Acta Neurol Scand DOI: 10.1111/ane.12255
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Clinical Commentary
Pregnancy outcomes in multiple sclerosis patients previously treated with cyclophosphamide Patti F, Messina S, D’Amico E, Lo Fermo S, Zappia M. Pregnancy outcomes in multiple sclerosis patients previously treated with cyclophosphamide. Acta Neurol Scand: DOI: 10.1111/ane.12255. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – Cyclophosphamide (Cyc) can induce ovarian failure and can have teratogenic effect. Few case reports of successful pregnancies after Cyc treatment in women with autoimmune diseases and malignancies have been described. To date, there are no data about Cyc effect on pregnancy outcomes in MS patients. Aim of the study – To describe pregnancy outcomes in multiple sclerosis (MS) patients treated with Cyc before conception. Methods – We reviewed retrospectively the medical records of all MS patients who received Cyc from 1st of January 1997 to 31st of March 2012, referring to the MS centre of the University of Catania. All pregnancies, occurred during the follow-up period after Cyc treatment, were recorded according to a computerized and standardized protocol (iMED). Results – We found a total of 105 MS women of childbearing age; eleven patients experienced a pregnancy (10.4%); 10 of them had a successful delivery; and one experienced a voluntary abortion. Five women had a preterm delivery. One child was small for gestational age. Conclusions – Although the favourable pregnancy outcomes, Cyc should be avoided in young women planning a pregnancy. However, Cyc might be considered as a possible alternative to licensed therapies in few selected cases of very aggressive MS, including women of childbearing age.
Introduction
Multiple sclerosis (MS) is a chronic T-cell-mediated inflammatory disease of the central nervous system (CNS), characterized by demyelination and axonal degeneration, affecting more women than men (1). Pregnancy can exert a positive effect on the disease course. Women experience fewer relapses during pregnancy but an increased number of relapses right after the delivery, suggesting a possible protective role of pregnancy hormones on the pathogenesis of MS (2). Based on these assumptions, sexual dimorphism in MS should be considered as a crucial aspect in the management of our patients. The majority of women with MS are of childbearing age, so the possible fertility and teratogenic effects of disease modifying drugs (DMDs) should be carefully
F. Patti*, S. Messina*, E. D’Amico, S. Lo Fermo, M. Zappia Department G.F. Ingrassia-section of Neurosciences, University of Catania, Catania, Italy
Key words: fertility; immunosuppression; multiple sclerosis; pregnancy outcome; teratogenicity; women M. Zappia, Department G.F. Ingrassia, Section of Neurosciences, Universita degli studi di Catania, Via S. Sofia 78, Catania 95123, Italy Tel.: +39 953782783 Fax: +39 953782900 e-mail: [email protected] *These authors contributed equally to this manuscript. Accepted for publication March 24, 2014
considered. Cyclophosphamide (Cyc) has been widely studied for the treatment of aggressive MS or for the stabilization of selected cases (3). It is well known that Cyc can induce ovarian failure and infertility and can also have teratogenic effect on the foetus (4–7). According to the classification of drug use during pregnancy, Cyc is classified as a category D drug (positive evidence of human foetal risk, but the benefit may outweigh the risk) (8, 9). There have been few case reports of successful pregnancy after Cyc treatment in women with autoimmune disease or malignancies (10). To date, there is no information available regarding the effect of maternal treatment with Cyc prior to pregnancy on pregnancy outcome of women with MS. We report 10 cases of successful childbearing in MS patients previously treated with Cyc. 1
Patti et al. Methods
We reviewed retrospectively the medical records of all MS patients referring to the MS centre of the University of Catania, treated with Cyc from 1st of January 1997 to 31st of March 2012. Clinical and demographic information was recorded according to computerized and standardized protocol (iMED; Serono International SA, Geneva, Switzerland) (11). We found 214 patients, 133 (62.1%) women and 81 (37.8%) men. Out of 133 female patients, 105 were between 16 and 44 years. We found 11 (10.4%) patients who experienced a pregnancy after having received Cyc treatment. Cyc was intravenously (i.v) administered from a dose of 500–1500 mg/m2 on a monthly basis according to a specific protocol previously reported (3). During Cyc administration, women were treated with leuprorelin every 3 months to induce a temporary menopause and to prevent ovarian failure (12). All the patients were affected by a clinically defined relapsing-remitting MS. All of them gave their signed written informed consent before starting therapy, after careful and detailed information on the possible risks (cancer, infertility, teratogenic effect) associated to Cyc therapy. The local ethics committee of the ‘Policlinico-Vittorio Emanuele’ hospital of Catania had previously given the approval of the off-label use of Cyc in selected cases of MS patients.
