Background

Recent US estimates suggest that the prevalence of multiple sclerosis (MS) is nearly 3 times higher in women, many of childbearing age. Oral delayed-release dimethyl fumarate (DMF) has demonstrated a favorable benefit-risk profile in trials and post-marketing surveillance. DMF should be used in pregnant women with MS only if the potential benefit justifies the potential risk to the fetus.

Objectives

To provide pregnancy outcomes and DMF exposure data as of 08 April 2020 in women with MS treated with DMF in an ongoing prospective international registry (NCT01911767, TecGistry).

Methods

Women exposed to DMF from the first day of their last menstrual period before conception or during pregnancy were evaluated. Data were obtained at enrolment, 6−7 months of gestation, 4 weeks after estimated due date, and 4, 12 and 52 weeks after birth. As reported previously, outcomes included live births, pregnancy loss, ectopic/molar pregnancies, birth defects and anomalies, and infant or maternal death after delivery. Gestational weight was classified by percentile (<10^th, 10^th−90^th, >90^th) based on standardized growth charts.

Results

As of 08 April 2020, 345 patients were enrolled, with a median age of 32 years. Median gestational week at first exposure to DMF was 1 (range: 0, 13) and at enrollment was 9 (0, 39.3). Median (range) duration of fetal DMF exposure duration was 5 (0, 40) weeks. Among discontinuations, one was due to a serious AE. Of the known outcomes, 277 were live births (122 with 52 weeks of follow-up), 19 fetal losses including 1 molar and 1 ectopic pregnancy resulting in spontaneous abortions. One neonatal death and no maternal deaths were reported. Of 274 infants of known gestational age, 249 (91%) were full term, and 25 (9%) premature (<37 weeks). Gestational weight data were available for 232 infants, of whom 26 (11%) were small, 190 (82%) appropriate, and 16 (7%) large. Overall, 8 infants had adjudicator-confirmed birth defects, including ventricular septal defect, congenital hydronephrosis, ureteral duplication, pyloric stenosis, transposition of the great vessels, unilateral developmental dysplasia of the hip, and 1 premature infant with multiple birth defects.

Conclusions

The pregnancy outcome frequencies observed in this updated analysis were consistent with previous reports and did not exceed those seen in the MS and general populations. No additional safety signals were identified.

Supported by: Biogen

Background

Interferon-betas (IFN-β) are cytokines, glatiramer acetate (GA) is a synthetic polypeptide. Both substances are large molecules and lack oral bioavailability. As of September 2019, IFN-β are the first and up to now the only multiple sclerosis (MS) therapy approved also during lactation. Published data are restricted but show only minimal concentrations of the drug in human milk. No data on GA excretion are available, but it seems unlikely the substance would pass into breast milk. Although the risk for the infant is most likely negligible, data on breastfeeding under IFN-β or GA are very restricted. The effects on infant development and health as well as on maternal relapse risk postpartum are yet unknown.

Objectives

To assess the safety of maternal IFN-β 1a or GA administration during lactation for the breastfed infant as well as to assess its effect on the occurrence of postpartum relapses.

Methods

So far, we identified 34 infants (one pair of twins) who were breastfed under GA and 28 infants who were breastfed under IFN-β 1a from the German MS and pregnancy registry (DMSKW). Cases were followed-up for at least one year postpartum. Data was generated via standardized interviews, conducted with the mother during pregnancy as well as at 1, 3, 6 and 12 months postpartum.

Results

Identification, inclusion and follow-up of additional cases are still ongoing; updated data as well as analysis of the total cohorts will be presented at the congress. Among the infants breastfed under GA there was no case of developmental delay, in the IFN-β 1a cohort there was one report of a delay regarding motor skills (4 %). Medians of weight, length and head circumference at several medical check-ups during the first year of life lay within the normal range (3^rd and 97^th percentile) of reference values for both cohorts. Hospitalizations and antibiotic treatments occurred only rarely. Within the first year postpartum 7 (21 %) women relapsed in the GA cohort as well as 7 (25 %) in the IFN-β 1a cohort.

