Multiple sclerosis and pregnancy

Transcription

revue neurologique 170 (2014) 247–265
Available online at
ScienceDirect
www.sciencedirect.com
Recommendations
Multiple sclerosis and pregnancy
Consensus formalisé d’experts : sclérose en plaques et
grossesse
E. Bodiguel a,*,b,c, C. Bensa d, D. Brassat e, D. Laplaud f,g, E. Le Page h,
J.-C. Ouallet i, H. Zephir j, J. De Seze k
a
Hôpital européen Georges-Pompidou, AP–HP, 20, rue Leblanc, 75015 Paris, France
Service de neurologie, centre hospitalier Sainte-Anne, 1, rue Cabanis, 75014 Paris, France
c
Faculté de médecine, université Paris Descartes, Sorbonne Paris Cité, 12, rue de l’École de Médecine,
75270 Paris cedex 06, France
d
Service de neurologie, fondation Rothschild, 25, rue Manin, 75019 Paris, France
e
Inserm U1043, pôle des neurosciences, hôpital Purpan, université Toulouse-3, place du Dr-Baylac, BP 3028,
31024 Toulouse cedex 3, France
f
Inserm UMR643, service de neurologie, pavillon Jean-Monnet, hôtel-Dieu, CHU de Nantes, 30,
boulevard Jean-Monnet, 44093 Nantes 01, France
g
Faculté de médecine de Nantes, 1, rue Gaston-Veı̈l, 44000 Nantes, France
h
CIC-P 0203 Inserm, pôle des neurosciences cliniques, CHU Pontchaillou, pavillon Clemenceau, 2,
rue Henri-Le-Guilloux, 35033 Rennes cedex 9, France
i
Pôle des neurosciences cliniques, université de Bordeaux Segalen, CHU de Bordeaux Pellegrin Tripode, 1,
place Amélie-Raba-Léon, 33076 Bordeaux cedex, France
j
Pôle de neurologie, hôpital Roger-Salengro, CHRU de Lille, avenue du Pr-Émile-Laine, 59037 Lille, France
k
Service de neurologie, laboratoire d’imagerie et de neurosciences cognitives (LINC), CNRS, centre d’investigation
clinique (CIC) de Strasbourg, université de Strasbourg, CHU de Strasbourg, 1, place de l’Hôpital, 67000 Strasbourg,
France
b
info article
abstract
Article history:
The question of pregnancy in patients with multiple sclerosis is regularly raised due to the
Received 26 July 2013
prevalence of the disease in middle age women. The multiple sclerosis think tank (Groupe de
Accepted 26 September 2013
Réflexion sur la Sclérose en Plaques [GRESEP]) decided to develop recommendations on this
Available online 28 March 2014
issue, with consideration to both the impact of multiple sclerosis on pregnancy, and that of
Keywords:
method was used. The working group was composed of hospital-based and private practice
Multiple sclerosis
neurologists. The reading group was composed of neurologists, anaesthetists and obste-
Pregnancy
tricians. Each recommendation is presented with the relevant level of consensus.
pregnancy on the disease. As with topics of previous works, the formal expert consensus
Delivery
# 2014 Elsevier Masson SAS. All rights reserved.
Epidural analgesia
* Corresponding author.
E-mail addresses: [email protected], [email protected] (E. Bodiguel).
http://dx.doi.org/10.1016/j.neurol.2013.09.010
0035-3787/# 2014 Elsevier Masson SAS. All rights reserved.
© 2014 Elsevier Masson SAS. Tous droits réservés. - Document téléchargé le 08/09/2014 par APHP CENTRE DOCUMENTATION (164588)
248
Breastfeeding
r é s u m é
Clinical practice guidelines
Rand Ucla appropriateness method
L’âge moyen des malades et la prédominance féminine expliquent que la problématique de
Mots clés :
groupe de réflexion sur la sclérose en plaques (GRESEP) a choisi d’élaborer des recomman-
Sclérose en plaques
dations sur ce thème, envisageant à la fois le retentissement de la sclérose en plaques sur la
la grossesse soit régulièrement posée chez les patientes atteintes de sclérose en plaques. Le
Grossesse
grossesse et celui de la grossesse sur la maladie. Comme pour les thèmes de travail
Accouchement
précédents, la méthode du consensus formalisé d’experts a été utilisée. Le groupe de travail
Analgésie péridurale
était composé de neurologues hospitaliers et libéraux. Le groupe de lecture était composé de
Allaitement
neurologues, d’anesthésistes et d’obstétriciens. Chaque recommandation est exposée avec
Recommandations de pratique
le degré de consensus dont elle a fait l’objet.
# 2014 Elsevier Masson SAS. Tous droits réservés.
clinique
Consensus formalisé d’experts
1.
Objectives
In this new work, the multiple sclerosis think tank (Groupe de
Réflexion sur la Sclérose en Plaques [GRESEP]) presents
recommendations for harmonizing pregnancy care in patients
with multiple sclerosis (MS), beginning before conception up
through the postpartum period.
2.
Methods
The methodology of the Formal Consensus of Experts was
presented in detail in a previous work [1] (Table 1). The
literature search strategy is shown in Table 2 and Fig. 1. Each
pair of the working group that was responsible for a clinical
question analyzed the literature, selected based on title and
abstract, using standardized reading grid and assisted by
voluntary members of the rating group. Recommendation
proposals were then drafted with their rationales. The
working document was subjected to three cycles of writing,
scoring and revision. The resulting consensual recommendations were submitted to the reading group. The comments of
the reading group were used by the steering committee to
rewrite certain recommendations and submit them for a 4th
scoring, and then a 5th for Recommendation 4.2 (Section 3.5).
The results of the last scoring are summarized in Table 3. One
discordant opinion could be discarded from the analysis of
this last scoring. The opinions of the reading group are
summarized in Table 4. The steering committee validated the
final document submitted for publication. Each recommendation is followed by its rationale and its level of consensus
amongst the scoring and reading groups (Table 5). The French
title of the recommendations is shown in Table 6.
3.
Recommendations
The objective of the present recommendations is to respond to
the following clinical questions: Should disease-modifying
therapy for MS be discontinued if pregnancy is planned? If so,
when and under what conditions? What effects does MS have
on pregnancy? How should relapse be treated during
pregnancy and in the postpartum period? Should the usual
pregnancy procedures (epidural analgesia, delivery route,
anaesthesia, etc.) be modified in the case of MS? Does the
postpartum management in MS differ from the usual
management? Is breastfeeding possible? When should
disease-modifying therapy be resumed following pregnancy?
Is medical termination of the pregnancy recommended for
women who became pregnant while on disease-modifying
therapy for MS?
3.1.
Clinical question 1: should disease-modifying therapy
for MS be discontinued if pregnancy is planned? If so, when
and under what conditions?
3.1.1.
Recommendations
Recommendation 1.1:
Continuation of immunomodulator therapy (interferonbeta or glatiramer acetate) is possible until the proof of
conception, with no harmful effects currently shown on
the embryo or fetus or on the course of the pregnancy
(strong professional agreement) (Table 7).
Recommendation 1.2:
In case of very active disease, continuation of immunomodulator therapy (interferon-beta or glatiramer acetate) throughout the entire pregnancy may also be
considered on a case-by-case basis, as absence of toxicity
is shown by data from studies and pharmacovigilance
registries (relative professional agreement) (Table 7).
Recommendation 1.3:
It is recommended that immunosuppressive treatments
(cyclophosphamide [off-label], mitoxantrone) be withdrawn when pregnancy is planned, due to their potential
toxicity in pre-therapeutic studies and due to their pharmacodynamic properties (relative professional agreement) (Table 7).
249
Table 1 – Methodology of the development of recommendations.
Panel
Steering committee
Actions
a
Definition of the clinical questions
Should disease-modifying therapy for MS be discontinued if pregnancy is planned? If so, when
and under what conditions?
What effects does MS have on pregnancy?
How should relapse be treated during pregnancy and in the postpartum period?
Should the usual pregnancy procedures (epidural analgesia, delivery route, anaesthesia, etc.)
be modified in the case of MS?
Does the postpartum management in MS differ from the usual management? Is breastfeeding possible?
When should disease-modifying therapy be resumed following pregnancy?
Is medical termination of the pregnancy recommended for women who became pregnant while on
disease-modifying therapy for MS?
Monitoring of the project with assistance from the methodology groupb
Working group
Analysis of the literature provided by the methodology group, with assistance from voluntary members of
the rating group
Drafting of proposals for recommendations and rationales
Question 1: C. Bensa, J.-C. Ouallet, Questions 2 and 3: F. Blanc, H. Zephir, Question 4: C. Bensa, J.-C. Ouallet,
Question 5: D. Brassat, D. Laplaud, Question 6: D. Brassat, Question 7: D. Laplaud
Consideration of the opinions of the rating and reading groups
Rating groupc
Critical reading of the recommendations and rationales
Rate of the level of agreement for the style and the content of each recommendation
Reading groupd
Critical reading of the recommendations and rationales
Vote (agree, undecided, disagree) on each consensual recommendation between the working and rating groups
a
J. De Seze (Strasbourg, President), C. Bensa (Paris), D. Brassat (Toulouse), D. Laplaud (Nantes), E. Le Page (Rennes), J.-C. Ouallet (Bordeaux),
H. Zephir (Lille).
b
E. Bodiguel (Paris), N. Charbonnier (Paris), N. Freynet (Paris).
c
E. Berger (Besançon), O. Casez (Grenoble), R. Colimaro (Vichy), I. Coman (Bobigny), M. Coustans (Quimper), T. Debroucker (Saint-Denis),
N. Derache (Caen), A. Fromont (Dijon), C. Gaultier (Colmar), A.M. Guennoc (Tours), M. Merienne (Saint-Malo), S. Pittion (Nancy), E. Planque
(Epinal), C. Renglewicz (Colmar), F. Rouhart (Brest), S. Wiertlewski (Nantes), C. Zaencker (Colmar).
d
G. Andre (Strasbourg), D. Audry Chaboud (Dijon), E. Azria (Paris), M.P. Bonnet (Paris), M. Bruyere (Kremlin-Bicêtre), A.F. Dalmas-Laurent (Lille),
S. Depret-Mosser (Lille), Z. Elias (Toulon), J.M. Faucheux (Agen), D. Ferriby (Tourcoing), E. Godet (Metz), F. Goffinet (Paris), J. Grimaud (Chartres),
C. Henry (Saint-Denis), D. Latombe (Lyon), A. Le Gouez (Clamart), M. Marcel (Lens), F. Richard (Paris), A. Rigouzzo (Paris), S. Roger-Christoph
(Bures-sur-Yvette), J. Rousset (Paris), T. Schmitz (Paris), O. Vandhuick (Rouen), M. Wagner (Metz).
