MS 6.2 - Pregnancy Gavin Giovannoni
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? 2
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 Background risk: Women - 1 in 400 Men - 1 in a 1000 Children of pwMS: Daughters - 1 in 40 Sons - 1 in 100 Borisow et al. EPMA J. 2012 Jun 22;3(1):9.
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? 6
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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? 8
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
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? 10 10
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 ovulation. 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
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? 12 12
Pregnancy and Multiple Sclerosis Vukusic et al, 2004 .
Pregnancy and disease course • Decrease of disease activity during pregnancy maximum during 3 rd 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.
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? 20 20
Breastfeeding and relapse rate Pakpoor et al. submitted 2012. .
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? 22 22
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 on 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 Safety Safety pregnancy breastfeeding Fatigue Amantadine (Symmetrel) C ? Modafinil (Provigil) C ? Methylphenidate (Ritalin) C ? Dextroamphetamine+amphetamine (Adderall) C - Bladder Oxybutinin (Ditropan) B ? dysfunction Trospium (Sanctura) C ? Solifenacin (Vesicare) C - Spasticity Baclofen C + Tizanidine (Zanaflex) C ? C (D 2 nd 1/2) Depression Sertraline (Zoloft) + Paroxetine (Paxil) D ? Duloxitine (Cymbalta) C ? Venlafaxine (Effexor) C ? Fluoxetine (Prozac) C ? Buproprion (Welbutrin) C - Pain Gabapentin (Neurontin) C ? Pregabalin (Lyrica) C ? Amitriptyline (Elavil) D -
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? 28 28
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 Breastfeeding Minimum time FDA category 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
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