Women’s issues in
neurology
Dr. Amy Yu
November 10th 2010
McGill University
Outline
Epilepsy
 Multiple sclerosis
 Headache

FDA safety rating system

>60% of drugs are risk Category C
FDA safety rating system

A – Adequate, well-controlled human studies have not shown an 
risk of fetal abnormalities to the fetus in any trimester of pregnancy.

B – Animal studies have revealed no evidence of harm to the fetus,
no adequate human studies OR Animal studies have shown an
adverse effect, but adequate human studies have failed to
demonstrate a risk to the fetus in any trimester.

C – Animal studies have shown an adverse effect without adequate
human studies OR Inadequate studies

D – Adequate well-controlled or observational studies in pregnant
women have demonstrated a risk to the fetus, but benefits may
outweigh the potential risk

X – Adequate well-controlled or observational studies in animals or
pregnant women have demonstrated positive evidence of fetal
abnormalities or risks. The use of the product is contraindicated in
women who are or may become pregnant.
Epilepsy & Pregnancy
24-year-old woman, diagnosed with a seizure
disorder since 13-year-old, treated with valproic
acid and lamotrigine, comes to your office for
pregnancy counselling. She currently uses oral
contraceptive pills, but wishes to become
pregnant. Last seizure was of GTCS type,
occurred 18 months ago. She asks:
1. Should I continue taking AED?
2. What are the risks to my baby?
3. What will happen if I have a seizure?

Women with epilepsy (WWE)
 AAN/AES
Practice Parameter 2009
 What I am not going to talk about
 Catamenial
seizure exacerbation
 Menstrual disorders and infertility
 Osteoporosis
Women with epilepsy (WWE)

Over 1 million WWE in the active
reproductive years (US data)
 24,000

Actual in utero exposure to AED may be
two times higher


births per year
H/a, chronic pain, mood disorder
Balancing act
 Teratogenic
risks versus seizure control
 For most WWE, withdrawal of AEDs prior to
pregnancy is not a realistic option
Pregnancy & seizure control

Physiologic and psychosocial changes
 Sex
hormones, AED metabolism
 clearance,  elimination, ∆ free available drug
  LTG and OXC d/t  glucuronidation

 Sleep
deprivation, new stressors
 Noncompliance to medication

Variable impact on seizures
 20-33%
increase in seizures
 50-83% no significant change
 7-25% decrease in seizures
Risks of seizures

GTCS: Hypoxia & acidosis
 Fetal
ICH, miscarriages, stillbirths
 1 brief GTCS   FHR for  20 minutes
 SE occurs in <2%, but high mortality rate

Nonconvulsive seizures, effect unclear
 CPS
during labor caused prolonged uterine
contraction with FHR deceleration

Trauma-related complications
 ROM,
infection, premature labor, abruptio
 Enforce seizure precautions (driving, heights)
Teratogenicity by AED
Infants of untreated WWE have similar
frequency of MCM as general population
 Anti-folate effects
 Free radicals and oxidative metabolites

 Polytherapy
 MCM
promotes epoxide production
rates
 General population 1.6 - 3.2%
 Monotherapy 2.3 - 7.8%
 Polytherapy 6.5 - 18.8%
AED impact on fetus

Minor anomalies (6-20%, RR: 2.5)
 Structural
deviation w/o threat to health
 Distal digital and nail hypoplasia
 Midline craniofacial anomaly (broad nasal
bridge, ocular hypertelorism, upturned nose,
altered lips, etc…)

Major congenital malformation (3.1-9%,
RR: 2-3)
 Interferes
significantly with function and/or
requires major intervention
 Most common MCM: CHD, cleft lip/palate,
urogenital defects, and neural tube defects
AED impact on fetus

Prenatal screening
 NTD:
maternal serum AFP 15-22 wks + structural U/S
16-20 wks (95% sensitive)

Amniocentesis if above equivocal (99% sensitive)
heart detailed U/S 18-20 wks  fetal
echocardiography (85% sensitive)
 Fetal

Perinatal complications
  SGA & 1-minute Apgar < 7 (RR:
 No substantially  perinatal death

2)
Neurodevelopment and risk for  cognition
 Insufficient
evidence if children of treated WWE in
general are at  risk
 Monotherapy with VPA/PHT/PB  cognition
 Polytherapy  cognition
 CBZ probably does not  poor cognitive outcome
Obstetrical complications

Seizure risk during labor & delivery









1-2% GTCS during labor & an additional 1-2% in 1st 24hrs
Risk highest in primary generalized epilepsy (lowest in partial)
Avoid meperidine as anesthesia choice
IV PB, PHT, VA, BZD (neonatal respiratory/cardiac depression)
Consider C/S if repeated GTCS,  LOC interfering in labor
C/S or late pregnancy bleeding (RR<2, probably no
substantially  risk)
Premature contractions, labor, delivery (RR<1.5,
probably no moderately  risk)
WWE who smoke: possibly substantially  risk of
premature contractions, labor, delivery
Inadequate evidence to determine if the newborns have
a substantially  risk of hemorrhagic complications
Which poison to give?