Recommendation 1.4:
Despite the lack of a formal contraindication in the
summary of product characteristics, it is recommended
to discontinue natalizumab 3 months before stopping
contraception, due to the absence of sufficient safety
data and to the pharmacodynamics. The switch to an
immunomodulator is possible (relative professional
agreement) (Table 7).
Recommendation 1.5:
Fingolimod should be discontinued at least 2 months
before contraception is stopped due to a teratogenic
risk shown in animals (relative professional agreement)
(Table 7).
3.1.2. Rationale: existing recommendations and summaries of
product characteristics
The recommendations concerning this problem are outdated.
The French guide ‘‘Affection de Longue Durée’’ advocates, ‘‘for
women of childbearing age, contraception proposed if
disease-modifying therapy, with discontinuation of the latter
at least 3 months before the start of a planned pregnancy’’ [2].
According to the Consensus Conference of the French
Federation of Neurology [3], ‘‘the treatment should be
discontinued if pregnancy is considered.’’ The British NICE
recommendations [4] did not address the subject of withdrawal of disease-modifying therapy during pregnancy. With
regard to harmful effects on the fetus or embryo, glatiramer
acetate (GA) is classified by the US FDA as a Category B drug
(absence of risk relative to studies done on animals), while
interferon-b (IFN) is Category C, as studies done in Rhesus
monkeys using 40 times the therapeutic dose showed a higher
risk of spontaneous abortion [5–7]. IFN is however a large
molecule that does not cross the placental barrier, and fetal
toxicity has not been demonstrated at therapeutic doses.
Contrary to the FDA recommendations, the French summary
of product characteristics (SPC) allows IFN treatment to be
prescribed during pregnancy for active disease in a less
restrictive way than for GA: ‘‘in the case of pregnancy in a
patient with a high rate of relapse before the start of
treatment, the risk of occurrence of severe relapse after
discontinuation of IFN treatment should be weighed against
the increased risk of spontaneous abortion.’’ This is not the
case however for GA: ‘‘the use of glatiramer acetate is not
recommended during pregnancy.’’
250
Table 2 – Document selection strategy.
Web site
Search date
Keywords
National Guideline Clearinghouse: www.guideline.gov
03/17/2011
‘‘Multiple sclerosis’’
Text search in pdf documents: ‘‘pregn’’, ‘‘breast’’
CISMeF (CHU de Rouen): http://doccismef.chu-rouen.fr
03/17/2011
‘‘Sclérose en plaques mr[MSH] and Grossesse mr[MSH]’’
Limitation: recommendations
HAS: www.has-sante.fr
03/17/2011
‘‘Sclérose en plaques’’
Limitation: good practice guidelines
AFSSAPS: http://afssaps.sante.fr/
03/17/2011
‘‘Sclérose en plaques’’
AFSSAPS: http://afssaps-prd.afssaps.fr/php/ecodex/
07/25/2011
‘‘Résumé des caractéristiques du produit’’
Drugs: methylprednisolone, interferon-b, glatiramer,
mitoxantrone, cyclophosphamide, methotrexate,
azathioprine
National Institute for Health and Clinical
Excellence: http://www.nice.org.uk/
03/17/2011
Limitation: ‘‘guidance documents’’
Cochrane Reviews: www.cochrane.org/reviews/
03/17/2011
Canadian Medical Association INFOBASE clinical
practice guidelines:
http://mdm.ca/cpgsnew/cpgs/index.asp
03/17/2011
Domain: ‘‘clinical practice guidelines’’
Ontario Guidelines Advisory Committee (GAC)
Recommended Clinical Practice Guidelines:
http://www.gacguidelines.ca
03/17/2011
AF Lemanissier Medical Library:
http://www.bmlweb.org/consensus.html
03/17/2011
‘‘Neurology section’’
Scottish Intercollegiate Guidelines Network (SIGN):
http://www.sign.ac.uk/index.html
03/17/2011
Domain: ‘‘guidelines’’
Institute for Clinical Systems Improvement:
http://www.icsi.org/knowledge/
03/17/2011
Domain: ‘‘guidelines and more’’
New Zealand Guidelines Group: http://www.nzgg.org.nz/
03/17/2011
Section: ‘‘guidelines and reports’’
Chapter: ‘‘neurology’’
Canadian Agency for Drugs and Technology in Health:
http://www.cadth.ca/
03/17/2011
Type of publication: ‘‘methods and guidelines’’
Medline: www.ncbi.nlm.nih.gov/pubmed
03/17/2011
Question 1 and 6: ‘‘Multiple sclerosis/drug therapy’’
[Mesh] and ‘‘Pregnancy’’ [Mesh]. Limits: English, French
Question 2: ‘‘Multiple sclerosis’’ [Mesh] and (‘‘Pregnancy, High-Risk’’ [Mesh] or ‘‘Pregnancy/abnormalities’’
[Mesh] or ‘‘Pregnancy outcome’’ [Mesh] or ‘‘Pregnancy
complications’’ [Mesh]). Limits: English, French
Question 3: ‘‘Multiple sclerosis, Relapsing-remitting/
drug therapy’’ [Mesh] and (‘‘Pregnancy’’ [Mesh] or
‘‘Postpartum period’’ [Mesh]). Limits: English, French
Question 4: ‘‘Multiple sclerosis’’ [Mesh] and ‘‘Delivery,
Obstetric’’ [Mesh]. Limits: English, French
Question 5: ‘‘Multiple sclerosis’’ [Mesh] and ‘‘Postpartum period’’ [Mesh] (limits: English, French). ‘‘Postpartum period’’ [Mesh]. Limits: Practice Guideline, English,
French
Question 7: ‘‘Multiple sclerosis/drug therapy’’ [Mesh]
and (‘‘Abortion, induced’’ [Mesh] or ‘‘Pregnancy outcome’’ [Mesh] or ‘‘Pregnancy complications’’ [Mesh] or
‘‘Pregnancy, unplanned’’ [Mesh] or ‘‘Pregnancy, unwanted’’ [Mesh]). Limits: English, French
Medline: www.ncbi.nlm.nih.gov/pubmed
09/08/2011
‘‘Multiple sclerosis’’ [Mesh] and ‘‘Postpartum period’’
[Mesh]. Limits: practice guideline, English, French
European Medicines Agency:
http://www.ema.europa.eu/ema/
07/25/2011
Summary of product characteristics
Drugs: Interferon-b-1A, interferon-b-1b, fingolimod, natalizumab
251
BIBLIOGRAPHIC RESEARCH
ON INTERNET
FRANCOPHONE AND
ANGLOPHONE
RECOMMANDATIONS,
DATA BASES
Internet sites of publication of
recommandations and
consensus : 27 documents
PUBLICATIONS WITH PEERREVIEWING
Medline document database:
50 documents
Medline document database:
425 références
First selection on title and
clinical topics addressed :
4 documents
First selection on title and
abstract: 179 references
Selection on quality
criteria: 3 references
Selection on reading
grid: 44 references
Documents added by the
experts and the Regional
Pharmacovigilance Center
(Georges-Pompidou
Hospital) : 17 documents
Publications added by the
experts : 13 references
Fig. 1 – Document selection strategy.
3.1.3. Rationale: first-line disease-modifying therapy
(interferon and flatiramer acetate)
In a multicenter, observational, prospective cohort study on
multiple sclerosis conducted by the MS study group of the
Italian Neurological Society [8] which included 88 exposed
pregnancies (mean exposure of 4 weeks post-conception) and
308 non-exposed pregnancies, no significant risk was found
with the use of immunomodulatory therapy (IFN or GA): the
odds ratio of miscarriage in the exposed vs. non-exposed
groups was 1.08 (non-significant). Birth length and weight
were somewhat less in the exposed children; a slightly
premature birth was noted only in patients on IFN, although
without pathological significance. No malformations or
significant developmental delays were found in this study.
In a descriptive cohort study (1996–2007), Weber-Schoendorfer and Schaefer [9] reported on the adverse effects
concerning 69 pregnancies exposed to IFN, and 31 to GA
during the first 6 to 8 weeks of pregnancy compared to 64
pregnancies in non-exposed MS patients and 1556 healthy
controls. They recorded fewer relapses with the use of IFN
(P = 0.01) and GA (P = 0.03) than in non-treated patients. One
club foot and one atrioventricular canal were reported in the
GA group. A high rate (27%) of miscarriage was found (nonsignificant for GA, all forms of IFN-b and IFN-b1a; significant
P = 0.002 for IFN-b1b). Birth weight was slightly lower with IFN.
The methodological quality of this study is insufficient
however for enabling a conclusion to be drawn. In their
discussion, the authors point out that 30 pregnancies occurred
during use of GA during the clinical studies and 215 in the postmarketing phase, with no significant complication reported
[10].
In an English observational, prospective study [11], 9
patients were exposed to GA throughout the entire pregnancy.
Taking into account the usual practice of switching to GA from
mitoxantrone in patients with active and aggressive MS, an MS
cohort with an active onset (frequent motor relapses with
sequelae, increased brain lesion load) was informed of both
the risk of relapse related to withdrawal of disease-modifying
252
Table 3 – Final rating of recommendation proposals.
Quality criteria
Median
1.1 (3)
Easily understood
Useful
Sufficient
9.0
9.0
8.5
1.2 (3)
Easily understood
Useful
Sufficient
1.3 (3)
1.4 (3)
Group opinion
Maximum
score
Minimum
score
Appropriate formulation
Appropriate recommendation
Sufficient recommendation
9
9
9
7
8
7
Strong agreement between group members
9.0
9.0
8.0
9
9
9
6
7
5
Relative agreement between group members
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
7
7
6
Easily understood
Useful
Sufficient
9.0
9.0
8.0
9
9
9
6
7
5
1.5 (3)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
8
8
6
Table 7 (4)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
7
7
6
2.1 (2)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
7
8
7
3.1 (2)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
6
7
6
3.2 (2)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
7
8
7
4.1 (4)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
7
8
5
4.2 (5)
Easily understood
Useful
Sufficient
8.0
8.0
8.0
9
9
9
7
7
7
5.1 (3)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
7
5
5
5.2 (2)
Easily understood
Useful
9.0
9.0
9
9
7
8
Level of agreement
Discordant votes
1 score of 4
1 score of 4
1 score of 4
1 score of 4
1 score of 4
Recommendation No.
(number of scorings
before consensus)
Table 3 (Continued )
Recommendation No.
(number of scorings
before consensus)
Quality criteria
Median
Group opinion
Maximum
score
Minimum
score
Level of agreement
9.0
9
8
5.3 (4)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
6
6
6
5.4 (2)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
7
7
7
5.5 (4)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
8
7
6
5.6 (3)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
7
6
8
6.1 (3)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
7
8
7
6.2 (3)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
8
7
7
7.1 (4)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
5
5
5
7.2 (4)
Easily understood
Useful
Sufficient
9.0
9.0
9.0
9
9
9
5
5
5
Sufficient
Discordant votes
253
254
Table 4 – Analysis of reading group results.
Recommendation No.
