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Natalizumab for the prevention of post-partum relapses in women with multiple sclerosis Sandra Vukusic, Françoise Durand-Dubief, Amandine Benoit, Romain Marignier, Bernard Frangoulis and Christian Confavreux Mult Scler published online 10 October 2014 DOI: 10.1177/1352458514554056 The online version of this article can be found at: http://msj.sagepub.com/content/early/2014/09/26/1352458514554056
Published by: http://www.sagepublications.com
On behalf of: European Committee for Treatment and Research in Multiple Sclerosis
Americas Committee for Treatment and Research in Multiple Sclerosis
Pan-Asian Committee for Treatment and Research in Multiple Sclerosis
Latin American Committee on Treatment and Research of Multiple Sclerosis
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research-article2014
MSJ0010.1177/1352458514554056Multiple Sclerosis JournalVukusic et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
Natalizumab for the prevention of post-partum relapses in women with multiple sclerosis Sandra Vukusic, Françoise Durand-Dubief, Amandine Benoit, Romain Marignier, Bernard Frangoulis and Christian Confavreux
Multiple Sclerosis Journal 1–3 DOI: 10.1177/ 1352458514554056 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract Objective: Our aim was to evaluate the impact of early redosing of natalizumab after delivery on the risk of post-partum relapses in six women with very active multiple sclerosis (MS). Methods: We undertook a retrospective analysis of data collected prospectively in the Lyon MS Cohort. Results: The annualized relapse rate (ARR) in the year before natalizumab treatment was 4.2 ±0.4, which decreased to 0.4 ±0.6 during the treatment period. The mean time between natalizumab withdrawal and onset of pregnancy was 9 months; one pregnancy was exposed to one infusion. The ARR between natalizumab withdrawal and onset of pregnancy was 1.8 ±0.7. Six relapses occurred before onset of pregnancy and seven during pregnancy. Natalizumab was restarted 7.8 days after delivery (between day 2 and 8 for five patients and on day 23 for one). Only one patient, who had restarted natalizumab 2 days after delivery, had a relapse 2 weeks later. The others five patients were relapse free after a mean of 14.2 ±9.1 months of follow-up. Conclusion: Despite a high risk of post-partum relapses, early redosing of natalizumab led to a complete disappearance of disease activity in all but one patient. These data suggest that natalizumab could be a good candidate for preventing early post-partum relapses.
Keywords: Multiple sclerosis, pregnancy, natalizumab, post-partum, relapses Date received: 29 July 2014; accepted: 04 September 2014
The Pregnancy in Multiple Sclerosis (PRIMS) study1 showed that the annualized relapse rate (ARR) of multiple sclerosis (MS) decreased during pregnancy, but increased in the first post-partum trimester. More effective in preventing relapses, second-line diseasemodifying drugs (DMDs) such as natalizumab have changed the perception of MS severity, allowing women with a very active MS to reconsider pregnancy. Insufficient pre-marketing data on the potential teratogenicity of natalizumab resulted, however, in recommending treatment withdrawal before conception.2 We report on six women with very active MS, in which natalizumab was controlling relapses but was stopped because they wanted a pregnancy, and re-introduced rapidly after delivery due to a significant increased disease activity prior to and during pregnancy.
Patients and methods Patients were identified through the Lyon MS Cohort, which includes all patients with a diagnosis of MS examined at least once in the department. Since 1990, data are retrospectively entered into the European Database for Multiple Sclerosis (EDMUS) software when the patient is first seen in the department and prospectively when the patient returns, at least yearly. Data confidentiality and protection conform with the recommendations of the French Commission Nationale Informatique et Libertés. All patients give informed consent for their data to be stored in the database. On 31 December 2012, 6367 MS patients were registered in the cohort and 352 had been treated with natalizumab; 247 (70.2%) were women; 24 (9.7%) had decided to stop natalizumab because they wanted to have a child. Six patients had worrisome clinical and/or
Correspondence to: Sandra Vukusic Service de Neurologie A, Hôpital Neurologique Pierre Wertheimer, 59 boulevard Pinel, 69677 BRON cedex, France. [email protected] Françoise Durand-Dubief Amandine Benoit Service de Neurologie A and Fondation Eugène Devic EDMUS contre la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France Sandra Vukusic Romain Marignier Bernard Frangoulis Christian Confavreux Service de Neurologie A and Fondation Eugène Devic EDMUS contre la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France/ Centre des Neurosciences de Lyon, INSERM 1028 et CNRS UMR5292, Equipe Neuro-oncologie et Neuroinflammation, Lyon, France/ Université de Lyon, Lyon, France/Université Lyon 1, Lyon, France
