Early postpartum treatment strategies and early postpartum relapses in women with active multiple sclerosis.

BACKGROUND: Relapse risk after delivery is increased in women with active multiple sclerosis (MS), the best strategy to reduce it is unknown. We aimed to assess the association of four different postpartum strategies with relapses during the first 6 months post partum. METHODS: This cohort study includes data prospectively collected through structured telephone interviews from the German Multiple Sclerosis and Pregnancy Registry. Pregnancies with active MS (fingolimod or natalizumab treatment OR relapse within 1 year before pregnancy) and postpartum follow-up of ≥6 months were included. We compared four strategies: (1) intention to breastfeed exclusively without disease-modifying therapy (DMT) (exclusive breast feeding ≥2 months or switching to non-exclusive/weaning within 2 weeks after a relapse during the first 2 months), (2) early treatment with natalizumab/fingolimod and (3) other DMT initiated within 6 weeks post partum before a relapse. If women did not or only partially breastfed, or started DMT≤6 weeks after delivery after a relapse or later, we assumed (4) no-DMT-no-exclusive- breastfeeding-strategy. Main outcome was time to postpartum MS relapses. RESULTS: In 867 women with 911 pregnancies, most (n=416) intended to breastfeed exclusively or had no-DMT-no-exclusive-breastfeeding-strategy (n=290); fewer started fingolimod (n=38), natalizumab (n=74) or another DMT (n=93) early. Recurrent time-to-event analysis showed a statistically significant reduction in relapse hazard only with the natalizumab/fingolimod-strategy as of months 3-4 post partum compared with intention-to-breastfeed-exclusively-strategy. The very early relapse risk was highest in no-DMT-no-exclusive-breastfeeding-strategy. CONCLUSION: In active MS, an early postpartum treatment strategy should be determined well before delivery. Natalizumab/fingolimod-strategy reduced postpartum relapse hazard from month 3, but none diminished the early postpartum relapse hazard.

Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions.

OBJECTIVE: Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. METHODS: Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients' questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. RESULTS: The median average concentration of mAb in breastmilk was low (OCR: 0.08 µg/mL, range 0.05-0.4; RTX: 0.03 µg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was <1% (OCR: 0.1%, range 0.07-0.7; RTX: 0.04%, range 0.005-0.3). Forty-three participants continued to breastfeed post-infusion. At 8-12 months, the proportion of infants' growth between the 3rd and 97th World Health Organization percentiles did not differ for breastfed (36/40) and non-breastfed (14/16, p > 0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. INTERPRETATION: These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant.

Glatiramer acetate or IFN-ß bridging therapy in women with relapsing multiple sclerosis planning a pregnancy.

Aim: To assess bridging glatiramer acetate (GA) or IFN-ß for relapse prevention in women with relapsing multiple sclerosis planning pregnancy. Materials & methods: Participants discontinued disease-modifying therapies (DMTs) and received GA/IFN (early- or delayed-start) or no DMT (control) until pregnancy. Results: Annualized relapse rate was lower in delayed-start GA/IFN cohort versus control during washout/bridging. During washout/bridging, bridging with GA/IFN in this cohort reduced clinical activity, while disease activity increased in controls versus baseline. Conclusion: More data on GA/IFN bridging are needed. Women with low relapsing multiple sclerosis activity in the year prior to DMT discontinuation due to pregnancy planning benefited from GA/IFN bridging with lower annualized relapse rate versus no treatment and reduced clinical activity versus baseline during washout/bridging and pregnancy.

When women with relapsing multiple sclerosis (RMS) plan a pregnancy, doctors must think about the possible effects of medicines. Patients can take medicines with a well-defined safety profile to reduce the risk of attacks after stopping strong treatments. In this study, women stopped taking their RMS medicines and either: took well-defined RMS medicines, glatiramer acetate (GA) or IFN-ß; or stopped all RMS medicines. The rate of attacks (in a year) was lower in patients who started taking GA/IFN a while after stopping their previous RMS medicines compared with patients who took no more medication. Women with low RMS activity in the year before stopping RMS treatment because of pregnancy planning may benefit from GA/IFN treatment prior to conception.

Multiple Sclerosis Disease Activity and Disability Following Cessation of Fingolimod for Pregnancy.

