Acta Neurol Scand 2014: 129: e27–e29 DOI: 10.1111/ane.12222
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Clinical Commentary
Normal outcome of pregnancy with ongoing treatment with natalizumab Fagius J, Burman J. Normal outcome of pregnancy with ongoing treatment with natalizumab. Acta Neurol Scand 2014: 129: e27–e29. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – Treatment of multiple sclerosis (MS) with natalizumab during pregnancy is not recommended due to potential risks for the foetus. Despite strong advice accidental pregnancies occur. Case – A 32-year old woman with MS since the age of 26 was treated with natalizumab since January 2008. Treatment was stopped April 2011 due to pregnancy plans, but was restarted following an MS relapse. The patient was thoroughly informed about potential foetal risks, but nevertheless she one year later disclosed that she was pregnant in gestational week 15. Treatment was continued, since the first trimester had passed. The pregnancy course was normal and a healthy daughter was born at full gestational term. Conclusions – This is the second known case where natalizumab treatment continued throughout the whole gestational period.
Introduction
Natalizumab is nowadays regarded the most effective treatment in routine practice for multiple sclerosis, MS (1). As with all relatively new pharmacologic substances, it is contraindicated during pregnancy, partly due to ‘principle of caution’. Increased abortion frequency has been shown in one of two studies on monkeys but no important teratogenic effects been described (2, 3). Herein, we report normal outcome of pregnancy in a woman treated by natalizumab throughout the gestation. The patient has given her consent to the report. Case report
The patient, aged 32, is otherwise healthy, nonsmoking. She is highly educated, with a PhD in biology. She experienced her first symptom of MS in spring 2006, a bifocal relapse with optic neuritis, diplopia and vertigo. A second relapse occurred before diagnosis was established in August 2006, and treatment with interferon-beta-1-a was initiated. In the succeeding 15 months, four further relapses occurred, that is, annualized relapse rate
J. Fagius1,2, J. Burman1,2 1 Department of Neuroscience/Neurology, Uppsala University, Uppsala, Sweden; 2Department of Neurology, University Hospital, Uppsala, Sweden
Key words: multiple sclerosis; pregnancy; natalizumab; teratogenecity J. Fagius, Department of Neurology, University Hospital/Akademiska sjukhuset, SE-751 85 Uppsala, Sweden Tel.: 46 18 6115032 Fax: 46 18 555463 e-mail: [email protected] Accepted for publication January 8, 2014
was around 3. Treatment was switched to natalizumab in January 2008; she had a mild relapse in the following month, but was then stable without relapses, EDSS score (4) returning to 0. Treatment was stopped in April 2011 since the patient wanted to get pregnant. In August 2011, before obtaining pregnancy, she developed a mild but bifocal relapse (optic neuritis and paraesthesiae in one hand); MRI displayed four contrastenhancing lesions. Her pregnancy plans were discarded, and natalizumab treatment was restarted. She recovered from all symptoms except fatigue. In October 2012, she disclosed that she was pregnant in gestational week 15. She was previously carefully informed that pregnancy should be avoided during treatment; she had further informed herself thoroughly and decided to go through with pregnancy without cessation of treatment. As the first trimester was passed with some weeks marginal when the pregnancy was revealed, and against the background of her strongly well-informed decision, we decided to continue treatment. She was followed prospectively from that on. The pregnancy course was normal, ultrasound examination of the foetus according to routine e27
Fagius & Burman (gestational week 19) showed nothing abnormal. The baby was delivered with Cesarian section (humanitarian indication) in April 2013 without any complications for mother or the daughter, who was normal according to routine neonatal examination. There were no signs of MS activity throughout the course of pregnancy and puerperal follow-up period. Thereafter, treatment has continued. The patient abstained from breastfeeding, in accordance with our strong recommendations. Development of the child was normal during the 8-month follow-up period. Discussion
