MS 6.2 - Pregnancy Gavin Giovannoni Case 1 26-yr woman with - - PowerPoint PPT Presentation

MS 6.2 - Pregnancy

Gavin Giovannoni

2

Case 1

26-yr woman with highly-active RRMS treated with alemtuzumab in 2017 and 2018. Now well. EDSS 3.5 with bladder dysfunction and weakness of R leg. I am keen to start a family, but am concerned I am going to pass ny MS onto my child. What are the risks? What would you advise?

.

MS has a genetic component?

Curtius in the 1930s showed clustering of the disease

Increasing relatedness to an MS patient increases your risk of getting the disease

Willer et al, 2003

Risk of MS to children

Borisow et al. EPMA J. 2012 Jun 22;3(1):9. Background risk: Women - 1 in 400 Men - 1 in a 1000 Children of pwMS: Daughters - 1 in 40 Sons - 1 in 100

6

Case 2

26-yr woman with highly-active RRMS treated with alemtuzumab in 2017 and 2018. Now well. EDSS 3.5 with bladder dysfunction and weakness of R leg. I am keen to start a family, but am concerned I will become disabled and will not be able to look after my child. What would you advise?

.

8

Case 3

23-yr woman with RRMS treated on glatiramer acetate is 6 months pregnant. You get a letter from her obstetrician asking if she needs anything special in relation to her pregnancy. What do you advise?

Labor, delivery and pregnancy outcomes in MS

• No issue with type of delivery mode and anesthesia
• Slight increase in labor induction and use of forceps or C-

section, especially with increasing disability for C-section or assisted vaginal delivery

• Rates of pregnancy loss, stillbirth or fetal malformation

similar to general population

Van der Kop 2011, Pasto 2012, Lu 2013

10 10

Case 4

39-yr woman with RRMS treated on glatiramer acetate 12 years is having difficulty falling pregnant and wants to have IVF. She is concerned that the IVF treatment will make her MS worse. What do you advise?

Effect of assisted reproduction technology on MS

• Relapsing-remitting MS (n=23, age 29.82 ± 5.38 years): 78

cycles of hormonal ART treatment:

• LHRH agonists (12 IVF, 21 ICSI) or LHRH antagonists (3

INSE, 9 ICSI) in combination with different gonadotropins (LH, FSH, HMG) and chorionic gonadotropin for induction of

• vulation. RR before: 0.62 ± 0.10; after: 0.95 ± 0.12, p=0.001
• Small (n=16) prospective study: GnRH agonists and

recombinant FSH may increase relapse risk (x7) and new MRI Gd+ lesions (x9)

Hellwig 2009, Correale 2012, Hellwig 2013

12 12

Case 5

30-yr woman with RRMS treated on natalizumab falls pregnant. She is unsure if she should stop natalizumab or continue natalizumab. What do you advise?

.

Pregnancy and Multiple Sclerosis

Vukusic et al, 2004

Pregnancy and disease course

• Decrease of disease activity during pregnancy

maximum during 3rd trimester

• Return of disease activity during 3 months

postpartum

• Women with higher relapse risk at baseline

more likely to relapse during postpartum

Vukusic et al, 2004

Pregnancy and MS outcome

Runmarker & Andersen. Brain. 1995 Feb;118 ( Pt 1):253-61.

Pregnancy and MS outcome

Runmarker & Andersen. Brain. 1995 Feb;118 ( Pt 1):253-61.

Pregnancy and MS outcome

Runmarker & Andersen. Brain. 1995 Feb;118 ( Pt 1):253-61.

Pregnancy and MS outcome

Ramagopalan et al. J Neurol Neurosurg Psychiatry. 2012 Aug;83(8):793-5.

20 20

Case 6

30-yr woman with RRMS treated on natalizumab falls pregnant. She is unsure if she should stop natalizumab or continue natalizumab. What about breastfeeding?

.

Breastfeeding and relapse rate

Pakpoor et al. submitted 2012.