BACKGROUND AND OBJECTIVE: Discontinuation of fingolimod ≥2 months before pregnancy is recommended to minimize potential teratogenicity. The magnitude of MS pregnancy relapse risk, particularly severe relapses, after fingolimod cessation is unclear, as is whether this risk is reduced by pregnancy or modifiable factors. METHODS: Pregnancies who stopped fingolimod treatment within 1 year before or during pregnancy were identified from the German MS and Pregnancy Registry. Data were collected through structured telephone-administered questionnaires and neurologists' notes. Severe relapses were defined as a ≥2.0 increase in Expanded Disability Status Scale (EDSS) or new or worsening relapse-related ambulatory impairment. Women who continued to meet this definition 1 year postpartum were classified as reaching the Severe Relapse Disability Composite Score (SRDCS). Multivariable models accounting for measures of disease severity and repeated events were used. RESULTS: Of the 213 pregnancies among 201 women (mean age at pregnancy onset 32 years) identified, 56.81% (n = 121) discontinued fingolimod after conception. Relapses during pregnancy (31.46%) and the postpartum year (44.60%) were common. Nine pregnancies had a severe relapse during pregnancy and additional 3 during the postpartum year. One year postpartum, 11 of these (6.32% of n = 174 with complete EDSS information) reached the SRDCS. Adjusted relapse rates during pregnancy were slightly higher compared with the year before pregnancy (relapse rate ratio = 1.24, 95% CI 0.91-1.68). Neither exclusive breastfeeding nor resuming fingolimod within 4 weeks of delivery were associated with a reduced risk of postpartum relapses. Most pregnancies relapsed during the first 3 months postpartum (n = 55/204, 26.96%). DISCUSSION: Relapses during pregnancy after fingolimod cessation are common. Approximately 6% of women will retain clinically meaningful disability from these pregnancy-related, fingolimod cessation relapses 1 year postpartum. This information should be shared with women on fingolimod desiring pregnancy, and optimizing MS treatment with nonteratogenic approaches should be discussed.

Safety evaluations of offspring breastfed by mothers receiving glatiramer acetate for relapsing multiple sclerosis.

BACKGROUND: Although the relapse risk is increased after birth in women with relapsing multiple sclerosis (RMS), only a very few disease-modifying therapies (DMTs) are approved during breastfeeding. Glatiramer acetate (GA, Copaxone®) is one of three DMTs that can be used in breastfeeding. The real-world safety of Copaxone® in Offsprings of Breastfeeding and treated RMS pAtients (COBRA) study demonstrated that offspring parameters (hospitalisations, antibiotic use, developmental delays, growth parameters) were similar between offspring breastfed by mothers taking GA or no DMT (control) during breastfeeding. COBRA data analyses were extended to provide further safety data on the impact of maternal GA treatment during breastfeeding on offspring. METHODS: COBRA was a non-interventional, retrospective study using German Multiple Sclerosis and Pregnancy Registry data. Participants had RMS, gave birth and had GA or no DMT during breastfeeding. Offspring total adverse events (AEs), non-serious AEs (NAEs) and serious AEs (SAEs) up to 18 months postpartum were assessed. Reasons for offspring hospitalisations and antibiotic treatments were explored. RESULTS: Baseline maternal demographics and disease characteristics were similar between cohorts. Each cohort had 60 offspring. Numbers of offspring AEs were comparable between cohorts; total AEs: 82 (GA) vs 83 (control); NAEs: 59 vs 61; SAEs: 23 vs 22. AEs in both cohorts were diverse with no specific patterns. Duration of GA-exposed breastfeeding was 6 to >574 days for offspring with any AE. For all-cause hospitalisations, 11 offspring had 12 hospitalisations (GA cohort) and 12 control offspring had 16 hospitalisations. Most common reason for hospitalisation was infection: 5/12 (41.7%; GA) vs 4/16 (25.0%, control). Two out of 12 (16.7%) hospitalisations due to infection occurred during GA-exposed breastfeeding; the others occurred 70, 192 and 257 days after discontinuation of GA-exposed breastfeeding. Median (range) duration of GA-exposed breastfeeding was 110 (56 to ≥285) days for offspring hospitalised for infections and 137 (88-396) days for those hospitalised for other reasons. Nine offspring had 13 antibiotic treatments (GA cohort) and nine control offspring had 10 treatments. Ten out of 13 (76.9%) antibiotic treatments occurred during GA-exposed breastfeeding, of which four were primarily due to double kidney with reflux. Other antibiotic treatments occurred 193, 229 and 257 days after discontinuation of GA-exposed breastfeeding. CONCLUSIONS: GA treatment of mothers with RMS during breastfeeding did not increase AEs, hospitalisations or antibiotic use in their offspring versus control offspring. These data support previous COBRA data that the benefit of maternal RMS treatment with GA during breastfeeding outweighs the potential, apparently low risk of untoward events, in their breastfed offspring.