The present experience is to our knowledge only the second where natalizumab treatment continued throughout the whole gestational period. Hoevenaren et al. (5) described two cases, with normal outcome as well, one of which continued the treatment throughout the gestation period, like our patient. Another long exposure with normal outcome was reported by Bayas and coworkers (6), where the gestation was not discovered until week 31 when treatment was discontinued, equating to seven natalizumab infusions during ongoing pregnancy. Two further pregnancies with prolonged exposure have been reported (7), one continuously until week 34, one with restarted treatment weeks 21–34 due to a severe relapse during pregnancy; outcome was normal in both cases. As of 23 November 2012, a total of 377 pregnancies exposed to natalizumab had been collected in the register run by the manufacturer of natalizumab (8, 9) with 364 known pregnancy outcomes. Of these, 30 children had some birth defect, that is, 8%, which is slightly higher than the rate in the general population. Major birth defects were few and on par with the background risk. No specific pattern of malformation was observed, and no increase rate in spontaneous abortion was noted. That summarizing report gives no information of how long in the gestation treatment was continued; a main rule is that treatment is discontinued when an accidental pregnancy is discovered. One detailed report of 35 pregnancies exposed to natalizumab (10) describes a minor malformation (hexadactylia) in one of 29 born children (there were five spontaneous and one elective abortion). In every case, the exposure was shortlasting – six women got their last infusion prior to last menstruation, and in the remaining 29 cases, treatment was stopped on average 23 days after last menstruation. e28
Treatment of MS during pregnancy is a serious consideration (11, 12), not the least concerning natalizumab, that is known to pass the placental barrier (12). Natalizumab blocks alpha-4-intergrins, which are considered to play a part in mammalian foetal development (2). Studies on monkeys performed by the manufacturer (2, 3) revealed minor changes in foetal haematopoiesis and leucocyte trafficking and an increased spleen weight, all of which was reversed with follow-up of the offspring. Two infants exposed until gestational week 34 were studied concerning immune responses (7), and a significant reduction in CXCL12-induced chemotaxis rate of T cells was observed, possibly compromising host defence in the neonate period. A similar study was not performed for the present infant. There is a documented risk for re-emergence of MS disease activity when natalizumab is discontinued (13). Our patient had already had that experience when deciding to go through with her pregnancy with continuous treatment. She was strongly discouraged from pregnancy during treatment; furthermore, she had informed herself from other sources, being well equipped to evaluate all available information. Against this background and risk evaluation, we saw no reason to discontinue treatment, when not being aware of the gestation until clearly after the first trimester with the foetal organ development already passed. This patient provides a further important example that pregnancy outcome may be normal, despite natalizumab treatment throughout the entire gestation course, to our knowledge the second report of such an experience. This is consistent with previous indications of relatively safety concerning natalizumab treatment during pregnancy. However, more data are still needed before the caution-based recommendation to avoid treatment during pregnancy can be changed. Conflicts of interest Jan Fagius has received unrestricted research grant from BiogenIdec, has been member of advisory board for MerckSerono, and has received speaker honoraria and travel grants from BayerSchering-Pharma, MerckSerono, BiogenIdec, SanofiAventis and Genzyme. Joachim Burman has received travel support and/or lecture honoraria from Almirall, BiogenIdec, Genzyme/SanofiAventis and MerckSerono, and has received an unconditional research grant from MerckSerono.
References 1. CHATAWAY J, MILLER DH. Natalizumab therapy for multiple sclerosis. Neurotherapeutics 2013;10:19–28.
Normal outcome of pregnancy with natalizumab 2. WEHNER NG, SHOPP G, ONEDA S, CLARKE J. Embryo/ fetal development in cynomolgus monkeys exposed to natalizumab, an alpha 4 intergrin inhibitor. Birth Defects Res B Dev Reprod Toxicol 2009;86:117–30. 3. WEHNER NG, SHOPP G, OSTERBERG I, FUCHS A, BUSE E, CLARKE J. Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an alpha4 intergrin inhibitor. Birth Defects Res B Dev Reprod Toxicol 2009;86:144–56. 4. KURTZKE JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–52. 5. 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. 6. BAYAS A, PENZIEN J, HELLWIG K. Accidental natalizumab administration to the third trimester of pregnancy in an adolescent patient with multiple sclerosis. Acta Neurol Scand 2011;124:290–2. 7. SCHNEIDER H, WEBER CE, HELLWIG K, SCHROTEN H, TENENBAUM T. Natalizumab treatment during pregnancy – effects on the neonatal immune system. Acta Neurol Scand 2013;127:e1–4.
8. TYSABRI Pregnancy Exposure Registry.www.clinicaltrials.gov/ct2/show/NCT00472992 (accessed 1 September 2013). 9. RICHMAN FS, BOZIC C, BLOOMGREN G. Evaluation of pregnancy outcomes from the TYSABRIâ (natalizumab) Pregnancy Exposure Registry. AAN 2013, Abstract/Poster P02.127. 10. 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. 11. HOUTCHENS MK, KOLB CM. Multiple sclerosis and pregnancy: therapeutic considerations. J Neurol 2013;260: 1202–14, Aug 25. 12. LU E, WANG BW, GUIMOND C et al. Safety of diseasemodifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance. Expert Rev Neurother 2013;13:251– 61. 13. O’CONNOR PW, GOODMAN A, KAPPOS L et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 2011;76: 1858–65.