22 22

Case 7

38-yr woman with RRMS treated on fingolimod falls pregnant. She is unsure if she should have a termination or not. What would you advise? What about foetal exposure to other DMTs?

Fertility and MS drugs

• In animal and humans:
• No effect of interferon, glatiramer acetate
• Mitoxantrone: amenorrhea (consider GnRH-a co-

therapy or banking)

• In animals:
• Natalizumab decreases fertility in female guinea

pigs (3 fold human regimen)

• Slight decrease of fertility with fingolimod

Paternal use of DMTs

• 46 pregnancies fathered by 32 men with MS who conceived while
• n DMT:
• 30 interferon beta,
• 12 glatiramer acetate,
• 2 natalizumab,
• 1 methotrexate,
• 1 azathioprine + interferon beta
• No effect on gestational age or birth weight vs. the general

population.

Hellwig 2010

Drug safety: pregnancy categories

• Category A: controlled studies in women fail to demonstrate a risk to

the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote

• Category B: no risk shown in animal studies; no adequate human

studies

• Category C: risk shown in animal studies; no adequate human

studies, but the benefits may outweigh the risks

• Category D: positive evidence of human fetal risk, but the benefits

may outweigh the risks

• Category X: studies in animals or humans have demonstrated fetal

abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit.

Lactation risk

• L1 (safest)
• L2 (safer)
• L3 (moderately safe)
• L4 (possibly hazardous)
• L5 (contraindicated)

Hale 2010

Symptomatic therapies

Fatigue Amantadine (Symmetrel) Modafinil (Provigil) Methylphenidate (Ritalin) Dextroamphetamine+amphetamine (Adderall) C C C C ? ? ?

• Bladder

dysfunction Oxybutinin (Ditropan) Trospium (Sanctura) Solifenacin (Vesicare) B C C ? ?

• Spasticity

Baclofen Tizanidine (Zanaflex) C C + ? Depression Sertraline (Zoloft) Paroxetine (Paxil) Duloxitine (Cymbalta) Venlafaxine (Effexor) Fluoxetine (Prozac) Buproprion (Welbutrin) C (D 2nd 1/2) D C C C C + ? ? ? ?

• Pain

Gabapentin (Neurontin) Pregabalin (Lyrica) Amitriptyline (Elavil) C C D ? ?

• Safety

pregnancy Safety breastfeeding

28 28

Case 8

36-yr woman with RRMS was on natalizumab, which was stopped in the 2nd trimester. Presents at 6 months gestation with acute paraparesis due to a probable severe spinal cord relapse. How are you going to manage her?

Relapse therapy

• IV methylprednisolone :
• pregnancy category C: teratogenicity in animals, no good data in human.
• possible increased risk of oral cleft when used during the first trimester of

pregnancy and low birth weight.

• metabolized to inactive forms by 11-b-hydroxysteroid dehydrogenase in the

placenta, allowing <10 % of maternal dose to reach the fetus

• PO dexamethasone:
• crosses placenta with minimal metabolism, leading to likely direct full-dose

effects on the fetus

• Steroids and breastfeeding: Eliminated in about 4 hours
• IV Immunoglobulins:
• pregnancy category C (EMA 2).
• L2

Imaging

• MRI:
• possible teratogenic effect during first trimester
• Gadolinium:
• Category C (avoid during pregnancy).

