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Multiple Sclerosis and pregnancy: Guidelines from the literature

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Multiple Sclerosis and pregnancy: Guidelines from the literature

  1. 1. MULTIPLE SCLEROSIS and PREGNANCY Emilie LOMMERS 5th year of the Master in Neurology CHU Liege, November 2014
  2. 2. OVERVIEW • MS impact on pregnancy outcome • Genetic risk? • Pregnancy and disease activity • Optimal conception timing /PRISMS • Therapeutic considerations during pregnancy • Post-partum issues
  3. 3. MS impact on pregnancy outcome • Fertility: - No direct impact of MS on fertility - Sexual dysfunctions delay conception - Higher incidence of endometriosis in MS patients
  4. 4. MS impact on pregnancy outcome • Pregnancy: - Occasional reports of lower birth weight, higher rates of induced labour and caesarean delivery - Recent meta-analysis: no significantly higher risk of obstetrical or neonatal complications 2 2. Finkelsztejn A, et al. 2011
  5. 5. OVERVIEW • MS impact on pregnancy outcome • Genetic risk? • Pregnancy and disease activity • Optimal conception timing /PRISMS • Therapeutic considerations during pregnancy • Post-partum issues
  6. 6. Genetic risk 0% 10 % 20 % 30% Monozyg. twins First-Degree Relative 2nd Degree Relative General population 1 in 4 1 in 50 1 in 100 1 in 500 - Monozygote twins: 25% concordance - Dizygote twins: 5% concordance - 1 parent has MS: 2- 4% - Lifetime risk of developing MS: 0.1- 0.2% Approximate risk of developing MS There is a 98% chance that children of a patient with MS will not develop MS Maria Houtchens, Management during pregnancy, TC04 Boston ECTRIMS 2014
  7. 7. OVERVIEW • MS impact on pregnancy outcome • Genetic risk? • Pregnancy and disease activity • Optimal conception timing /PRISMS • Therapeutic considerations during pregnancy • Post-partum issues
  8. 8. Pregnancy and disease activity • Effect on clinical activity: - 70% reduction in ARR during third trimester compared to pre-pregnancy - Rebound to 70% above pre-pregnancy level during first 3 months post- partum 3 3. Confavreux et al. 1998, Airas et al. 2007, Harbo et al. 2013
  9. 9. Pregnancy and disease activity 4. Paavilainen et al. 2007 • Effect on MRI: - New or enlarging lesions detected as soon as 4 weeks after delivery in half of the patients (14/28) 4 - Significant increase in the number of T2 lesions and Gadolinium-enhancing lesions 4
  10. 10. Pregnancy and disease activity 5. Vukusic et al. 2004, 6. Verdru et al. 1994, 7. D’Hooghe 2010, 8. D’Hooghe 2011 • Effect on disability progression: - No ‘net’ effect of a single pregnancy on disability on a 2 year follow-up study (PRISMS study) 5 - 2 retrospective studies assessed the time from onset to reach ambulatory milestones in progression and found a longer time in patients who had children after MS onset when compared with women who did not 6, 7 - Reporting at least two pregnancies or children was associated with a decreased likelihood to reach EDSS 6 8
  11. 11. Pregnancy and disease activity • Susceptibility to develop MS: - Increasing gravidity and parity and offspring number was associated with reduced probability of conversion from CIS to definite MS.7 - RIS patients followed during 7 yrs: pregnancy is associated with increased MRI and clinical disease activity 8 7. Ponsonby et al. 2012, 8. Lebrun et al. 2012
  12. 12. Immune changes during pregnancy
  13. 13. • Pregnancy = immuno-tolerant state • Important biological changes occur during pregnancy 9: 1. Hormone level increase 2. Immune cell shift 3. Fetal antigens interact with and modulate the maternal immune system 9. Patas et al., 2014
  14. 14. 1. Hormonal changes
  15. 15. - Shift in cytokines production - Downregulation of adhesion molecule expression - Decrease antigen presentation - Induction of regulatory T cells - SNC protection and remyelination promotion Hormones have potent immunomodulatory and neuroprotective properties 10 10. Robinson and Klein 2012, Voskuhl and Gold 2012, Spence and Voskuhl 2012
  16. 16. • The protective effect of oestrogens has been widely demonstrated in EAE (effect dependent on ERα)10,11 • Erβ ligand treatment may be protective in EAE by reducing demyelination and promoting remyelination 12 • Estrogen levels induced by oral contraception and HRT do not seem to be protective. • Infertility treatement may increase MS disease in the 3 months after treatment particulary when using GnRH agonist 13, 14 11. Kim et al. 1999, Bebo et al. 2001, 12. Tiwari et al. 2007, 13. Michel et al. 2012, 14. Hellwig et al. 2009.
