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Multiple sclerosis
Original research
Exposure to natalizumab throughout pregnancy: effectiveness and safety in an Italian cohort of women with multiple sclerosis
  1. Doriana Landi1,
  2. Francesca Bovis2,
  3. Alfonso Grimaldi1,
  4. Pietro Osvaldo Annovazzi3,
  5. Antonio Bertolotto4,
  6. Alessia Bianchi5,
  7. Giovanna Borriello6,
  8. Vincenzo Brescia Morra7,
  9. Sebastiano Bucello8,
  10. Maria Chiara Buscarinu9,
  11. Francesca Caleri10,
  12. Marco Capobianco4,
  13. Ruggero Capra11,
  14. Maria Cellerino12,
  15. Diego Centonze13,14,
  16. Raffaella Cerqua15,
  17. Clara Grazia Chisari16,
  18. Marinella Clerico17,
  19. Eleonora Cocco18,
  20. Gaia Cola1,
  21. Cinzia Cordioli11,
  22. Erica Curti19,
  23. Alessandro d'Ambrosio20,
  24. Emanuele D'Amico16,
  25. Giovanna De Luca21,
  26. Massimiliano Di Filippo22,
  27. Sonia Di Lemme14,
  28. Roberta Fantozzi14,
  29. Diana Ferraro23,
  30. Elisabetta Ferraro24,
  31. Antonio Gallo20,
  32. Claudio Gasperini25,
  33. Franco Granella19,
  34. Matilde Inglese12,26,
  35. Roberta Lanzillo7,
  36. Lorena Lorefice27,
  37. Giacomo Lus28,
  38. Simona Malucchi4,
  39. Monica Margoni29,
  40. Giorgia Mataluni1,
  41. Massimiliano Mirabella30,
  42. Lucia Moiola31,
  43. Carolina Gabri Nicoletti1,
  44. Viviana Nociti30,
  45. Francesco Patti16,
  46. Federica Pinardi32,
  47. Emilio Portaccio33,
  48. Carlo Pozzilli34,
  49. Paolo Ragonese5,
  50. Sarah Rasia11,
  51. Giuseppe Salemi5,
  52. Elisabetta Signoriello28,
  53. Francesca Vitetta35,
  54. Rocco Totaro36,
  55. Maria Pia Sormani2,
  56. Maria Pia Amato33,37,
  57. Girolama Alessandra Marfia1
  1. 1 Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, University of Rome Tor Vergata, Roma, Italy
  2. 2 Department of Health Sciences, Section of Biostatistics, University of Genova, Genoa, Italy
  3. 3 Multiple Sclerosis Center, Neurology II Unit, ASST Valle Olona, Gallarate Hospital, Gallarate, Italy
  4. 4 Multiple Sclerosis Center (CRESM), Department of Neurology, 'San Luigi Gonzaga' University Hospital, Orbassano, Italy
  5. 5 Unit of Neurology, Department of Biomedicine, Neurosciences and Advanced Diagnostics, Palermo University, Palermo, Italy
  6. 6 Multiple Sclerosis Center, 'S. Andrea' Hospital, Sapienza University of Rome, Rome, Italy
  7. 7 Department of Neurosciences Reproductive Sciences and Odontostomatology, Multiple Sclerosis Center, Federico II University, Naples, Italy
  8. 8 Multiple Sclerosis Center, "E. Muscatello" Hospital - ASP8, Augusta (SR), Italy
  9. 9 Department of Neuroscience, Mental Health and Sensory Organs, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
  10. 10 Multiple Sclerosis Center, Department of Neurology, 'F. Tappeiner' Hospital, Merano (BZ), Italy
  11. 11 Multiple Sclerosis Center, Spedali Civili of Brescia, Montichiari (BS), Italy
  12. 12 Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genova, Italy
  13. 13 Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
  14. 14 Unit of Neurology, IRCCS Neuromed, Pozzilli (IS), Italy
  15. 15 Neurological Clinic, Department of Experimental and Clinical Medicine, Ospedali Riuniti, Ancona, Italy
  16. 16 Department of Medical and Surgical Sciences and Advanced Technologies 'G.F. Ingrassia', Section of Neurosciences, University of Catania, Catania, Italy
  17. 17 Clinical and Biological Sciences Department, Neurology Unit, University of Torino, 'San Luigi Gonzaga' Hospital, Orbassano, Italy
  18. 18 Multiple Sclerosis Center, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy
  19. 19 Unit of Neurology, Department of General and Specialized Medicine, Parma University Hospital, Parma, Italy
  20. 20 I Division of Neurology, Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", Napoli, Italy
  21. 21 Multiple Sclerosis Center, 'SS Annunziata' Hospital, 'Gabriele d'Annunzio' University Chieti-Pesacara, Chieti, Italy
  22. 22 Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
  23. 23 Department of Biomedical Metabolic and Neurosciences, University of Modena and Reggio Emilia, Modena, Italy
  24. 24 Neurology Unit, Presidio Ospedaliero 'San Filippo Neri', Roma, Italy
  25. 25 Department of Neurosciences, 'San Camillo Forlanini' Hospital, Rome, Italy
  26. 26 Department of Neurology, Policlinico 'San Martino Hospital'—Sistema Sanitario Regione, Genoa, Italy
  27. 27 Multiple Sclerosis Centre, Binaghi Hospital, ATS Sardegna—Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
  28. 28 Department of Advanced Medical and Surgical Sciences, II Division of Neurology, Multiple Sclerosis Center, University of Campania 'L. Vanvitelli', Naples, Italy
  29. 29 Multiple Sclerosis Center of the Veneto Region, Department of Neurosciences, University of Padua, Padua, Italy
  30. 30 Department of Neurosciences, Centro di Ricerca Sclerosi Multipla (CERSM), Università Cattolica del Sacro Cuore, Rome, Italy, 'A.Gemelli' University Hospital, Rome, Italy
  31. 31 Multiple Sclerosis Center, Neurology Department, San Raffaele Hospital IRCCS, Milan, Italy
  32. 32 UOSI Multiple Sclerosis Rehabilitation, IRCCS Istituto delle scienze neurologiche, Bologna, Italy
  33. 33 Division Neurological Rehabilitation, Department of NEUROFARBA, University of Florence, Florence, Italy
  34. 34 Multiple Sclerosis Center, Department of Human Neurosciences, 'S.Andrea' Hospital, Sapienza University of Rome, Rome, Italy
  35. 35 Neurology Unit, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy
  36. 36 Demyelinating Disease Center, Neurology Unit, University of L'Aquila, L'Aquila, Italy
  37. 37 IRCCS, Fondazione Don Carlo Gnocchi, Florence, Italy
  1. Correspondence to Dr Doriana Landi, Multiple Sclerosis Clinical and Research Unit, Departmenr of Systems Medicine, University of Rome Tor Vergata, Roma, Lazio, Italy; doriana.landi{at}gmail.com

