m




      





@ Relationship @ Risk of birth

between female defects
hormones and @ Prenatal testing
seizures @ Pregnancy
@ Contraception complications
@ Folate @ Vitamin K
@ Fertility @ Breast feeding
@ Seizure control @ Parenting advice
during pregnancy
     

@ 
  of general population have

epilepsy
@ Over  million WWE (USA)in their
reproductive years
@ 3 births to WWE ()
@  babiesyear
@ One of the most common chronic
disorders affecting women of reproductive
age
mm

 
    
 
     !" #! $" #%$&

@ Oormones effect excitability of the

CNS and can increase seizures
@ Spread of seizure activity to
subcortical structures effects the
hypothalamus and pituitary and
interferes with reproductive health
   m

 
  

@ Pituitary hormones: FSO LO &

prolactin
@ Developing ovarian follicle: estrogen
@ Corpus luteum: progesterone
@ Estrogen is excitatory; progesterone
is inhibitory
   m

 
   
% '!'!!()!

@ Estrogen
@ Reduces effectiveness of GABA transmission at
the GABA A receptor
@ Enhances excitation at the glutamate receptor
@ Increases the number of excitatory synapses
@ Progesterone
@ Enhances GABA mediated inhibition
@ Increases GABA synthesis
@ Increases GABAA receptors
   m

 
   
$! $

@ Women with epilepsy (WWE)

experience changes in seizures
during:
@ Puberty
@ Over the menstrual cycle
@ Pregnancy
@ Menopause
 
  
 

@ Most common just before or at onset

of menses
@ Also occur with ovulation
@ 3 ( ) of patients
@ Not related to seizure type
@ Seizures more severe during
anovulatory cycles
  

 


@ Ovulation: ovulatory estrogen surge

when progesterone is relatively low
@ Perimenstrual period: progesterone
withdrawal
@ Anovulatory cycles: estrogen level
remains high without the protective
effect of progesterone which is
normally secreted by the corpus
luteum
 
  



@ Firstline AED appropriate for seizure type

@ Adjust levels one week before menses
@ Diamox
@ Progesterone
@ Ganaxolone
@ Not helpful
@ Menopause
@ Oysterectomy
@ BCP
   

@ OCPs do not worsen seizure control

@ Contraceptive failure is higher (

year) if inducing AEDs are used
(PB PRM PO  CBZ OXC and PM)
@ Binding and metabolism of steroid
hormones is increased
@ Minipill (3 micrograms) is not
enough
      
 
  

@ Reduce: PB PRM PO  CBZ

OXC PM
@ No effect or increase: VPA FBM
@ No effect: GBP L G GB LEV ZNM
VGB

u


 
  


 



 

  
   

@ Mid cycle spotting may be a sign of

ovulation and the potential for
contraceptive failure
@ *Women taking enzyme inducing
AEDs should use alternative
contraception or receive
contraceptives containing 
micrograms or more of the estrogen
component
 #$ *+!!,

@ uhis is one hypothesis for the

pathogenesis of congenital malformations
and anomalies in infants of WWE
@ PHu CBZ and PB impair folate absorption
@ VPA inhibits glutamate formyl transferase
@ Preconceptional folate supplementation
clearly reduces risk of neural tube defects
for women without epilepsy
 

@  risk with VPA monotherapy or

polytherapy
@   risk with CBZ polytherapy
@ Avoid VPA and CBZ in patients with
positive family history of N D
 

@ Supplement WWE with at least 

mg as
per the general population[ common
practice is to give 0.8 which is the amount in
OuC prenatal MVI
@ å mg is recommended for those with prior child
with Nu
or (+) family history
@ Folate must be present
ays 1-2å (missed
menstrual cycle noted
ay 15)
    

@ |ust do it!
 

