborn. But, several case control
studies observed no increase in neonatal bleeding born to women taking
EIAED [15]. On the basis of these studies only NICE has recommended
against the prenatal administration of Vit K. However, 1 mg I.M Vit K
is routinely given to the neonate after birth. Vitamin K administration
in late pregnancy to prevent post partum hemorrhage is still a matter of
discussion till now and no studies are available.
Intrapartum Care
The risk of seizures during labor is low provided adequate analgesia
and appropriate care of labor is given to minimize the risk factors like
insomnia, stress and dehydration. EURAP registry observed 3.5%
incidence of seizures of WWE in labor [4]. Hence, the delivery should
be conducted in a center where appropriate facilities for maternal and
neonatal resuscitation is available. Epilepsy is no contraindication
for normal vaginal delivery and early delivery is also not indicated.
There is also no evidence of AED affecting labor inducing agents.
WWE should continue her AED and good intravenous line should
be secured. Seizures precipitating factors like pain, hyperventilation,
stress, dehydration should be avoided. Continuous CTG monitoring is
recommended in an event of seizures or women high risk of seizures in
labor. Seizures during labor should be terminated at earliest to prevent
maternal and fetal hypoxia. Benzodiazepines are the drug of choice for
seizures in labor.
J Preg Child Health, an open access journal
ISSN: 2376-127X
Postpartum Care
The peripartum period especially, 3 days peripartum has shown
maximal seizure exacerbation. The risk is highest in women who had
seizures in a month prior to pregnancy compared with those who were
seizure free during same period (OR 3.7) [16]. Neurological consultation
should be sought within 10 days for any alteration in any drug dosing
as maternal drug levels can fluctuate. If doses during pregnancy were
increased, toxicity can occur as AED demand decreases.
WWE are also at increased risk of postpartum depression as
compared to women without epilepsy (29% versus 11% in control)
[17]. All AEDs are secreted in breast milk. Newer AEDs are secreted
more than the older ones. Newer generation drug like lamotrigine,
levetiracetam, oxcarbazepine should be recommended for breast
feeding only when benefits outweigh the risk. Further data is required
to establish the safety of newer drugs.
Individualized approach for monitoring of withdrawal symptoms
and toxicity should be used especially in premature babies. Breastfeeding
has not shown any cognitive changes at 3 years of age in children exposed
to lamotrigine, valproate, phenytoin or carbamazepine monotherapy.
The safety of mother and neonate at home is another issue that
needs to be addressed at the time of discharge. Safety strategies
include nursing baby on floor, shallow bath and bathing should not be
unattended and avoid risk factors for seizures and use of another help.
Lastly, family and social support is not an overemphasized fact.
Contraception
Contraceptive advice is challenging in case of WWE. It prevents
unplanned pregnancies and unnecessary stress. The efficacy of hormonal
contraception is going to be reduced in women taking EIAED like
phenytoin, carbamazepine, oxcarbazepine, topiramate. EIAED induce
hepatic enzymes and increase excretion of drug [18,19]. Also, the level
of sex hormone binding globulin (SHBG) are increased which decreases
free level of circulating hormone [19]. The non enzyme inducing AEDs
like valproate, benzodiazepines, gabapentin, pregabalin, levetiracetam,
tigabine and vigabatrin do not alter hormonal contraception efficacy
[19].
EIAEDs cause increased metabolism of estrogen and progestogens in
COC pills. Contraceptive alternatives like depot medroxyprogesterone
acetate (DMPA), levonorgestrel releasing intrauterine contraceptive
device (Mirena) or barrier methods are considerably safe in women
taking EIAEDs [20,21]. Traditionally, higher doses of COCs were
prescribed (50 mcg ethinyl estradiol) [22,23]. Whereas now, the studies
have revealed that increase in progestin is also required for ovulation
suppression. Hence, the recommendation is to increase both progestin
and estrogen. Tricyclic pills with shorten pill free interval are also
recommended for further efficacy [20]. Barrier contraception should
be used add on to COCs for better results [24]. Recent studies suggest
that consumption of combined oral contraceptives (COC) increases
lamotrigine metabolism by increasing glucoronidation and reducing
the level by 50% and worsening the seizure control [18,21,25]. Hence,
increment in dose of lamotrigine is required while women on COC.