19109 11629.5 mg (min 8400 max 51700 mg) with administration of 19 doses on average (min 6, max 33). The time lapse between the last dose of Cyc and conception was an average of 3.7 1.5 years (range 0.33–5.9 years). Of the 11 cases, one patient had a voluntary abortion at 4-week gestation because the foetus was exposed to Cyc in utero. As represented in Table 1, five patients had a preterm delivery (before 37th gestational week), and one child was small for gestational age (below the 10th percentile). The patient who delivered a child small for gestational age received a total dose of 19,350 mg (higher than the mean cumulative dose of the cohort) and 24 doses (higher than the mean number of doses). The time lapse between the last dose of Cyc and conception was 72.1 months (higher than the mean time lapse in months: 44.9). The patients who had a preterm delivery received a mean cumulative dose of 13,960 mg and 17 doses on average (both lower than the mean cumulative dose and the mean number of doses of the cohort). The mean time lapse in months between the last dose of Cyc and conception was 34.5 months (lower than the mean time lapse of the whole cohort). Four patients delivered their babies via C section, whereas six patients had a natural delivery. No history of malignancies was reported in children follow-up (current mean age 2.6 2.1 years), and all children correctly achieved the developmental milestones.
Results
At the beginning of Cyc treatment, the mean age of selected women was 26.5 3.8 years (range 22–36). The age at the time of conception was 31.6 2.7 years (range 28–38). They received an average cumulative dose of Cyc of
Discussion
Cyc is commonly used to treat malignancies and several autoimmune diseases, including MS, although it does not have a formal Food and Drug Administration and European Medicines
Table 1 Clinical characteristics and pregnancy outcomes
Disease category 1 2 3 4 5 6 7 8 9 10 11
RR RR RR RR RR RR RR RR RR RR RR
Age at beginning of Cyc (years)
Number of relapse 1 year before Cyc
EDSS before Cyc
Cumulative dose (mg)
Lapse of time Therapy-pregnancy (months)
Age at beginning of pregnancy (years)
Week of gestation (number)
Baby weight (g)
Delivery (V/C)
26 23 26 28 27 28 24 22 28 36 24
2 1 1 4 2 1 3 2 1 1 6
4 1 2 1.5 2 1.5 2 1.5 1.5 2 3.5
16,500 19,350 15,700 16,500 12,700 8400 11,950 51,700 24,000 13,350 20,050
42.7 72.1 4.0 37.6 42.7 45.6 65.3 54.4 41.4 N.A. 43.3
33 31 28 30 32 32 30 30 34 38 30
37 40 36 29 35 37 38 39 38 N.A. 41
3200 2500 2870 3100 2900 3115 3100 3600 2930 N.A. 3380
C V V V C C C V V N.A. V
RR, relapsing remitting; Cyc, cyclophosphamide; V/C, vaginalis/C section; N.A., not applicable.