1.1
1.2
1.3
1.4
1.5
Table 1
2.1
3.1
3.2
4.1 (secondarily divided into 4.1 and 4.2)
5.1
5.2
5.3
5.4
5.5
5.6
6.1
6.2
7.1
7.2
Number of
agreements
Number of
undecided
Number of
disagreements
Percentage of
agreement
Number
of votes
23
22
24
22
24
23
23
24
23
19
23
24
22
24
18
24
25
23
20
22
2
2
1
2
1
2
2
1
2
2
2
0
3
1
5
1
0
2
4
2
0
0
0
1
0
0
0
0
0
4
0
1
0
0
2
0
0
0
1
1
92
92
96
88
96
92
92
96
92
76
92
96
88
96
72
96
100
92
80
88
25
24
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
therapy, and the possibility and risks of maintaining treatment up until conception and during pregnancy. Twenty-two
patients received this information, 13 of whom conceived
while on GA (resulting in 14 pregnancies), 6 after treatment
withdrawal, and 3 were still pregnant at the time of publication.
In the cohort of exposed patients, no malformation was
reported, and the births were full term, except for a pair of
twins born prematurely at 33 weeks of pregnancy. Birth weights
were average. Two spontaneous abortions were noted.
In 2005, Sandberg-Wollheim et al. [12] analyzed the
individual data of 3361 women on IFN-b1a treatment, who
were included in 8 clinical studies conducted between 1994
and 2003. Sixty-nine pregnancies were recorded, 41 of which
had had in utero-exposure (treatment withdrawal during
pregnancy or in the 2 weeks before conception). The 41 in
utero-exposures resulted in 20 healthy, full term pregnancies,
one healthy premature baby, 8 spontaneous abortions, 9
therapeutic abortions, one fetal death and one congenital
malformation (hydrocephaly). One patient was lost to followup. In all, of the 31 pregnancies with potential of going to term,
21 births occurred normally. In this study, the rate of
spontaneous abortions appeared higher than that of the
general population.
In 2010, the same authors [13] analyzed the postmarketing data, both prospective and retrospective, and data
from the original studies concerning 1022 pregnancies with
subcutaneous IFN-b-1a exposure. The outcomes were known
for 679 of them. The mean duration of fetal exposure was 28
days. The retrospectively reported pregnancies were associated with an undesirable outcome (spontaneous abortion,
fetal malformation, congenital malformations, ectopic pregnancies) about 3 times more often than those that were
Table 5 – Determination of the level of consensus for each recommendation.
Rating
Level of validation
by the rating group
% of agreement
within the reading
group
Level of professional agreement
(synthesis of the opinions of the rating
and reading groups)
Median between 7 and
9 for each of the
3 rating criteria
No more than a score of
< 7 for each of the criteria
Median between 7 and
9 for each of the
3 scoring criteria
More than a score of < 7
No more than a score of < 4
Strong consensus
90%
Strong professional agreement
Between 80 and 90%
Relative professional agreement
Relative consensus
Between 80 and 90%
Median < 7
More than a score of < 4
Regardless of the
level of consensus
< 80%
Either the recommendation is to be reworked
then new rating
Or the working group does not give his opinion
Or the working group decides to keep the
recommendation while pointing out the
absence of consensus within the reading group
255
Table 6 – French titles of the recommendations.
Question clinique 1 : faut-il arrêter un traitement de fond de la sclérose en plaques (SEP) lorsqu’une grossesse est envisagée ? Si oui, quand et selon quelles
modalités ?
Recommandation 1.1 – La poursuite d’un traitement immunomodulateur (interféron bêta ou acétate de glatiramère) est possible jusqu’à la
preuve de la conception, sans effet délétère actuellement démontré sur l’embryon ou le fœtus ni sur le déroulement de la grossesse
(accord professionnel fort)
Recommandation 1.2 – Dans le cas des maladies très actives, la poursuite du traitement immunomodulateur (interféron bêta ou acétate de
glatiramère) durant toute la grossesse peut être également discutée au cas par cas, en l’absence de toxicité actuellement démontrée
par les données des études et les registres de pharmacovigilance (accord professionnel relatif)
Recommandation 1.3 – Il est recommandé d’arrêter les traitements immunosuppresseurs (cyclophosphamide [hors AMM], mitoxantrone)
lorsqu’une grossesse est envisagée, du fait de leur toxicité potentielle dans les études pré-thérapeutiques et du fait de leur
pharmacodynamie (accord professionnel relatif)
Recommandation 1.4 – Malgré l’absence d’interdiction formelle formulée dans le Résumé des Caractéristiques du Produit, il est recommandé
d’arrêter le natalizumab 3 mois avant l’arrêt de la contraception, en l’absence de données de sécurité suffisantes et du fait des données de
pharmacodynamie. Le relais par un immunomodulateur est possible (accord professionnel relatif)
Recommandation 1.5 – Le fingolimod doit être interrompu au moins 2 mois avant l’arrêt de la contraception, du fait d’un risque tératogène
démontré chez l’animal (accord professionnel relatif)
Question clinique 2 : quel est l’impact de la sclérose en plaques sur la grossesse ?
Recommandation 2.1 – La SEP n’est pas une contre-indication à la grossesse. Elle n’a de répercussion délétère ni sur la fertilité, ni sur le
déroulement d’une grossesse, ni sur l’accouchement, ni sur le nouveau-né. Un suivi obstétrical classique est préconisé (accord
professionnel fort)
Question clinique 3 : comment traiter une poussée pendant la grossesse et en post-partum ?
Recommandation 3.1 – Il n’y a pas de contre-indication à réaliser des bolus intraveineux de méthylprednisolone aux doses habituelles en cas
de poussée de SEP (accord professionnel relatif)
Recommandation 3.2 – L’allaitement ne constitue pas une contre-indication à réaliser des bolus de méthylprednisolone. Il est recommandé
de ne pas allaiter durant la perfusion et de respecter un délai minimal de 4 heures entre la fin de la perfusion de méthylprednisolone et la
reprise des tétées (accord professionnel fort)
Question clinique 4 : les procédures habituelles d’accouchement (péridurale, voie d’accouchement, anesthésie. . .) doivent-elles être modifiées en cas de SEP ?
Recommandation 4.1 – Il n’est pas recommandé de modifier les procédures d’accouchement chez les patientes présentant une SEP. Seuls les
critères obstétricaux sont à prendre en compte pour le choix du mode d’accouchement (accord professionnel relatif)
Recommandation 4.2 – Il est recommandé de privilégier le recours à l’analgésie péridurale et d’utiliser des anesthésiques de faible
concentration. L’indication d’une rachianesthésie ou d’une extension de péridurale avec des anesthésiques locaux concentrés doit être
discutée au cas par cas. Ces techniques sont à éviter en cas de poussée médullaire (accord professionnel relatif)
Question clinique 5 : la prise en charge du post-partum en cas de SEP diffère-t-elle de la prise en charge habituelle ? L’allaitement est-il possible ?
Recommandation 5.1 – L’allaitement est possible dans le post-partum dans la mesure où la maladie ne justifie pas la reprise rapide d’un
traitement de fond. Si la reprise d’un traitement de fond est nécessaire durant l’allaitement, seul l’interféron bêta est envisageable (accord
professionnel relatif)
Recommandation 5.2 – Du point de vue obstétrical, la prise en charge du post-partum des patientes ayant une SEP ne diffère pas de la prise
en charge habituelle (accord professionnel fort)
Recommandation 5.3 – En cas de grossesse chez une patiente non ambulatoire ayant une SEP, il est nécessaire de sensibiliser l’équipe
soignante obstétricale à la prise en charge du handicap (accord professionnel relatif)
Recommandation 5.4 – Il est recommandé de sensibiliser les patientes à la pratique de la rééducation périnéale au cours du post-partum.
Celle-ci devra être adaptée à la présence éventuelle de troubles vésico-sphinctériens (accord professionnel fort)
Recommandation 5.5 – Il n’est pas recommandé de prescrire systématiquement des perfusions mensuelles de méthylprednisolone en
prévention des poussées du post-partum (accord professionnel relatif)
Recommandation 5.6 – Il n’est pas recommandé de prescrire un traitement par immunoglobulines polyvalentes en prévention des poussées
du post-partum (accord professionnel relatif)
Question clinique 6 : quand doit-on reprendre un traitement de fond après une grossesse ?
Recommandation 6.1 – Après un accouchement, la reprise du traitement de fond de la SEP est conseillée dès que possible aux patientes à
risque de poussée dans le post-partum (patientes ayant fait au moins une poussée dans l’année précédant la grossesse et/ou au cours de la
grossesse) (accord professionnel fort)
Recommandation 6.2 – L’allaitement peut être laissé au libre choix des patientes mais empêchera la reprise d’un traitement de fond de la SEP
autre qu’un interféron bêta (accord professionnel fort)
Question clinique 7 : faut-il recommander une interruption médicale de grossesse à une femme qui a débuté une grossesse alors qu’elle suivait un traitement de
fond pour une SEP ?
Recommandation 7.1 – En cas de conception sous immunomodulateur ou sous azathioprine, il n’y a pas de raison de recommander une
interruption médicale de grossesse. Pour la mitoxantrone, le natalizumab et le fingolimod, il n’y a pas de donnée suffisante pour faire une
recommandation (accord professionnel relatif)
Recommandation 7.2 – En cas de grossesse débutée sous immunosuppresseur (sauf l’azathioprine), la patiente devra être informée de
l’absence de recommandation spécifique vis-à-vis d’une interruption médicale de grossesse. Un suivi échographique dans un centre de
référence des grossesses à risque sera conseillé. En cas d’anomalie, la patiente pourra être adressée à un centre pluridisciplinaire de
diagnostic prénatal (accord professionnel relatif)
256
Table 7 – Modalities of withdrawal of disease-modifying treatment when pregnancy is planned (relative professional
agreement).
Drugs
Standard disease course
Very active disease
Interferon
Glatiramer acetate
Natalizumab
Withdrawal as soon as pregnancy is confirmed
Withdrawal as soon as pregnancy is confirmed
Withdrawal 3 months before pregnancy
Continuation possible throughout entire pregnancy
Continuation possible throughout entire pregnancy
Withdrawal 3 months before pregnancy
(continuation possible during pregnancy if
justified by the clinical condition after validation
in multidisciplinary meeting)
Fingolimod
Cyclophosphamide (off-label)
Mitoxantrone
Azathioprine (off-label)
Withdrawal 2 months
Withdrawal 3 months
Withdrawal 3 months
Continuation possible
before pregnancy
before pregnancy
before pregnancy
throughout entire pregnancy
prospectively recorded. Of the prospective studies (n = 425),
the spontaneous abortion rate was 11.5%, approximate to that
of the general population (10–20%). Fetal malformations
remained rare and were not organ-specific. The frequency of
congenital malformations was lower (0.9%) than in the
general population (2–4%).