@ Reduced by 33
@ Social issuesstigma
@ MisinformationFear
@ ransmitting epilepsy
@ Birth defects from AEDs
@ Unfit parents
@ Physiologic
 
    

@ Steroid hormones abnormalities

@ Metabolism of steroid hormones is induced by
some AEDs
@ Sex hormone binding globulin is increased
with consequent decreased free active
hormone
 
   

@ Pituitary hormone abnormalities

@ Due to disruption in hypothalamic input to
pituitary due to seizures resulting in
inappropriate release
@ Results in anovulatory cycles (esp LE)
polycystic ovaries and fetal loss (regulates
endometrial lining)
@ Prolactin levels are increased 3 times after
complex partial and G C seizures
 
   

@ ·Disturbances in LO concentration
and pulsatile release
@ Anovulatory cycles (3 of cycles)
@ Irregular cycles
@ Abnormal cycle length (<3 or >3
days)
@ Premature ovarian failure
 

 




@ Oyperandrogenic chronic anovulation

@ Oirsutism acne obesity hypofertility
hyperandrogenemia & menstrual disorders
@ Polycystic ovaries andor hyperandrogenism:
 incidence in general population;
 in
WWE
@ ? Increased with VPA
@ POS is associated with DM cardiovascular
disease and endometrial carcinoma
   


@ 
 have more frequent or more
severe seizures
@ Especially during 8th
th week
@ Due to:
@ Noncompliance
@ Pharmacokinetic changes

@ 3 stay the same 3 improve

 
 

@ u
 eves decine f r  AEDs

@ Decresed

 b und eves due
:
@ Incresed v ume f dis
ribu
i n
@ Incresed hep
ic me
b ism
@ Incresed ren cernce
@ Incresed free eves due
:
@ Dr p in serum pr
eins

@ ·Leves rise in p s
pr
um peri d

 

@ For highly protein bound drugs monitor

the free level
@ No consensus regarding frequency but
monitor at least prepregnancy each
trimester in the last month and within 8
weeks postpartum
@ Since many of the newer AEDs are renally
excreted and renal clearance is increased
during pregnancy monitoring is
recommended
   

@ 3x increased risk of major

malformation
@ Midline facial (cleft lippalate)
cardiac (VSD) & urogenital
@ For WWE on one AED risk of major
malformation is
8 (
 for
general population)
@ Risk is higher with polytherapy
() and higher serum AED levels
  

@ Minor congenital anomalies also x

as likely
@ Oypertelorism epicanthal folds
shallow philtrum broad nasal bridge
distal digital hypoplasia and simian
creases
@ ƏFetal AED syndromeƐ
@ May be outgrown in early childhood


  

@ Genetic predisposition
@ Free radical (oxide) metabolite
formation
@ Folate deficiency
@ Other?
  

@ Standard drugs: Category D

(+ evidence of risk)
@ Newer drugs: Category C
(donƍt know canƍt rule out)
@ Animal studies are reassuring (ZNM?)
@ Ouman experience is limited
    m
m

@ Not enough experience to be

conclusive
@ Information from postmarketing
surveys
@ Need  pregnancies to know
whether a drug is teratogenic
@ Prospective AED pregnancy registries
established
    m
m

@ In the meantime selection of a

newer AED is appropriate if this
achieves the most efficacious and
besttolerated outcome
@ Refer pregnant patients taking AEDs
to the North American AED
Pregnancy Registry (88833
33
or 888AEDAED
;
http:neurowww harvard )
  

  

@ 8
3
@ 8
 deliveries
@ anticonvulsant embryopathy
@ major malformations
@ growth retardation
@ hypoplasia of the midface and fingers

O
O
  

O  O   

    
 
  
!"##$%&''($$&")$$&*
  

  

@ 223 infants exposed to one AED (20.6%)

@ 93 infants exposed to two or more AEDs
(28%)
@ 98 infants whose mothers had epilepsy
but took no AEDs (no increase)
@ 508 controls (8.5%) (unexposed to AEDs
and mothers did not have epilepsy)
O
O
  

O  O   

    
 
  
!"##$%&''($$&")$$&*
  

++!*#+ -. '

@ Same incidence of major

malformations if maternal seizures
involved loss of consciousness vs
other types of szs
@ Same incidence of major
malformations if AEDs were used for
nonseizure indications

O
O
  

O  O   

    
 
  
!"##$%&''($$&")$$&*
 

@ Maternal serum alphafetoprotein at 



weeks   false negatives
@ Oi resolution ultrasound at 
 weeks 
 accuracy
@ Both increases accuracy to 

@ Amniocentesis at 
8 weeks  

accuracy; but only in select cases (age>3
or + family Ox)
 

  

@ Oyperemesis gravidarum
@ Vaginal bleeding
@ Anemia


  
.*# -. '