2
Cyclophosphamide and pregnancy in multiple sclerosis Agency approval for MS. Cyc can promote a switch towards a Th2 response, by increasing the production of IL-4, IL-5, IL-10 and decreasing the levels of IFNm and IL-12 (13). Ovarian failure is one of the most common side effects of Cyc treatment in women of childbearing age. Nevertheless, many authors reported successful pregnancies after Cyc treatment in lupus and chronic myeloid leukaemia patients (10). Animal studies have demonstrated Cyc can affect female germ cells, inducing genetic abnormalities, raising concerns regarding the risk of abortion and congenital abnormalities. It has been shown in mice that the effect of Cyc on fertility and malformation depends on the time of exposure to treatment and on oocyte maturation, showing a higher rate of pregnancy failures and malformations in mice treated 1 week before mating (14). Cases of teratogenesis induced by inadvertent exposure to Cyc during the first trimester of pregnancy have been described in women affected by lupus (15). The most common observed malformations are hydrocephalus, microretrognathia, ectrodactyly, cleft palate and exencephaly (6). However, a cohort study did not show increased risk of congenital abnormalities among offspring of cancer survivors, treated with radiotherapy or an alkylating agent, suggesting that possibly a long lapse of time between exposure and pregnancy could induce DNA mechanism repair in primordial follicles (14, 16). Ramsey-Goldman et al. (17) reported pregnancy outcome of systemic lupus erythematosus patients who received immunosuppressive agents 3 years before conception, suggesting that a long period of time between treatment and conception could not affect both fertility and foetal development. Furthermore, they did not report any history of malignancies in children. Our patients were young and received Cyc treatment in the earlier phases of MS (see Table 1). They become pregnant with a time lapse between last Cyc administration to conception of about 3 years. Considering that the prevalence of ovarian failure increases with age (5), we can hypothesize that young age at the time of treatment can reduce the risk of amenorrhoea and infertility due to Cyc therapy. A recent study showed women with rheumatologic disease receiving GnRH during Cyc treatment were more likely to have regular menses (18). The use of leuprorelin and a longer lapse of time between Cyc administration and conception could be related to a recovery of the impaired ovarian function and to a reduced negative impact on foetal development.
Of the 10 cases, four patients had a preterm delivery and one child was small for age. Despite the possible teratogenic effect of Cyc, none of the children presented any birth defects or a delay in the achievement of developmental milestones. However, Cyc could exert long-term teratogenic effects, although the babies had not been exposed to Cyc in utero, and thus, we cannot exclude possible effects in the future. Moreover, the determination of possible adverse effect on children born from women exposed to Cyc requires longer, additional follow-up as previously reported for different diseases (19). Given the small number of patients in our cohort and the relative short follow-up period of children, definitive conclusions cannot be drawn. Although our findings seem to support that previous Cyc exposure does not affect pregnancy outcomes, we suggest that until information regarding safety is available, Cyc should be avoided in young women planning a pregnancy and a birth control method should be always required. On the grounds of our experience reporting favourable pregnancy outcomes in women who had been previously exposed to Cyc, its use in few selected cases of very aggressive MS, including women of childbearing age, could be considered as a possible alternative to licensed therapies for MS. Funding
This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors. Acknowledgements The authors have no acknowledgements to declare.
Conflict of interest None.
References 1. WEINSHENKER BG, BASS B, RICE GP et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989;112(Pt 1):133–46. 2. TSUI A, LEE MA. Multiple sclerosis and pregnancy. Curr Opin Obstet Gynecol 2011;23:435–9. 3. PATTI F, CATALDI ML, NICOLETTI F, REGGIO E, NICOLETTI A, REGGIO A. Combination of cyclophosphamide and interferon-beta halts progression in patients with rapidly transitional multiple sclerosis. J Neurol Neurosurg Psychiatry 2001;71:404–7.
3
Patti et al. 4. WANG CL, WANG F, BOSCO JJ. Ovarian failure in oral cyclophosphamide treatment for systemic lupus erythematosus. Lupus 1995;4:11–4. 5. BOUMPAS DT, AUSTIN HA 3rd, VAUGHAN EM, YARBORO CH, KLIPPEL JH, BALOW JE. Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 1993;119:366–9. 6. OZOLINS TR. Cyclophosphamide and the Teratology Society: an awkward marriage. Birth Defects Res B Dev Reprod Toxicol 2010;89:289–99. 7. ENNS GM, ROEDER E, CHAN RT, ALI-KHAN CATTS Z, COX VA, GOLABI M. Apparent cyclophosphamide (cytoxan) embryopathy: a distinct phenotype? Am J Med Genet 1999;86:237–41. 8. US Food and Drug Administration. Requirements on content and format of labeling for human prescription drug and biological products. Final rule. Fed Reg. 2006;71:3921–97. 9. HOUTCHENS MK, KOLB CM. Multiple sclerosis and pregnancy: therapeutic considerations. J Neurol 2013;260: 1202–14. 10. GUPTA R, DEEPANJALI S, THABAH MM, KAUR P, GUPTA S. Successful twin pregnancy while on cyclophosphamide therapy in a patient with lupus nephritis. Rheumatol Int 2009;29:1503–5. 11. MECHATI SP-S-PH. iMed: a new electronic database for monitoring patients with multiple sclerosis. Mult Scler 2001;7:S31. 12. SOMERS EC, MARDER W, CHRISTMAN GM, OGNENOVSKI V, MCCUNE WJ. Use of a gonadotropin-releasing hormone analog for protection against premature ovar-
4
13.