Abstract

Objective Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG_EXP) compared with women interrupting treatment before (NO_EXP) and within >−30 days and ≤90 days from conception (SHORT_EXP), and describing newborns’ outcomes.

Methods Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO_EXP, SHORT_EXP, LONG_EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis.

Results 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG_EXP (n=66, 0.02 (0.001–0.09)) compared with NO_EXP (n=31, 0.43 (0.21–0.75), p=0.002) and SHORT_EXP (n=73, 0.46 (0.30–0.66), p=0.0004) during pregnancy, and in LONG_EXP (0.12 (0.05–0.24)) compared with SHORT_EXP (0.30 (0.17–0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG_EXP (n=6/50, 2.00%) compared with NO_EXP (n=9/21, 42.86%) and SHORT_EXP after delivery (n=17/49, 34.69%, p=0.010).

Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns’ weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG_EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population.

Conclusions Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns’ outcomes.

  • multiple sclerosis
  • MRI
  • obstetrics

Data availability statement

Data are available on reasonable request. Anonymised data will be shared with qualified investigators by request.

https://doi.org/10.1136/jnnp-2022-329657

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    Data availability statement

    Data are available on reasonable request. Anonymised data will be shared with qualified investigators by request.

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    Footnotes

    • Twitter @alessia_bia, @dottcapobianco

    • Contributors Guarantor: DL. Concept and design: DL, AGr, GAM. Acquisition, analysis or interpretation of data: DL, FB, AGr, PA, ABe, ABi, GB, VBM, SB, MCB, FC, MCa, RC, MCl, DC, RC, CGC, MCe, ECo, GC, CC, ECu, ADA, EDA, GDL, MDF, SDL, RF, DF, EF, AGa, CG, FG, MI, RL, LL, GL, SM, MM, GM, MM, LM, CGN, VN, FPa, FPi, EP, CP, PR, SR, GS, ES, FV, RT, MPS, MPA, GAM. Drafting of the manuscript: DL, FB, AGr, PA, ABe, ABi, GB, VBM, SB, MCB, FC, MCa, RC, MCe, DC, RC, CGC, MCl, ECo, GC, CC, ECu, ADA, EDA, GDL, MDF, SDL, RF, DF, EF, AGa, CG, FG, MI, RL, LL, GL, SM, MM, GM, MM, LM, CGN, VN, FPa, FPi, EP, CP, PR, SR, GS, ES, FV, RT, MPS, MPA, GAM. Critical revision of the manuscript for important intellectual content: DF, MPS, GAM, MPA. Statistical analysis: FB and MPS. Supervision: GAM, MPS, MPA.

    • Funding DL was partially funded by the Italian Ministry of Health (grant GR-2016-02363749). Biogen Italia S.r.l provided an unconditional research grant for the conduction of the study (grant IT-TYS-11863).