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© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Clinical Commentary
Normal outcome of pregnancy with ongoing treatment with natalizumab Fagius J, Burman J. Normal outcome of pregnancy with ongoing treatment with natalizumab. Acta Neurol Scand 2014: 129: e27–e29. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – Treatment of multiple sclerosis (MS) with natalizumab during pregnancy is not recommended due to potential risks for the foetus. Despite strong advice accidental pregnancies occur. Case – A 32-year old woman with MS since the age of 26 was treated with natalizumab since January 2008. Treatment was stopped April 2011 due to pregnancy plans, but was restarted following an MS relapse. The patient was thoroughly informed about potential foetal risks, but nevertheless she one year later disclosed that she was pregnant in gestational week 15. Treatment was continued, since the first trimester had passed. The pregnancy course was normal and a healthy daughter was born at full gestational term. Conclusions – This is the second known case where natalizumab treatment continued throughout the whole gestational period.
Introduction
Natalizumab is nowadays regarded the most effective treatment in routine practice for multiple sclerosis, MS (1). As with all relatively new pharmacologic substances, it is contraindicated during pregnancy, partly due to ‘principle of caution’. Increased abortion frequency has been shown in one of two studies on monkeys but no important teratogenic effects been described (2, 3). Herein, we report normal outcome of pregnancy in a woman treated by natalizumab throughout the gestation. The patient has given her consent to the report. Case report
The patient, aged 32, is otherwise healthy, nonsmoking. She is highly educated, with a PhD in biology. She experienced her first symptom of MS in spring 2006, a bifocal relapse with optic neuritis, diplopia and vertigo. A second relapse occurred before diagnosis was established in August 2006, and treatment with interferon-beta-1-a was initiated. In the succeeding 15 months, four further relapses occurred, that is, annualized relapse rate
J. Fagius1,2, J. Burman1,2 1 Department of Neuroscience/Neurology, Uppsala University, Uppsala, Sweden; 2Department of Neurology, University Hospital, Uppsala, Sweden
Key words: multiple sclerosis; pregnancy; natalizumab; teratogenecity J. Fagius, Department of Neurology, University Hospital/Akademiska sjukhuset, SE-751 85 Uppsala, Sweden Tel.: 46 18 6115032 Fax: 46 18 555463 e-mail: [email protected] Accepted for publication January 8, 2014
was around 3. Treatment was switched to natalizumab in January 2008; she had a mild relapse in the following month, but was then stable without relapses, EDSS score (4) returning to 0. Treatment was stopped in April 2011 since the patient wanted to get pregnant. In August 2011, before obtaining pregnancy, she developed a mild but bifocal relapse (optic neuritis and paraesthesiae in one hand); MRI displayed four contrastenhancing lesions. Her pregnancy plans were discarded, and natalizumab treatment was restarted. She recovered from all symptoms except fatigue. In October 2012, she disclosed that she was pregnant in gestational week 15. She was previously carefully informed that pregnancy should be avoided during treatment; she had further informed herself thoroughly and decided to go through with pregnancy without cessation of treatment. As the first trimester was passed with some weeks marginal when the pregnancy was revealed, and against the background of her strongly well-informed decision, we decided to continue treatment. She was followed prospectively from that on. The pregnancy course was normal, ultrasound examination of the foetus according to routine e27
Fagius & Burman (gestational week 19) showed nothing abnormal. The baby was delivered with Cesarian section (humanitarian indication) in April 2013 without any complications for mother or the daughter, who was normal according to routine neonatal examination. There were no signs of MS activity throughout the course of pregnancy and puerperal follow-up period. Thereafter, treatment has continued. The patient abstained from breastfeeding, in accordance with our strong recommendations. Development of the child was normal during the 8-month follow-up period. Discussion
The present experience is to our knowledge only the second where natalizumab treatment continued throughout the whole gestational period. Hoevenaren et al. (5) described two cases, with normal outcome as well, one of which continued the treatment throughout the gestation period, like our patient. Another long exposure with normal outcome was reported by Bayas and coworkers (6), where the gestation was not discovered until week 31 when treatment was discontinued, equating to seven natalizumab infusions during ongoing pregnancy. Two further pregnancies with prolonged exposure have been reported (7), one continuously until week 34, one with restarted treatment weeks 21–34 due to a severe relapse during pregnancy; outcome was normal in both cases. As of 23 November 2012, a total of 377 pregnancies