Family planning considerations in people with multiple sclerosis.

Multiple sclerosis is often diagnosed in patients who are planning on having children. Although multiple sclerosis does not negatively influence most pregnancy outcomes, less is known regarding the effects of fetal exposure to novel disease-modifying therapies (DMTs). The withdrawal of some DMTs during pregnancy can modify the natural history of multiple sclerosis, resulting in a substantial risk of pregnancy-related relapse and disability. Drug labels are typically restrictive and favour fetal safety over maternal safety. Emerging data reporting outcomes in neonates exposed to DMTs in utero and through breastfeeding will allow for more careful and individualised treatment decisions. This emerging research is particularly important to guide decision making in women with high disease activity or who are treated with DMTs associated with risk of discontinuation rebound. As increasing data are generated in this field, periodic updates will be required to provide the most up to date guidance on how best to achieve multiple sclerosis stability during pregnancy and post partum, balanced with fetal and newborn safety.

Cladribine and pregnancy in women with multiple sclerosis: The first cohort study.

BACKGROUND: As cladribine is contraindicated in pregnancy, data to pregnancy outcomes and disease control are scarce. OBJECTIVE: To investigate the effects of Cladribine use, in the last 6 months prior (56.4%) to or after (43.6%) the last menstrual period in a population of women with multiple sclerosis, on pregnancy outcomes and relapse rate during pregnancy and postpartum. METHODS: Data were collected prospectively in regular telephone interviews. RESULTS: Of 39 pregnancies, 27 babies have been born so far and one major congenital malformation occurred. Disease control was excellent among the cohort both during pregnancy and the postpartum period, with only one relapse recorded in each time period. CONCLUSIONS: Although most newborns are healthy, reinforced councelling on effective contraception 6 months after the last cladribine dosing is necessary.

Peginterferon beta-1a concentrations in breast milk of lactating multiple sclerosis patients.

BACKGROUND: Peginterferon beta-1a is an interferon beta-1a formulation that has been pegylated, resulting in a longer half-life than other interferon beta formulations. We examined concentrations of peginterferon beta-1a in breast milk of lactating patients with multiple sclerosis (MS) receiving peginterferon beta-1a as their postpartum disease-modifying therapy. METHODS: After completion of titration to a full dose of peginterferon beta-1a and following a single full dose peginterferon beta-1a injection (125 µg), breast milk samples (≥10 mL) were collected by 5 women on days 1-14 post injection. Peginterferon beta-1a concentrations in breast milk samples were measured by a qualified enzyme-linked immunosorbent assay (detection threshold: 15 pg/mL). Mean and median daily concentrations and median maximum concentration (Cmax), time of Cmax (Tmax), time of last measurable concentration (Tlast), area under the concentration-time curve (AUClast), and relative infant dose (RID) were determined. RESULTS: After receiving a single full dose peginterferon beta-1a injection, the maximum breast milk concentration recorded in an individual patient was 126.2 pg/mL (0.00013 µg/mL) on day 6. The remaining patients all had maximum breast milk concentrations <72 pg/mL. The geometric mean of Cmax was 48.9 pg/mL and the median Tmax and Tlast were 4 and 7 days, respectively. The median AUClast was 210.9 day*pg/mL. Among the 5 study patients, the mean breast milk concentration across all study days was 35.95 pg/mL, with an estimated RID of 0.0054% of the maternal dose. CONCLUSION: Minimal concentrations of peginterferon beta-1a were detected in the breast milk samples. These findings may be useful for clinicians considering postpartum MS treatment options.

Multiple Sclerosis Disease Activity and Disability Following Discontinuation of Natalizumab for Pregnancy.

