Multiple sclerosis and pregnancy.

revue neurologique 170 (2014) 247–265

Available online at

ScienceDirect www.sciencedirect.com

Recommendations

Multiple sclerosis and pregnancy Consensus formalise´ d’experts : scle´rose 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

Hoˆpital europeén Georges-Pompidou, AP–HP, 20, rue Leblanc, 75015 Paris, France Service de neurologie, centre hospitalier Sainte-Anne, 1, rue Cabanis, 75014 Paris, France c Faculte´ de me´decine, universite´ Paris Descartes, Sorbonne Paris Cite´, 12, rue de l’Ećole de Me´decine, 75270 Paris cedex 06, France d Service de neurologie, fondation Rothschild, 25, rue Manin, 75019 Paris, France e Inserm U1043, poˆle des neurosciences, hoˆpital Purpan, universite´ Toulouse-3, place du Dr-Baylac, BP 3028, 31024 Toulouse cedex 3, France f Inserm UMR643, service de neurologie, pavillon Jean-Monnet, hoˆtel-Dieu, CHU de Nantes, 30, boulevard Jean-Monnet, 44093 Nantes 01, France g Faculte´ de me´decine de Nantes, 1, rue Gaston-Veı¨l, 44000 Nantes, France h CIC-P 0203 Inserm, poˆle des neurosciences cliniques, CHU Pontchaillou, pavillon Clemenceau, 2, rue Henri-Le-Guilloux, 35033 Rennes cedex 9, France i Poˆle des neurosciences cliniques, universite´ de Bordeaux Segalen, CHU de Bordeaux Pellegrin Tripode, 1, place Ame´lie-Raba-León, 33076 Bordeaux cedex, France j Poˆle de neurologie, hoˆpital Roger-Salengro, CHRU de Lille, avenue du Pr-E´mile-Laine, 59037 Lille, France k Service de neurologie, laboratoire d’imagerie et de neurosciences cognitives (LINC), CNRS, centre d’investigation clinique (CIC) de Strasbourg, universite´ de Strasbourg, CHU de Strasbourg, 1, place de l’Hoˆpital, 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

Re´flexion sur la Scle´rose 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 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. All rights reserved.

248


Breastfeeding

r e´ s u m e´

Clinical practice guidelines Rand Ucla appropriateness method

L’aˆge moyen des malades et la pre´dominance fe´minine expliquent que la proble´matique de

Mots cle´s :

groupe de re´flexion sur la scle´rose en plaques (GRESEP) a choisi d’e´laborer des recomman-

Scle´rose en plaques

dations sur ce the`me, envisageant a` la fois le retentissement de la scle´rose en plaques sur la

la grossesse soit re´gulie`rement poseé chez les patientes atteintes de scle´rose en plaques. Le

Grossesse

grossesse et celui de la grossesse sur la maladie. Comme pour les the`mes de travail

Accouchement

preće´dents, la me´thode du consensus formalise´ d’experts a e´te´ utiliseé. Le groupe de travail

Analge´sie pe´ridurale

e´tait compose´ de neurologues hospitaliers et libe´raux. Le groupe de lecture e´tait compose´ de

Allaitement

neurologues, d’anesthe´sistes et d’obste´triciens. Chaque recommandation est exposeé avec

Recommandations de pratique

le degre´ de consensus dont elle a fait l’objet. # 2014 Elsevier Masson SAS. Tous droits re´serve´s.

clinique Consensus formalise´ d’experts

1.

Objectives

In this new work, the multiple sclerosis think tank (Groupe de Re´flexion sur la Scle´rose 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-Biceˆtre), 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 Dureé’’ 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

‘‘Scle´rose en plaques mr[MSH] and Grossesse mr[MSH]’’ Limitation: recommendations

HAS: www.has-sante.fr

03/17/2011

‘‘Scle´rose en plaques’’ Limitation: good practice guidelines

AFSSAPS: http://afssaps.sante.fr/

03/17/2011

‘‘Scle´rose en plaques’’

AFSSAPS: http://afssaps-prd.afssaps.fr/php/ecodex/

07/25/2011

‘‘Re´sume´ des caracte´ristiques 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

‘‘Multiple sclerosis’’ Limitation: ‘‘guidance documents’’

Cochrane Reviews: www.cochrane.org/reviews/

03/17/2011

‘‘Multiple sclerosis’’

Canadian Medical Association INFOBASE clinical practice guidelines: http://mdm.ca/cpgsnew/cpgs/index.asp