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Multiple Sclerosis Journal magnetic resonance imaging (MRI) activity after stopping natalizumab and despite pregnancy, which led to proposing early redosing after delivery. None of them was willing to breastfeed. Results In our six patients, the mean age at MS onset was 26.1 ±4.1 years. The ARR in the year before natalizumab treatment was 4.2 ±0.4, and the mean Expanded Disability Status Score (EDSS) was 4.3. Natalizumab was stopped after a mean of 28.3 infusions [range 18–44]. During the treatment period, the ARR was 0.4 ±0.6. All patients had either stable or decreased MRI lesion load compared with the pretreatment baseline scan. The mean duration between natalizumab withdrawal and onset of pregnancy was 9 months [3–11] in five patients; one patient became pregnant while on treatment and was exposed to one infusion. All patients experienced at least one relapse before and one during pregnancy. There were 13 relapses [1–4] during the mean 14.4 ±4.2 months [8.4–19.5] off-treatment period. The ARR was 1.8 ±0.7 and the mean delay between natalizumab withdrawal and the first relapse was 5 ±0.7 months [4–6]. Six relapses occurred before onset of pregnancy and seven during pregnancy (four, one and two during the first, second and third trimester respectively). Four patients had at least one MRI scan performed during the off-treatment period: one had three pseudotumoral lesions that developed during the first trimester of pregnancy, two had new brain or spinal cord lesions, and one patient was stable. The mean age at delivery was 31.4 ±4.4 years. Natalizumab was restarted 7.8 days after delivery (between day 2 and 8 in five patients, on day 23 in one). Five patients had a new MRI scan before redosing and after delivery: four had new lesions, with gadolinium enhancement in three, and one was stable. Further MRI follow-up, when available, showed improved or stable disease. Only one patient experienced a relapse 2 weeks after restarting natalizumab on day 2. The other five patients remained relapse free after a mean of 14.2 ±9.1 months of follow-up. Discussion We report six cases of very active MS before, during and after pregnancy, for which natalizumab redosing immediately after delivery led to both clinical and radiological improvement and prevented post-partum relapses.
These patients had high disease activity prior to pregnancy, which led to proposing natalizumab as a secondline therapy. All decided to consider pregnancy and stopped treatment. Clinical and radiological disease activity recurred rapidly before and during pregnancy. Early natalizumab redosing after delivery resulted in complete disappearance of disease activity in all but one patient. A higher risk of post-partum relapse is associated with relapses in the year before and during pregnancy.4 These results, obtained before DMDs were available, are difficult to extrapolate to women treated with active drugs, since pre-pregnancy activity may be confounded by the treatment effect leading to false assurance. Different strategies have been assessed in the prevention of post-partum relapses. Intravenous immunoglobulins failed to show a significant effect in the only randomized controlled phase III trial.5,6 Highdose methylprednisolone was evaluated in a casecontrol study with historical controls, but the positive results have not been confirmed.7 The POPARTMUS study, a French and Italian phase III controlled trial, failed to demonstrate the efficacy of progesterone in preventing post-partum relapses.8 First-line therapies, such as interferons and glatiramer acetate, are not supposed to be good candidates, because of their delayed action, unlike natalizumab that leads to a more rapid anti-inflammatory effect and prevention of relapses.9 Our study suggests that natalizumab could prevent early post-partum relapses in high-risk women, provided criteria are fulfilled to restart this second-line treatment and the benefits have been weighed against the potential risk of progressive multifocal leucoencephalopathy. It also raises the question of maintaining natalizumab until conception and, perhaps, during the whole pregnancy, but there are insufficient data to exclude reproductive risk with natalizumab. Thus it is classified as FDA pregnancy category C and not recommended during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus.10 Stopping treatment may also be harmful to mothers, so it is essential to collect as much data as possible on pregnancies exposed to treatments to answer these questions. Acknowledgements The authors would like to thank Margaret Haugh (MediCom Consult) and Véronique Millot for language editing.
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S Vukusic, F Durand-Dubief et al. Author contributions Dr. Vukusic: Study concept and design, acquisition of data, analysis and interpretation, writing. Dr. Durand-Dubief: Acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Dr. Benoit: Acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Dr. Marignier: Critical revision of the manuscript for important intellectual content. Dr. Frangoulis: Acquisition of data. Dr. Confavreux: Critical revision of the manuscript for important intellectual content. Conflicts of interest None declared. Funding Dr. Vukusic has received consulting and lecturing fees, travel grants and research support from BayerSchering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi Aventis and Teva Pharma. Dr. Durand-Dubief has received lecturing fees, travel grants and research support from Bayer-Schering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi Aventis and Teva Pharma. Dr. Benoit has no financial disclosure to declare. Dr. Marignier has received consulting and lecturing fees, travel grants and research support from BayerSchering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi Aventis and Teva Pharma. Dr. Frangoulis has no financial disclosure to declare. Dr Confavreux has received consulting and lecturing fees, travel grants and research support from BayerSchering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi Aventis and Teva Pharma.
