Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy

Sandberg‐Wollheim, Magnhild; Alteri, Enrica; Moraga, Margaretha Stam; Kornmann, Gabrielle

doi:10.1177/1352458510394610

Cited by 115 publications

(87 citation statements)

References 19 publications

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“…In a recent study, 425 pregnancies had in utero exposure to interferon b with 324 healthy births, 5 congenital abnormalities (4 live births, 1 stillbirth), and 49 spontaneous abortions. 28 A similar pattern was observed in an earlier study in which 41 pregnancies were exposed in utero to interferon b, resulting in 20 healthy offspring, 1 congenital anomaly (hydrocephalus), 1 fetal death, and 8 spontaneous abortions. 29 Two further studies in which in utero exposure to interferon b occurred (n 5 88, n 5 69) reported no significant drug-related congenital defects.…”

Section: (78)supporting

confidence: 55%

Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis

et al. 2014

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Objective: To report outcomes of pregnancies that occurred during the fingolimod clinical development program.Methods: Pregnancy outcomes from phase II, phase III, and phase IV clinical studies (with optional extensions) were reported by clinical trial investigators. Fingolimod exposure in utero was defined as fingolimod treatment at the time of conception or in the 6 weeks before conception.Results: As of October 31, 2011, 89 pregnancies were reported in completed or ongoing clinical studies, with 74 in fingolimod treatment arms. Of 66 pregnancies with in utero exposure to fingolimod, there were 28 live births, 9 spontaneous abortions, 24 elective abortions, 4 ongoing pregnancies, and 1 pregnancy with an unknown outcome (patient lost to follow-up). Two infants were born with malformations: 1 with congenital unilateral posteromedial bowing of the tibia and 1 with acrania. Elective abortions were performed for 1 case each of tetralogy of Fallot, spontaneous intrauterine death, and failure of fetal development. There were 5 cases (7.6%; 95% confidence interval 3%-17%) of abnormal fetal development in the 66 pregnancies that had in utero exposure to fingolimod. In all 5 cases, fetal exposure to the drug took place in the first trimester of pregnancy. Conclusions:The number of patients becoming pregnant during fingolimod therapy remains small and does not permit firm conclusions to be drawn about fetal safety of fingolimod in humans. Given the known risks of teratogenicity in animals and the present data, women of childbearing potential should use effective contraception during fingolimod therapy and for 2 months after discontinuation. Neurology ® 2014;82:674-680 GLOSSARY CI 5 confidence interval; MS 5 multiple sclerosis.Multiple sclerosis (MS) is predominant among women of reproductive age, in whom approximately 50% of all pregnancies are unplanned.1 Fingolimod (FTY720; Gilenya, Novartis Pharma AG, Basel, Switzerland) is a sphingosine 1-phosphate receptor modulator that has been approved as a once-daily oral therapy for relapsing MS. Two phase II studies, 3 large-scale phase III studies, and their ongoing extension studies have indicated that fingolimod has a manageable safety profile and is generally well tolerated at the approved dose of 0.5 mg. [2][3][4][5][6] As preclinical studies indicate a risk of fetal toxicity, 7 fingolimod clinical study protocols require a negative pregnancy test at enrollment and that women of childbearing potential use reliable contraception throughout the studies. We report the outcomes of pregnancies that occurred in the fingolimod clinical development program despite these measures.METHODS Standard protocol approvals, registrations, and patient consents. Pregnancy outcomes are reported from 9 clinical studies in patients with relapsing MS: the phase III FREEDOMS study 3

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Section: (78)supporting

confidence: 55%

Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis

et al. 2014

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“…This finding may be explained by subclinical levels of circulating AQP4-IgG, which may be present years before clinical presentation. 24,25 The miscarriage rate of 42.9% is outside the 95% CI that would be expected if the true miscarriage rate post-NMOSD was equal to reported rates in multiple sclerosis (expected 95% CI 1.29%-40.9%) 26,27 and just within the expected range calculated from published rates in systemic lupus erythematosus (expected 95% CI 2.56%-45.5%). 28 This suggests that the miscarriage rate in patients with NMOSD is higher than in patients with multiple sclerosis, although larger prospective studies with adequate control groups are needed to test this hypothesis.…”