03/17/2011

‘‘Multiple sclerosis’’ Domain: ‘‘clinical practice guidelines’’

Ontario Guidelines Advisory Committee (GAC) Recommended Clinical Practice Guidelines: http://www.gacguidelines.ca

03/17/2011

‘‘Multiple sclerosis’’

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

‘‘Multiple sclerosis’’ 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

‘‘Multiple sclerosis’’ 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)


1.3 (3)

1.4 (3)

Group opinion

Maximum score

Minimum score

Level of agreement

Appropriate formulation Appropriate recommendation Sufficient recommendation

9 9 9

7 8 7

Strong agreement between group members Strong agreement between group members Strong agreement between group members

9.0 9.0 8.0


9 9 9

6 7 5

Relative agreement between group members Strong agreement between group members Relative agreement between group members


9.0 9.0 9.0


9 9 9

7 7 6

Strong agreement between group members Strong agreement between group members Relative agreement between group members


9.0 9.0 8.0


9 9 9

6 7 5


1.5 (3)


9.0 9.0 9.0


9 9 9

8 8 6


Table 7 (4)


9.0 9.0 9.0


9 9 9

7 7 6


2.1 (2)


9.0 9.0 9.0


9 9 9

7 8 7


3.1 (2)


9.0 9.0 9.0


9 9 9

6 7 6


3.2 (2)


9.0 9.0 9.0


9 9 9

7 8 7


4.1 (4)


9.0 9.0 9.0


9 9 9

7 8 5


4.2 (5)


8.0 8.0 8.0


9 9 9

7 7 7


5.1 (3)


9.0 9.0 9.0


9 9 9

7 5 5

Strong agreement between group members Relative agreement between group members Relative agreement between group members

5.2 (2)

Easily understood Useful

9.0 9.0

Appropriate formulation Appropriate recommendation

9 9

7 8

Strong agreement between group members Strong agreement between group members

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

Sufficient recommendation

9

8

Strong agreement between group members

5.3 (4)


9.0 9.0 9.0


9 9 9

6 6 6

Relative agreement between group members Relative agreement between group members Relative agreement between group members

5.4 (2)


9.0 9.0 9.0


9 9 9

7 7 7


5.5 (4)


9.0 9.0 9.0


9 9 9

8 7 6


5.6 (3)


9.0 9.0 9.0


9 9 9

7 6 8

Strong agreement between group members Relative agreement between group members Strong agreement between group members

6.1 (3)


9.0 9.0 9.0


9 9 9

7 8 7


6.2 (3)


9.0 9.0 9.0


9 9 9

8 7 7


7.1 (4)


9.0 9.0 9.0


9 9 9

5 5 5


7.2 (4)