All AED have been associated with features of fetal
anticonvulsant syndrome
Valproic acid (VPA)






Carbamazepine (CBZ)


“Probably” contribute to MCM as part of polytherapy
“Possibly” with monotherapy
Compared to CBZ: “Highly probable” associated with er MCM
Compared to PHT or LTG: “Possibly” associated with er MCM
Probable relationship between dose and risk of MCM
“Probably” does not substantially increase the risk of MCM
Insufficient evidence on LTG or other specific AEDs on 
risk of MCM

Probable relationship between dose of LTG and risk of MCM
Which poison to give?

Notable findings for specific types of MCM:
 PHT
possibly contributes to the risk of cleft
palate.
 CBZ possibly contributes to the risk of
posterior cleft palate.
 VPA probably contributes to neural tube
defects and facial clefts & possibly contributes
to hypospadias.
 PB possibly contributes to cardiac
malformations
Postpartum care

 AED levels (plateau by 10 wks PP)
 LTG

may need anticipatory adjustment
Breast feeding is supported
 PRM
& LEV probably transfer into breast milk in
amounts that may be clinically important (cf VA, PB,
PHT, CBZ are not)
 NEAD study: Mental developmental index scores
higher in breastfed children at 2 yrs (nonsignificant
after maternal IQ adjustment)

Vulnerable period  extra precautions
 Harness when carrying BB
 Stroller in house
 Diaper and clothes changes on floor
 Never perform bathing alone
 Sharing night-time feedings and daytime
naps
Epilepsy & Pregnancy
24-year-old woman, diagnosed with a seizure
disorder since 13-year-old, treated with valproic
acid and lamotrigine, comes to your office for
pregnancy counselling. She currently uses oral
contraceptive pills, but wishes to become
pregnant. Last seizure was of GTCS type,
occurred 18 months ago. She asks:
1. Should I continue taking AED?
2. What are the risks to my baby?
3. What will happen if I have a seizure?

Take home message
Confirm the presence of seizures
 Confirm the need for an antiepileptic drug
 Confirm the need to continue an
antiepileptic drug
 VA has been associated with a higher rate
of malformations and lowers verbal IQ

 Consider

transition to LTG or LVT
AED monotherapy
 Aim
to achieve lowest effective dose
 Establish baseline “ideal” AED level
Take home message

Presentation after conception
 Still
aim for monotherapy
 Avoid new medication trials & cross-over
  teratogenic and seizure risk

Monitoring AED level during & after
 concentration of LTG, PHT, +/CBZ (to a lesser extent)
 Possibly  PB, LEV, OXC
  Individual variability  consider monthly
monitoring
 Probable
Take home message

Supplemental folic acid 4-5mg/d
 Prior
to conception and during pregnancy
 Folate 0.4mg/d for all WWE of childbearing
age (50% of all pregnancy is unplanned)
No strong evidence for Vitamin K
supplementation
 ? Selenium supplementation 200mcg/d

Take home message

2-3 times higher MCM
 Most
infants exposed in utero are healthy
 Most MCM can be detected by prenatal
ultrasound and some are treatable
No substantial increased risk of obstetrical
complications (< 2 times expected)
 Breastfeeding is safe
 Continue AED level monitoring postpartum
 Reinforce seizure precautions

Birth control and AED

Inducers of hepatic cytochrome P-450
patch and vaginal ring also  failure rate
 Medroxyprogesterone IM q8-10wks (usually q12wks)
 *** OCP significantly  in lamotrigine levels
 Transdermal

1998 AAN guideline
 High
dose estradiol 50mcg (no supportive studies)
 Backup barrier method, IUD (Mirena has local effect)
Multiple sclerosis & Pregnancy
17-year-old girl, new diagnosis MS after 2
optic neuritis within 1 year and moderate
burden of disease on MRI. You discuss
with her interferon therapy.
 1. Will I ever become pregnant?
 2. Will my children have MS?
 3. How will having kids affect my disease?