exposed to natalizumab had been collected in the register run by the manufacturer of natalizumab (8, 9) with 364 known pregnancy outcomes. Of these, 30 children had some birth defect, that is, 8%, which is slightly higher than the rate in the general population. Major birth defects were few and on par with the background risk. No specific pattern of malformation was observed, and no increase rate in spontaneous abortion was noted. That summarizing report gives no information of how long in the gestation treatment was continued; a main rule is that treatment is discontinued when an accidental pregnancy is discovered. One detailed report of 35 pregnancies exposed to natalizumab (10) describes a minor malformation (hexadactylia) in one of 29 born children (there were five spontaneous and one elective abortion). In every case, the exposure was shortlasting – six women got their last infusion prior to last menstruation, and in the remaining 29 cases, treatment was stopped on average 23 days after last menstruation. e28
Treatment of MS during pregnancy is a serious consideration (11, 12), not the least concerning natalizumab, that is known to pass the placental barrier (12). Natalizumab blocks alpha-4-intergrins, which are considered to play a part in mammalian foetal development (2). Studies on monkeys performed by the manufacturer (2, 3) revealed minor changes in foetal haematopoiesis and leucocyte trafficking and an increased spleen weight, all of which was reversed with follow-up of the offspring. Two infants exposed until gestational week 34 were studied concerning immune responses (7), and a significant reduction in CXCL12-induced chemotaxis rate of T cells was observed, possibly compromising host defence in the neonate period. A similar study was not performed for the present infant. There is a documented risk for re-emergence of MS disease activity when natalizumab is discontinued (13). Our patient had already had that experience when deciding to go through with her pregnancy with continuous treatment. She was strongly discouraged from pregnancy during treatment; furthermore, she had informed herself from other sources, being well equipped to evaluate all available information. Against this background and risk evaluation, we saw no reason to discontinue treatment, when not being aware of the gestation until clearly after the first trimester with the foetal organ development already passed. This patient provides a further important example that pregnancy outcome may be normal, despite natalizumab treatment throughout the entire gestation course, to our knowledge the second report of such an experience. This is consistent with previous indications of relatively safety concerning natalizumab treatment during pregnancy. However, more data are still needed before the caution-based recommendation to avoid treatment during pregnancy can be changed. Conflicts of interest Jan Fagius has received unrestricted research grant from BiogenIdec, has been member of advisory board for MerckSerono, and has received speaker honoraria and travel grants from BayerSchering-Pharma, MerckSerono, BiogenIdec, SanofiAventis and Genzyme. Joachim Burman has received travel support and/or lecture honoraria from Almirall, BiogenIdec, Genzyme/SanofiAventis and MerckSerono, and has received an unconditional research grant from MerckSerono.
References 1. CHATAWAY J, MILLER DH. Natalizumab therapy for multiple sclerosis. Neurotherapeutics 2013;10:19–28.
Normal outcome of pregnancy with natalizumab 2. WEHNER NG, SHOPP G, ONEDA S, CLARKE J. Embryo/ fetal development in cynomolgus monkeys exposed to natalizumab, an alpha 4 intergrin inhibitor. Birth Defects Res B Dev Reprod Toxicol 2009;86:117–30. 3. WEHNER NG, SHOPP G, OSTERBERG I, FUCHS A, BUSE E, CLARKE J. Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an alpha4 intergrin inhibitor. Birth Defects Res B Dev Reprod Toxicol 2009;86:144–56. 4. KURTZKE JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–52. 5. 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. 6. BAYAS A, PENZIEN J, HELLWIG K. Accidental natalizumab administration to the third trimester of pregnancy in an adolescent patient with multiple sclerosis. Acta Neurol Scand 2011;124:290–2. 7. SCHNEIDER H, WEBER CE, HELLWIG K, SCHROTEN H, TENENBAUM T. Natalizumab treatment during pregnancy – effects on the neonatal immune system. Acta Neurol Scand 2013;127:e1–4.
8. TYSABRI Pregnancy Exposure Registry.www.clinicaltrials.gov/ct2/show/NCT00472992 (accessed 1 September 2013). 9. RICHMAN FS, BOZIC C, BLOOMGREN G. Evaluation of pregnancy outcomes from the TYSABRIâ (natalizumab) Pregnancy Exposure Registry. AAN 2013, Abstract/Poster P02.127. 10. 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. 11. HOUTCHENS MK, KOLB CM. Multiple sclerosis and pregnancy: therapeutic considerations. J Neurol 2013;260: 1202–14, Aug 25. 12. LU E, WANG BW, GUIMOND C et al. Safety of diseasemodifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance. Expert Rev Neurother 2013;13:251– 61. 13. O’CONNOR PW, GOODMAN A, KAPPOS L et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 2011;76: 1858–65.
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