  17. 17. 15. Sicotte et al. 2002, 16. AAN 2013, • Phase I clinical trial of Estriol (8 mg od)in females with RRMS: decreased Gd enhancing lesions on brain MRI 15 • Phase 2 clinical trial in 164 females with RRMS - Estriol (8 mg od) + Copaxone vs Placebo+ Copaxone: at 12months Estriol group had a 47% reduction in confirmed relapses compared to placebo group. No difference in relapse rate reduction at 24 months 16
  18. 18. • Phase III clinical trial (POPARTMUS) examining the effects of progestin and estradiol vs placebo on post-partum relapse in RRMS (3 months post-partum): => no significant results for ARR and MRI outcomes at 12 and 12- 24 post-partum 17 17. ECTRIMS 2012
  19. 19. 2. Immune Cell shift
  20. 20. OVERVIEW • MS impact on pregnancy outcome • Genetic risk? • Pregnancy and disease activity • Optimal conception timing • Therapeutic considerations during pregnancy • Post-partum issues
  21. 21. Optimal conception timing • No published data • Pregnancy is a personal decision • PRISMS study showed significant correlation between post- partum exacerbation of MS and: 18 - the number of relapses in pre-pregnancy year - the EDSS at pregnancy onset - the number of relapses during pregnancy • Probably helpful to stabilize an active patient with more effective therapies for 12 months prior to attempting conception 18. Vukusic at al. 2004, Houtchens, Management during pregnancy, TC04 Boston ECTRIMS 2014
  22. 22. • Assistive reproductive technologies: - ART is possible in well-controlled MS patients - Education about possible increase of disease activity - Avoidance of GnRH agonsit (?) in MS patients - DMT during hormonal stimulation? Optimal conception timing Houtchens, Management during pregnancy, TC04 Boston ECTRIMS 2014
  23. 23. OVERVIEW • MS impact on pregnancy outcome • Genetic risk? • Pregnancy and disease activity • Optimal conception timing • Therapeutic considerations during pregnancy • Post-partum issues
  24. 24. Therapeutic considerations
  25. 25. Glatiramer Acetate (FDA category B) • > 300 pregnancies under GA 19 • No increase risk of: - Malformations - Abortions - Preterm birth - Reduced birth weight • Washout period: not necessery 19. Lu et al. 2012
  26. 26. Interferon Beta (FDA category C) • > 1000 pregnancies under IFN19 • No increase risk of: - Miscarriages - Malformation • Lower mean birth weight/ lower mean birth length • Increased risk of preterm birth • Washout period: 0-1 months 19. Lu et al. 2012
  27. 27. Natalizumab (FDA category C) • > 360 patients with early pregnancy exposure to NTZ ( TPER)20 • No increase risk of: - Miscarriages - Malformation • 9 patients treated during pregnancy (1 to 9 infusions)21 - Mild to moderate hematologic abnormalities in 8 children (thrombocytopenia, hypogammaglobulinemia and haemolytic anaemia) - Transplacental transport of NTZ observed • Washout period: 3 months 20. Cristiano et al. 2011, 21. Haghikia et al 2013 (poster AAN 2013)
  28. 28. Fingolimod (FDA category C) • 280 pregnancies under fingolimod tracked 22 - 21 spontaneous abortions - 39 induced abortions - 59 healthy newborns • 8 newborns with abnormalities (Fallot’s tetralogy, acrania, renal dysplasia, patent ductus arteriosus,…) • Washout period: 2 months 22. Geissbuhler 2012, ECTRIMS