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 arreˆter un traitement de fond de la scle´rose en plaques (SEP) lorsqu’une grossesse est envisageé ? Si oui, quand et selon quelles modalite´s ? Recommandation 1.1 – La poursuite d’un traitement immunomodulateur (interfe´ron beˆta ou ace´tate de glatirame`re) est possible jusqu’a` la preuve de la conception, sans effet de´le´te`re actuellement de´montre´ sur l’embryon ou le fœtus ni sur le de´roulement de la grossesse (accord professionnel fort) Recommandation 1.2 – Dans le cas des maladies tre`s actives, la poursuite du traitement immunomodulateur (interfe´ron beˆta ou ace´tate de glatirame`re) durant toute la grossesse peut eˆtre e´galement discuteé au cas par cas, en l’absence de toxicite´ actuellement de´montreé par les donneés des e´tudes et les registres de pharmacovigilance (accord professionnel relatif) Recommandation 1.3 – Il est recommande´ d’arreˆter les traitements immunosuppresseurs (cyclophosphamide [hors AMM], mitoxantrone) lorsqu’une grossesse est envisageé, du fait de leur toxicite´ potentielle dans les e´tudes pre´-the´rapeutiques et du fait de leur pharmacodynamie (accord professionnel relatif) Recommandation 1.4 – Malgre´ l’absence d’interdiction formelle formuleé dans le Re´sume´ des Caracte´ristiques du Produit, il est recommande´ d’arreˆter le natalizumab 3 mois avant l’arreˆt de la contraception, en l’absence de donneés de sećurite´ suffisantes et du fait des donneés de pharmacodynamie. Le relais par un immunomodulateur est possible (accord professionnel relatif) Recommandation 1.5 – Le fingolimod doit eˆtre interrompu au moins 2 mois avant l’arreˆt de la contraception, du fait d’un risque te´ratoge`ne de´montre´ chez l’animal (accord professionnel relatif) Question clinique 2 : quel est l’impact de la scle´rose en plaques sur la grossesse ? Recommandation 2.1 – La SEP n’est pas une contre-indication a` la grossesse. Elle n’a de re´percussion de´le´te`re ni sur la fertilite´, ni sur le de´roulement d’une grossesse, ni sur l’accouchement, ni sur le nouveau-ne´. Un suivi obste´trical classique est prećonise´ (accord professionnel fort) Question clinique 3 : comment traiter une pousseé pendant la grossesse et en post-partum ? Recommandation 3.1 – Il n’y a pas de contre-indication a` reáliser des bolus intraveineux de me´thylprednisolone aux doses habituelles en cas de pousseé de SEP (accord professionnel relatif) Recommandation 3.2 – L’allaitement ne constitue pas une contre-indication a` reáliser des bolus de me´thylprednisolone. Il est recommande´ de ne pas allaiter durant la perfusion et de respecter un de´lai minimal de 4 heures entre la fin de la perfusion de me´thylprednisolone et la reprise des te´teés (accord professionnel fort) Question clinique 4 : les proce´dures habituelles d’accouchement (pe´ridurale, voie d’accouchement, anesthe´sie. . .) doivent-elles eˆtre modifieés en cas de SEP ? Recommandation 4.1 – Il n’est pas recommande´ de modifier les proce´dures d’accouchement chez les patientes pre´sentant une SEP. Seuls les crite`res obste´tricaux sont a` prendre en compte pour le choix du mode d’accouchement (accord professionnel relatif) Recommandation 4.2 – Il est recommande´ de privile´gier le recours a` l’analge´sie pe´ridurale et d’utiliser des anesthe´siques de faible concentration. L’indication d’une rachianesthe´sie ou d’une extension de pe´ridurale avec des anesthe´siques locaux concentre´s doit eˆtre discuteé au cas par cas. Ces techniques sont a` e´viter en cas de pousseé me´dullaire (accord professionnel relatif) Question clinique 5 : la prise en charge du post-partum en cas de SEP diffe`re-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 ou` la maladie ne justifie pas la reprise rapide d’un traitement de fond. Si la reprise d’un traitement de fond est nećessaire durant l’allaitement, seul l’interfe´ron beˆta est envisageable (accord professionnel relatif) Recommandation 5.2 – Du point de vue obste´trical, la prise en charge du post-partum des patientes ayant une SEP ne diffe`re 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 nećessaire de sensibiliser l’e´quipe soignante obste´tricale a` la prise en charge du handicap (accord professionnel relatif) Recommandation 5.4 – Il est recommande´ de sensibiliser les patientes a` la pratique de la reé´ducation pe´rineále au cours du post-partum. Celle-ci devra eˆtre adapteé a` la pre´sence e´ventuelle de troubles ve´sico-sphincte´riens (accord professionnel fort) Recommandation 5.5 – Il n’est pas recommande´ de prescrire syste´matiquement des perfusions mensuelles de me´thylprednisolone en pre´vention des pousseés du post-partum (accord professionnel relatif) Recommandation 5.6 – Il n’est pas recommande´ de prescrire un traitement par immunoglobulines polyvalentes en pre´vention des pousseés du post-partum (accord professionnel relatif) Question clinique 6 : quand doit-on reprendre un traitement de fond apre`s une grossesse ? Recommandation 6.1 – Apre`s un accouchement, la reprise du traitement de fond de la SEP est conseilleé de`s que possible aux patientes a` risque de pousseé dans le post-partum (patientes ayant fait au moins une pousseé dans l’anneé preće´dant la grossesse et/ou au cours de la grossesse) (accord professionnel fort) Recommandation 6.2 – L’allaitement peut eˆtre laisse´ au libre choix des patientes mais empeˆchera la reprise d’un traitement de fond de la SEP autre qu’un interfe´ron beˆta (accord professionnel fort) Question clinique 7 : faut-il recommander une interruption me´dicale de grossesse a` une femme qui a de´bute´ 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 me´dicale de grossesse. Pour la mitoxantrone, le natalizumab et le fingolimod, il n’y a pas de donneé suffisante pour faire une recommandation (accord professionnel relatif) Recommandation 7.2 – En cas de grossesse de´buteé sous immunosuppresseur (sauf l’azathioprine), la patiente devra eˆtre informeé de l’absence de recommandation spećifique vis-a`-vis d’une interruption me´dicale de grossesse. Un suivi ećhographique dans un centre de re´fe´rence des grossesses a` risque sera conseille´. En cas d’anomalie, la patiente pourra eˆtre adresseé a` un centre pluridisciplinaire de diagnostic preńatal (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 Re´fe´rence sur les Agents Te´ratoge`nes [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 Sećurite´ du Me´dicament et des Produits de Sante´ (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 (Socie´te´ Française d’Anesthe´sie Reánimation [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 Dureé 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: Affinite´s Sante´ (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 Re´gional de Pharmacovigilance, Hoˆpital Europeén Georges-Pompidou (Paris); Dr. Beghin, Centre de Re´fe´rence sur les Agents Te´ratoge`nes (CRAT), Hoˆpital 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 Autorite´ de sante´. Guide affection longue dureé no 25 : scle´rose en plaques; 2006 [www.has-sante.fr]. [3] Fe´de´ration française de neurologie. Confe´rence de consensus : la scle´rose en plaques.. Agence nationale d’accre´ditation et d’e´valuation en sante´; 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] Re´sume´ des caracte´ristiques du produit : ace´tate de glatirame`res (mai 2013). http://agence-prd.ansm.sante.fr/ php/ecodex/rcp/R0222708.htm. [6] Re´sume´ des caracte´ristiques du produit : interfe´ron beˆta-1a (mars 2007), http://ec.europa.eu/health/documents/ community-register/1997/199703132933/anx_2933_fr.pdf. [7] Re´sume´ des caracte´ristiques du produit : inte´rferon beˆta-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 Andre´s C, Te´llez N, Tintore´ 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, Pasto` 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 a` jour du 12 septembre 2011. Re´sume´ des caracte´ristiques 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 reúnion du mardi 25 janvier 2011; 2011 [http://ansm.sante.fr/var/ansm_site/storage/original/ application/0cf9c1dcc65b0dfdcfe0ece0b13f2093.pdf]. Re´sume´ des caracte´ristiques 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. Re´sume´ des caracte´ristiques du produit : fingolimod (mars 2011), http://www.ema.europa.eu/docs/fr_FR/ document_library/EPAR_-_Product_Information/human/ 002202/WC500104528.pdf.