Levonorgestrel implants like Norplant and implanon have observed
lower levonorgestrel levels in women taking EIAEDs and subsequent
higher failure rates have been reported [26,27]. Despite failure of
subcutaneous progestin implants, high dose of DMPA provide effective
contraception in women taking EIAEDs. Additionally, DMPA has
been shown to reduce the frequency of seizure episodes [19]. The
Volume 4 • Issue 4 •1000342
Citation: Priya B, Singh N (2017) Pregnant Women with Epilepsy: Management Issues. J Preg Child Health 4: 342. doi:10.4172/2376-127X.1000342
Page 3 of 5
levonorgestrel releasing intrauterine device (mirena) is considered to
be the first line contraceptive method for WWE taking EIAEDs. It acts
locally and it has very low failure rate of 1% in the women [28]. The
recommended emergency contraception for women taking EIAEDs
is copper intrauterine device. Other emergency contraception like
levonorgestrel or ulipristal acetate pills are not effective as their levels get
altered [24]. Hence, effective contraception is required for stabilization
of epilepsy and to optimize the outcome of pregnancy.
Preconception Counselling
Preconceptional counselling is a must in WWE as the disease has
effect on pregnancy and vice versa. The special importance should be
given on reproductive dysfunction and subfertility affecting reproductive
outcomes. The pregnancy itself is a high risk state for epilepsy, hence,
optimizing the dose of AEDs before planning pregnancy is necessary.
The women should also be discussed about teratogenic effect of AED
and folic acid supplementation and also the delayed neurocognitive
changes in child.
Reproductive dysfunction and subfertility
Reproductive dysfunction and subfertility are two to three times
more common than general population [29]. Seizure activity leads to
increased serum prolactin levels in WWE [30]. Menstrual abnormalities
in 50% and higher rates of anovulatory cycles are reported in WWE.
The prevalence of polycystic ovarian disorder (PCOD) is also higher
which is 41% [31,32]. Reduction in libido has also been reported in
one third of women. Women on AED also have reproductive and
endocrine disorders. AED affects hypothalamus pituitary ovarian axis,
EIAED increase SHBG results in fall in biologically active estradiol
and testosterone. Valproic acid is associated with increased rate of
hyperandrogenism, PCOD and ovulatory dysfunction especially in
young women [32].
However, these observations are not so classical, as earlier said, as it
did not match in any of the study. A recent Scandavian study suggested
that the results are relatively modest. The birth rate was lower in WWE
than women without epilepsy [33].
Optimizing AEDs for pregnancy
Preconceptional counseling regarding effect of AED over pregnancy
is an essential issue. Teratogenic risks are the most important concerns
of AED, but the benefit of stopping or continuing or changing the AED
should be weighed against the risk of developing seizures. There are
lot of variation between risk of malformation and the different AEDs
when used as monotherapy. The general guidelines to stop the AEDs
are also followed here. Women with a seizure free interval of 2-5 years
(well controlled) are eligible candidate for reducing or switching to
monotherapy or stopping the drug. The risk of seizure relapse is low
in women with normal IQ, EEG and neuroimaging pattern. Women
with juvenile myoclonic epilepsy is one of the exception where AEDs
should continue despite seizure free interval as it has higher relapse rate
[34]. In brief, the teratogenic risk depends on type number and dosage
of AED.
Genetic counselling should be offered to women with a risk
of inheritance or if both partner have epilepsy. Women should be
counselled about increased risk of teratogenicity if there is previous
history of congenital malformations (CM) [35].
The risk of CM by AEDs can also be minimized by folic acid
supplementation. There are no set guidelines for dosage of folic acid.
American academy of Neurology and American epilepsy society
J Preg Child Health, an open access journal
ISSN: 2376-127X
recommend 0.4 mg/day but NICE recommend 5 mg/day [36,37]. This
is left to physicians discretion to treat the women.a definite association
has been seen with risk of CM in women with no or low folate levels
[37,38].
The main target before planning pregnancy remains that women
should be on minimal and least teratogenic drug and at least 12 month
seizure free [5,39,40].
Teratogenic effects of epilepsy and AEDs
The major concern with epilepsy is CM which is higher in WWE
due to AEDs. Women taking AEDs have a 4-14% chance of CM
as compared to 2-3% n the general population [41]. Per se, WWE
not exposed to AEDs, have a similar incidence of CM as in general
population [42]. Risk of CM is dose dependent, but this has been
demonstrated in valproate only [43]. Also, in polytherapy, the CM risk
are associated with drug combinations that were not documented when
each individual drug was used as monotherapy [44]. The variation of
risk increases to 17% when AEDs are used as polytherapy [45,46].