Conclusions

Our preliminary analysis revealed no hints that treatment with GA or IFN-β 1a during lactation negatively affects development or health of breastfed infants. The effect on postpartum relapses has still to be determined. Our results support the recent label extension of IFN-β and suggest that treatment with GA is probably compatible with breastfeeding as well.

Background

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody associated disease (MOG-AD) are orphan diseases with high impact on quality of life and to date unknown socio-economic burden.

Objectives

The aim of this study was to evaluate costs and health-related quality of life of NMOSD and MOG-AD from the societal perspective.

Methods

In a multicenter cross-sectional study throughout Germany between 04/2017 and 04/2019, the primary data on retrospective consumption of medical and non-medical resources and work ability related to NMOSD and MOG-AD were assessed via standardized and pre-tested paper-based patient questionnaires. Health-related quality of life was captured by the EuroQoL Group EQ-5D-5L questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database. Patient recruitment took place at 17 German NEMOS centers. Costs were analyzed in EUR for 2018.

Results

During the recruitment period, 218 of 275 adult patients were screened for eligibility. 212 patients (80.2% women; mean age 49 ± SD 15 years; mean disease duration 9 ± SD 8.5 years; Expanded Disability Status Scale (EDSS) 3.7 ± SD 2.1) were analyzed. The mean total annual per capita cost of illness accounted for EUR 59 576 and the mean index value of the EQ-5D-5L was 0.693. Given an estimated prevalence of NMOSD in Germany of 1.3/100 000, the annual burden from the societal perspective adds to EUR 64.3 Mio for Germany. The most important cost drivers were informal care costs (27.6% of total costs), indirect costs (23.3%; particularly loss of salary) and drugs, especially immunotherapeutics (16.4%). Costs showed a significant positive correlation with disease severity (p<0.0001); in the EDSS 6.5-8.5 subgroup the annual costs were EUR 129 436. Moreover, the health-related quality of life revealed a negative correlation with disease severity (p<0.0001); in the EDSS 6.5-8.5 subgroup the mean index value was 0.195.

Conclusions

These German data from the era without approved standard medications show enormous effects of the disease on costs and quality of life and might be helpful for estimating the impact and cost-effectiveness of new therapeutic approaches.

Background

“Spinal pain”, girdle-like dysesthesia, and painful spasms were noted already in earliest disease descriptions in the 18^th century. Nowadays it has become clear that pain is a frequent and one of the most disabling symptoms in these patients. Due to the rarity of NMOSD most previous studies of pain and depression were relatively small or included a mixed population AQP4-IgG-seropositive and seronegative patients, while recent clinical trials clearly indicate that pathogenetic mechanisms are different in these forms.

Objectives

To evaluate prevalence, clinical characteristics and predictive factors of pain, depression and their impact on the quality of life (QoL) in a large European seropositive neuromyelitis optica spectrum disease (NMOSD) cohort.

Methods

We included 166 patients with aquaporin-4-seropositive NMOSD from 13 tertiary referral centers of Neuromyelitis Optica Study Group (NEMOS). Clinical data, including expanded disability status scale and localization of spinal lesions on MRI, were retrieved from the NEMOS database or local electronic patient records. Data on pain, depression and quality of life were captured by self-reporting questionnaires.

Results

125 (75.3%) patients suffered from chronic NMOSD-associated pain. Of these, 65.9% had neuropathic pain, 68.8% reported spasticity-associated pain and 26.4% painful tonic spasms. Number of previous myelitis attacks (OR 1.27, p=0.018) and involved upper thoracic segments (OR 1.31, p=0.018) were the only predictive factors for chronic pain. Interestingly, the latter was specifically associated with spasticity-associated (OR 1.36, p=0.002), but not with a neuropathic pain. 39.8% suffered from depression (moderate to severe in 51.5%). Pain severity (OR 1.81, p<0.001) and especially neuropathic character (OR 3.44, P<0.001) were strongly associated with depression. 70.6% of patients with moderate or severe depression and 42.5% of those with neuropathic pain had no specific medications. 64.2% of those under symptomatic treatment still reported moderate to severe pain. Retrospectively, 39.5% of pain-sufferers reported improvement of pain after start of immunotherapy: 37.3% under rituximab, 40.0% under azathioprine, 33.3% under mycophenolate mofetil and 66.7% under tocilizumab. However, there was no difference in terms of pain prevalence or intensity in patients with different immunotherapies. Pain intensity, walking impairment and depression could explain 56% of the physical QoL variability, while depression was the only factor, explaining 46% of the mental QoL variability.

