Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study

Susan Friend, Sandra Richman, Gary Bloomgren, Lynda M Cristiano, Madé Wenten, Susan Friend, Sandra Richman, Gary Bloomgren, Lynda M Cristiano, Madé Wenten

Abstract

Background: Patients with multiple sclerosis (MS) or Crohn's disease (CD) being treated with natalizumab (Tysabri®, Biogen) who are planning to become pregnant or discover they are pregnant after exposure to natalizumab are currently advised to balance the potential benefits and potential risks of exposure when considering treatment options. This study was undertaken to evaluate pregnancy outcomes of women with MS or CD who were exposed to natalizumab at any time within 3 months prior to conception or during pregnancy. A pregnancy registry was created to better understand the effect of natalizumab exposure on pregnancy outcomes.

Methods: The Tysabri Pregnancy Exposure Registry was a global, observational exposure registration and follow-up study. Evaluations included spontaneous abortions (<22 weeks gestational age), fetal losses (≥22 weeks gestational age), ectopic pregnancies, elective or therapeutic terminations, stillbirths, birth defects, and live births. Birth defects were reviewed and coded in accordance with the Metropolitan Atlanta Congenital Defects Program (MACDP) classification of birth defects.

Results: A total of 369 patients with MS and 7 patients with CD were enrolled prospectively, of whom 355 patients (99.4 %; 349 MS and 6 CD) had known pregnancy outcomes (including 8 twin sets). The spontaneous abortion rate was 9.0 % (n = 32; 95 % confidence interval [C. I.], 6.3-12.5 %). An independent advisory committee review determined the major birth defect rate to be 5.05 % (16 of 316 live births + 1 elective abortion; 95 % C. I., 2.9-8.1 %). The mean gestational age of the live-born infants was 38.3 weeks, and the mean birth weight was 3158.3 g.

Conclusions: Although the overall rate of birth defects was higher than that observed by the MACDP, these registry outcomes showed no specific pattern of malformations that would suggest a drug effect, and the spontaneous abortion rate was consistent with that of the general population.

Trial registration: ClinicalTrials.gov NCT00472992 (11 May 2007).

Keywords: Fetal development; Follow-up studies; Live birth; Multiple sclerosis; Pregnancy outcome; Spontaneous abortion.

Figures

Fig. 1
Fig. 1
Patients enrolled and outcome of pregnancy. aEight completed pregnancies resulted in twin births