[28] Re´sume´ des caracte´ristiques 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 a` jour du 3 novembre 2010. [30] Re´sume´ des caracte´ristiques du produit : azathioprine (fe´vrier 2010), http://agence-prd.ansm.sante.fr/php/ecodex/ rcp/R0168346.htm. [31] CRAT. http://www.lecrat.org, article azathioprine, mise a` 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, Caćeres 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 a` 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. ¨ st L, Wettrell G, Bjo¨rkhem I, Rane A. Prednisolone [57] O 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] Durufle´ A, Petrilli S, Nicolas B, Robineau S, Guille´ 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 pe´ri-me´dullaires 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, Pirttila¨ 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 Autorite´ de sante´. Recommandations de bonne pratique. Grossesses a` risque : orientation des femmes enceintes entre les maternite´s 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, Fa¨rkkila¨ 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 reúnion du mardi 25 novembre 2008; 2008 [http://ansm.sante.fr/var/ansm_site/storage/original/ application/725565619b641740d119ba326f37c5dd.pdf].

Pregnancy and multiple sclerosis.

Pregnancy in multiple sclerosis.

Pregnancy, oral contraceptives and multiple sclerosis.

Pregnancy, birth, gynecologic operations and multiple sclerosis.

Pregnancy in multiple sclerosis: a questionnaire study.

Multiple sclerosis and vitamin D during pregnancy and lactation.

Multiple sclerosis and pregnancy: a single-centre prospective comparative study.

Pregnancy, sex and hormonal factors in multiple sclerosis.

Multiple sclerosis and pregnancy in the 'treatment era'.

Pregnancy outcomes in multiple sclerosis patients previously treated with cyclophosphamide.

Does pregnancy alter the long-term course of multiple sclerosis?

Systemic sclerosis and pregnancy.

Relation between Carp (multiple-sclerosis associated) agent and multiple sclerosis.

Albumin and multiple sclerosis.

Multiple sclerosis and malabsorption.

Diet and multiple sclerosis.

Multiple Sclerosis and Schizophrenia.

[Multiple sclerosis and retroviruses].

Iron and multiple sclerosis.

Sexuality and multiple sclerosis.

Cyclosporine and multiple sclerosis.

Vision and multiple sclerosis.

Photoimmunology and Multiple Sclerosis.

[Eye and multiple sclerosis].