Conclusions

Myelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD. Although pain intensity was lower than in previous studies, pain and depression remain undertreated and strongly affect QoL. Interventional studies on targeted treatment strategies for pain are urgently needed in NMOSD.

Background

Assessment of the impact of fingolimod exposure on pregnancy outcomes is essential for the management of multiple sclerosis in pregnant women or those planning to conceive.

Objectives

To report the prevalence of major congenital malformations (MCMs) in infants following fingolimod exposure before (up to 8 weeks before last menstrual period) or during pregnancy.

Methods

Cumulative pregnancy outcome data are reported from prospective cases in the Novartis Safety database (NSDB) and Multinational Gilenya^®Pregnancy Exposure Registry (GPR, which comprises a subset of NSDB cases also). For data in the NSDB and GPR, prospective cases were those for which pregnancy outcome was unknown and condition of the fetus was not assessed through prenatal testing at the time of enrolment. For the NSDB, if prenatal testing was not performed and results were either normal/not known, cases were also considered prospective. The prevalence (95% confidence interval [CI]) of MCMs in live births was estimated.

Results

As of 28^th February 2020, 1762 prospective cases of maternal fingolimod exposure during pregnancy were reported in the NSDB and 177 in the GPR. Of all pregnancies with a known outcome, live births were: 754 (70.9%) in NSDB and 130 (85.0%) in GPR. Estimated prevalence of MCMs among live births was 3.19% (95% CI: 2.05; 4.71) in the NSDB and 4.6% (95% CI: 1.7; 9.8) in the GPR. As per recent meta-analysis, MCM prevalence in untreated MS is estimated to be 4.2% (95% CI: 2.7; 6.1), which is in line with that reported in this study. As per European Registration of Congenital Anomalies and Twins (EUROCAT), MCM prevalence in general population is 2.6% (95% CI: 2.6; 2.6). No clear discernible pattern of specific malformation was observed in the GPR. In the NSDB, the estimate of the proportion of live births with major cardiovascular anomalies (1.33% [95% CI: 0.64; 2.43]) was larger than, but not significantly different from the corresponding EUROCAT prevalence estimate (0.69%). This may be attributable to the difference in data collection and processing methodologies between EUROCAT and the NSDB.

Conclusions

The overall prevalence estimates of MCMs among live births in the NSDB and GPR are similar to that from the untreated MS population. Although both prevalence estimates are higher than the EUROCAT general population prevalence, it is within 95% CIs for both databases. The wide 95% CI in the GPR prevents firm conclusions regarding increased risk of MCMs in fingolimod exposed patients.

Background

In disease modifying therapy (DMT)-unexposed pregnancies of multiple sclerosis (MS) patients, relapse rate decreases significantly during pregnancy, followed by an increase in the first 12 weeks postpartum, but little is known about the relapse pattern and the associated steroid use in interferon-β (IFN-β) -exposed pregnancies, which might not show the typical disease course.

Objectives

To determine disease activity during pregnancy in women with MS and IFN-β treatment 12 months prior to the last menstrual period (LMP).

Methods

Pregnancies were prospectively collected in the German MS and pregnancy registry up to 10.2018. Pregnancies with a duration of at least 22 gestational weeks and IFN-β treatment 12 months prior to conception were compared in two groups: pre-LMP group stopping IFN-β between 365 and 1 day before LMP and post-LMP group stopping IFN-β between LMP and 84 days afterwards.