References 1. Confavreux C, Hutchinson M, Hours MM, et al. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998; 339: 285–291. 2. Lu E, Wang BW, Guimond C, et al. Disease-modifying drugs for multiple sclerosis in pregnancy: A systematic review. Neurology 2012; 79: 1130–1135. 3. Killestein J, Vennegoor A, Strijbis EM, et al. Natalizumab drug holiday in multiple sclerosis: Poorly tolerated. Ann Neurol 2010; 68: 392–395. 4. Vukusic S, Hutchinson M, Hours M, et al, for the Pregnancy in Multiple Sclerosis Group. Pregnancy and multiple sclerosis (the PRIMS study): Clinical predictors of post-partum relapse. Brain 2004; 127: 1353–1360. 5. Achiron A, Kishner I, Dolev M, et al. Effect of intravenous immunoglobulin treatment on pregnancy and post-partum related relapses in multiple sclerosis. J Neurol 2004; 251: 1133–1137. 6. Haas J and Hommes OR. A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. Mult Scler 2007; 13: 900–908. 7. De Sèze J, Chapelotte M, Delalande S, et al. Intravenous corticosteroids in the postpartum period for reduction of acute exacerbations in multiple sclerosis. Mult Scler 2004;10: 596–597. 8. Vukusic S, Ionescu I, El-Etr M, et al. The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART’MUS) trial: Rationale, objectives and state of advancement. J Neurol Sci 2009; 286: 114–118. 9. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348: 15–23. 10. Hellwig K, Haghikia A and Gold R. Pregnancy and natalizumab: Results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult Scler 2011; 17: 958–963.
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Natalizumab for the prevention of post-partum relapses in women with multiple sclerosis Sandra Vukusic, Françoise Durand-Dubief, Amandine Benoit, Romain Marignier, Bernard Frangoulis and Christian Confavreux Mult Scler published online 10 October 2014 DOI: 10.1177/1352458514554056 The online version of this article can be found at: http://msj.sagepub.com/content/early/2014/09/26/1352458514554056
Published by: http://www.sagepublications.com
On behalf of: European Committee for Treatment and Research in Multiple Sclerosis
Americas Committee for Treatment and Research in Multiple Sclerosis
Pan-Asian Committee for Treatment and Research in Multiple Sclerosis
Latin American Committee on Treatment and Research of Multiple Sclerosis
Additional services and information for Multiple Sclerosis Journal can be found at: Email Alerts: http://msj.sagepub.com/cgi/alerts Subscriptions: http://msj.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Downloaded from msj.sagepub.com at TEMPLE UNIV on November 1, 2014
>> OnlineFirst Version of Record - Oct 10, 2014 What is This?
Downloaded from msj.sagepub.com at TEMPLE UNIV on November 1, 2014
554056
research-article2014
MSJ0010.1177/1352458514554056Multiple Sclerosis JournalVukusic et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
Natalizumab for the prevention of post-partum relapses in women with multiple sclerosis Sandra Vukusic, Françoise Durand-Dubief, Amandine Benoit, Romain Marignier, Bernard Frangoulis and Christian Confavreux
Multiple Sclerosis Journal 1–3 DOI: 10.1177/ 1352458514554056 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract Objective: Our aim was to evaluate the impact of early redosing of natalizumab after delivery on the risk of post-partum relapses in six women with very active multiple sclerosis (MS). Methods: We undertook a retrospective analysis of data collected prospectively in the Lyon MS Cohort. Results: The annualized relapse rate (ARR) in the year before natalizumab treatment was 4.2 ±0.4, which decreased to 0.4 ±0.6 during the treatment period. The mean time between natalizumab withdrawal and onset of pregnancy was 9 months; one pregnancy was exposed to one infusion. The ARR between natalizumab withdrawal and onset of pregnancy was 1.8 ±0.7. Six relapses occurred before onset of pregnancy and seven during pregnancy. Natalizumab was restarted 7.8 days after delivery (between day 2 and 8 for five patients and on day 23 for one). Only one patient, who had restarted natalizumab 2 days after delivery, had a relapse 2 weeks later. The others five patients were relapse free after a mean of 14.2 ±9.1 months of follow-up. Conclusion: Despite a high risk of post-partum relapses, early redosing of natalizumab led to a complete disappearance of disease activity in all but one patient. These data suggest that natalizumab could be a good candidate for preventing early post-partum relapses.
