Dr Peter Brex presented an update on managing pregnancy in multiple sclerosis (MS). The key points were: 1) It is important to provide pre-pregnancy counseling to understand medication management during pregnancy and establish links with local obstetric teams. 2) While there are no clinical trials of disease-modifying therapies (DMTs) in pregnancy, data from pregnancy registries can provide guidance on safety. 3) Recommended time periods for stopping various DMTs prior to conception range from 5 months to over 2 years depending on the medication.

1. Dr Peter Brex
Consultant Neurologist, King’s College Hospital NHS Foundation Trust
MS Trust Annual Conference
3 - 5 November 2019, Jurys Inn Hinckley Island Hotel
Managing pregnancy in MS – an update
(Since 2016)

2. Learning Outcomes
• Understand the importance of pre-pregnancy counselling
• Know where to find out how to manage medications during
pregnancy
• Establish links with local Obstetric teams

3. Disclosures
In the past 5 years I have received honoraria for consultancy work / presentations
and / or support to attend / host educational meetings from:

5. Comi et al. Lancet 2017;389:1347-1356 No Evidence of Disease Activity
Importance of Early Treatment

6. EMA; European Medicines Agency; s/c=sub-cutaneous; i/m=intramuscular; i/v=intravenous; po=by mouth
DMTs: Year of EMA approval
1995 2000 2005 2010 2015 2020
INFB-1bs/c(1995)
IFBN-1ai/m(1996)
IFBN-1as/c(1998)
GAs/c(2001)
Natalizumabi/v(2006)
Fingolimodpo(2011)
Teriflunomidepo
Alemtuzumabi/v(2013)
DMFpo
Peg-IFNb-1as/c(2014)
Cladribinepo(2017)
Daclizumabs/c(2016)
Ocrelizumabi/v
Fingolimodinchildren>10years(2018)
Advances in MS Treatment

7. Safety of DMDs in Pregnancy
• No clinical trials in MS and Pregnancy
• Mandatory pregnancy registries
• Many years of use to gain sufficient experience to
confidently make recommendation

11. Approximately 40% WwMS are not on a DMD in 12 months prior to conception

12. ?Stop DMD prior to conception

13. Recommended time from stopping DMD until conception
0 5 10 15 20 25 30
Teriflunomide
Ocrelizumab
Natalizumab
IFNB
GA
Fingolimod
DMF
Clabribine
Alemtuzumab
* Use accelerated elimination procedure – natural washout time between 9 -24 months Time (months)
*

14. www.babycentre.co.uk
Fertility
WwMS may remain untreated for many months whilst trying to conceive

15. ALWAYS consider pregnancy when prescribing DMDs
Unplanned pregnancies

16. Injectables: IFNB & GA

17. 2017

18. 2019

19. Pregnancy In
MS (PRIMS)
Study Group

20. DMF

21. Conclusions:
Consistent with previous reports, no safety signal
was observed for DMF exposure in relation to
pregnancy outcomes based on data from an interim
analysis of this ongoing international registry
• The rate of spontaneous abortions from the
interim analysis was similar to the rate observed in
clinical trials of DMF (8%)5 and below the estimated
rates (12–16%)10 in the general population
• The rate of birth defects from the interim analysis
was similar to the rate observed in the MS
population (4%)and the general population (2–5%)

22. Teriflunomide

24. The risk of male-mediated
embryo-fetal toxicity through
teriflunomide treatment is
considered low. The
estimated female plasma
exposure via the semen of a
treated patient is expected to
be 100 times lower than the
plasma exposure after 14 mg
of oral teriflunomide.
SPC – accessed 05/19

25. 2019

26. Conclusions:
Outcomes were consistent
with the general
population.
Current human data do not
indicate a teratogenic
signal in teriflunomide-
exposed pregnancies.

27. Fingolimod

30. Approx. 25% of women discontinuing fingolimod for pregnancy will relapse

31. Natalizumab

32. 36.5%1 / 42%2 of WwMD
discontinuing Natalizumab for
pregnancy will relapse.
Severe relapses resulting in
permanent disability occur in
15%3
1 Portaccio E, Moiola L, Martinelli V, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: maternal risks. Neurology 2018;90(10):e832–e839.
doi:10.1212/WNL.0000000000005068.
2 Esters N, Spicher C, Thiel S, et al. Disease activity and disability after Natalizumab (NTZ) withdrawal due to planning a pregnancy in women with multiple sclerosis. Poster presented at: 70th American Academy of Neurology Annual
Meeting; April 21–27, 2018; Los Angeles, CA.