14.
15.
16.
17.
18.
19.
ian failure during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum 2005;52:2761–7. ELKHALIFA A, WEINER H. Cyclophosphamide treatment of MS: current therapeutic approaches and treatment regimens. Int MS J 2010;17:12–8. MEIROW D, EPSTEIN M, LEWIS H, NUGENT D, GOSDEN RG. Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations. Hum Reprod 2001;16:632–7. PALADINI D, VASSALLO M, D’ARMIENTO MR, CIANCIARUSO B, MARTINELLI P. Prenatal detection of multiple fetal anomalies following inadvertent exposure to cyclophosphamide in the first trimester of pregnancy. Birth Defects Res A Clin Mol Teratol 2004;70:99–100. SIGNORELLO LB, MULVIHILL JJ, GREEN DM et al. Congenital anomalies in the children of cancer survivors: a report from the childhood cancer survivor study. J Clin Oncol 2012;30:239–45. RAMSEY-GOLDMAN R, MIENTUS JM, KUTZER JE, MULVIHILL JJ, MEDSGER TA Jr. Pregnancy outcome in women with systemic lupus erythematosus treated with immunosuppressive drugs. J Rheumatol 1993;20:1152–7. HARWARD LE, MITCHELL K, PIEPER C, COPLAND S, CRISCIONE-SCHREIBER LG, CLOWSE ME. The impact of cyclophosphamide on menstruation and pregnancy in women with rheumatologic disease. Lupus 2013;22: 81–6. SANDERS JE, HAWLEY J, LEVY W et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996;87:3045–52.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Clinical Commentary
Pregnancy outcomes in multiple sclerosis patients previously treated with cyclophosphamide Patti F, Messina S, D’Amico E, Lo Fermo S, Zappia M. Pregnancy outcomes in multiple sclerosis patients previously treated with cyclophosphamide. Acta Neurol Scand: DOI: 10.1111/ane.12255. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – Cyclophosphamide (Cyc) can induce ovarian failure and can have teratogenic effect. Few case reports of successful pregnancies after Cyc treatment in women with autoimmune diseases and malignancies have been described. To date, there are no data about Cyc effect on pregnancy outcomes in MS patients. Aim of the study – To describe pregnancy outcomes in multiple sclerosis (MS) patients treated with Cyc before conception. Methods – We reviewed retrospectively the medical records of all MS patients who received Cyc from 1st of January 1997 to 31st of March 2012, referring to the MS centre of the University of Catania. All pregnancies, occurred during the follow-up period after Cyc treatment, were recorded according to a computerized and standardized protocol (iMED). Results – We found a total of 105 MS women of childbearing age; eleven patients experienced a pregnancy (10.4%); 10 of them had a successful delivery; and one experienced a voluntary abortion. Five women had a preterm delivery. One child was small for gestational age. Conclusions – Although the favourable pregnancy outcomes, Cyc should be avoided in young women planning a pregnancy. However, Cyc might be considered as a possible alternative to licensed therapies in few selected cases of very aggressive MS, including women of childbearing age.