References

    1. Alcalde-Cabero E, Almazán-Isla J, García-Merino A, de Sá J, de Pedro-Cuesta J. Incidence of multiple sclerosis among European Economic Area populations, 1985-2009: the framework for monitoring. BMC Neurol. 2013;13:58. doi: 10.1186/1471-2377-13-58.
    1. Bennett KA. Pregnancy and multiple sclerosis. Clin Obstet Gynecol. 2005;48:38–47. doi: 10.1097/01.grf.0000153881.20014.86.
    1. Cossburn M, Ingram G, Hirst C, Ben-Shlomo Y, Pickersgill TP, Robertson NP. Age at onset as a determinant of presenting phenotype and initial relapse recovery in multiple sclerosis. Mult Scler. 2012;18:45–54. doi: 10.1177/1352458511417479.
    1. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140:1785–94. doi: 10.1053/j.gastro.2011.01.055.
    1. Coyle PK, Christie S, Fodor P, Fuchs K, Giesser B, Gutierrez A, et al. Multiple sclerosis gender issues: clinical practices of women neurologists. Mult Scler. 2004;10:582–8. doi: 10.1191/1352458504ms1083oa.
    1. Biogen. Tysabri (natalizumab) injection, for intravenous use US prescribing information. 2015. . Accessed 16 June 2015.
    1. Rudick R, Polman C, Clifford D, Miller D, Steinman L. Natalizumab: bench to bedside and beyond. JAMA Neurol. 2013;70:172–82. doi: 10.1001/jamaneurol.2013.598.
    1. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992;356:63–6. doi: 10.1038/356063a0.
    1. Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353:1912–25. doi: 10.1056/NEJMoa043335.
    1. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899–910. doi: 10.1056/NEJMoa044397.
    1. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al. SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354:911–23. doi: 10.1056/NEJMoa044396.
    1. Wehner NG, Shopp G, Oneda S, Clarke J. Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol. 2009;86:117–30. doi: 10.1002/bdrb.20190.
    1. Wehner NG, Skov M, Shopp G, Rocca MS, Clarke J. Effects of natalizumab, an alpha4 integrin inhibitor, on fertility in male and female guinea pigs. Birth Defects Res B Dev Reprod Toxicol. 2009;86:108–16. doi: 10.1002/bdrb.20191.
    1. Wehner NG, Shopp G, Osterburg I, Fuchs A, Buse E, Clarke J. Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol. 2009;86:144–56. doi: 10.1002/bdrb.20193.
    1. Houtchens MK, Kolb CM. Multiple sclerosis and pregnancy: therapeutic considerations. J Neurol. 2013;260:1202–14. doi: 10.1007/s00415-012-6653-9.
    1. Wehner NG, Shopp G, Rocca MS, Clarke J. Effects of natalizumab, an alpha4 integrin inhibitor, on the development of Hartley guinea pigs. Birth Defects Res B Dev Reprod Toxicol. 2009;86:98–107. doi: 10.1002/bdrb.20189.
    1. Hellwig K, Haghikia A, Gold R. Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult Scler. 2011;17:958–63. doi: 10.1177/1352458511401944.
    1. Hoevenaren IA, de Vries LC, Rijnders RJ, Lotgering FK. Delivery of healthy babies after natalizumab use for multiple sclerosis: a report of two cases. Acta Neurol Scand. 2011;123:430–3. doi: 10.1111/j.1600-0404.2010.01426.x.
    1. Mattioda A, Masera S, Romagnolo A, Matta M, Superti G, Caligiana L, et al. Healthy baby delivery after conception during natalizumab exposure: a case report [abstract] Mult Scler. 2011;17:S455–S6.
    1. Totaro R, Rossi M, Casalena A, Carolei A. Pregnancy, delivery, and birth outcome after natalizumab use for multiple sclerosis: a report of two cases [abstract] Mult Scler. 2011;17:S227–S8.
    1. Committee for Medicinal Products for Human Use. Guideline on the exposure to medicinal products during pregnancy: need for post-authorisation data. . 2005. . Accessed 21 Nov 2014.
    1. US Food and Drug Administration. Guidance for industry: establishing pregnancy exposure registries. 2002. . Accessed 7 Nov 2014.
    1. US Food and Drug Administration. Guidance for industry: good pharmacovigilance practices and pharmacoepidemiologic assessment. 2005. . Accessed 30 Apr 2015.
    1. Correa-Villaseñor A, Cragan J, Kucik J, O’Leary L, Siffel C, Williams L. The Metropolitan Atlanta Congenital Defects Program: 35 years of birth defects surveillance at the Centers for Disease Control and Prevention. Birth Defects Res A Clin Mol Teratol. 2003;67:617–24. doi: 10.1002/bdra.10111.