Results

We identified 47 pregnancies in pre-LMP group and 165 pregnancies in post-LMP group, without differences in baseline characteristics (age, BMI, disease duration, IFN-β treatment duration, annualized relapse rate (ARR) before pregnancy) and a median postpartum follow up of 610 days (range 17 – 2,799). 35 of 212 women (16.5%) had at least one relapse during pregnancy, 14 (29.8%) in pre-LMP group and 21 (12.7%) in post-LMP group (p=0.011). 14 (6.6%) women experienced a relapse in trimester 1, 21 (9.9%) in trimester 2 and 7 (3.3%) in trimester 3. Notably, significantly more women in the pre-LMP group experienced a relapse in trimester 2 (OR= 4.68, CI[1.82;12.2], p=0.002). Corticosteroid use did not differ significantly between groups; neither in overall pregnancy (p= 0.399) nor per trimena (trimester 1: p= 0.686, trimester 2: p= 0.266, trimester 3: p= 0.124).
214 pregnancy outcomes were observed (including two twin pregnancies). Preterm births differed significantly with more preterm births in the pre-LMP group (pre-LMP: 8/17.02%; post-LMP: 10/6.06%; OR 3.12, p=0.03). Medically confirmed major malformations did not differ between groups (pre-LMP: 1/47 (2.13%); post-LMP: 7/167 (4.20%); OR: 0.433, p=0.687)). No stillbirth was observed.

Conclusions

The withdrawal of IFN-β before pregnancy is associated with a higher relapse risk, especially in trimester 2 and a higher chance of preterm birth, though not higher steroid use during pregnancy, but more data is needed. At the time of the meeting, updated results on disease activity especially relapse rates will be presented.

Background

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for the treatment of relapsing and primary progressive multiple sclerosis (MS). As many MS patients are women of reproductive age, pregnancy outcomes in OCR-exposed patients are of relevance.

Objectives

To report an update on pregnancy outcomes in women with MS receiving OCR in clinical trials and post-marketing.

Methods

Analysis includes pregnancies in women receiving OCR in clinical trials/post-marketing (global safety database). Women of childbearing potential should use contraception while on treatment and for 6 or 12 months after the last OCR infusion, depending on local regulations. Based on the average terminal half-life of 26 days and the lack of relevant placental transfer in the 1^st trimester, a fetus was considered to have fetal OCR exposure if the last infusion occurred within 3 months of conception, during pregnancy, or if the date was unknown.

Results

As of March 27, 2020, 726 total pregnancies exposed to OCR in women with MS (n=608) or unknown indication (n=118) were reported. Of the 608 MS pregnancies, 234 were considered to have fetal OCR exposure, 102 were not, and 272 had unknown exposure. Preliminary outcomes of total MS pregnancies (n/%) were: 156/64.2% live births, 37/15.2% elective/therapeutic abortions, 42/17.3% spontaneous abortions, 3/1.2% stillbirths, 5/2.1% ectopic pregnancies; 134 pregnancies were ongoing, 80 lost to follow-up (FU) and 151 had unknown/not reported (NR) outcomes. Of the 156 total live births, 6 congenital malformations were reported. Preliminary outcomes of MS pregnancies with fetal OCR exposure (n/%) were: 62/59.6% live births, 24/23.1% elective/therapeutic abortions, 15/14.4% spontaneous abortions, 2/1.9% stillbirths, 1/1.0% ectopic pregnancies; 55 pregnancies were ongoing, 37 lost to FU and 38 had unknown/NR outcomes. Infant health questionnaires were received from 13 live births with up to 1-year FU and will continue to be collected, including data on vaccinations and infections: 9 infants had no infections and 1 had a resolved infection.

Conclusions

Cases reviewed to date do not suggest an increased risk of adverse pregnancy outcomes (including spontaneous abortions or malformations) with OCR use, whether or not fetal exposure occurred or was unknown. The updated outcomes remain in line with prior reports and within the expected epidemiologic range. Data continue to be collected and assessed as per post-authorization commitments.

Background

Recent US estimates suggest that the prevalence of multiple sclerosis (MS) is nearly 3 times higher in women, many of childbearing age. Oral delayed-release dimethyl fumarate (DMF) has demonstrated a favorable benefit-risk profile in trials and post-marketing surveillance. DMF should be used in pregnant women with MS only if the potential benefit justifies the potential risk to the fetus.

Objectives

To provide pregnancy outcomes and DMF exposure data as of 08 April 2020 in women with MS treated with DMF in an ongoing prospective international registry (NCT01911767, TecGistry).