In 2007, a Sicilian team [14] reported on 38 pregnancies, 14
of which had had in utero-exposure. The originality of this
study was due to the follow-up of the children for one year.
There were no significant differences found between the
exposed and non-exposed groups with regard to the pregnancy course, the birth or the development of the child.
In a Spanish retrospective study, De Las Heras et al. [15]
observed 88 pregnancies in 74 patients. Sixty-six percent had
been exposed to an immunomodulator (conception occurred
less than 4 weeks after treatment withdrawal). The exposed
group did not have a higher spontaneous abortion rate. The
authors did not report any malformations or obstetrical
complications. The recent retrospective series presented at
international conferences confirm these data in the literature
for IFN [16–18] and for GA [18,19], with an absence of significant
increased risk associated with exposure during pregnancy. On
the other hand, the pharmacovigilance data from different
pharmaceutical laboratories, which include hundreds of
patients exposed during pregnancy to IFN-b or to GA since
they were put on the market over 10 years ago, also did not
report any teratogenic or fetotoxic effects relative to the
expected risk. The detailed data are not available however.
Finally, with regard to IFN-b, the French reference center on
teratogens (Centre de Référence sur les Agents Tératogènes
[CRAT]) [20] points out: ‘‘there is abundant and reassuring data
published on pregnant women exposed to IFN-b in the first
trimester. Placental transfer of IFN-b was not studied, but due to
its structural similarities with IFN-alpha, there is every reason
to believe that it does not cross the placenta. IFN-b is not
teratogenic in animals. An increase in miscarriages was
described in monkeys at doses higher than those used
therapeutically. In practice, when anticipating a pregnancy,
IFN-b can be continued until conception, or even throughout
the pregnancy. The patient should be reassured during
pregnancy with regard to the risk of malformations with IFNb. The use of IFN-b is possible at any stage of pregnancy.’’
No significant risk was demonstrated in light of all these
IFN-b and GA exposure data. The numbers of patients reported
in the studies and the registries are still insufficient however,
and the methodological quality of the studies, often done
retrospectively, is limited. Consequently, the level of proof is
low for determining the benefit-risk balance relative to the use
of these treatments in pregnancy. The numerous concordant
series and the 10 years of post-marketing experience argue in
favour of a low overall risk, thus enabling consideration of
continuing treatment with immunomodulator therapy during
pregnancy in cases of aggravating MS, which would expose the
patient to significant disease-related risk.
3.1.4.
Rationale: natalizumab
The toxicity data on natalizumab in humans are not well
known. The preclinical study data in animals mentioned in the
SPC [21] did not demonstrate toxicity on the pregnancy. The SPC
does not formally rule out its prescription during pregnancy
since the label states: ‘‘natalizumab must not be administered
during pregnancy except if the clinical condition of the patient
requires treatment with natalizumab.’’ The French Agence
Nationale de Sécurité du Médicament et des Produits de Santé
(ANSM, formerly AFSSAPS) analyzed the pharmacovigilance
data in January 2011 [22]: ‘‘since the beginning of national
monitoring, 50 pregnancies have been recorded. In the majority
of cases, pregnancy is identified rapidly, resulting in early
treatment withdrawal. In 3 cases, [natalizumab] was stopped
late, at 3 and 6 months of pregnancy. The outcomes of the
pregnancies were reported in 31 cases, including 20 favourable
outcomes; 2 therapeutic abortions (including one case of
cerebral malformation in a patient exposed up until the 6th
month of pregnancy, and 1 case for worsening MS); 4 voluntary
abortions; and 5 miscarriages. Worldwide, 661 pregnancies
have been consecutively reported, with 19 diverse malformations. There does not seem to be an increased risk related to
exposure during pregnancy.’’ The SPC for natalizumab also
states that ‘‘in the event of treatment discontinuation, the
physician should be advised that natalizumab remains present
in the blood and exerts pharmacodynamic effects (e.g.
increased lymphocytes) for approximately 12 weeks after the
last administration’’ [21]. The declaration of pregnancies with
exposure to treatment, within registries or post-marketing
studies, should be continued.
3.1.5.
Rationale: mitoxantrone
Mitoxantrone is contraindicated in pregnancy due to its
mechanism of action (topoisomerase II inhibitor) and potential
risk of fetal DNA damage [23]. Nevertheless, there are no
published series that are able to determine the identified risks
during pregnancy in patients with multiple sclerosis. About 20
cases of sporadic exposure to mitoxantrone in other diseases
have been reported, with normal births in the majority of cases,
and no teratogenic effects or abnormal fetal development
reported, with the exception of possible growth delay in rare
cases [24]. Data found both in the DRUGDEX database and in the
literature drew the same conclusions [25]. One isolated case of
Pierre Robin malformation was however recently reported in a
patient exposed to mitoxantrone at the time of conception [26].
As stated on the mitoxantrone SPC, ‘‘due to the toxicity of
mitoxantrone on DNA related to its mechanism of action,
women of childbearing age should use an effective means of
contraception in the month prior to the start of treatment,
throughout the entire length of treatment and for 3 months
after treatment withdrawal.’’ This time period is due to the
long terminal elimination half-life (23 hours to 9 days, 3 days
on average). Therefore about 45 days (5 half-lives) are needed
for 97% of mitoxantrone to be eliminated from the plasma.
3.1.6.
Rationale: fingolimod
Fingolimod is contraindicated during pregnancy due to its
action on the receptors involved in formation of the vascular
system during embryogenesis [27]. The SPC moreover stipulates that ‘‘animal studies showed reproductive toxicity,
including fetal loss and organ malformations, notably patent
ductus arteriosus and interventricular septal defect [. . .]. As
fingolimod is eliminated from the body approximately two
months after treatment discontinuation, the potential risk for
the fetus can persist, and contraception should be continued
during this period.’’ These animal data reporting teratogenic
effects and embryo-fetal mortality are also documented in rats
and rabbits in the DRUGDEX database. There are no published
series that are able to determine the identified risks during
pregnancy in patients with multiple sclerosis.
3.1.7.
Rationale: cyclophosphamide
Cyclophosphamide does not have a marketing authorization
for the treatment of MS, and therefore the literature search did
not include this treatment. It is nevertheless sometimes used
in practice. The SPC gives the following information [28]: ‘‘in
the clinical setting, some cases of malformation (limb
anomalies, craniostenosis, facial dysmorphism) have been
reported after exposure in the first trimester [. . .]. At the end of
pregnancy, some cases of anemia and even pancytopenia have
been reported. There is also a theoretical risk of cardiotoxicity
(rhythm disorders, heart failure).’’
These data are confirmed by the French reference center on
teratogens [29], which examined the state of knowledge:
‘‘there are about ten observations of children or fetuses with
malformations reported in the literature. The presentation of
malformations is quite homogenous, with intrauterine growth
restriction; limb deformities, including aplasia or hypoplasia
of the fingers (particularly the thumbs), toes or long bones; eye
damage, including microphtalmia and hypoplasia of the optic
nerve; facial dysmorphism, including saddle nose deformity,
ear anomalies, cleft palate and narrow palpebral fissures; skull
damage, including craniostenosis; and central nervous system
damage, including hydrocephaly and microcephaly.
The frequency of this presentation cannot be calculated
since it is only seen in isolated cases. A threshold dose cannot
be defined; malformations have been observed at a minimum
257
total dose of 400 mg. In the children and/or fetuses with
malformations, the mothers were being treated for autoimmune diseases in half the cases. The risk period includes at
least the first trimester. Approximately 15 normal children
without malformations have also been described following
maternal exposure in the first trimester, including at high
doses in cancerology.’’ In practice, the French reference center
on teratogens advises [29]: ‘‘cyclophosphamide should not be
used in pregnant women, with the exception of unavoidable
maternal indications (cancerology), and preferably after the
first trimester.’’ Even though the half-life of cyclophosphamide is short (4 to 8 hours), with complete elimination from
the plasma compartment in 48 hours, the tissue diffusion and
especially impregnation and the long-lasting effects on the
cellular DNA can persist for several months after treatment
discontinuation. Due to the lack of sufficient studies, an
interval of at least 3 months (identical to that recommended
for other chemotherapy such as mitoxantrone) between the
end of treatment with cyclophosphamide and discontinuation
of the contraceptive use seems appropriate.
3.2.
Rationale: azathioprine
Azathioprine does not have a marketing authorization for the
treatment of MS, therefore the literature search did not
address this treatment. It is nevertheless sometimes used as a
disease-modifying therapy. The SPC [30] stipulates that, ‘‘in
humans, hundreds of observations of exposed pregnancies to
date have ruled out the hypothesis of a malformation risk of
azathioprine on the fetus. However, based on the preclinical
toxicology data, it is advisable, if the maternal disease allows
it, to discontinue treatment during pregnancy, since the longterm follow-up of children of treated mothers is insufficient.
Leukopenia and/or thrombocytopenia have been reported in
newborns whose mothers had been treated with azathioprine
during pregnancy. In order to avoid the occurrence of these
effects, it is recommended that the maternal dosage be
reduced when possible. Births of premature and low-birth
weight children have been reported after exposure of mothers
to azathioprine, particularly in the case of co-administration
with corticosteroids.’’
These data were confirmed by the French reference center
on teratogens, which summarized the current knowledge [31]:
‘‘there is a very large amount of published data on women
exposed to azathioprine, and no malformative effect has been
described to date.’’ In practice, the CRAT recommendations
are as follows: ‘‘when planning a pregnancy, if azathioprine is
necessary for maternal health, discontinuation or modification of the treatment is not justified.’’
3.3.
Clinical question 2: what effects do MS have on
pregnancy?
Recommendation 2.1:
MS is not a contraindication to pregnancy. It has no
harmful repercussions on fertility, on the course of
pregnancy, on delivery or on the newborn. Standard
obstetrical monitoring is advised (strong professional
agreement).
258
Perinatal morbidity-mortality in patients with MS is
identical to that of the general population. Lower intrauterine
growth and birth weight with no pathological significance has
been reported in the literature. There is a trend towards more
instrumental procedures and Caesarean sections during
delivery, with no reported justification. There is no proof in
the literature that MS can adversely influence the course of
pregnancy and delivery. No evidence has been found of
increased risk of miscarriage, ectopic pregnancy, prematurity,
pre-eclampsia, oligo- and polyhydramnios or stillbirth [3,32–
51].
than four hours after the corticosteroid administration [57].
Given this data, CRAT recommends a 4-hour interval between
the end of the methylprednisolone bolus and resumption of
breastfeeding. If a secretion of milk occurs during the infusion
or within the following 4 hours, it is advisable to express the
milk and then discard it [52].
3.5.
Clinical question 4: should the usual pregnancy
procedures (epidural analgesia, delivery route, anesthesia,
etc.) be modified in the case of MS?
3.5.1.
Recommendations
3.4.
Clinical question 3: how should relapse be treated
during pregnancy and in the postpartum period?