Introduction
Multiple sclerosis (MS) is a chronic T-cell-mediated inflammatory disease of the central nervous system (CNS), characterized by demyelination and axonal degeneration, affecting more women than men (1). Pregnancy can exert a positive effect on the disease course. Women experience fewer relapses during pregnancy but an increased number of relapses right after the delivery, suggesting a possible protective role of pregnancy hormones on the pathogenesis of MS (2). Based on these assumptions, sexual dimorphism in MS should be considered as a crucial aspect in the management of our patients. The majority of women with MS are of childbearing age, so the possible fertility and teratogenic effects of disease modifying drugs (DMDs) should be carefully
F. Patti*, S. Messina*, E. D’Amico, S. Lo Fermo, M. Zappia Department G.F. Ingrassia-section of Neurosciences, University of Catania, Catania, Italy
Key words: fertility; immunosuppression; multiple sclerosis; pregnancy outcome; teratogenicity; women M. Zappia, Department G.F. Ingrassia, Section of Neurosciences, Universita degli studi di Catania, Via S. Sofia 78, Catania 95123, Italy Tel.: +39 953782783 Fax: +39 953782900 e-mail: [email protected] *These authors contributed equally to this manuscript. Accepted for publication March 24, 2014
considered. Cyclophosphamide (Cyc) has been widely studied for the treatment of aggressive MS or for the stabilization of selected cases (3). It is well known that Cyc can induce ovarian failure and infertility and can also have teratogenic effect on the foetus (4–7). According to the classification of drug use during pregnancy, Cyc is classified as a category D drug (positive evidence of human foetal risk, but the benefit may outweigh the risk) (8, 9). There have been few case reports of successful pregnancy after Cyc treatment in women with autoimmune disease or malignancies (10). To date, there is no information available regarding the effect of maternal treatment with Cyc prior to pregnancy on pregnancy outcome of women with MS. We report 10 cases of successful childbearing in MS patients previously treated with Cyc. 1
Patti et al. Methods
We reviewed retrospectively the medical records of all MS patients referring to the MS centre of the University of Catania, treated with Cyc from 1st of January 1997 to 31st of March 2012. Clinical and demographic information was recorded according to computerized and standardized protocol (iMED; Serono International SA, Geneva, Switzerland) (11). We found 214 patients, 133 (62.1%) women and 81 (37.8%) men. Out of 133 female patients, 105 were between 16 and 44 years. We found 11 (10.4%) patients who experienced a pregnancy after having received Cyc treatment. Cyc was intravenously (i.v) administered from a dose of 500–1500 mg/m2 on a monthly basis according to a specific protocol previously reported (3). During Cyc administration, women were treated with leuprorelin every 3 months to induce a temporary menopause and to prevent ovarian failure (12). All the patients were affected by a clinically defined relapsing-remitting MS. All of them gave their signed written informed consent before starting therapy, after careful and detailed information on the possible risks (cancer, infertility, teratogenic effect) associated to Cyc therapy. The local ethics committee of the ‘Policlinico-Vittorio Emanuele’ hospital of Catania had previously given the approval of the off-label use of Cyc in selected cases of MS patients.
19109 11629.5 mg (min 8400 max 51700 mg) with administration of 19 doses on average (min 6, max 33). The time lapse between the last dose of Cyc and conception was an average of 3.7 1.5 years (range 0.33–5.9 years). Of the 11 cases, one patient had a voluntary abortion at 4-week gestation because the foetus was exposed to Cyc in utero. As represented in Table 1, five patients had a preterm delivery (before 37th gestational week), and one child was small for gestational age (below the 10th percentile). The patient who delivered a child small for gestational age received a total dose of 19,350 mg (higher than the mean cumulative dose of the cohort) and 24 doses (higher than the mean number of doses). The time lapse between the last dose of Cyc and conception was 72.1 months (higher than the mean time lapse in months: 44.9). The patients who had a preterm delivery received a mean cumulative dose of 13,960 mg and 17 doses on average (both lower than the mean cumulative dose and the mean number of doses of the cohort). The mean time lapse in months between the last dose of Cyc and conception was 34.5 months (lower than the mean time lapse of the whole cohort). Four patients delivered their babies via C section, whereas six patients had a natural delivery. No history of malignancies was reported in children follow-up (current mean age 2.6 2.1 years), and all children correctly achieved the developmental milestones.