@ rauma from falls @ Developmental or

or burns learning difficulties
@ Premature labor @ Fetal anoxia
@ Abruptio placentae @ Acidosis
@ Miscarriages @ Oeart rate
@ Intracranial suppression
bleeding


  
.  %#  )$( ,

@ Premature labor
@ Failure to progress
@ Abruptio placentae
@ Increased rate of Caesarean sections
@ Seizures during labor are an
indication for csection
  
   

 m

@ Decreased viability
@ Stillbirths miscarriages
@ Neonatal infant mortality
@ Decreased growth parameters
@ Intrauterine growth retardation low
birth weight
@ Microcephaly
   

@ Neonatal hemorrhage in the first 2å hours of life

@ Mild vitamin K deficiency related to AE
s
@ PB PRM CBZ & PHu competitively inhibit
Vitamin K transport across the placenta
@ Infant has prolonged Pu and Puu due to
deficiency in clotting factors II VII IX & X.
@ uhe AAN recommends the mother receive
Vitamin K1 10 mg/day in the last å weeks of
pregnancy.
  
   

 m

@ Despite all this negative information

over  of children born to WWE
are normal!
@ Most women experience no change
in their seizures during pregnancy or
postpartum complications
  /

@ AE
s appear in breast milk in amounts inversely

proportional to their protein binding
@ In some cases a therapeutic level is achieved
@ Sedation feeding difficulties and rarely adverse
hepatic or hematological effects occur
@ Not contraindicated[ in fact encouraged but
infants should be monitored for sedation
irritability feeding & weight gain
' 


@ PB å0% @ LuG 65%

@ PRM 60% @ uPM ?/13-17%PB
@ PHu 30% @ uGB ?/96% PB
@ CBZ å5% @ LEV ?/<10%PB
@ VPA 2% @ OXC present/å0-
@ ESM 90% 50% PB
@ FBM present @ ZNM 90%/13-
@ GBP ?/no PB 37%PB
@ VGB no PB
Õ
 
 

@ In general:
@ Enlist the help of others for night
feedings to avoid sleep deprivation
@ If no support is available use a home
health agency
 

@ For those who lose consciousness:

@ Fence yards
@ Use safety gates and playpens
@ Use a child harness or wrist bungee
cord especially when traveling
@ Use a Əpotty chairƐ rather than a child
booster seat on the toilet
 

@ For those who fall with seizures

@ Change diapers on the floor
@ Avoid carrying the infant when alone
@ Avoid the use of front or back infant
carriers
@ Use an Əumbrella strollerƐ for transport
 

@ Bathing
@ Set water thermostats low
@ Bathe infants only with another adult
presentor sponge baths on the floor
with a separate container of water

  

@ hough estrogen levels decline with cessation of

ovarian function so do progesterone levels
@ 3 improve 3 worse
@ AEDs influence replacement hormonal therapy
just as they do OCP
@ Oormonal replacement with estrogen may
worsen seizures
@ Natural progestin replacement may improve
seizures
 ' ) 

@ Altered bone metabolism and bone

density associated with PO  CBZ &
PB
@ Osteoporosis osteopenia
osteomalacia & fractures especially
in menopausal women
@ Oormonal replacement calcium
supplementation regular weight
bearing exercise
 

 

@ Choice of AE
is based on seizure type

@ Monotherapy
@ Optimize AE
therapy before conception
@
iscuss effectiveness of contraception
@ Use at least 50 micrograms of ethinyl
estradiol or mestranol if hormonal
contraception is chosen


  0#*12

@ Folic acid at least 

mgday
@ Monitor free AED levels before conception
at each trimester in the last month and
through 8 weeks postpartum
@ Prenatal diagnostic testing should be
offered to include alphafetoprotein at 


weeks a structural ultrasound at 

weeks & an amniocentesis if indicated
@ Vitamin K  mgd during last month of
pregnancy
   

@ AE
(Harvard)Pregnancy Registry for

pregnant women taking any AE
 1-888-
233-233å or 1-888-AE
-AE
å (toll free)
@ EFA literature or information sheets
available for patients and health care
providers on hormones sexual
relationships fertility family planning
pregnancy parenting teenage girls
menopause and more
  0 12

@ âuality Standards Subcommittee of

the American Academy of Neurology
Practice Parameter: management
issues for women with epilepsy
(summary statement) Neurology
8;:


8