There are many unresolved queries about pregnancy and effect of
AED. Until recently, it was stated that newer generation AED are as
effective as older ones. But, no consolidated data is available on efficacy
of these drugs in pregnancy. The risk estimation of CM is incomplete
due to confounders like type of epilepsy, family history, exposure to
additional teratogenic agent. There is no consensus on minor anomalies
and effect of AED on long term neuro cognitive behavior. Hence, the
formation of AEDs registries has solved this problem and provided
a large scale systematic data. There are different types of registries,
independent academic registries, pharmaceutical drug registries and
population based registries. The European and International registry
of Anti epileptic drugs and Pregnancy (EURAP) is independent
registry. It includes 42 countries of Europe, Asia, Oceania and South
America [47].
The North American Anti epileptic drug pregnancy registry,
the United Kingdom Epilepsy and Pregnancy group and Australian
pregnancy registry and Kerala pregnancy registry are also independent
academic registries [48-50]. The Australian and Kerala registries have
recently merged into EURAP. The pharmaceutical registries are, the
Glaxosmithkline’s International Lamotrigine Pregnancy Registry and
recently launched UCB AED Registry [51].
While these ED registries provide most consolidated data on CM
risks, there are certain limitations also. There are methodological
differences among the different registries. It is calculated that study over
approximately 500 AED monotherapy is needed to confidently identify
differences in CM between AEDs [52].
The risk for spina bifida for carbamazepine monotherapy (OR 2.6,
95% CI1.2-5.3) when compared with no AED exposure [53]. The Major
CM rates for lamotrigine exposure was 3.2% (95% CI 2.1-4.9) [54]. The
teratogenic effects of levetiracetam are virtually unknown. UK Epilepsy
and Pregnancy Registry 2006 failed to find CM in their 39 women on
levetiracetam monotherapy [55]. However, Holmes et al. revealed 2.03%
CM rates on levetiracetam monotherapy [56]. Meador et al. observed
a 4.9% CM rates with phenobarbital [52]. Phenytoin is associated with
fetal hydantoin syndrome, comprising of hypoplasia and irregular
ossification of distal phalynx, facial dysmorphism, epicanthal folds,
hypertelorism, broad nasal bridge and mental retardation. Hanson et al.
reported 11% prevalence of fetal hydantion syndrome and additionally,
30%, when in utero exposure [57]. Hunt et al. reported a cm rate of
4.8% (95% CI 1.7-13.3) on topiramate exposure, which almost tripled
Volume 4 • Issue 4 •1000342
Citation: Priya B, Singh N (2017) Pregnant Women with Epilepsy: Management Issues. J Preg Child Health 4: 342. doi:10.4172/2376-127X.1000342
Page 4 of 5
AED
Risk in Percentage
(95% confidence interval)
Carbamazepine
Morrow et al. [55]
Meador et al. [60]
Holmes et al. [48]
2.2% (1.4-3.4)
4.6%
2.6%
Phenytoin
Hanson et al. [57]
11%
Valproic acid
Meador et al. [52]
North American pregnancy registry [61]
UK pregnancy registry [61]
Neurodevelopmental effect of antiepileptic drugs
study group [63]
10.7% (8.16-13.29)
10.7%
6.2%
20.3% (CM+fetal death)
AED drug and dosage optimization and with proper instruction to
WWE for newborn care. This also includes contraceptive counseling.
Most women have good maternal outcome but pre pregnancy
counseling is necessary to optimize god maternal and fetal outcome.
This includes improving fertility and decreasing sexual dysfunction,
optimize AED for next pregnancy. Women should be counseled about
teratogenic side effects and dose optimization and about effects of AED
over infants.
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Meador et al. [52]
4.9%
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Neurocognitive effects
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parental cognitive functions.
Conclusion
WWE is a common neurological disorder and can be dealt by
multidisciplinary approach. Pregnant WWE should have ultrasound
for detection of fetal anomalies, adequate screening for obstetric
complications. The AEDs should be optimized for pregnancy related
changes and if required, drug monitoring can also be offered. During
delivery, all stress factors should be allayed and seizure protocol should
be maintained. The discharge of women should be planned only after
J Preg Child Health, an open access journal
ISSN: 2376-127X
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