Teratogenic in animals at repeated high doses

• Breast feeding? less than 0.04% of the maternal

dose of IV gadolinium passes into the breast milk. Recommendation: discard breast milk for 24h post-gadolinium

Kubik-Huch 2000, Okuda 1999

Disease-modifying therapies for MS

Pregnancy FDA category Breastfeeding Minimum time between treatment discontinuation and conception Interferon beta C L3 >2 weeks Glatiramer acetate B L3 ? Natalizumab C L3 ? Fingolimod C L4 >2 months Mitoxantrone D L5 > 1 month? Teriflunomide X ? > 8 months or cholestyramine Fumaric acid C ? ? Alemtuzumab C L4 ? Ocrelizumab C L3 Several months? Modified from Houtchens 2012

Pregnancy and DMT

• 50% pregnancies are not planned
• General recommendation is to stop DMT 5 half

lives before conception (except teriflunomide)

• Discussions about risks with DMT should occur:
• at time of DMT initiation
• regularly during treatment especially for drugs

with possibility of rebound following discontinuation

Henshaw in Fam Plann Perspect 1998

Interferon beta exposure

• Crosses very poorly the placental barrier
• No teratogenicity in animals but abortifacient activity at doses 2-

100 times equivalent to human dose

• Compared with unexposed pregnancies, fair- to good-quality

prospective cohort studies reported:

• lower mean birth weight,
• shorter mean birth length,
• preterm birth (<37 weeks),
• But not low birth weight (2,500 g), cesarean delivery, congenital

anomaly (including malformation), or spontaneous abortion.

• No increased risk of developmental abnormalities reported

(limited follow-up: 1 year and 2.1 years)

Lu 2012 systematic review, Sandberg-Wollheim 2006/2011, Fernandez 2009, Weber-Schoendorfer 2009, Amato 2010, Boskovic 2006, Patti 2008

Glatiramer acetate exposure

• Does not cross the placental barrier
• No risk reported in pregnant rabbits and rats (up to x36)
• Pregnancy outcome: fair-quality level 3 evidence:
• No association with lower mean birth weight, lower mean

gestational age, preterm birth (<37 weeks), congenital anomaly, or spontaneous abortion

• One case of hypospadias reported in 22 live births
• Developmental outcome: 1/11 babies exposed in utero to

GA (mean = 7 months) with inadequate language performance

• Manufacturer’s safety database: 5 cases of congenital

malformations in 215 pregnancies

Coyle 2003, Weber-Schoendorfer 2009, Fragoso 2010, Salminen 2010, Hellwig 2011, Lu 2012, Houtchens 2012, Cree 2013

Natalizumab exposure

• In animals:
• No teratogenic effect (up to x7)
• Decreased guinea pig pup survival (7x human dose)
• Fetal hematologic effect in monkeys (2.3x human dose)
• Decreased fertility in female guinea pig (2.3x human dose)
• In humans:
• IgG can cross the placental barrier mostly 2nd/3rd trimesters
• Crohn’s disease: 102 pregnancies of which 55 live births (all

normal)

Hellwig 2011, Cree 2013

Portaccio I/II, Neurology 2018

Natalizumab up to 12 weeks of gestation associated with increased risk (OR=3.9) of spontaneous abortion (risk=17%) but remains within limits of control population, no increase in major congenital anomalies, but shorter and lighter babies (like with IFNB)

Fingolimod exposure

• Crosses the placenta
• In rats and rabbits, developmental toxicity, including teratogenicity

(rats) and embryolethality.

• In rats, the highest no-effect dose < human dose of 0.5 mg/day on a

mg/m2 basis. Most common fetal visceral malformations include persistent truncus arteriosus and ventricular septal defect.

• Data from ongoing registry:
• 76 exposed pregnancies,
• 27 normal births,
• 27 elective abortions,
• 3 malformations (tibial malformation, tetralogy of Fallot, acrania)
• 8 spontaneous abortions

Collins AAN 2011

Teriflunomide exposure

• Crosses placenta
• In animals: teratogenicity (craniofacial, axial, appendicular

skeletal defects)

• Upon discontinuing, consider accelerated elimination procedure

and verification of [plasma]< 0.02 mg/L (minimal risk)

• Otherwise average of 8 months to reach [plasma]< 0.02 mg/L,

but up to 2 years

• Elimination can be accelerated by :
• Administration of cholestyramine 8 g every 8 hours for 11
• days. If cholestyramine 8 g three times a day is not well

tolerated, cholestyramine 4 g three times a day can be used.