Multiple sclerosis

#1 neurologic disease affecting people in
their productive years of young adulthood
 High
incidence in ♀ in childbearing age
T-cell mediated autoimmune disease
 Lifetime risk 0.1%

Genetics and MS

15% of MS pt have ≥1 family mb with MS
 Close
or distant
 Co-occurrence of disease in the family is most
likely due to genetic factors


Higher concordance in mono vs. dizygotic twins
1 parent with MS: 4% risk in child
 40%
increase
 2 parents with MS: 20% risk in child

No current specific gene tests available
Pregnancy in MS

Pregnancy and MS (PRIMS), Brain 2004
 254
women (269 pregnancies, 2 years f/u)
 72% no relapse for the entire study period
 Relapse rates (relapses/year):




Pre-pregnancy 0.7
3rd trimester 0.2
1st 3 months postpartum 1.2
Unchanged annualized RR in 21 mths postpartum
 Postpartum



relapse associated with:
Relapse rate in year preceding pregnancy
Relapse during pregnancy
EDSS at the beginning of pregnancy
 Disability
at 2 years not related to pregnancy
Pregnancy in MS

Conversion to progressive disease
is 3.2 times higher in non-pregnant ♀
 Rate of progression in disability is most rapid
in nulliparous women
 Cannot R/O bias that women with more
severe disease have less children
 Some studies show no association
 Risk
Obstetrical outcomes in MS
No CI to C/S or vaginal delivery
 Variable reports with regards to

 Risk
of malformations, fetal BW, duration of
pregnancy

Neurology 2009
 2003-2005
study time
 10,000 MS obstetric hospitalization
 30%  risk for C/S, 70%  rate of IUGR
 Adjusted for maternal race and age
 Similar rate of HTN disorder and PROM
Take home message

Most patients undergo pregnancy without
relapses
rates decrease in 3rd trimester
 Higher in the 1st 3 months postpartum
 Relapse

Pregnancy not been shown to be harmful


Not associated with  relapses or disability
Effects of MS on pregnancy outcomes do
not appear to adversely affect the child’s
health or directly influence the mother’s
health.
Management of MS in pregnancy
D/C immunomodulating therapy 1-4 weeks
prior to attempts to conceive
 Stable disease (no attacks, no new MRI
lesion, no disability progression for 1 year)

 Conception
attempts for 6 months off meds
 MRI/clinical review of disease activity
 If inactive  continue for another 6 months
 If active, consider during the next 6 months:
 Return
to regular therapy
 Solumedrol 1gm IV q1mth, immediately after each
menstrual cycle if pregnancy test negative
Management of MS in pregnancy

Active disease w/in preceding year despite
therapy with good compliance
 Discuss
changing platform therapy for 3-6
months prior to conception attempts
 If not, consider monthly Solumedrol regimen
No immuno-modulating/-suppressive
therapy should be used in pregnancy
 IV steroids can be used in major
exacerbations

 Consult
obstetrician
 More acceptable after 1st trimester
Postpartum management
Follow-up 2-3 months after delivery
 MRI within that time frame
 Stable disease prior and during pregnancy

 Breastfeeding

off MS medications is possible
Active/aggressive disease
 Return
to MS treatments immediately
 If breastfeeding: consider steroids monthly
 Resume breastfeeding 24 hrs after steroids
infusion
Management in NMO

IVIG monthly is safe in pregnancy
 Consider
in active NMO to stabilize disease
 Can be continued until 12 weeks postpartum

Shown to lower postpartum relapse
A few more things to consider…
Discuss reproductive wishes in choosing
choices of therapy
 Chemotherapy treatment

 Pregnancy
test prior to each treatment
 Counsel to use 2 methods of birth control
Question 3: Headaches





34-year-old woman, smoker, known migraines with
aura, presents at 34 weeks GA. Since the onset of
pregnancy, she had been free of headache until 2
days ago when she developed severe headaches
much like her usual migraines, without preceding
aura. Due to high levels of stress at work, she had
been unable to quit smoking. Examination is normal.
1. Is improvement in migraines expected in
pregnancy?
2. What is your differential diagnosis in this case?
3. Is it safe for this patient to undergo CT/MRI?
4. What are the treatment options during
pregnancy?
Headache & Pregnancy

Headache is #1 reason for neurology
referral
 Migraines
affects 1/5 women in the
reproductive years
Menstrual migraine: h/a -2 to +3 days after
the onset of menstrual flow (day 1)
 Menstrually related migraine: some
headache menstrually related but headache
present at other times of the month

2ry headaches & complications

H/A in Pregnant ♀, more likely benign
 Primary

migraine or tension-type
Secondary causes
 Infections
 Eclampsia/pre-eclampsia
 Vascular
disease
Aneurysm, AVM, dissection, pituitary apoplexy
 Acute strokes, cerebral venous thrombosis