Results
At the beginning of Cyc treatment, the mean age of selected women was 26.5 3.8 years (range 22–36). The age at the time of conception was 31.6 2.7 years (range 28–38). They received an average cumulative dose of Cyc of
Discussion
Cyc is commonly used to treat malignancies and several autoimmune diseases, including MS, although it does not have a formal Food and Drug Administration and European Medicines
Table 1 Clinical characteristics and pregnancy outcomes
Disease category 1 2 3 4 5 6 7 8 9 10 11
RR RR RR RR RR RR RR RR RR RR RR
Age at beginning of Cyc (years)
Number of relapse 1 year before Cyc
EDSS before Cyc
Cumulative dose (mg)
Lapse of time Therapy-pregnancy (months)
Age at beginning of pregnancy (years)
Week of gestation (number)
Baby weight (g)
Delivery (V/C)
26 23 26 28 27 28 24 22 28 36 24
2 1 1 4 2 1 3 2 1 1 6
4 1 2 1.5 2 1.5 2 1.5 1.5 2 3.5
16,500 19,350 15,700 16,500 12,700 8400 11,950 51,700 24,000 13,350 20,050
42.7 72.1 4.0 37.6 42.7 45.6 65.3 54.4 41.4 N.A. 43.3
33 31 28 30 32 32 30 30 34 38 30
37 40 36 29 35 37 38 39 38 N.A. 41
3200 2500 2870 3100 2900 3115 3100 3600 2930 N.A. 3380
C V V V C C C V V N.A. V
RR, relapsing remitting; Cyc, cyclophosphamide; V/C, vaginalis/C section; N.A., not applicable.
2
Cyclophosphamide and pregnancy in multiple sclerosis Agency approval for MS. Cyc can promote a switch towards a Th2 response, by increasing the production of IL-4, IL-5, IL-10 and decreasing the levels of IFNm and IL-12 (13). Ovarian failure is one of the most common side effects of Cyc treatment in women of childbearing age. Nevertheless, many authors reported successful pregnancies after Cyc treatment in lupus and chronic myeloid leukaemia patients (10). Animal studies have demonstrated Cyc can affect female germ cells, inducing genetic abnormalities, raising concerns regarding the risk of abortion and congenital abnormalities. It has been shown in mice that the effect of Cyc on fertility and malformation depends on the time of exposure to treatment and on oocyte maturation, showing a higher rate of pregnancy failures and malformations in mice treated 1 week before mating (14). Cases of teratogenesis induced by inadvertent exposure to Cyc during the first trimester of pregnancy have been described in women affected by lupus (15). The most common observed malformations are hydrocephalus, microretrognathia, ectrodactyly, cleft palate and exencephaly (6). However, a cohort study did not show increased risk of congenital abnormalities among offspring of cancer survivors, treated with radiotherapy or an alkylating agent, suggesting that possibly a long lapse of time between exposure and pregnancy could induce DNA mechanism repair in primordial follicles (14, 16). Ramsey-Goldman et al. (17) reported pregnancy outcome of systemic lupus erythematosus patients who received immunosuppressive agents 3 years before conception, suggesting that a long period of time between treatment and conception could not affect both fertility and foetal development. Furthermore, they did not report any history of malignancies in children. Our patients were young and received Cyc treatment in the earlier phases of MS (see Table 1). They become pregnant with a time lapse between last Cyc administration to conception of about 3 years. Considering that the prevalence of ovarian failure increases with age (5), we can hypothesize that young age at the time of treatment can reduce the risk of amenorrhoea and infertility due to Cyc therapy. A recent study showed women with rheumatologic disease receiving GnRH during Cyc treatment were more likely to have regular menses (18). The use of leuprorelin and a longer lapse of time between Cyc administration and conception could be related to a recovery of the impaired ovarian function and to a reduced negative impact on foetal development.
Of the 10 cases, four patients had a preterm delivery and one child was small for age. Despite the possible teratogenic effect of Cyc, none of the children presented any birth defects or a delay in the achievement of developmental milestones. However, Cyc could exert long-term teratogenic effects, although the babies had not been exposed to Cyc in utero, and thus, we cannot exclude possible effects in the future. Moreover, the determination of possible adverse effect on children born from women exposed to Cyc requires longer, additional follow-up as previously reported for different diseases (19). Given the small number of patients in our cohort and the relative short follow-up period of children, definitive conclusions cannot be drawn. Although our findings seem to support that previous Cyc exposure does not affect pregnancy outcomes, we suggest that until information regarding safety is available, Cyc should be avoided in young women planning a pregnancy and a birth control method should be always required. On the grounds of our experience reporting favourable pregnancy outcomes in women who had been previously exposed to Cyc, its use in few selected cases of very aggressive MS, including women of childbearing age, could be considered as a possible alternative to licensed therapies for MS. Funding
This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors. Acknowledgements The authors have no acknowledgements to declare.