  29. 29. Teriflunomide (FDA category X) • 70 pregnancies (elimination procedure with cholestyramine or activated charcoal) 23 - 29 induced abortions - 8 spontaneous abortions - 26 healthy newborns • So far no pattern of malformation in about 100 leflunomid-exposed pregnancies 24 • Formal washout to lower drug level 23. Kieseler et al abstract ECTRIMS 2012, 24. Chambers et al 2010
  30. 30. Dimethyl Fumarate (FDA category C) • Embryo and foeto-toxicity at very high doses in rats • 38 pregnancies in clinical trials (limited exposure)25: - 22 healthy newborns - 3 spontaneous abortions - 7 elective abortions • Pregnancy registry ongoing • Washout period: 0-1 months 25. Gold et al. AAN 2013
  31. 31. Alemtuzumab (FDA category C) • 72 pregnancies (Genzyme registry) • 10 after de first cycle: 4 healthy babies, 2 miscarriages, 4 abortions • 62 after second cycle: 28 terms newbonrs, 3 preterm, 14 miscarriages, 5 abortions, 1 stillbirth, 11 unknow • Washout period: 3-4 months after last cycle Houtchens, Management during pregnancy, TC04 Boston ECTRIMS 2014
  32. 32. Relapses management during pregnancy • Corticosteroids are broadly used in obstetric to speed fetal lung maturity: not associated with a negative impact on fetus development26 • Intravenous CS are thus probably safe in the 2nd and 3thd trimester. • Should be avoid during 1st trimester because of risk of cleft palate and lower birth weight27, 28 • CS should be reserved for treatement of serious relapse. 26. Roberts et al. 2006, 27. Elliot et al. 2010, 28. Hoes et al., 2007
  33. 33. Relapses management during pregnancy • No fetal effect of MRI during pregnancy documented. • However guidelines are precautionary and recommend MRI only if essential • Contrast is not recommended because Gadolinium compounds cross the placenta. 29. Bove et Klein, 2004.
  34. 34. OVERVIEW • MS impact on pregnancy outcome • Genetic risk? • Pregnancy and disease activity • Optimal conception timing • Therapeutic considerations during pregnancy • Post-partum issues
  35. 35. Breastfeeding • Meta-analysis of collective data of > 1500 pregnancies : decreased risk for post-partum relapse in women breastfeeding30 30. Pakpoor and Giovannoni, 2012.
  36. 36. Breastfeeding • Exclusive breastfeeding is associated with a protective effect in postpartum relapse rate31, 32 • Other studies report that breastfeeding has no effect on MS relapses. • Breastfeeding delay DMT reintroduction 31.Langer-Gould et al. 200, 32. Hellwig et al. 2012.
  37. 37. Breastfeeding • Predictors of postpartum relapses and current clinical status should influence the decision to breastfeed or not. • Probably best to try exclusive breastfeeding (2 months) • Washout period of 24-48h recommended after Gadolinium injection and intravenous CS. 31.Langer-Gould et al. 200, 32. Hellwig e al. 2012.
  38. 38. Treatment • DMT (IFN and GA) have delayed onset of efficacy beyond the peak of the postpartal exacerbations33 • GAMmaglobulin Post Partum (GAMPP) study: lower postpartum relapse risk in IVIg group (10g following delivery/ 10g every 4 weeks of 6 months)34 • 6 monthly IV CS in postpartum period: beneficial effect on postpartum relapse rate35 33. Comi et al. 2001, 34. Hellwing et al. 2009 , 35. de Seze et al. 2004.
  39. 39. Although there are many unmet research needs, the reviewed data support the conclusion that in the majority of cases, women with MS can safely choose to become pregnant, give birth, and breastfeed children. Clinical management should be individualized to optimize both the mother's reproductive outcomes and MS course.

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