Keywords: Multiple sclerosis, pregnancy, natalizumab, post-partum, relapses Date received: 29 July 2014; accepted: 04 September 2014
The Pregnancy in Multiple Sclerosis (PRIMS) study1 showed that the annualized relapse rate (ARR) of multiple sclerosis (MS) decreased during pregnancy, but increased in the first post-partum trimester. More effective in preventing relapses, second-line diseasemodifying drugs (DMDs) such as natalizumab have changed the perception of MS severity, allowing women with a very active MS to reconsider pregnancy. Insufficient pre-marketing data on the potential teratogenicity of natalizumab resulted, however, in recommending treatment withdrawal before conception.2 We report on six women with very active MS, in which natalizumab was controlling relapses but was stopped because they wanted a pregnancy, and re-introduced rapidly after delivery due to a significant increased disease activity prior to and during pregnancy.
Patients and methods Patients were identified through the Lyon MS Cohort, which includes all patients with a diagnosis of MS examined at least once in the department. Since 1990, data are retrospectively entered into the European Database for Multiple Sclerosis (EDMUS) software when the patient is first seen in the department and prospectively when the patient returns, at least yearly. Data confidentiality and protection conform with the recommendations of the French Commission Nationale Informatique et Libertés. All patients give informed consent for their data to be stored in the database. On 31 December 2012, 6367 MS patients were registered in the cohort and 352 had been treated with natalizumab; 247 (70.2%) were women; 24 (9.7%) had decided to stop natalizumab because they wanted to have a child. Six patients had worrisome clinical and/or
Correspondence to: Sandra Vukusic Service de Neurologie A, Hôpital Neurologique Pierre Wertheimer, 59 boulevard Pinel, 69677 BRON cedex, France. [email protected] Françoise Durand-Dubief Amandine Benoit Service de Neurologie A and Fondation Eugène Devic EDMUS contre la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France Sandra Vukusic Romain Marignier Bernard Frangoulis Christian Confavreux Service de Neurologie A and Fondation Eugène Devic EDMUS contre la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France/ Centre des Neurosciences de Lyon, INSERM 1028 et CNRS UMR5292, Equipe Neuro-oncologie et Neuroinflammation, Lyon, France/ Université de Lyon, Lyon, France/Université Lyon 1, Lyon, France
http://msj.sagepub.com 1
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Multiple Sclerosis Journal magnetic resonance imaging (MRI) activity after stopping natalizumab and despite pregnancy, which led to proposing early redosing after delivery. None of them was willing to breastfeed. Results In our six patients, the mean age at MS onset was 26.1 ±4.1 years. The ARR in the year before natalizumab treatment was 4.2 ±0.4, and the mean Expanded Disability Status Score (EDSS) was 4.3. Natalizumab was stopped after a mean of 28.3 infusions [range 18–44]. During the treatment period, the ARR was 0.4 ±0.6. All patients had either stable or decreased MRI lesion load compared with the pretreatment baseline scan. The mean duration between natalizumab withdrawal and onset of pregnancy was 9 months [3–11] in five patients; one patient became pregnant while on treatment and was exposed to one infusion. All patients experienced at least one relapse before and one during pregnancy. There were 13 relapses [1–4] during the mean 14.4 ±4.2 months [8.4–19.5] off-treatment period. The ARR was 1.8 ±0.7 and the mean delay between natalizumab withdrawal and the first relapse was 5 ±0.7 months [4–6]. Six relapses occurred before onset of pregnancy and seven during pregnancy (four, one and two during the first, second and third trimester respectively). Four patients had at least one MRI scan performed during the off-treatment period: one had three pseudotumoral lesions that developed during the first trimester of pregnancy, two had new brain or spinal cord lesions, and one patient was stable. The mean age at delivery was 31.4 ±4.4 years. Natalizumab was restarted 7.8 days after delivery (between day 2 and 8 in five patients, on day 23 in one). Five patients had a new MRI scan before redosing and after delivery: four had new lesions, with gadolinium enhancement in three, and one was stable. Further MRI follow-up, when available, showed improved or stable disease. Only one patient experienced a relapse 2 weeks after restarting natalizumab on day 2. The other five patients remained relapse free after a mean of 14.2 ±9.1 months of follow-up. Discussion We report six cases of very active MS before, during and after pregnancy, for which natalizumab redosing immediately after delivery led to both clinical and radiological improvement and prevented post-partum relapses.