• Administration of 50 g oral activated charcoal powder every 12

hours for 11 days.

Teriflunomide Disposition of pregnancy cases

Reports of Pregnancies Exposed to Teriflunomide in Female Patientsa (N=231)b

Retrospective (reported after kowledge of status fetus/pregn) (n=30) Prospective (reported bf pre- natal test) (n=37) Postmarketing cases (2012- 2016)(excluding preg registry) (n=169) Clinical study cases (n=62) Known outcomes (n=67) Known outcomes (n=62) Prospective (n=62)

aExposed cases included pregnancies occurring within 2 years of last dose when there was no AEP performed; bas of May 17, 2016.

• 1. Vukusic et al. Oral presentation 205, ECTRIMS 2017. 2. Vukusic et al. AAN 2018, P361

Outcomes in teriflunomide-exposed pregnancies

Pregnancy Outcome, n (%) Clinical Study Cases (n=62) Postmarketing Cases Prospective (n=37) Retrospective (n=30) Live birth 22 (35.5) 20 (54.1) 10 (33.3) Pre-term live birth (<37 weeks) 3/22 (13.6) 2/20 (10.0) 1/10 (10) Spontaneous abortion 8 (12.9) 9 (24.3) 10 (33.3) Elective abortion 30 (48.4) 8 (21.6) 9 (30.0) Ectopic pregnancy 2 (3.2) Fetal death 1 (3.3)a

a Fetal death occurred at 35 weeks, cause and details are unknown.

• 1. Vukusic et al. Oral presentation 205, ECTRIMS 2017. 2. Vukusic et al. AAN 2018, P361. 3. Nybo Andersen et al. BMJ. 2000;320(7251):1078-1712.
• Mean age of patients with spontaneous abortions was 33.4 years1
• Rate of spontaneous abortions increases with maternal age in the general population3

‒ 15% at ages 20–30, 23% at age 35, and 43% at age 40

129 pregnancies with known outcomes resulted in 54 live births, including 2 sets of twins1 Courtesy of Dr Hellwig

3 structural malformations reported

Source of Case Maternal Age Malformation Timing of Last Dose/AEP Use Gestational Age at Birth Infant Outcome CS 34 Obstructive defects of renal pelvis and ureter (Ureteropyeloectasia) 1st trimester/ AEP performed Pre-term live infanta (36 weeks) Discharged from ICU after 2.5 weeks PM 26 Congenital hydrocephalus, (Minor cerebral ventriculomegaly <9 mm) 1st trimester/ AEP not performed Full-term live infant (37 weeks) No issues >1 year post-birth PM Unknown Cystic hygroma detected in fetus in antenatal ultrasound 1st trimester/ AEP unknown Unknown Unknown

• AEP, accelerated elimination procedure; CS, clinical study; ICU, intensive care unit; PM, postmarketing.
• aThe infant was a twin.
• 1. Vukusic et al. Oral presentation 205, ECTRIMS 2017. 2. Vukusic et al. AAN 2018, P361

No pattern in the type of malformations seen in these cases Malformations differed from those seen in animals No malformations were reported with elective abortions Preliminary review of additional data from May to November 2016 revealed no additional birth defect cases

Fumaric acid exposure

• In guinea pigs: no teratogenicity
• In rats: doses > 178 mg/kg associated with

malformations in organs, coccyx, skull bones

• Category C

Courtesy of Dr Hellwig

Courtesy of Dr Hellwig

Alemtuzumab exposure

• No animal reproduction studies
• Category C
• Crosses placental barrier mostly 2nd/3rd

trimesters

• Unknown how much crosses in breast milk

(but IgG can)

Outcomes n=972 All pregnancies, n 248 Completed pregnancies with known outcomes, n (%) 218 (87.9) Ongoinga 14 (5.6) Outcome unknown 16 (6.5) Completed pregnancies with known outcomes, n 218 Live births, n (%) 147 (67.4) Spontaneous abortionb 48 (22.0) Elective abortion 22 (10.1) Stillbirthc 1 (0.5)