Recommendation 3.1:
The administration of intravenous methylprednisolone
bolus at standard doses is not contraindicated in the
event of MS relapse (relative professional agreement).
There are no reports in the French drug database VIDAL, on
the CRAT website [52] or in the medical literature of harmful
effects on the pregnancy or unborn child from a short course
of intravenous methylprednisolone, even at high doses, in the
first, second or third trimesters [32,37,53]. In a multicenter,
observational, prospective cohort of 88 pregnancies exposed
to IFN or GA [8], 9.5% of the women received methylprednisolone infusions for relapse (58% in the first trimester, 32% in
the second and 8% in the last), which were well tolerated.
Several cases of cleft palate were reported in association with
corticosteroid boluses given in the first trimester of pregnancy
[15,54]. These isolated cases do not constitute a contraindication to the use of corticosteroid boluses, regardless of
pregnancy trimester. The methylprednisolone doses used
are the same as those in non-pregnant women [55]. The use of
intravenous polyvalent immunoglobulins is not recommended, even if the tolerance is satisfactory, as they have not been
shown to have an effect on the duration or recovery from
relapse [55].
Recommendation 3.2:
Breastfeeding does not constitute a contraindication to
the administration of methylprednisolone boluses. It is
recommended not to breastfeed during the infusion, and
there should be a minimum interval of 4 hours between
the end of the methylprednisolone infusion and resumption of breastfeeding (strong professional agreement).
Methylprednisolone infusions are possible in the postpartum period, even when breastfeeding. To date, no
particular incident has been found in the literature, in the
VIDAL database or on the CRAT website [52] in children
breastfed by mothers treated with intravenous bolus of
methylprednisolone [47,56]. Although one study shows that
5 to 25% of the corticosteroid dose passes into breast milk, the
transfer to the child is minimal if breastfeeding is done more
Recommendation 4.1:
It is not recommended to modify the delivery procedures
in patients with MS. Only obstetrical criteria should be
taken into consideration for the choice of delivery method (relative professional agreement).
Recommendation 4.2:
The use of epidural analgesia is recommended, as is the
use of low concentration anaesthetics. The indication for
spinal anesthesia or extension of the epidural with
concentrated local anaesthetics should be discussed
on a case-by-case basis. These techniques should be
avoided in the event of spinal cord relapse (relative
professional agreement).
The consensus conference of the French Federation of
Neurology [3] highlighted the fact that multiple sclerosis does
not modify the obstetrical or neonatal risk, and that epidural
anesthesia does not influence the course of the disease. The
British recommendations from the National Institute for
Health and Care Excellence [4] confirm that there is no
association between epidural analgesia and relapse. When
giving birth, women with MS should receive the most
appropriate and acceptable method of analgesia for them,
without fear of affecting the disease.
3.5.2. Rationale: influence of multiple sclerosis on the delivery
procedure
In a Finnish multicenter, prospective, observational study that
aimed to evaluate the frequency of pregnancy complications
and the risks related to delivery in MS, a cohort of 60 patients
(61 pregnancies) was followed between 2003 and 2005, and the
results were compared to those of the medical registry of
Finnish births [45]. The authors did not observe more
pregnancy complications than in the general population of
pregnant Finnish women. Previous data that showed lower
birth weight and more frequent premature deliveries in MS
patients were not confirmed. MS patients with vaginal
deliveries were more likely to have assisted extraction
procedures (16.4% vs. 6.5%), and more deliveries without
anesthesia were observed in the patients with MS (23.5% vs.
13.8%; P = 0.0440). Between 2003 and 2006 in the United States,
patient hospitalization reports were taken from 1054 hospitals
that were stratified to obtain a sample representative of 20% of
community hospitals in the USA [46]. The pregnancy course
and delivery were compared with that of the general
population in 3 groups of patients: those with MS, epilepsy
and diabetes. Age during delivery was higher in MS patients
(31.6 years) than in the general population (27.5 years). More
antepartum hospitalizations were noted compared to the
general population (23% vs. 18.8%). After adjusting for
maternal age and ethnicity, intrauterine growth restriction
(ultrasound data) (2.7% vs. 1.9%) and the practice of Caesarean
section (42.4% in MS and 32.8% for the controls) were more
frequent than in the general population, which partially
explained the longer hospitalization lengths. A Taiwanese
study [34] compared data from two national data banks: the
birth certificates registry (nearly exhaustive), and the health
insurance registry (98% of the population, 22 million people).
One hundred and seventy-four patients with MS who had
given birth between 2001 and 2003 were compared with 1392
matched controls. The existence of MS was independently
associated with a 2.25 times greater risk of premature birth
and a 1.89 times greater risk of having a small for gestational
age baby. Mothers with MS were also more likely to have had
Caesarean deliveries (adjusted OR: 1.47). A study published in
2006 [58] using the Norwegian birth registry over the period
from 1988 to 2002 recorded the medical procedures and data
from deliveries of 449 MS patients compared to 851,000 vaginal
control births. Labour appeared to be slower, especially in the
second phase, with an increased use of forceps. Birth weights
and lengths were lower on average, but with no pathological
consequence. Neonatal mortality and the rate of malformations did not differ from the control group. More Caesarean
deliveries were reported, and there were more scheduled
deliveries. These data could be explained by the increased
fatigue during labour and pelvic neurological damage in
patients with MS.
In order to better understand the influence of maternal MS
on the course of pregnancy and delivery, a second Norwegian
study [40] compared, using the national registries, the
pregnancies of MS patients occurring during 3 periods, with
the patients serving as their own controls: before the first
event (pre-MS), after a clinically isolated syndrome (CIS), and
after the diagnosis (MS). Between 1967 and 2002, in 1368
women, there were 1910 births recorded in ‘‘pre-MS’’ patients,
555 births in CIS patients, and 308 births in patients with
confirmed MS. The rate of delivery complications and the need
for Caesarean section were identical among the 3 groups.
However, birth weights were lower for full term deliveries in
the confirmed MS group compared to the pre-MS group (after
adjustment).
With regard to urinary disorders, an open-label, retrospective study from Rennes, France [59] analyzed the obstetrical and urological data from a cohort of 368 MS patients
followed between 1999 and 2000. The urinary disorders
appeared to be related more to the duration and severity of
the disease than to the pregnancy or delivery mode. Fear of
sphincter disorders should therefore not be an argument in
favour of Caesarean delivery in MS patients, and the decision
regarding the mode of delivery should be based on obstetrical
criteria.
259
3.6.
Rationale: consequences of multiple sclerosis on
anesthesia
The French Society of Anesthesia and Resuscitation (Société
Française d’Anesthésie Réanimation [SFAR]) published in 2006
recommendations for the clinical practice of spinal anesthesia
techniques [60]. These take into consideration the in vitro
neurotoxic effects of local anaesthetics, which reach high
concentrations when administered by spinal route. Although
there is no clinical data, the high concentrations of local
anaesthetics administered via spinal route could be neurotoxic in cases of current or recent spinal cord relapse. According
to the SFAR recommendations, apart from MS relapse, the
recommended methods of epidural anesthesia for labour are
unchanged compared to the standard procedures using low
concentrations of local anaesthetics (0.1% or 0.2% bupivacaine, ropivacaine). On the other hand, spinal anesthesia
should be discussed on a case-by-case basis, as should the
spinal administration of high concentrations of local anaesthetics (xylocaine, lidocaine).
An observational study in Great Britain [61] aimed to
describe the methods of obstetrical anesthesia that were most
often used in patients with MS. A questionnaire was sent to all
members of the Obstetric Anaesthetists’ Association of Great
Britain with a 60% response rate. It showed that the need for
preliminary information was more important for MS patients
than for the general population. Few health care practitioners
changed their usual practices with MS patients, but in the case
of Caesarean delivery about one-quarter of anaesthetists
preferred to avoid spinal anesthesia and maintain the
epidural. In the PRIMS study, Confavreux et al. [62] prospectively monitored a cohort of 254 patients (269 pregnancies),
42 of whom had epidural anesthesia during delivery. The
comparison of the risk of relapse between patients that used
and did not use epidural analgesia showed an odds ratio of 1.5
(0.7–3.2; P = 0.51, non-significant). It also showed no difference
in the subsequent progression of the disease with the use of an
epidural analgesia (P = 0.66) [63]. In the study by Amato et al.
[8], 66 women had epidural analgesia with no particular
reported complication. Finkelsztejn et al. [64] performed a
meta-analysis of 22 studies that, since 1983, had compiled a
total of 13,144 pregnant patients with MS. The study did not
demonstrate a significant risk of delivery complications.
Caesarean sections were performed somewhat more frequently, but social factors unrelated to the disease prevented a
conclusion to be drawn regarding the significance of this
increase. The study showed a possible slight decrease in birth
weight and a slight increase in the risk of prematurity. These
last data however did not appear to reach a pathological
threshold. Overall there was no detection of a significant
problem apart from the increased risk of relapse during the 3
months following the birth. However the lack of control group
and detailed statistical evaluation pose methodological
limitations on this study, with only several questions actually
analyzed, concerning birth weight, prematurity, frequency of
Caesareans and frequency of malformations.
In conclusion, the analysis of the literature found in some
studies (though not in all) a possible moderate decrease in
birth weight and moderate prematurity, without pathological
relevance. Labour seemed longer in certain patients, with a
260
somewhat increased use of extraction procedures and
Caesareans, but these data are also variable depending on
the studies and do not seem to have pathological significance.
It appears that epidural analgesia does not pose a particular
risk for patients. These data therefore generally support the
recommendation to continue with the usual delivery procedures for women with multiple sclerosis. The indication for
vaginal delivery or Caesarean section is based on obstetrical
and not neurological factors [63].
3.7.
Clinical question 5: does the postpartum
management in MS differ from the usual management? Is
breastfeeding possible?
Recommendation 5.1:
Breastfeeding is possible in the postpartum period if the
disease does not require rapid resumption of the diseasemodifying therapy. If resumption of the disease-modifying therapy is necessary while breastfeeding, only interferon-beta can be considered (relative professional
agreement).
Breastfeeding does not increase the risk of relapse in the
postpartum period [62]. The ‘‘protective effect’’ of breastfeeding with regard to the risk of relapse during the first 3 months
of the postpartum period remains controversial. Several
studies [15,56,65–67] found that patients who breastfed had
a tendency to have fewer relapses in the first postpartum
phase, especially if breastfeeding was exclusive and maintained for 2 to 3 months. Nevertheless, patients who chose to
breastfeed had less active disease (fewer relapses in the year
preceding the pregnancy), which may explain their choice to
breastfeed.
Breastfeeding contraindicates the use of disease-modifying
therapy due to the potential excretion in breast milk, with the
exception of IFN-b. According to the French reference center
on teratogens [20], ‘‘due to its high molecular weight and its
structural similarities with IFN-alpha, there is every reason to
believe that the excretion of IFN-b in breast milk is negligible.