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confidence: 65%

Pregnancy outcomes in aquaporin-4–positive neuromyelitis optica spectrum disorder

et al. 2016

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Objective: To investigate the association between neuromyelitis optica spectrum disorder (NMOSD) and pregnancy outcome.Methods: An international cohort of women with aquaporin-4 antibody-positive NMOSD and $1 pregnancy was studied retrospectively. Multivariate logistic regression was used to investigate whether pregnancy after NMOSD onset was associated with an increased risk of miscarriage (cohort of 40 women) or preeclampsia (cohort of 57 women).Results: Miscarriage rate was higher in pregnancies after NMOSD onset (42.9% [95% confidence interval 17.7%-71.1%] vs 7.04% [2.33%-15.7%]). Pregnancies conceived after, or up to 3 years before, NMOSD onset had an increased odds ratio of miscarriage (7.28 [1.03-51.6] and 11.6 [1. , respectively), independent of maternal age or history of miscarriage. Pregnancies after, or up to 1 year before, NMOSD onset ending in miscarriage were associated with increased disease activity from 9 months before conception to the end of pregnancy, compared to viable pregnancies (mean annualized relapse rate 0.707 vs 0.100). The preeclampsia rate (11.5% [6.27%-18.9%]) was significantly higher than reported in population studies. The odds of preeclampsia were greater in women with multiple other autoimmune disorders or miscarriage in the most recent previous pregnancy, but NMOSD onset was not a risk factor.Conclusions: Pregnancy after NMOSD onset is an independent risk factor for miscarriage, and pregnancies conceived at times of high disease activity may be at increased risk of miscarriage. Women who develop NMOSD and have multiple other autoimmune disorders have greater odds of preeclampsia, independent of NMOSD onset timing. Neurology ® 2016;86:79-87 GLOSSARY AQP4 5 aquaporin-4; ARR 5 annualized relapse rate; CI 5 confidence interval; IgG 5 immunoglobulin G; NMO 5 neuromyelitis optica; NMOSD 5 neuromyelitis optica spectrum disorder; ON 5 optic neuritis; OR 5 odds ratio.Neuromyelitis optica spectrum disorder (NMOSD) is a severe recurrent antibody-mediated inflammatory disorder of the CNS, mainly characterized by optic neuritis (ON) and longitudinally extensive transverse myelitis, 1 but also affecting other areas in the CNS (e.g., brainstem and hypothalamus). The presence of immunoglobulin G (IgG) that binds to aquaporin-4 (AQP4), 2,3 known to be key in the pathogenic process of this disorder, distinguishes NMOSD from other CNS inflammatory disorders.1 NMOSD is up to 8 times more prevalent in women, 4 many of whom have active disease during childbearing years. [5][6][7] Recently, experimental and clinical reports have demonstrated the presence of AQP4 in human and animal placenta, and have linked AQP4-mediated placental inflammation to fetal death. [8][9][10] It is clear that the annualized relapse rate (ARR) of NMOSD is significantly increased in the 0-to 3-month postpartum period, 11-13 but there is a lack of information on the influence of NMOSD on the course of pregnancy.We investigated the effect of NMOSD on miscarriage and preeclampsia rates using multivariate logistic regre...

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“…Boskovic et al [4] showed that the usage of IFNb in the first 3 months of pregnancy caused foetal loss and low birth weight when compared to healthy pregnant control group and unexposed pregnant women with MS. On the contrary, Hellwig et al [17] stated that congenital anomalies were in the normal rate in pregnant women used IFNb and concluded the drug not to have any teratogenic risk. Sandberg-Wollhem et al [40] investigated the teratogenic effects of IFNb-1a on 425 MS patients treated with IFNb-1a in the process of pregnancy by injection under the skin for at least 45 days. They determined 49 spontaneous abortions, 4 stillbirth and 4 children with congenital anomalies; the incidence of spontaneous abortion and congenital anomalies have been noted within normal range.…”

Section: Discussionmentioning

confidence: 99%

The potential teratogenic effects of interferon beta-1a and interferon beta-1b on in vitro embryonic development

et al. 2016

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Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy

Cited by 115 publications

References 19 publications

Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis

Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis

Pregnancy outcomes in aquaporin-4–positive neuromyelitis optica spectrum disorder

The potential teratogenic effects of interferon beta-1a and interferon beta-1b on in vitro embryonic development

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