    1. Correa A, Cragan JD, Kucik JE, Alverson CJ, Gilboa SM, Balakrishnan R, et al. Reporting birth defects surveillance data 1968-2003 [published correction appears in Birth Defects Res A Clin Mol Teratol 2008;82:41-62] Birth Defects Res A Clin Mol Teratol. 2007;79:65–186.
    1. Anokute CC. Epidemiology of spontaneous abortions—the effect of previous abortions. J R Soc Health. 1987;107:31–3. doi: 10.1177/146642408710700114.
    1. Jones RK, Kost K. Underreporting of induced and spontaneous abortion in the United States: an analysis of the 2002 National Survey of Family Growth. Stud Fam Plann. 2007;38:187–97. doi: 10.1111/j.1728-4465.2007.00130.x.
    1. Weber-Schoendorfer C, Schaefer C. Multiple sclerosis, immunomodulators, and pregnancy outcome: a prospective observational study. Mult Scler. 2009;15:1037–42. doi: 10.1177/1352458509106543.
    1. Martin JA, Hamilton BE, Osterman MJ, Curtin SC, Matthews TJ. Births: final data for 2013. Natl Vital Stat Rep. 2015;64:1–65.
    1. Grazioli A, Alves CS, Konstantopoulos K, Yang JT. Defective blood vessel development and pericyte/pvSMC distribution in alpha 4 integrin-deficient mouse embryos. Dev Biol. 2006;293:165–77. doi: 10.1016/j.ydbio.2006.01.026.
    1. Kwee L, Baldwin HS, Shen HM, Stewart CL, Buck C, Buck CA, et al. Defective development of the embryonic and extraembryonic circulatory systems in vascular cell adhesion molecule (VCAM-1) deficient mice. Development. 1995;121:489–503.
    1. Sueoka K, Shiokawa S, Miyazaki T, Kuji N, Tanaka M, Yoshimura Y. Integrins and reproductive physiology: expression and modulation in fertilization, embryogenesis, and implantation. Fertil Steril. 1997;67:799–811. doi: 10.1016/S0015-0282(97)81388-X.
    1. Wagner N, Müller W. Functions of alpha 4- and beta 7-integrins in hematopoiesis, lymphocyte trafficking and organ development. Curr Top Microbiol Immunol. 1998;231:23–32.
    1. Yang JT, Rayburn H, Hynes RO. Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development. 1995;121:549–60.
    1. Fässler R, Meyer M. Consequences of lack of beta 1 integrin gene expression in mice. Genes Dev. 1995;9:1896–908. doi: 10.1101/gad.9.15.1896.
    1. Centers for Disease Control and Prevention . Pediatric and Pregnancy: Nutrition Surveillance System. 2009.
    1. Fagius J, Burman J. Normal outcome of pregnancy with ongoing treatment with natalizumab. Acta Neurol Scand. 2014;129:e27–e9. doi: 10.1111/ane.12222.
    1. Haghikia A, Langer-Gould A, Rellensmann G, Schneider H, Tenenbaum T, Elias-Hamp B, et al. Natalizumab use during the third trimester of pregnancy. JAMA Neurol. 2014;71:891–5. doi: 10.1001/jamaneurol.2014.209.
    1. Honein MA, Paulozzi LJ, Cragan JD, Correa A. Evaluation of selected characteristics of pregnancy drug registries. Teratology. 1999;60:356–64. doi: 10.1002/(SICI)1096-9926(199912)60:6<356::AID-TERA8>;2-B.
    1. Kang JH, Chen YH, Lin HC. Comorbidities amongst patients with multiple sclerosis: a population-based controlled study. Eur J Neurol. 2010;17:1215–9. doi: 10.1111/j.1468-1331.2010.02971.x.
    1. Marrie RA, Yu BN, Leung S, Elliott L, Caetano P, Warren S, et al. CIHR Team in the Epidemiology and Impact of Comomrbidity on Multiple Sclerosis. The utility of administrative data for surveillance of comorbidity in multiple sclerosis: a validation study. Neuroepidemiology. 2013;40:85–92. doi: 10.1159/000343188.
    1. Marrie R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. High frequency of adverse health behaviors in multiple sclerosis. Mult Scler. 2009;15:105–13. doi: 10.1177/1352458508096680.
    1. Tsui A, Lee MA. Multiple sclerosis and pregnancy. Curr Opin Obstet Gynecol. 2011;23:435–9. doi: 10.1097/GCO.0b013e32834cef8f.
    1. Coyle PK, Sinclair SM, Scheuerle AE, Thorp JM, Jr, Albano JD, Rametta MJ. Final results from the Betaseron (interferon β-1b) Pregnancy Registry: a prospective observational study of birth defects and pregnancy-related adverse events. BMJ Open. 2014;4:e004536. doi: 10.1136/bmjopen-2013-004536.

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