No particular event has been published to date in breastfed
children. Moreover, IFN-b is not absorbed in the digestive tract.
Due to these factors, with no particular risk for children
expected, the use of IFN-b may be considered while breastfeeding’’.
Recommendation 5.2:
From an obstetrical perspective, the postpartum care of
patients with MS does not differ from the usual care
(strong professional agreement).
According to the Consensus Conference of the French
Federation of Neurology [3], there are no modifications in the
obstetrical or neonatal risks with MS. The care of patients
should therefore be similar to that of the general population. It
is commonly believed that MS does not influence pregnancy
[37], and that no specific obstetrical care should be planned for
patients with MS. In the Finnish multicenter, observational,
prospective study that was previously cited in the rationale of
Recommendation 4.1 (Section 3.5) [45], a cohort of 60 patients
(61 pregnancies) was followed from 2003 to 2005, and the
results were compared to those from the medical registry of
Finnish births. The authors did not observe more pregnancy
complications in patients with MS than in the general
population of pregnant Finnish women.
Recommendation 5.3:
When non-ambulatory patients with MS become pregnant, the obstetrical care team requires increased awareness in the management of disability (strong professional
agreement).
This recommendation is not specific to MS. In the absence
of appropriate care, a neurological disability may result in
local complications (pressure sores, for example). NICE even
recommends the identification in obstetric departments of an
obstetrician capable of managing the disability and its
complications relative to MS [4]. Before obstetrical care is
provided, the French National Authority for Health (HAS)
recommends to ensure that ‘‘the equipment and paramedical
skills are adapted to the disability of the pregnant woman’’
[68].
Recommendation 5.4:
It is recommended that patients be made aware of the
practice of pelvic floor exercises in the postpartum period. These will need to be adapted to the possible presence
of bladder/sphincter disorders (strong professional
agreement).
This recommendation is not specific to MS. It is recommended in the general population though is still not
completely implemented. As patients with MS are particularly
at risk for current or future neurological injury, such a
recommendation is fully warranted.
Recommendation 5.5:
It is not recommended to systematically prescribe
monthly infusions of methylprednisolone for the prevention of postpartum relapse (relative professional
agreement).
There is a single, non-randomized, retrospective study that
suggests relapse is reduced through monthly boluses of
methylprednisolone [69]. The disease course of a group of
20 patients treated from 1999 and 2001 with monthly infusions
of one gram of methylprednisolone for the first 6 months of
the postpartum period was compared to that of a group of 22
patients who had given birth between 1996 and 1998 and had
received no treatment in the 6 postpartum months. An
increase in the rate of relapse was observed in both groups
261
Two studies that evaluated intravenous immunoglobulins
had contradictory results [70,71]. The positive study [70] had a
very small number of patients, making any definitive conclusion impossible.
in the 1st and 2nd trimesters, then to 0.2 in the 3rd trimester
[P < 0.001]), it increased significantly to 1.2 in the first postpartum phase (P < 0.001). The occurrence of relapse in this
period however was not inevitable, since 72% of patients did
not experience it. The risk of relapse in the first 3 months
postpartum was correlated to the number of relapses in the
year preceding the pregnancy and during the pregnancy, as
well as the duration of the disease. It should be noted that
these predictive factors were not discriminant on an individual basis. These observations were also reported in the
EMEMAR study [42]. In a Finish study on 28 patients, MRI was
not useful in differentiating the most at risk patients [72].
The use of treatment that is compatible with breastfeeding
was evaluated in several studies. Two of them evaluated
intravenous immunoglobulins and had contradictory results
[70,71] (see rationale of Recommendation 5.6, Section 3.7). As
developed in the rationale of Recommendation 5.5 (Section
3.7), the monthly administration of one gram methylprednisolone for 6 months following the birth could decrease the risk
of relapse in patients who are particularly at risk. Finally, ‘‘the
use of IFN-b may be considered while breastfeeding’’ [20].
3.8.
Clinical question 6: when should disease-modifying
therapy be resumed following pregnancy?
3.9.
Clinical question 7: is medical termination of the
pregnancy recommended for women who became pregnant
while on disease-modifying therapy for MS?
but less so in the treated group (annual relapse rate 0.8 0.4
versus 2.2 0.66 in the non-treated group; P < 0.018). The
retrospective, observational and unique nature of this study
justify that this treatment only be proposed on a case-by-case
basis in patients that are considered particularly at risk for
relapse in the postpartum period [32,56]. If chosen, administration will begin the day following the birth, independent of
the desire to breastfeed and whether disease-modifying
therapy is resumed.
Recommendation 5.6:
It is not recommended to prescribe polyvalent immunoglobulin treatment as prevention of postpartum relapse
(relative professional agreement).
Recommendation 6.1:
After delivery, the resumption of disease-modifying therapy for MS is advisable as soon as possible in patients at
risk for relapse in the postpartum period (patients who
had at least one relapse in the year preceding the pregnancy and/or during the pregnancy) (strong professional
agreement).
Recommendation 7.1:
In the event of conception when using immunomodulators or azathioprine, there is no reason to recommend
medical termination of pregnancy. For mitoxantrone,
natalizumab and fingolimod, there is not sufficient data
for making a recommendation (relative professional
agreement).
Recommendation 6.2:
The decision to breastfeed may be left to the patient, but
it will prevent resumption of disease-modifying therapy
for MS, with the exception of interferon-beta (strong
professional agreement).
Recommendation 7.2:
If pregnancy occurs when using immunosuppressants
(except azathioprine), the patient should be informed of
the absence of specific recommendations with regard to
medical termination of pregnancy. Ultrasound monitoring in a referral center for high-risk pregnancy is advisable. In the event of an anomaly, the patient can be
referred to a multidisciplinary center for prenatal diagnosis (relative professional agreement).
The existing recommendations cannot answer this question. The French guide ‘‘Affection de Longue Durée no 25’’ [2]
and the Consensus Conference of the French Federation of
Neurology [3] did not provide any clarification as to the
resumption of treatment in the postpartum period. The British
NICE recommendations [4] only specify that ‘‘the relapse rate
increases during the first three months postpartum,’’ without
mentioning the consequences relevant to restarting or not
restarting disease-modifying therapy.
Several studies demonstrated a risk of recurrence during
the first phase of the postpartum period. In a large European
multicenter, observational study [62,63], 227 patients with MS
were studied over the 2 years following a full term birth.
Although the frequency of relapse decreased during pregnancy, especially in the 3rd trimester (annual relapse rate
going from 0.7 in the year prior to the pregnancy to 0.5 and 0.6
3.9.1.
Rationale: immunomodulators
The Summaries of Product Characteristics of immunomodulator treatments specify that for IFN-b1a [6], ‘‘fertility studies
were conducted in Rhesus monkeys with a similar form of IFNb1a. At very high doses, [. . .] no teratogenic or fetal
developmental effects were observed, but data relative to
IFN-b1a during the peri- and postnatal periods are limited
[. . .]’’. For GA, it has been shown that ‘‘there are no reliable data
on teratogenesis in animals. In the clinical setting, there is
currently not enough relevant data for evaluating potential
malformations or fetotoxic effects of GA when administered
262
during pregnancy. Consequently, the use of GA is not
advisable during pregnancy.’’ ‘‘If pregnancy occurs [when
taking IFN-b1a or b1b] [. . .], the patient should be informed of
the potential risks, and treatment withdrawal should be
considered.’’ The implied risk is that of miscarriage and not a
teratogenic risk. In addition, it is stated that continuation of
the treatment during pregnancy can be considered: ‘‘in the
case of pregnancy in patients who had a high relapse rate
before the treatment was started, the risk of severe consecutive relapse upon discontinuation of treatment with [IFN-b1a
or b1b] [. . .] should be weighed against the risk of spontaneous
abortion.’’
Increased knowledge has been gained about the risks of
malformation during pregnancies exposed to disease-modifying therapy for MS. Sporadic cases of fetal malformations
have been described, without the ability to establish a formal
link with exposure to an immunomodulator treatment. These
malformations included: one case of papillorenal syndrome in
a pregnancy exposed to IFN in the first trimester [73]; one case
of ureteral stenosis; one case of heart malformation; and one
case of hip dysplasia, identified in the Argentinean EMEMAR
study [42], which concluded that there was an increase in the
risk of fetal malformation when conception occurred with the
use of immunomodulators. The methodology however was
very questionable, being retrospective, and the data was very
incomplete, since out of 409 identified patients (with MS and
who had given birth to one or more children after the
diagnosis), only 81 were interviewed. In a Canadian prospective, follow-up study of 23 pregnancies exposed to IFN,
there were reports of one case of X-linked anomaly and one
case of Down’s syndrome [74]. In an analysis of pregnancies
identified in 8 therapeutic trials [12], one case of congenital
hydrocephalus was declared out of 41 pregnancies exposed
early to IFN-b1a treatment. Other authors have published
reassuring data on the teratogenic risk of immunomodulators.
In a report on 14 pregnancies exposed to IFN [14], no
malformation was reported. In a Spanish study [15], the
neurologists who specialized in MS from 16 hospital centres
compiled data from 74 patients followed after 88 pregnancies,
34 of which had been exposed to immunomodulators. No
malformation was identified. A Brazilian database [44] was
established in 2008 by neurologists involved in MS research by
declaring patients who had been pregnant in the 5 years
preceding the study. These included 47 women with 49
pregnancies, 17 of which had been exposed to IFN, 15 to GA
(treatment not discontinued in 12 patients) and one to
methotrexate. No malformation was reported. In Germany
[75], a database was established following an announcement
on the website of the German MS Society and other
associations, announcements in patient newspapers, requests
from neurologists to whom patients had been referred, and
from the neurology unit at the University of Bochum, in order
to compile retrospective data from patients who had been
pregnant in the 10 years preceding the study. They were then
interviewed using a standardized questionnaire. Out of the 220
identified pregnancies, 17 had been exposed to IFN in the first
trimester of pregnancy (mean exposure duration of 4.7 weeks).
No malformation was observed in the 15 full term births; 2
miscarriages occurred at 9 and 20 weeks of pregnancy (severe
growth delay and absence of interventricular septum). Two
cohort studies then provided more relevant arguments, as
they were based on a better methodology and had a larger
number of patients. It was in Germany [9] that the first
prospective follow-up was initiated of a cohort of all
pregnancies inadvertently exposed to disease-modifying
therapy for MS, which were declared from 1996 to 2007 to
the German information service regarding teratogenicity. The
patient and/or her neurologist and/or pediatrician filled out a
questionnaire early in the pregnancy and then 2 months after
the estimated date of delivery. A pregnancy was considered
exposed to a treatment if the treatment was received in the
first trimester. The main objective was to identify the number
of malformations related to medical, surgical or cosmetic
treatment. The study was done on 69 pregnancies exposed to
IFN and 31 to GA compared to 64 non-exposed pregnancies in
MS patients and a control group of 1557 women without MS
and who were not exposed to teratogenic factors during their
pregnancies (during the same period as the cohort). With the
use of IFN, no significant malformation was reported. Three
minor malformations were described, including one mild hip
dysplasia, one abnormal foot posture and one small facial
lesion. With the use of GA, two significant but non-specific
malformations were reported: club feet in a pregnancy with 6
weeks of exposure, and one complex, non-genetic heart
anomaly in a pregnancy exposed for one week. Finally, the
largest study was Italian [8]. Neurologists from 21 MS referral
centers prospectively declared the pregnancies occurring in
women with MS from January 2002 to January 2008. They were
evaluated every 6 months and interviewed 6 months after the
pregnancy. The pregnancy was considered to have been
exposed to treatment if it was received during the pregnancy
or in the 4 weeks preceding conception. Out of 415 women who
experienced 423 pregnancies, the data were complete for 396
pregnancies, with a median duration of follow-up of 2.1 years.