Pregnancy Outcomes in Female Patients Treated With Alemtuzumab 12 or 24 mg

• Of the 147 live births:

‒ No congenital anomalies or birth defects were observed ‒ Five infants were born prematurely (range, 31–36 weeks)

• There was 1 stillbirth due to nuchal cord and amniotic band syndrome with abnormalities of the left hand

‒ Fetal demise occurred at 38 weeks and 4 days gestation and was 4 years after the last alemtuzumab dose

aAs of April 1, 2017. b<20 weeks’ gestation. c≥20 weeks’ gestation.

Rog D et al. ACTRIMS-ECTRIMS 2017, P749.

Courtesy of Dr Hellwig

Anti-CD20 monoclonal antibodies

• Half life elimination reported for rituximab is about 18

days (mean terminal half life) and around 4 months for

• crelizumab?
• Crosses placental barrier mostly during 2nd/3rd

trimesters

• Occurs progressively from month 4 to 9
• In monkeys: no malformations up to 100 mg/kg
• futumumab
• B cell depletion at birth in babies born from women

treated during late pregnancy

Cladribine

Year 1 Year 2

Cladribine is potentially genotoxic Very few pregnancies in humans 6 months after last cycle no pregnancy for men and women Double contraception for women in the first 4 weeks after the cycle Breastfeeding 1 week after the cycle ok

Courtesy of Dr Hellwig

Planning pregnancy and post-partum

• 50% pregnancies = unplanned --> early discussions
• Plan if medications need to be switched or discontinued and how,

taking in account disease severity to balance risks

• Ideally DMT should be discontinued before conception, for most,

but unclear for how long

• When to stop DMT: depends on clearance and possible risk of

birth defect.

• Teriflunomide should be stopped months before pregnancy

unless accelerated elimination.

• IFN/GA probably ok to stop when pregnancy identified

Planning pregnancy and post-partum

• Beware of rebound: relapse rate higher during

pregnancy when previously on fingolimod or natalizumab (Alroughani 2018)

• No category A DMT but some with interesting

features that can be leveraged for pregnancy or breastfeeding

• Active participation in ongoing pregnancy

registries is recommended

• No recommendation for pregnancy termination

Drugs with rebound risk

• If severe MS consider bridging suing DMT with long

lasting efficacy such as rituximab or ocrelizumab.

• Could be given just before conception.
• Probably ok if given during first trimester and if

necessary as single infusion.

Case 9: 18 year old female with RRMS

• Onset at age 15:
• Diplopia, dysarthria and ataxia with EDSS 6.5. Recovered to 3.5
• Brain MRI showed >20 T2 hyperintense lesions in the supra and

infratentorial, some enhancing. OCB+

• Natalizumab or rituximab considered but JCV+. Rituximab denied by

insurance so natalizumab initiated with plan to transition to ocrelizumab

• nce FDA approved
• Natalizumab treatment for 25 months: clinically stable but accrued a few

silent brain lesions

• Switch to ocrelizumab planned

Case courtesy of Emmanuelle Waubant

• Pregnancy course:
• Pregnancy discovered ~ 3 weeks after last natalizumab infusion.
• Initially patient planned termination
• ~ 18 week gestation patient decided to continue pregnancy
• given severity of disease and possible risk of rebound off natalizumab

decision made to treat with ocrelizumab

• Ocrelizumab 300mg IV infusion x 1 administered at ~ 19 week gestational

age

• 3 months after infusion = CD19+ < 1%
• Pre-eclampsia and difficult delivery with fetal distress
• Post-pregnancy course:
• B-cell count at delivery
• Patient’s CD19+ count <26, <1%
• Baby’s cord blood CD19+ 217, 12%
• 2nd infusion of ocrelizumab ~ 2 months postpartum
• 3 months postpartum, patient clinically stable. Baby doing well.