    • Competing interests DL received travel funding from Biogen, Merck-Serono, Sanofi-Genzyme, Teva, speaking or consultations fees from Sanofi-Genzyme, Merck-Serono, Teva, Biogen, Roche; FB received teaching honoraria from Novartis; AGr reports no disclosures relevant to the manuscript; PA received travel support, compensation for serving on scientific advisory boards and speaker's fees from Almirall, Biogen, Celgene, Merck-Serono, Mylan, Novartis, Sanofi-Genzyme and Teva; ABe reports no disclosures relevant to the manuscript; ABi reports no disclosures relevant to the manuscript; GB received honoraria for speaking or consultation fee from Almirall, Biogen, Merck, Novartis, Sanofi, Teva, Roche; VB received fees for consultancies or public speaking from Merck, Novartis, Biogen, Roche, Genzyme and Biogen; SB has been founded for advisory board, academic purposes and speech honoraria by Genzyme, Roche, Biogen, Merck-Serono, Novartis and Almirall; MCB has advisory board membership and honoraria for speaking from Teva, Novartis, Sanofi, Merck-Serono and Biogen; FC received honoraria for advisory board and/or for public speaking, and/or travel grant, from Biogen, Merck, Teva, Sanofi-Genzyme, Roche; RCa received lecture fees and/or travel grants from Novartis, Biogen, Roche, Celgene and Merck; DC is an Advisory Board member of Almirall, Bayer-Schering, Biogen, GW Pharmaceutical, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva and received honoraria for speaking or consultation fee from Almirall, Bayer-Schering, Biogen, GW Pharmaceuticals, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva. He is also the principal investigator in clinical trials for Bayer-Schering, Biogen, Merck-Serono, Novartis, Roche, Sanofi-Genzyme; RCe has received funding for travel and/or speaker honoraria from Sanofy, Biogen Idec, Merck-Serono and Roche; CGC received grants for congress participation from Almirall, Biogen, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; MCa received personal compensation for speaking/advising/consulting from Merck, Sanofi-Genzyme, Biogen, Novartis, Roche, Teva, EMF Serono; was supported in travelling expenses for congresses from Merck, Sanofi-Genzyme, Biogen, Novartis, Roche, Teva, Almirall; received research grants from Italian MS Foundation (FISM), Italian Ministry of Research, Merck, Sanofi-Genzyme, Biogen, Novartis; ECo received travel grant, speaker fee and consultancy from Biogen Idec, Teva, Genzyme, Merck-Serono, Novartis, Roche and Admirall; CC received personal compensation for advisory board and speaking from: Biogen, Roche, Novartis, Almirall, Merck-Serono; ECu received fees for advisory boards and speaking honoraria from Merck-Serono, Novartis and Biogen, travel funding from Biogen, Sanofi-Genzyme, Merck-Serono, Roche, Novartis and Teva; AD reports no disclosures relevant to the manuscript; EDA received speaking honoraria from Biogen, Merck-Serono, Novartis, Sanofi-Genzyme, Bayer-Schering; GDL served on scientific advisory boards for Merck, Sanofi-Genzyme and Roche, and has received travel and/or speaker honoraria from Merck, Roche, Teva, Biogen, Novartis and Sanofi-Genzyme; MDF participated on advisory boards for and received speaker or writing honoraria and funding for travelling from Bayer, Biogen Idec, Genzyme, Merck, Mylan, Novartis, Roche and Teva; DF has received travel grants, speaker honoraria and/or research support to her institution by Merck-Serono, Biogen, Roche, Genzyme, Novartis, Teva and Binding Site; AGa received speaker and consulting fees from Actelion, Biogen, Coloplast, Merck-Serono, Mylan, Roche, Sanofi-Genzyme, Teva; CG received fee as speaker or advisory board from Merck, Biogen, Teva, Bayer, Roche, Sanofi, Almirall; FG received