Pregnant

NOUFAL.A

Epilepsy is a common neurological disorder with a prevalence rate of approximately 0.5% in most communities. It is estimated that there are over 2.5 million women with epilepsy (WWE) in India,with up to 52% of them being in the reproductive age group Some 30% of the 75,000 women with epilepsy (WWE) in Kerala come under the reproductive age group

Effect of pregnancy on epilepsy Effect of epilepsy on pregnancy Effect of epilepsy and AEDs on fetus Mechanism of AEDs teratogenicity Newer AEDs and fetal outcome Management of epilepsy in pregnancy Management of Postpartum phase

Effect of pregnancy on Effect of pregnancy on epilepsyepilepsy

Some women may experience seizures only during pregnancy, which is termed gestational epilepsy . Such women would be seizure-free between pregnancies

Another subgroup (gestational onset epilepsy) may have their first seizure during pregnancy and thereafter may continue to get spontaneous recurrent seizures.

Approximately 1-2% of WWE may experience status epilepticus (SE) during pregnancy, which is associated with high morbidity and mortality.

Effect of pregnancy on seizure Effect of pregnancy on seizure frequency frequency

Seizure frequency may remain unchanged or decreases in two-third of WWE, whereas it increases in others

Reproductive hormones, noncompliance and decrease in blood levels of free form of AED, influence seizures during pregnancy

Hormonal aspects of epilepsyHormonal aspects of epilepsy Seizures are influenced by the Seizures are influenced by the

female sex hormones estrogen female sex hormones estrogen and progesterone and progesterone

Eestrogen elevate the seizure Eestrogen elevate the seizure frequency and progesterone frequency and progesterone decrease it decrease it

Catamenial epilepsy :-is a disorder :-is a disorder that affects up to 70% of women that affects up to 70% of women with epilepsy. It is characterized with epilepsy. It is characterized by seizures that cluster around by seizures that cluster around specific points in the menstrual specific points in the menstrual cycle or pregnancy cycle or pregnancy

Estrogen Estrogen

There are three biologically active forms of There are three biologically active forms of estrogen: estrogen:

Estriol, the major form of estrogen during , the major form of estrogen during pregnancy; pregnancy;

Estrone, which is prevalent after menopause. , which is prevalent after menopause. Estradiol has been shown in many studies to has been shown in many studies to

have significant proconvulsant effect. It have significant proconvulsant effect. It facilitates various forms of induced seizures and facilitates various forms of induced seizures and has been shown to worsen seizures in women has been shown to worsen seizures in women with epilepsy with epilepsy

ProgesteroneProgesterone Progesterone has long been known to have Progesterone has long been known to have

anticonvulsant properties.anticonvulsant properties. In human clinical studies have shown the In human clinical studies have shown the

efficacy of progesterone in reducing both the efficacy of progesterone in reducing both the frequency and severity of seizures. frequency and severity of seizures.

The clustering of seizures around the The clustering of seizures around the beginning of menstruation corresponds with a beginning of menstruation corresponds with a significant drop in the levels of progesterone significant drop in the levels of progesterone circulating in the body and an increase in the circulating in the body and an increase in the estrogen: progesterone ratio estrogen: progesterone ratio

ALTERATION OF DRUG ALTERATION OF DRUG PHARMACOKINETICPHARMACOKINETIC

The conc: of AEDs decline as The conc: of AEDs decline as pregnancy progresses pregnancy progresses

Due to the marked change in plasma Due to the marked change in plasma protein binding resulting in a high protein binding resulting in a high proportion of free and unbound proportion of free and unbound medication that is available for medication that is available for metabolism and clearance metabolism and clearance

Effect of epilepsy on pregnancy Effect of epilepsy on pregnancy

InfertilityInfertility Complications of pregnancyComplications of pregnancy

Infertility

WWE have reduced fertility rate Both the epileptic disorder and the antiepileptic

treatment play different roles in the development of reproductive endocrine disorders

WWE have an increased tendency for Polycystic ovarian disease

Valproate, cause insulin resistance and elevated androgen levels

Mechanisms Underlying the Occurrence of PCOS in Epilepsy

An alteration in gonadotropin-releasing hormone secretion results in increased luteinizing hormone (LH) secretion