 Increased
ICP
Symptomatic brain tumour
 Benign intracranial hypertension

Headache changes in pregnancy

50% of migraineurs will improve during
pregnancy (up to 80%)
 Estrogen
increases pain threshold
 More common in migraine without aura and
menstrual migraines
 If ongoing h/a by the end of 1st trimester 
unlikely to have significant improvement later
 Return 2-4 weeks postpartum
Migraines & complications



 Pregnancy-related
HTN (OR=2.85)
 LBW infant
(OR=1.97)
Migraine with aura

ischemic stroke
(OR=16.9)

NOT associated with
 malformations
Postpartum period & headache

39% of ♀ dvlp h/a postpartum (often benign)
 Study

followed 985 women over 3 months PP
2/3 postpartum headache is caused by migraine
or tension-type
 MSK/cervicogenic,

spinal low pressure
Beware of 2ry causes in severe h/a occurring
>24 hrs postpartum
 Eclampsia (late-onset)
 4x more likely to be associated with headache
 Pituitary mass/hemorrhage (3%)
 Cerebral venous thrombosis (3%)
 Cerebral
vasculopathy (2%)
 Thalamic lesion (1%)
 Subarachnoid hemorrhage (1%)
Breastfeeding & headache

Delays the return of pre-pregnancy headache
patterns
 Effective
Migraine Treatment in Pregnant and Lactating
Women. Springer 2009
H/A evaluation in pregnancy
History & examination as usual
 CSF examination is safe and interpretation
is same as in non-pregnant (including OP)
 MRI preferred (non-emergent/-traumatic)

 Retrospective
review, Am J Neuroradiol 2007
 73% normal or incidental findings
 Sinusitis 8%, CVST 6%, PRES/eclampsia 6%,
IIH 3%, intracranial hemorrhage 3%
 19% of abnormal scan had initial normal
neuro exam
A few notes on contrast studies
11th European Symposium on Urogenital
Radiology
 Contrast agents can be used when
deemed necessary

 Iodinated
contrast agents: no animal fetal risk
 Can depress fetal thyroid  screen for T4
 Gadolinium: potential animal fetal toxicity
 Risk vs “overwhelming” benefit

Safe to continue nursing after exposure
MRI & neonatal hearing loss

Neonatal Cochlear Function:
Measurement after Exposure to Acoustic
Noise during in Utero MR Imaging
(Radiology. 2010 Sep 27)
 96
neonates, 1% prevalence of hearing
impairment
 Fetal exposure to 1.5-T MRI during the 2nd &
3rd trimesters of pregnancy is not associated
with an increased risk of substantial neonatal
hearing impairment
Treatments

Although most women will have a desire to
avoid medications, most will continue to
use it
 Norwegian
study
 No change in medication use in the 6 months
prior to pregnancy vs. the first 5 months of
pregnancy
Non-pharmacological
Pain management techniques
 Exercise
 Smoking cessation

 Nicotine

linked to increase h/a activity
Sleep management
 Evaluate

for obstructive sleep apnea
Lifestyle regulation
Pharmacological – Acute
Do not medicate mild h/a
 Treat nausea and avoid dehydration

 Mild:
dietary restrictions, P6 acupressure
point, Vit B6 30mg QD +/- ginger 1 gm QD
 Mod-Severe: Ondansetron & metoclopramide
Acute migraine drugs in pregnancy
What about triptans?

Swedish database (n=658)
not statistically significant  preterm
and  LBW babies
 No change in congenital malformations
 Small,

Sumatriptan registry (n=558)
4.7%, occurring with 1st trimester
exposure
 MCM
Acute migraine drugs in lactation
Prophylactic pharmacotherapy

Recommended during pregnancy
 Magnesium
oxide or Riboflavin (400mg QD)
 Propranolol
 Gabapentin


Use in T3 may interfere with bony growth & dvlpmt
Avoid
 Atenolol,

in 1st and 2nd trimester
Divalproex, Paroxetine
Compatible with nursing
 Divalproex
(with adequate contraception)
 Magnesium
 Propranolol, Timolol, Verapamil
ED treatment
Take home message

Think about your differential
 50%
of migraine patients improve during pregnancy
 They are at  risk to certain conditions




If needed, neuroimaging can be safely done
Promote non-pharmacological lifestyle
modifications
Use medications safely: choose wisely, lowest
dose, shortest duration, use as late in pregnancy
as possible
If breastfeeding, use drug after nursing or pump
& discard milk after dosing