research funding from Sanofi-Genzyme and Biogen, fees for advisory boards and speaking honoraria from Biogen, Novartis, Sanofi-Genzyme, Merck-Serono and Roche, travel funding from Biogen, Sanofi-Genzyme, Merck-Serono and Roche; MI received grants from NIH, NMSS, FISM; received fees for consultation from Roche, Genzyme, Merck, Biogen and Novartis; RL received fees for consultancies or public speaking from Merck, Novartis, Biogen, Roche, Genzyme and Biogen; LL received travel grant, speaker fee and consultancy from Biogen Idec, Teva, Genzyme, Merck-Serono, Novartis, Roche and Admirall; GL received speaker honoraria and/or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, Almirall, Roche; MM received personal fees from Sanofi-Genzyme, Merck-Serono, Novartis and Almirall; MM has scientific advisory board membership of Bayer-Schering, Biogen, Sanofi-Genzyme, Merck, Novartis, Teva; consulting and/or speaking fees, research support or travel grants from Almirall, Bayer-Schering, Biogen, CSL, Sanofi-Genzyme, Merck, Novartis, Teva, Roche, Ultragenix; principal investigator in clinical trials for Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Teva, Ultragenix, CSL Behring; LM received honoraria for speaking activity at scientific meetings and/or advisory boards from Biogen Idec, Merck-Serono, Sanofi-Genzyme, Novartis, Roche; CGN received travel funding from Almirall, Biogen, Novartis and Sanofi-Genzyme, Merck-Serono; VN has received consulting fees from Novartis, Roche, Mylan, Biogen Idec, Merk and Bayer; speaker and writing honoraria from Mylan, Teva, Biogen Idec, Bayer, Sanofi-Genzyme and Merk; travel grants from Teva, Biogen Idec, Sanofi-Genzyme, Roche and Novartis; FPa received honoraria for speaking activities by Almirall, Bayer-Schering, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; he also served as advisory board member the following companies: Bayer-Schering, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; he was also funded by Pfizer and FISM for epidemiological studies; he received grants for congress participation from Almirall, Bayer Shering, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; EP received compensation for travel grants, participation in advisory board and/or speaking activities from Biogen, Merck-Serono, Sanofi, Teva and Novartis; serves on the editorial board of Frontiers in Neurology and Brain Sciences; CP received honoraria for speaking or consultation fee from Almirall, Biogen, Merck, Novartis, Sanofi, Teva, Roche; PR received travel expenses or honoraria for speaking or participating to advisory board by: Biogen, Merck, Sanofi-Genzyme, Novartis, Teva, Roche; GS received travel expenses or honoraria for speaking or participating to advisory board by: Biogen idec, Sanofi-Genzyme, Novartis, Roche; ESi received speaker honoraria and/or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, Almirall, Roche; FV has received travel grants and/or speaker honoraria by Merck-Serono, Biogen, Roche, Genzyme, Novartis and Teva; RT has served on advisory boards and/or received honoraria for speaking or consultation fees from Almirall, Biogen, Laborest, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; MPS received personal fees from Biogen, Merck, Teva, Novartis, Sanofi-Genzyme, Roche, GeNeuro and Medday, outside the submitted work; MPA received research grants and honoraria as a speaker and member of advisory boards by: Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Teva, Almirall, Celgene and Roche; GAM received speaking or consultation fees from Almirall, Bayer-Schering, Biogen, Genzyme, Merck-Serono, Novartis, Teva, Sanofi-Genzyme.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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