Conflict of interest None.
References 1. WEINSHENKER BG, BASS B, RICE GP et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989;112(Pt 1):133–46. 2. TSUI A, LEE MA. Multiple sclerosis and pregnancy. Curr Opin Obstet Gynecol 2011;23:435–9. 3. PATTI F, CATALDI ML, NICOLETTI F, REGGIO E, NICOLETTI A, REGGIO A. Combination of cyclophosphamide and interferon-beta halts progression in patients with rapidly transitional multiple sclerosis. J Neurol Neurosurg Psychiatry 2001;71:404–7.
3
Patti et al. 4. WANG CL, WANG F, BOSCO JJ. Ovarian failure in oral cyclophosphamide treatment for systemic lupus erythematosus. Lupus 1995;4:11–4. 5. BOUMPAS DT, AUSTIN HA 3rd, VAUGHAN EM, YARBORO CH, KLIPPEL JH, BALOW JE. Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 1993;119:366–9. 6. OZOLINS TR. Cyclophosphamide and the Teratology Society: an awkward marriage. Birth Defects Res B Dev Reprod Toxicol 2010;89:289–99. 7. ENNS GM, ROEDER E, CHAN RT, ALI-KHAN CATTS Z, COX VA, GOLABI M. Apparent cyclophosphamide (cytoxan) embryopathy: a distinct phenotype? Am J Med Genet 1999;86:237–41. 8. US Food and Drug Administration. Requirements on content and format of labeling for human prescription drug and biological products. Final rule. Fed Reg. 2006;71:3921–97. 9. HOUTCHENS MK, KOLB CM. Multiple sclerosis and pregnancy: therapeutic considerations. J Neurol 2013;260: 1202–14. 10. GUPTA R, DEEPANJALI S, THABAH MM, KAUR P, GUPTA S. Successful twin pregnancy while on cyclophosphamide therapy in a patient with lupus nephritis. Rheumatol Int 2009;29:1503–5. 11. MECHATI SP-S-PH. iMed: a new electronic database for monitoring patients with multiple sclerosis. Mult Scler 2001;7:S31. 12. SOMERS EC, MARDER W, CHRISTMAN GM, OGNENOVSKI V, MCCUNE WJ. Use of a gonadotropin-releasing hormone analog for protection against premature ovar-
4
13.
14.
15.
16.
17.
18.
19.
ian failure during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum 2005;52:2761–7. ELKHALIFA A, WEINER H. Cyclophosphamide treatment of MS: current therapeutic approaches and treatment regimens. Int MS J 2010;17:12–8. MEIROW D, EPSTEIN M, LEWIS H, NUGENT D, GOSDEN RG. Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations. Hum Reprod 2001;16:632–7. PALADINI D, VASSALLO M, D’ARMIENTO MR, CIANCIARUSO B, MARTINELLI P. Prenatal detection of multiple fetal anomalies following inadvertent exposure to cyclophosphamide in the first trimester of pregnancy. Birth Defects Res A Clin Mol Teratol 2004;70:99–100. SIGNORELLO LB, MULVIHILL JJ, GREEN DM et al. Congenital anomalies in the children of cancer survivors: a report from the childhood cancer survivor study. J Clin Oncol 2012;30:239–45. RAMSEY-GOLDMAN R, MIENTUS JM, KUTZER JE, MULVIHILL JJ, MEDSGER TA Jr. Pregnancy outcome in women with systemic lupus erythematosus treated with immunosuppressive drugs. J Rheumatol 1993;20:1152–7. HARWARD LE, MITCHELL K, PIEPER C, COPLAND S, CRISCIONE-SCHREIBER LG, CLOWSE ME. The impact of cyclophosphamide on menstruation and pregnancy in women with rheumatologic disease. Lupus 2013;22: 81–6. SANDERS JE, HAWLEY J, LEVY W et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996;87:3045–52.
