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 2009What I am not going to talk about

Catamenial seizure exacerbationMenstrual disorders and infertilityOsteoporosis

Women with epilepsy (WWE) Over 1 million WWE in the active

reproductive years (US data)24,000 births per year

Actual in utero exposure to AED may be two times higher H/a, chronic pain, mood disorder

Balancing actTeratogenic risks versus seizure controlFor 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 stressorsNoncompliance to medication

Variable impact on seizures20-33% increase in seizures50-83% no significant change7-25% decrease in seizures

Risks of seizures GTCS: Hypoxia & acidosis

Fetal ICH, miscarriages, stillbirths1 brief GTCS FHR for 20 minutesSE occurs in <2%, but high mortality rate

Nonconvulsive seizures, effect unclearCPS during labor caused prolonged uterine

contraction with FHR deceleration Trauma-related complications

ROM, infection, premature labor, abruptioEnforce 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 promotes epoxide productionMCM 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 healthDistal digital and nail hypoplasiaMidline 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 interventionMost 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) Fetal heart detailed U/S 18-20 wks fetal

echocardiography (85% sensitive) Perinatal complications

SGA & 1-minute Apgar < 7 (RR: 2) No substantially perinatal death

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)

“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

Carbamazepine (CBZ) “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 IQConsider transition to LTG or LVT

AED monotherapyAim to achieve lowest effective doseEstablish baseline “ideal” AED level

Take home message Presentation after conception

Still aim for monotherapyAvoid new medication trials & cross-over teratogenic and seizure risk

Monitoring AED level during & afterProbable concentration of LTG, PHT, +/-

CBZ (to a lesser extent)Possibly PB, LEV, OXC Individual variability consider monthly

monitoring

Take home message

Supplemental folic acid 4-5mg/dPrior to conception and during pregnancyFolate 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 healthyMost 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

Transdermal patch and vaginal ring also failure rate Medroxyprogesterone IM q8-10wks (usually q12wks) *** OCP significantly in lamotrigine levels

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 adulthoodHigh 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 distantCo-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 child40% increase2 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 diseaseRisk is 3.2 times higher in non-pregnant ♀Rate of progression in disability is most rapid

in nulliparous womenCannot R/O bias that women with more

severe disease have less childrenSome studies show no association

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 20092003-2005 study time10,000 MS obstetric hospitalization30% risk for C/S, 70% rate of IUGRAdjusted for maternal race and ageSimilar rate of HTN disorder and PROM

Take home message Most patients undergo pregnancy without

relapsesRelapse rates decrease in 3rd trimesterHigher in the 1st 3 months postpartum

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 medsMRI/clinical review of disease activity

If inactive continue for another 6 months If active, consider during the next 6 months:

Return to regular therapySolumedrol 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 complianceDiscuss 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 exacerbationsConsult obstetricianMore 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 monthlyResume breastfeeding 24 hrs after steroids

infusion

Management in NMO

IVIG monthly is safe in pregnancyConsider in active NMO to stabilize diseaseCan 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 treatmentPregnancy test prior to each treatmentCounsel 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

referralMigraines 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

InfectionsEclampsia/pre-eclampsiaVascular 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 thresholdMore common in migraine without aura and

menstrual migraines If ongoing h/a by the end of 1st trimester

unlikely to have significant improvement laterReturn 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 200773% normal or incidental findingsSinusitis 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 riskCan depress fetal thyroid screen for T4Gadolinium: potential animal fetal toxicityRisk 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

impairmentFetal 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 itNorwegian studyNo 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)Small, not statistically significant preterm

and LBW babiesNo change in congenital malformations

Sumatriptan registry (n=558)MCM 4.7%, occurring with 1st trimester

exposure

Acute migraine drugs in lactation

Prophylactic pharmacotherapy Recommended during pregnancy

Magnesium oxide or Riboflavin (400mg QD)PropranololGabapentin in 1st and 2nd trimester

Use in T3 may interfere with bony growth & dvlpmt

AvoidAtenolol, Divalproex, Paroxetine

Compatible with nursingDivalproex (with adequate contraception)MagnesiumPropranolol, 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