Methods

Women exposed to DMF from the first day of their last menstrual period before conception or during pregnancy were evaluated. Data were obtained at enrolment, 6−7 months of gestation, 4 weeks after estimated due date, and 4, 12 and 52 weeks after birth. As reported previously, outcomes included live births, pregnancy loss, ectopic/molar pregnancies, birth defects and anomalies, and infant or maternal death after delivery. Gestational weight was classified by percentile (<10^th, 10^th−90^th, >90^th) based on standardized growth charts.

Results

As of 08 April 2020, 345 patients were enrolled, with a median age of 32 years. Median gestational week at first exposure to DMF was 1 (range: 0, 13) and at enrollment was 9 (0, 39.3). Median (range) duration of fetal DMF exposure duration was 5 (0, 40) weeks. Among discontinuations, one was due to a serious AE. Of the known outcomes, 277 were live births (122 with 52 weeks of follow-up), 19 fetal losses including 1 molar and 1 ectopic pregnancy resulting in spontaneous abortions. One neonatal death and no maternal deaths were reported. Of 274 infants of known gestational age, 249 (91%) were full term, and 25 (9%) premature (<37 weeks). Gestational weight data were available for 232 infants, of whom 26 (11%) were small, 190 (82%) appropriate, and 16 (7%) large. Overall, 8 infants had adjudicator-confirmed birth defects, including ventricular septal defect, congenital hydronephrosis, ureteral duplication, pyloric stenosis, transposition of the great vessels, unilateral developmental dysplasia of the hip, and 1 premature infant with multiple birth defects.

Conclusions

The pregnancy outcome frequencies observed in this updated analysis were consistent with previous reports and did not exceed those seen in the MS and general populations. No additional safety signals were identified.

Supported by: Biogen

Background

Assessment of the impact of fingolimod exposure on pregnancy outcomes is essential for the management of multiple sclerosis in pregnant women or those planning to conceive.

Objectives

To report the prevalence of major congenital malformations (MCMs) in infants following fingolimod exposure before (up to 8 weeks before last menstrual period) or during pregnancy.

Methods

Cumulative pregnancy outcome data are reported from prospective cases in the Novartis Safety database (NSDB) and Multinational Gilenya^®Pregnancy Exposure Registry (GPR, which comprises a subset of NSDB cases also). For data in the NSDB and GPR, prospective cases were those for which pregnancy outcome was unknown and condition of the fetus was not assessed through prenatal testing at the time of enrolment. For the NSDB, if prenatal testing was not performed and results were either normal/not known, cases were also considered prospective. The prevalence (95% confidence interval [CI]) of MCMs in live births was estimated.

Results

As of 28^th February 2020, 1762 prospective cases of maternal fingolimod exposure during pregnancy were reported in the NSDB and 177 in the GPR. Of all pregnancies with a known outcome, live births were: 754 (70.9%) in NSDB and 130 (85.0%) in GPR. Estimated prevalence of MCMs among live births was 3.19% (95% CI: 2.05; 4.71) in the NSDB and 4.6% (95% CI: 1.7; 9.8) in the GPR. As per recent meta-analysis, MCM prevalence in untreated MS is estimated to be 4.2% (95% CI: 2.7; 6.1), which is in line with that reported in this study. As per European Registration of Congenital Anomalies and Twins (EUROCAT), MCM prevalence in general population is 2.6% (95% CI: 2.6; 2.6). No clear discernible pattern of specific malformation was observed in the GPR. In the NSDB, the estimate of the proportion of live births with major cardiovascular anomalies (1.33% [95% CI: 0.64; 2.43]) was larger than, but not significantly different from the corresponding EUROCAT prevalence estimate (0.69%). This may be attributable to the difference in data collection and processing methodologies between EUROCAT and the NSDB.

Conclusions

The overall prevalence estimates of MCMs among live births in the NSDB and GPR are similar to that from the untreated MS population. Although both prevalence estimates are higher than the EUROCAT general population prevalence, it is within 95% CIs for both databases. The wide 95% CI in the GPR prevents firm conclusions regarding increased risk of MCMs in fingolimod exposed patients.