These patients had high disease activity prior to pregnancy, which led to proposing natalizumab as a secondline therapy. All decided to consider pregnancy and stopped treatment. Clinical and radiological disease activity recurred rapidly before and during pregnancy. Early natalizumab redosing after delivery resulted in complete disappearance of disease activity in all but one patient. A higher risk of post-partum relapse is associated with relapses in the year before and during pregnancy.4 These results, obtained before DMDs were available, are difficult to extrapolate to women treated with active drugs, since pre-pregnancy activity may be confounded by the treatment effect leading to false assurance. Different strategies have been assessed in the prevention of post-partum relapses. Intravenous immunoglobulins failed to show a significant effect in the only randomized controlled phase III trial.5,6 Highdose methylprednisolone was evaluated in a casecontrol study with historical controls, but the positive results have not been confirmed.7 The POPARTMUS study, a French and Italian phase III controlled trial, failed to demonstrate the efficacy of progesterone in preventing post-partum relapses.8 First-line therapies, such as interferons and glatiramer acetate, are not supposed to be good candidates, because of their delayed action, unlike natalizumab that leads to a more rapid anti-inflammatory effect and prevention of relapses.9 Our study suggests that natalizumab could prevent early post-partum relapses in high-risk women, provided criteria are fulfilled to restart this second-line treatment and the benefits have been weighed against the potential risk of progressive multifocal leucoencephalopathy. It also raises the question of maintaining natalizumab until conception and, perhaps, during the whole pregnancy, but there are insufficient data to exclude reproductive risk with natalizumab. Thus it is classified as FDA pregnancy category C and not recommended during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus.10 Stopping treatment may also be harmful to mothers, so it is essential to collect as much data as possible on pregnancies exposed to treatments to answer these questions. Acknowledgements The authors would like to thank Margaret Haugh (MediCom Consult) and Véronique Millot for language editing.
2 http://msj.sagepub.com
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S Vukusic, F Durand-Dubief et al. Author contributions Dr. Vukusic: Study concept and design, acquisition of data, analysis and interpretation, writing. Dr. Durand-Dubief: Acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Dr. Benoit: Acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Dr. Marignier: Critical revision of the manuscript for important intellectual content. Dr. Frangoulis: Acquisition of data. Dr. Confavreux: Critical revision of the manuscript for important intellectual content. Conflicts of interest None declared. Funding Dr. Vukusic has received consulting and lecturing fees, travel grants and research support from BayerSchering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi Aventis and Teva Pharma. Dr. Durand-Dubief has received lecturing fees, travel grants and research support from Bayer-Schering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi Aventis and Teva Pharma. Dr. Benoit has no financial disclosure to declare. Dr. Marignier has received consulting and lecturing fees, travel grants and research support from BayerSchering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi Aventis and Teva Pharma. Dr. Frangoulis has no financial disclosure to declare. Dr Confavreux has received consulting and lecturing fees, travel grants and research support from BayerSchering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi Aventis and Teva Pharma.
References 1. Confavreux C, Hutchinson M, Hours MM, et al. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998; 339: 285–291. 2. Lu E, Wang BW, Guimond C, et al. Disease-modifying drugs for multiple sclerosis in pregnancy: A systematic review. Neurology 2012; 79: 1130–1135. 3. Killestein J, Vennegoor A, Strijbis EM, et al. Natalizumab drug holiday in multiple sclerosis: Poorly tolerated. Ann Neurol 2010; 68: 392–395. 4. Vukusic S, Hutchinson M, Hours M, et al, for the Pregnancy in Multiple Sclerosis Group. Pregnancy and multiple sclerosis (the PRIMS study): Clinical predictors of post-partum relapse. Brain 2004; 127: 1353–1360. 5. Achiron A, Kishner I, Dolev M, et al. Effect of intravenous immunoglobulin treatment on pregnancy and post-partum related relapses in multiple sclerosis. J Neurol 2004; 251: 1133–1137. 6. Haas J and Hommes OR. A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. Mult Scler 2007; 13: 900–908. 7. De Sèze J, Chapelotte M, Delalande S, et al. Intravenous corticosteroids in the postpartum period for reduction of acute exacerbations in multiple sclerosis. Mult Scler 2004;10: 596–597. 8. Vukusic S, Ionescu I, El-Etr M, et al. The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART’MUS) trial: Rationale, objectives and state of advancement. J Neurol Sci 2009; 286: 114–118. 9. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348: 15–23. 10. Hellwig K, Haghikia A and Gold R. Pregnancy and natalizumab: Results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult Scler 2011; 17: 958–963.
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