LH hypersecretion is a characteristic hallmark of PCOS. LH is secreted in a pulsatile manner. Women with PCOS have an increase in both the LH pulse frequency and amplitude, resulting in increased 24-hour secretion. This increase in LH secretion is thought to occur as a result of increased frequency of hypothalamic gonadotropin-releasing hormone (GnRH) pulses. Increased LH, in turn, leads to an increase in androgen production by the theca cells within the ovary

Mechanisms by Which Valproate Mechanisms by Which Valproate Causes Elevated Androgens and Causes Elevated Androgens and

PCOD PCOD An alteration in insulin secretion and insulin An alteration in insulin secretion and insulin

action results in hyperinsulinemia and insulin action results in hyperinsulinemia and insulin resistance resistance

Valproate induces androgen synthesis in the Valproate induces androgen synthesis in the ovary, likely as a result of multiple ovary, likely as a result of multiple mechanisms mechanisms

Valproate exacerbating an already disturbed Valproate exacerbating an already disturbed system, which is unable to compensate for system, which is unable to compensate for its androgen-promoting actions. its androgen-promoting actions.

Complications of pregnancy Complications of pregnancy

WWE showed that the frequencies of WWE showed that the frequencies of several complications of pregnancy in several complications of pregnancy in WWE were comparable with those without WWE were comparable with those without epilepsyepilepsy

Pregnancy can increase seizure frequencyPregnancy can increase seizure frequency Most studies shows that the increase Most studies shows that the increase

tends to occur towards the end of tends to occur towards the end of pregnancy pregnancy

Complications of pregnancyComplications of pregnancy Vaginal hemorrhage Vaginal hemorrhage Anemia Anemia Hyperemesis gravidarum Hyperemesis gravidarum ToxemiaToxemia Induced laborInduced labor Premature rupture of membaranePremature rupture of membarane Cesarean sectionCesarean section Seizure Seizure

Effect of epilepsy and AED on Effect of epilepsy and AED on fetus fetus

MaldevelopmentMaldevelopment

MicrocephalyMicrocephaly

AnomaliesAnomalies

Malformation Malformation DeathDeath

StillbirthStillbirth

Neonatal deathNeonatal death

Perinatal death Perinatal death

Hemorrhagic Hemorrhagic diseasedisease

OthersOthers

Low birth weightLow birth weight

PrematurityPrematurity

Feeding Feeding difficultiesdifficulties

Drug withdrawal Drug withdrawal

Hypoxia Hypoxia

MicrocephalyMicrocephaly

MicrocephalyMicrocephaly is a is a neurological disorder neurological disorder in which the in which the circumference of the circumference of the head is significantly head is significantly smaller than average smaller than average for the person's age for the person's age and sex and sex

Congenital anomaliesCongenital anomalies

Fetal trimethadone syndromeFetal trimethadone syndrome Fetal hydantoin syndromeFetal hydantoin syndrome Primidone embryopathy Primidone embryopathy Fetal valproate syndrome Fetal valproate syndrome Fetal carbamazepine syndrome Fetal carbamazepine syndrome

The symptoms of this disorders The symptoms of this disorders include include – Abnormalities of the skull and facial Abnormalities of the skull and facial

featuresfeatures– Growth deficienciesGrowth deficiencies– Underdeveloped nails of the fingers and Underdeveloped nails of the fingers and

toestoes– Delayed mental development Delayed mental development

Infant with fetal valproate Infant with fetal valproate syndromesyndrome

Long philtrum, narrow upper lip, hypertelorism, and narrow arched eyebrows

Congenital malformation Congenital malformation

First trimester seizure were First trimester seizure were associated with a 12.3% risk of associated with a 12.3% risk of congenital malformation congenital malformation compared with risk among compared with risk among offspring exposed to maternal offspring exposed to maternal seizure at other time seizure at other time

Neural tube defects Neural tube defects Orofacial cleftOrofacial cleft

Neonatal hemorrhage Neonatal hemorrhage

Infants of WWE are at increased risk Infants of WWE are at increased risk for neonatal hemorrhagefor neonatal hemorrhage

This occur first 24 hr of lifeThis occur first 24 hr of life

Enzyme-inducing AEDs like PB, Enzyme-inducing AEDs like PB, PRM,PHT and CBZPRM,PHT and CBZ