Of these pregnancies, 88 had been exposed to IFN and 17 to GA.
No malformation was reported.
3.9.2.
Rationale: immunosuppressants
Although the literature provides sufficient indications for not
recommending termination of a pregnancy that begins while
receiving immunomodulator therapy, the situation differs for
immunosuppressants, with the exception of azathioprine,
which is widely used in various indications during pregnancy
(particularly rheumatologic). This drug has never been
associated with fetal malformations in humans. The enzyme
responsible for the active form of the product is missing in the
fetus, which may explain this absence of teratogenic effect.
Azathioprine has been rarely associated with intrauterine
growth restriction, premature births and low-birth weight
[32,53].
With regard to natalizumab, the toxicity data are not well
known in humans, and the preclinical study data in animals
mentioned in the SPC did not demonstrate toxicity in
pregnancy. The SPC did not formally rule out its prescription
during pregnancy, since the label states: ‘‘natalizumab must
not be administered during pregnancy except if the clinical
condition of the patient requires treatment with natalizumab’’
[21]. The French National Security Agency of Medicines and
Health Products (ANSM, formerly AFSSAPS) analyzed the
pharmacovigilance data in November 2008 and January 2011.
In 2008, the periodic safety update report described 164
exposed pregnancies, in which there were 63 cases with a
favourable outcome, 28 abortions and 29 miscarriages, with 38
pregnancies still in progress at the time of the report [76]. The
last report in 2011 compiled 50 additional pregnancies. In 3
cases, natalizumab was stopped late, at 3 and 6 months of
pregnancy. The outcomes of the pregnancies were reported in
31 cases, with 20 favourable cases; 2 therapeutic abortions,
one of which was a case of cerebral malformation in a patient
exposed until 6 months of pregnancy (cysts were detected on
ultrasound at 31 weeks postmenstrual; the anatomopathological exam showed hypotrophic placenta and the presence of
frontal and occipital cystic lesions suggestive of resorbed
haemorrhagic events) and one case for worsening of MS; 4
abortions and 5 miscarriages [22]. Worldwide, 661 pregnancies
were reported in all, with 19 various malformations. Nevertheless, these data are still insufficient for formulating a
recommendation with regard to possible termination of
pregnancy. The declaration of pregnancies exposed to
treatment, within the framework of the registries or postmarketing studies, is to continue.
With regard to mitoxantrone, the SPC states: ‘‘proof of the
harmlessness of mitoxantrone has not been established in
pregnant women. Studies [. . .] in rats and rabbits have not
demonstrated [. . .] teratogenic effects’’ [23]. Mitoxantrone in
rodents is associated with low-birth weight and kidney
damage. The efficacy of the drug is furthermore based on
the inhibition of topoisomerase, and similar drugs result in
chromosome breaks. However no studies in humans have
shown the presence or absence of teratogenic effects of the
drug [53]. Due to the lack of studies, no recommendation can
be made.
Finally, the SPC of fingolimod states: ‘‘animal studies have
shown toxicity on reproduction, including fetal loss and organ
malformations, in particular patent ductus arteriosus and
interventricular septal defects [. . .]. Moreover, the target
receptor of fingolimod (sphingosine-1-phosphate receptor) is
involved in the embryogenesis of the vascular system. There is
very limited data on the use of fingolimod in pregnant
women’’ [27]. Again, the data do not allow a recommendation
to be made with regard to possible termination of pregnancy.
The declaration of pregnancies exposed to treatment, within
the framework of the registries and post-marketing studies, is
to continue.
Disclosure of interest
E.B.: occasional remunerated interventions for this work:
Affinités Santé (Paris).
C.B.: occasional remunerated interventions for BiogenIdec, Teva Pharma, Genzyme Sanofi-Aventis.
D.B.: occasional remunerated interventions for BiogenIdec, Bayer Schering, Merck-Serono, Teva Pharma, Genzyme
Sanofi-Aventis, Almirall. Invitations in medical congresses
and meetings by Biogen-Idec, Bayer Schering, Merck-Serono,
Teva Pharma, Genzyme Sanofi-Aventis, Almirall. Remunerated congress reports for Biogen-Idec, Bayer Schering, MerckSerono, Teva Pharma, Genzyme Sanofi-Aventis, Almirall.
263
D.L. received consulting fees and non-personal research
grants from Novartis, Biogen-Idec, Teva Pharma and Genzyme
Sanofi-Aventis.
E.L.P. has received consultancy fees and non-personal
research grants from Novartis, Biogen-Idec, Teva Pharma and
Genzyme Sanofi-Aventis.
J.-C.O. has received consulting fees, speaker fees, research
grants (non-personal) and honoraria from Novartis, BiogenIdec, Merck-Serono, Roche, Teva Pharma and Genzyme
Sanofi-Aventis.
H.Z. received consulting fees from Biogen-Idec, Bayer,
Teva, Genzyme Sanofi-Aventis, Novartis, Merck-Serono. She
was invited in national and international medical congresses
and meetings by Biogen-Idec, Bayer, Teva Pharma, Genzyme
Sanofi-Aventis, Novartis, Merck-Serono. She received
research support from Teva Pharma.
J.D.S.: occasional remunerated interventions or funding of
conference participation: Biogen-Idec, Merck-Serono, Bayer
Schering, Sanofi-Aventis, Teva, LFB, Novartis, Allergan and
Almirall Laboratories.
BIOGEN-Idec France contributed financially to the practical
organisation of work seminars and to the distribution of
bibliographic documents selected by the experts.
Acknowledgements
We would like to thank the following for their quality of
provided assistance:
Drs. Fulda and Lillo-Le Louet, Centre Régional de Pharmacovigilance, Hôpital Européen Georges-Pompidou (Paris);
Dr. Beghin, Centre de Référence sur les Agents Tératogènes
(CRAT), Hôpital Armand-Trousseau (Paris).
references
[1] Ouallet JC, Bodiguel E, Bensa C, Blanc F, Brassat D, Laplaud
D, et al. Recommendations for useful serum testing with
suspected multiple sclerosis. Rev Neurol (Paris)
2013;169:37–46.
[2] Haute Autorité de santé. Guide affection longue durée
no 25 : sclérose en plaques; 2006 [www.has-sante.fr].
[3] Fédération française de neurologie. Conférence de
consensus : la sclérose en plaques.. Agence nationale
d’accréditation et d’évaluation en santé; 2001.
[4] The National Collaborating Centre for Chronic Conditions.
Multiple sclerosis. National clinical guideline for diagnosis
and management in primary and secondary care; 2004.
[5] Résumé des caractéristiques du produit : acétate de
glatiramères (mai 2013). http://agence-prd.ansm.sante.fr/
php/ecodex/rcp/R0222708.htm.
[6] Résumé des caractéristiques du produit : interféron bêta-1a
(mars 2007), http://ec.europa.eu/health/documents/
community-register/1997/199703132933/anx_2933_fr.pdf.
[7] Résumé des caractéristiques du produit : intérferon bêta-1b
(janvier 2006), http://ec.europa.eu/health/documents/
community-register/2012/20120525123294/
anx_123294_fr.pdf.
[8] Amato MP, Portaccio E, Ghezzi A, Hakiki B, Zipoli V,
Martinelli V, et al. Pregnancy and fetal outcomes after
264
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
interferon-b exposure in multiple sclerosis. Neurology
2010;75:1794–802.
Weber-Schoendorfer C, Schaefer C. Multiple sclerosis,
immunomodulators, and pregnancy outcome: a
prospective observational study. Mult Scler 2009;15:
1037–42.
Coyle PK, Johnson K, Pardo L, Stark K. Pregnancy outcomes
in patients with multiple sclerosis treated with glatiramer
acetate. J Neurol Neurosurg Psychiatry 2003;74:443 [poster].
Salminen HJ, Leggett H, Boggild M. Glatiramer acetate
exposure in pregnancy: preliminary safety and birth
outcomes. J Neurol 2010;257:2020–3.
Sandberg-Wollheim M, Frank D, Goodwin TM, Giesser B,
Lopez-Bresnahan M, Stam-Moraga M, et al. Pregnancy
outcomes during treatment with interferon-beta-1a in
patients with multiple sclerosis. Neurology 2005;65:802–6.
Sandberg-Wollheim M, Alteri E, Stam-Moraga M,
Kornmann G. Pregnancy outcomes in multiple sclerosis
following subcutaneous interferon-beta-1a therapy. Mult
Scler 2011;17:423–30.
Patti F, Cavallaro T, Lo Fermo S, Nicoletti A, Cimino V,
Vecchio R, et al. Is in utero early-exposure to interferonbeta a risk factor for pregnancy outcomes in multiple
sclerosis? J Neurol 2008;255:1250–3.
De Las Heras V, De Andrés C, Téllez N, Tintoré M, EMPATIE
Study Group. Pregnancy in multiple sclerosis patients
treated with immunomodulators prior to or during part of
the pregnancy: a descriptive study in the Spanish
population. Mult Scler 2007;13:981–4.
Foulds P, Richman S, Friend S, Hyde R. Post-marketing
utilisation and safety of intramuscular interferon-beta-1a.
Mult Scler 2010;16:S161.
Foulds P, Richman S, Glick G, Onigman T, Hyde R.
Pregnancy outcomes from the Avonex (interferon-beta-1a)
pregnancy exposure registry. Mult Scler 2010;16:S315.
Fragoso YD, Aguayo-Arcelis A, Almeida SMG, Alves-Leon
SV, Arruda WO, Brooks JBB, et al. The effects of long-term
exposure to disease-modifying drugs during pregnancy.
Mult Scler 2011;17:S467.
Giannini M, Portaccio E, Ghezzi A, Hakiki B, Pastò L,
Razzolini L, et al. Pregnancy and foetal outcomes after
glatiramer acetate exposure in patients with multiple
sclerosis. Mult Scler 2011;17:S303–4.
CRAT. http://www.lecrat.org/article.php3?id_article=699,
mise à jour du 12 septembre 2011.