Case courtesy of Emmanuelle Waubant

Postpartum relapse prevention

• No consistent effect of IVIG (studies small and with sub-optimal

methodology)

• No convincing effect of pulse steroids
• Several studies suggest a benefit from exclusive breast-feeding
• n relapse prevention
• Risk of DVT in postpartum: probably increased with IVIG and

pulse steroids

• Limited data on rituximab/ocrelizumab and natalizumab given

while breast feeding but studies are ongoing as concentration in breast-milk of patients receiving monoclonal antibodies likely very small

• Rituximab/ocrelizumab just before pregnancy likely to decrease

relapse risk during postpartum

Slide courtesy of Emmanuelle Waubant

Recommendations vs practice

• Some neurologists use GA throughout the pregnancy
• Some ask patients to stop GA, IFNB or fumaric acid when

find out they are pregnant

• Some use natalizumab until patient pregnant (but risk of

rebound during pregnancy)

• Some use natalizumab throughout the pregnancy for

severe MS

• Some use rituximab/ocrelizumab during first trimester in

severe cases

Slide courtesy of Emmanuelle Waubant

Good prognosis - ‘mild MS’

• Stop DMT before pregnancy
• Resume after delivery if not breastfeeding or after done

with breastfeeding

Slide courtesy of Emmanuelle Waubant

Intermediate prognosis - ‘moderate MS’

• Consider:
• stopping DMT such as GA, IFNB, fumaric acid,

natalizumab, rituximab/ocrelizumab once pregnant

• GA throughout pregnancy
• B cell therapy just before conception
• natalizumab or B cell therapy immediately after delivery

Slide courtesy of Emmanuelle Waubant

Poor prognosis - ‘severe MS’

• Consider:
• Treating with B cell therapies until early pregnancy M1-3

(switch or treatment continuation)

• Using lower dose B cell therapy if used during pregnancy

M4-9

• Using natalizumab throughout pregnancy
• Resuming/starting monoclonal antibody therapy just after

delivery if breastfeeding as very little goes in the milk (consider starting 2nd week post-partum as less going into breast milk compared with colostrum)

Slide courtesy of Emmanuelle Waubant

60 60

Question: What about pregnancy?

• Does MS affect my fertility?
• Will pregnancy affect the course of my MS?
• Will I be able to breastfeed after delivery?
• How long before I fall pregnant must I stop my DMT?
• If I fall pregnant on a DMT will this affect the baby?
• Can I breastfeed on my DMT?
• Will I be able to be a good parent if I become disabled from my MS?
• If I become disabled or unemployed as a result of MS will I be able to support my children?
• What is the risk of my children getting MS?
• Can I do anything to prevent them from getting MS?
• Am I more likely to need an assisted delivery because I have MS?
• Will I be able to have a normal vaginal delivery?
• Will I be able to have an epidural during labour?

61 61

Question: What about pregnancy?

• How do you treat hyperemesis gravidarum during pregnancy?
• Should I continue taking my other drugs for my MS symptoms during pregnancy?
• What is the best treatment strategy for my MS? Should I go onto a DMT and get my MS under

control before starting a family or should I start my family first?

• What is the best treatment strategy for my MS to maximise my chances of having a family and

keeping my MS under control?

• How will having neutralizing anti-IFN beta antibodies affect my baby?
• Can I have in vitro fertilization? Will the drugs that are used to induce ovulation affect my MS?
• What dose of vitamin D do you advise during pregnancy?
• Are oral contraceptives safer for my MS? Which contraceptive do you recommend?

Conclusions

• 1. MS is a pink-ribbon disease
• 2. Pregnancy is a common clinical issue

a.Family planning b.Issues related to parenting

• 3. Pregnancy and breastfeeding modifies the course of the

disease

• 4. Impact on prescribing DMTs

a.Complex b.Require DMT specific knowledge

.