Determined by assay ofDetermined by assay of PIVKA ((Proteins Induced by Vitamin K Antagonism ) in mother:- ) in mother:- Thrombotest

Mechanism Mechanism Maternal use of anticonvulsants may Maternal use of anticonvulsants may

interfere with the metabolism of Vitamin K interfere with the metabolism of Vitamin K and synthesis of coagulation factors in the and synthesis of coagulation factors in the fetusfetus

Absence of Prothrombin precursor, is Absence of Prothrombin precursor, is a protein induced Vit K absence a protein induced Vit K absence

PIVKA II ----------> ProthrombinPIVKA II ----------> Prothrombin For this Vit k is necessaryFor this Vit k is necessary The amount of PIVKA II in the blood The amount of PIVKA II in the blood

is a measure of vitamin K deficiency.is a measure of vitamin K deficiency.

AED can act as warfarin and can AED can act as warfarin and can inhibit Vit k transport across the inhibit Vit k transport across the placenta. This can be over come by placenta. This can be over come by supplement of large concentration of supplement of large concentration of vit Kvit K

After birth successful treatment After birth successful treatment requires fresh frozen plasma IV requires fresh frozen plasma IV

Anthropometric effect Anthropometric effect

Low birth weight and reduced length and head circumference

Infants exposed to AEDs may have increased tendency for minor facial anthropometric variations when compared to normal babies

Developmental delay Developmental delay

Higher rate of mental retardation Higher rate of mental retardation is reported is reported

Due to AED or maternal seizure Due to AED or maternal seizure during pregnancy during pregnancy

VPA has high risk VPA has high risk

Mechanism of AED Mechanism of AED teratogenicity teratogenicity

Arene oxide formationArene oxide formation Genetic defect in epoxide Genetic defect in epoxide

hydrolase hydrolase Free radicals formation Free radicals formation Genetic defect in free radical Genetic defect in free radical

scavenging enzyme activityscavenging enzyme activity Folate deficiency Folate deficiency

Arene oxide formationArene oxide formation

Some of the AEDs form Some of the AEDs form intermediate oxide metabolites, intermediate oxide metabolites, which are known to be embryotoxic.which are known to be embryotoxic.

They are electrophilic and may elicit They are electrophilic and may elicit carcinogenic, mutagenic and other carcinogenic, mutagenic and other toxic effect by covalent binding to toxic effect by covalent binding to critical cell macromolecules critical cell macromolecules

Detoxification of EpoxidesDetoxification of Epoxides

Conversion to dihydrodiols catalyzed Conversion to dihydrodiols catalyzed by epoxide hydrolase in the cytoplasmby epoxide hydrolase in the cytoplasm

Conjugation with glutathione in the Conjugation with glutathione in the microsomes microsomes

Epoxide hydrolase activity is much Epoxide hydrolase activity is much lower in fetal livers than in adult livers lower in fetal livers than in adult livers

Free radicals formation Free radicals formation

Free radicals are formed during Free radicals are formed during the drug metabolismthe drug metabolism

They are covalently bind to cell They are covalently bind to cell macro molecule macro molecule

Folate deficiency Folate deficiency

Folate deficiency is another important Folate deficiency is another important mechanism of teratogenesis, mechanism of teratogenesis, especially for neural tube defects especially for neural tube defects (NTD)(NTD)

Neural tube defects are birth defects Neural tube defects are birth defects of the brain and spinal cord of the brain and spinal cord

Spina bifida and anencephaly is the Spina bifida and anencephaly is the most commonly reported NTDsmost commonly reported NTDs

Mechanism of Folate Mechanism of Folate deficiency deficiency

Folate is a coenzyme necessary for Folate is a coenzyme necessary for the development of red and white the development of red and white blood cells and for proper function of blood cells and for proper function of the central nervous systemthe central nervous system

Low levels of serum folate (<6.6 Low levels of serum folate (<6.6 ng/mL) and red blood cell folate (< ng/mL) and red blood cell folate (< 140 ng/mL) are associated with 140 ng/mL) are associated with hyperhomocystinemia, which may hyperhomocystinemia, which may be associated with NTDs.be associated with NTDs.