Résumé des caractéristiques du produit : natalizumab (juin
2006), http://www.ansm.sante.fr/content/download/12064/
144005/version/1/file/lp080502_rcp-notice.pdf.
ANSM. Commission nationale de pharmacovigilance.
Compte rendu de la réunion du mardi 25 janvier 2011; 2011
[http://ansm.sante.fr/var/ansm_site/storage/original/
application/0cf9c1dcc65b0dfdcfe0ece0b13f2093.pdf].
Résumé des caractéristiques du produit :
mitoxantrone(janvier 2012). http://agenceprd.ansm.sante.fr/php/ecodex/rcp/R0205954.htm.
Briggs CG, Freeman RK, Yaffe SJ. Drugs in pregnancy and
lactation. 9th edition, Philadelphia: Lipincott Williams and
Wilkins; 2011.
De Santis M, Straface G, Cavaliere AF, Rosati P, Batocchi AP,
Caruso A. The first case of mitoxantrone exposure in early
pregnancy. Neurotoxicology 2007;28:696–7.
Hellwig K, Schimrigk S, Chan A, Epplen J, Gold R. A
newborn with Pierre Robin sequence after preconceptional
mitoxantrone exposure of a female with multiple sclerosis.
J Neurol Sci 2011;307:164–5.
Résumé des caractéristiques du produit : fingolimod (mars
2011), http://www.ema.europa.eu/docs/fr_FR/
document_library/EPAR_-_Product_Information/human/
002202/WC500104528.pdf.
[28] Résumé des caractéristiques du produit :
cyclophosphamide (novembre 2005), http://agenceprd.ansm.sante.fr/php/ecodex/rcp/R0139134.htm.
[29] CRAT. http://www.lecrat.org/article.php3?id_article=710,
mise à jour du 3 novembre 2010.
[30] Résumé des caractéristiques du produit : azathioprine
(février 2010), http://agence-prd.ansm.sante.fr/php/ecodex/
rcp/R0168346.htm.
[31] CRAT. http://www.lecrat.org, article azathioprine, mise à
jour du 8 juin 2011.
[32] Argyriou AA, Makris N. Multiple sclerosis and reproductive
risks in women. Reprod Sci 2008;15:755–64.
[33] Bennett KA. Pregnancy and multiple sclerosis. Clin Obstet
Gynecol 2005;48:38–47.
[34] Chen YH, Lin HL, Lin HC. Does multiple sclerosis increase
risk of adverse pregnancy outcomes? A population-based
study. Mult Scler 2009;15:606–12.
[35] Chofflon M, Lalive PH. Multiple sclerosis and pregnancy.
Rev Med Suisse 2009;5:936 [938–40].
[36] Confavreux C, Vukusic S. Natural history of multiple
sclerosis: implications for counselling and therapy. Curr
Opin Neurol 2002;15:257–66.
[37] Cook SD, Troiano R, Bansil S, Dowling PC. Multiple sclerosis
and pregnancy. Adv Neurol 1994;64:83–95.
[38] Dahl J, Myhr KM, Daltveit AK, Hoff JM, Gilhus NE.
Pregnancy, delivery, and birth outcome in women with
multiple sclerosis. Neurology 2005;65:1961–3.
[39] Dahl J, Myhr KM, Daltveit AK, Skjaerven R, Gilhus NE. Is
smoking an extra hazard in pregnant MS women? Findings
from a population-based registry in Norway. Eur J Neurol
2007;14:1113–7.
[40] Dahl J, Myhr KM, Daltveit AK, Gilhus NE. Pregnancy,
delivery and birth outcome in different stages of maternal
multiple sclerosis. J Neurol 2008;255:623–7.
[41] Damek DM, Shuster EA. Pregnancy and multiple sclerosis.
Mayo Clin Proc 1997;72:977–89.
[42] Fernandez Liguori N, Klajn D, Acion L, Cáceres F, Calle A,
Carra A, et al. Epidemiological characteristics of pregnancy,
delivery, and birth outcome in women with multiple
sclerosis in Argentina (EMEMAR study). Mult Scler
2009;15:555–62.
[43] Ferrero S, Pretta S, Ragni N. Multiple sclerosis:
management issues during pregnancy. Eur J Obstet Gynecol
Reprod Biol 2004;115:3–9.
[44] Fragoso YD, Finkelsztejn A, Comini-Frota ER, da Gama PD,
Grzesiuk AK, Khouri JM, et al. Pregnancy and multiple
sclerosis: the initial results from a Brazilian database. Arq
Neuropsiquiatr 2009;67:657–60.
[45] Jalkanen A, Alanen A, Airas L, Finnish Multiple Sclerosis
and Pregnancy Study Group. Pregnancy outcome in women
with multiple sclerosis: results from a prospective
nationwide study in Finland. Mult Scler 2010;16:950–5.
[46] Kelly VM, Nelson LM, Chakravarty EF. Obstetric outcomes
in women with multiple sclerosis and epilepsy. Neurology
2009;73:1831–6.
[47] Lee M, O’Brien P. Pregnancy and multiple sclerosis. J Neurol
Neurosurg Psychiatry 2008;79:1308–11.
[48] Moreau T, Brunot S, Couvreur G, Fromont A. Pregnancy and
multiple sclerosis. Presse Med 2010;39:389–94.
[49] Mueller BA, Zhang J, Critchlow CW. Birth outcomes and
need for hospitalization after delivery among women with
multiple sclerosis. Am J Obstet Gynecol 2002;186:446–52.
[50] Sadovnick AD, Baird PA. Reproductive counselling for
multiple sclerosis patients. Am J Med Genet 1985;20:349–54.
[51] Worthington J, Jones R, Crawford M, Forti A. Pregnancy and
multiple sclerosis: a 3-year prospective study. J Neurol
1994;241:228–33.
[52] CRAT. http://www.lecrat.org/article.php3?id_article=663,
mise à jour du 18 octobre 2011.
[53] Ferrero S, Esposito F, Pretta S, Ragni N. Fetal risks related to
the treatment of multiple sclerosis during pregnancy and
breastfeeding. Expert Rev Neurother 2006;6:1823–31.
[54] Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique
L, Hunnisett L, et al. Birth defects after maternal exposure
to corticosteroids: prospective cohort study and metaanalysis of epidemiological studies. Teratology
2000;62:385–92.
[55] Laplaud D, Bodiguel E, Bensa C, Blanc F, Brassat D,
Magy L, et al. Recommendations for the management
of multiple sclerosis relapses. Rev Neurol (Paris)
2012;168:425–33.
[56] Vukusic S, Hutchinson M, Hours M, Moreau T, CortinovisTourniaire P, Adeleine P, et al. Pregnancy and multiple
sclerosis (the PRIMS study). Clinical predictors of
postpartum relapse. Brain 2004;127:1353–60.
[57] Öst L, Wettrell G, Björkhem I, Rane A. Prednisolone
excretion in human milk. J Pediatr 1985;106:1008–11.
[58] Dahl J, Myhr KM, Daltveit AK, Gilhus NE. Planned vaginal
births in women with multiple sclerosis: delivery and birth
outcome. Acta Neurol Scand Suppl 2006;183:51–4.
[59] Duruflé A, Petrilli S, Nicolas B, Robineau S, Guillé F, Edan G,
et al. Effects of pregnancy and child birth on urinary
symptoms and urodynamics in women with multiple
sclerosis. Int Urogynecol J Pelvic Floor Dysfunct
2006;17:352–5.
[60] SFAR. Les blocs péri-médullaires chez l’adulte.
Recommandations pour la pratique clinique; 2006.
[61] Drake E, Drake M, Bird J, Russell R. Obstetric regional blocks
for women with multiple sclerosis: a survey of UK
experience. Int J Obstet Anesth 2006;15:115–23.
[62] Confavreux C, Hutchinson M, Hours MM, CortinovisTourniaire P, Moreau T. Rate of pregnancy-related relapse
in multiple sclerosis. Pregnancy in Multiple Sclerosis
Group. N Engl J Med 1998;339:285–91.
[63] Vukusic S, Confavreux C. Multiple sclerosis and pregnancy.
Rev Neurol (Paris) 2006;162:299–309.
[64] Finkelsztejn A, Brooks J, Paschoal Jr F, Fragoso Y. What can
we really tell women with multiple sclerosis regarding
pregnancy? A systematic review and meta-analysis of the
literature. BJOG 2011;118:790–7.
265
[65] Airas L, Jalkanen A, Alanen A, Pirttilä T, Marttila RJ.
Breastfeeding, postpartum and prepregnancy disease
activity in multiple sclerosis. Neurology 2010;75:474–6.
[66] Hellwig K, Haghikia A, Agne H, Beste C, Gold R. Protective
effect of breastfeeding in postpartum relapse rate
of mothers with multiple sclerosis. Arch Neurol
2009;66:1580–1.
[67] Nelson LM, Franklin GM, Jones MC. Risk of multiple
sclerosis exacerbation during pregnancy and breastfeeding.
JAMA 1988;259:3441–3.
[68] Haute Autorité de santé. Recommandations de bonne
pratique. Grossesses à risque : orientation des femmes
enceintes entre les maternités en vue de l’accouchement;
2009 [www.has-sante.fr].
[69] de Seze J, Chapelotte M, Delalande S, Ferriby D, Stojkovic T,
Vermersch P. Intravenous corticosteroids in the
postpartum period for reduction of acute exacerbations in
multiple sclerosis. Mult Scler 2004;10:596–7.
[70] Achiron A, Kishner I, Dolev M, Stern Y, Dulitzky M, Schiff E,
et al. Effect of intravenous immunoglobulin treatment on
pregnancy and postpartum-related relapses in multiple
sclerosis. J Neurol 2004;251:1133–7.
[71] Haas J. High dose IVIG in the postpartum period for
prevention of exacerbations in MS. Mult Scler
2000;6(Suppl. 2):S18–20 [discussion S33].
[72] Paavilainen T, Kurki T, Parkkola R, Färkkilä M, Salonen O,
Dastidar P, et al. Magnetic resonance imaging of the brain
used to detect early postpartum activation of multiple
sclerosis. Eur J Neurol 2007;1411:1216–21.
[73] Gucev ZS, Kirovski I, Jancevska A, Popjordanova N, Tasic V.
Papillorenal syndrome after beta-interferon treatment in
pregnancy. Ren Fail 2009;31:602–5.
[74] Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The
reproductive effects of beta-interferon therapy in pregnancy:
a longitudinal cohort. Neurology 2005;65:807–11.
[75] Hellwig K, Agne H, Gold R. Interferon-beta, birth weight and
pregnancy in multiple sclerosis. J Neurol 2009;256:830–1.
[76] ANSM. Commission nationale de pharmacovigilance.
Compte rendu de la réunion du mardi 25 novembre 2008;
2008 [http://ansm.sante.fr/var/ansm_site/storage/original/
application/725565619b641740d119ba326f37c5dd.pdf].

Multiple sclerosis and pregnancy

Transcription

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