33. MS = Multiple Sclerosis; CD = Crohn’ Disease; MACDP = Metropolitan Atlanta Congenital Defects Program

34. Haghikia A et al. JAMA Neurol 2014;71(7):891-895
• NTZ crosses blood placental barrier after 28 weeks
• Can interfere with fetal haematopoiesis
• 12 women with 13 pregnancies and highly active MS who were treated with NTZ during their T3
• Haematological abnormalities in 10 of the 13 newborns - thrombocytopenia, anaemia, and leukocytosis
• Mostly self limiting during the 4 months after birth
RECOMMENDATIONS
■ Use of NTZ in late pregnancy should be a last resort
■ Where a use of NTZ after 28 weeks, neonatal team should be informed
■ Hospital delivery with attendance of neonatal team in labour should be planned
■ Postnatally neonatal investigations include full blood cell count, bilirubin lactate dehydrogenase,
transaminases, and haptoglobin

35. While in the CP group, the expected
temporal profile of disease activity was
observed, in the NP group relapse rate
increased both during pregnancy (with a
peak in the first trimester) and after
delivery
NP = Natalizumab pregnancies (n= 74); CP = control pregnancies (n=350)

36. The authors recommended treating until around 30/40 then stopping

37. Late Breaking News – ECTRIMS 2019

38. Group 1
30 Pregnancies
Suspending NTZ within 90
days from LMP
30 Newborns

39. Group 1:

41. Induction Therapies:
Cladribine & Alemtuzumab

42. • Oral cladribine – use contraception (women AND MEN*) for at least
SIX MONTHS but thereafter opportunity to get pregnant
• Alemtuzumab – use contraception for at least FOUR MONTHS after
treatment but there after opportunity to get pregnant
• Important to continue to monitor for recognised long-term complications
of treatment, e.g. thyroid disease
*’As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore,
male patients must take precautions to prevent pregnancy of their partner during cladribine treatment and for at least 6
months after the last dose’ - SPC – accessed 05/19

46. Over 8 years, 122 pregnancies
met the inclusion criteria; onset
of pregnancy after at least 1 dose
of Alemtuzumab
72% > 1 year after last dose
18% 4-12 months after last dose
10% < 4 months after last dose
14% received 1 dose
62% received 2 doses
24% received > 2 doses
2019

47. Anti-CD20 MAbs:
*Rituximab & Ocrelizumab
*Not licensed to treat MS

48. Swedish MS register (1/1/2006 – 12/12/2016)
3116 pregnancies among 2224 WwMS
3 groups included:
• 40 RTX within 6 months prior to conception
• 45 NTZ within 6 months prior to conception
• 782 pregnancies untreated within 1-year prior to conception
• Relapse rate 1-year post-partum significantly higher in NTZ-
compared with RTX-treated pregnancies
• No post-partum increase in RR MS in group overall

53. Pregnancy and Family Planning in Multiple Sclerosis By Annette M. Langer-Gould.
CONTINUUM (MINNEAP MINN) 2019;25(3, MULTIPLE SCLEROSIS AND OTHER CNS INFLAMMATORY DISEASES):773–792.
• Rituximab* author’s preferred
drug for active MS
• Perform a pregnancy test prior
to administration
• Advises conception for one
month post treatment -
rituximab does not transfer
across placenta in 1st trimester
• Avoid treating with rituximab
during pregnancy due to risk
of B cell depletion in infant
• Less data for ocrelizumab and
animal data suggest it may be
more harmful
*Rituximab is not licensed for he treatment of MS

54. What about breastfeeding?

55. Breastfeed or DMTs
MSJ Oct 2013

56. Pregnancy and Family Planning in Multiple Sclerosis By Annette M.
Langer-Gould. CONTINUUM (MINNEAP MINN) 2019;25(3, MULTIPLE
SCLEROSIS AND OTHER CNS INFLAMMATORY DISEASES):773–792.
SPC recommends discontinuing
breastfeeding whilst receiving
Natalizumab and Rituximab /
Ocrelizumab

58. Next steps

59. https://pn.bmj.com Published on-line 5th January 2019 and in the April 2019 print edition of Practical Neurology

61. 1st UK MS Pregnancy Register Meeting
Belfast (17th January 2019)
Mr Rod Middleton & Mr Chris Roberts (UK MS Register, Swansea), Dr Peter Brex (London), David Rog (Manchester)
Dr Owen Pearson (Swansea), Dr Katy Murray (Edinburgh), Dr Ruth Dobson (London), Dr Stella Hughes (Belfast)

62. Expected Due Date: 2020
We are grateful for a generous donation from the Horne Family Trust to support the
development of a UK MS Pregnancy Register
Mother site:
UK MS Register
Swansea University
MS Society

63. Thank You