Valproate and lamotrigine are Valproate and lamotrigine are folate antagonists folate antagonists

carbamazepine, increase the carbamazepine, increase the metabolism of folate by enzyme metabolism of folate by enzyme induction induction

Fetal spinal column doesn't close Fetal spinal column doesn't close completely during the first month of completely during the first month of

pregnancy pregnancy

Anencephaly is a cephalic disorder Anencephaly is a cephalic disorder that results from NTD that occurs that results from NTD that occurs when the cephalic (head) end of when the cephalic (head) end of the neural tube fails to close, the neural tube fails to close, usually between the 23rd and 26th usually between the 23rd and 26th day of pregnancy, resulting in the day of pregnancy, resulting in the absence of a major portion of the absence of a major portion of the brain, skull, and scalp brain, skull, and scalp

Advantage of Advantage of older AEDs AEDs

Broad familiarity and long term Broad familiarity and long term experienceexperience

Known efficacyKnown efficacy Low costLow cost Pregnancy category DPregnancy category D

Management of epilepsy in preconception periodManagement of epilepsy in preconception period

ENTRYENTRY

EPILEPSY DEFINITEEPILEPSY DEFINITE

NEED FOR AEDNEED FOR AED

CHANGE AEDCHANGE AED

FOLIC ACIDFOLIC ACID

PREGNACYPREGNACY

EXCLUDEEXCLUDE

NEW AEDNEW AED

NO

NO

NOYESYES

YES

Algorithm for management of epilepsy and pregnancyAlgorithm for management of epilepsy and pregnancy

A/N VISITA/N VISIT

<12Wk<12Wk

II A/N VIST

28 Wk28 Wk

36 Wk36 Wk

Titrate AED

Titrate AED

Titrate AED

YesScreen Cong Mal

No

Folic acid

Vit KVit K

Delivery Delivery

Contraception Contraception

Baby Baby Breast feeding Breast feeding

1 yr1 yr

5 yr5 yr

TerminateTerminate

Management of pregnancy and delivery in

women with epilepsy Optimizing treatment of epilepsy Folic acid prophylaxis Screening for serious malformations in

the fetus Preterm vitamin K Delivery Postpartum phase

PostpartumPostpartum phasephase

BreastfeedingBreastfeeding ContraceptionContraception Neonatal Neonatal

evaluation.evaluation. Echo and USS at 3 Echo and USS at 3

months.months. Developmental Developmental

assessment at one assessment at one year.year.

Non pharmacological approaches Non pharmacological approaches

Surgery Surgery VNSVNS

ConclusionConclusion

There is a complex interaction between There is a complex interaction between epilepsy, pregnancy and AEDs. It is epilepsy, pregnancy and AEDs. It is reassuring to observe that the vast reassuring to observe that the vast majority of pregnancies end in safe majority of pregnancies end in safe confinement and healthy babies. confinement and healthy babies. However, WWE deserve special medical However, WWE deserve special medical attention during pregnancy and delivery.attention during pregnancy and delivery.

REFERENCEREFERENCE

Risk and management of prenancy in women Risk and management of prenancy in women with epilepsy; Marks S Yerby, Pter kaplan, with epilepsy; Marks S Yerby, Pter kaplan, Trease Tran; Cleveland Clinical Jr of MedicineTrease Tran; Cleveland Clinical Jr of Medicine

Antiepileptic drug use and Pregnancy; Mark Antiepileptic drug use and Pregnancy; Mark S Yerby; North Pacific Epilepsy S Yerby; North Pacific Epilepsy Reserch;Portland OregonReserch;Portland Oregon

The Management of pregnacy in women with The Management of pregnacy in women with Epilepsy; Scottish obstetric guideline and Epilepsy; Scottish obstetric guideline and audit projectaudit project

Epilepsy, Pregnancy and Child:Janz, D., Dam, M., Richens, A., Bossi, L., Helge, H. and Schmidt, D; Raven Press, New York, 1980, pp. 3–14.

Management of Epilepsy and Pregnancy Thomas Sanjeev V; Jr Of Thomas Sanjeev V; Jr Of Post Graduate Medicine; 2006-52(1) Post Graduate Medicine; 2006-52(1) pp 57-64pp 57-64

ThThaank nk You…….You…….