Importance: The magnitude of risk of pregnancy-related multiple sclerosis relapses, particularly severe relapses, following natalizumab cessation is unclear, as is whether this risk is reduced by pregnancy or other modifiable factors. Objective: To determine the association of early natalizumab withdrawal before or during pregnancy with risk of severe relapses and relapse-related disability. Design, Setting, and Participants: This prospective cohort study used data from the German Multiple Sclerosis and Pregnancy Registry, which enrolled participants between November 2006 and February 2018. Data were collected through structured telephone-administered questionnaires and review of neurologists' notes. Registry patients who stopped natalizumab treatment within the 2 years before or in the first trimester of pregnancy were included in this analysis. Data were analyzed between January and November 2021. Exposures: Cessation of natalizumab before pregnancy or until the first trimester. Main Outcomes and Measures: Severe and significant relapse-related disability was defined as at least a 2.0-point increase on the expanded disability status scale or new or worsening relapse-related ambulatory impairment. Multivariable models accounting for measures of disease severity and repeated events were used. Results: The cohort comprised 255 women with 274 pregnancies (mean [SD] age at pregnancy onset, 31.25 [4.27] years) who stopped natalizumab before pregnancy (n = 85; median time before last menstrual period, 14.29 weeks [IQR, 3.14-42.43 weeks]) or in the first trimester (n = 189). During pregnancy and the postpartum year, relapses were reported in 183 pregnancies (66.78%), severe relapses in 44 pregnancies (16.05%), and potentially life-threatening relapses in 3 pregnancies (1.10%). One year post partum, significant relapse-related disability was accrued in 29 pregnancies (10.58%). Relapses during pregnancy (n = 109; 39.78%) and in the postpartum period (n = 135; 49.27%) were common. Pregnancy (as a time-dependent covariate) was not associated with a reduced relapse risk (adjusted HR, 0.90; 95% CI, 0.64-1.27). Neither exclusive breastfeeding (adjusted HR, 1.34; 95% CI, 0.86-2.10) nor restarting natalizumab within 4 weeks post partum (adjusted HR, 1.06; 95% CI, 0.48-2.36) were associated with a reduced risk of early postpartum relapses 6 months after delivery. However, the relapse rate ratio during 12 months post partum was lower (0.49; 95% CI, 0.28-0.86) when natalizumab was restarted in the first 4 weeks after birth. Conclusions and Relevance: This cohort study's finding suggest that 10% of women may retain clinically meaningful disability from pregnancy-related natalizumab cessation relapses 1 year post partum. This information should be shared with women on natalizumab who desire pregnancy to weigh the high risk of pregnancy-related relapses and disability to the partly uncertain risks of continuing natalizumab throughout pregnancy or switching to depleting agents before conception.

The German Multiple Sclerosis and Pregnancy Registry: rationale, objective, design, and first results.

OBJECTIVES: Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) predominantly affect women of reproductive age. During the last few decades many disease-modifying therapies (DMTs) have been approved. It is therefore important to provide epidemiological structures for the collection of safety information on exposed pregnancies. Data on disease activity after withdrawal of DMTs are in high demand especially as severe relapses have been described after ceasing highly effective DMTs. Although breastfeeding is recommended, it is still unclear if the early reintroduction, especially of highly effective DMTs, has a beneficial effect on postpartum relapse risk or a combination of both, however safety data are lacking. METHODS: The German MS and Pregnancy Registry (DMSKW) is a nationwide, observational, cohort study of pregnant women with MS or NMOSD, founded in 2006. As the study procedure has undergone important adaptation in recent years, described here is the updated methodology including data source and acquisition as well as variables collected within the DMSKW. RESULTS: As of December 2020, the DMSKW database comprises 2579 pregnancies, 2568 with MS and 11 with NMOSD. Women are enrolled at a median gestational week of 11 (range: 0.02-42.1), have a median postpartum follow up of 1.2 years (range: 0-9.2) with 76% of all pregnancies being exposed to a DMT, mostly in the first trimester. Spontaneous abortion and preterm birth occurred in 7% and 10%, respectively; 19% of all women suffered from at least one relapse during pregnancy, with a minimum of 6% during the third trimester of pregnancy. CONCLUSION: The DMSKW is a valuable structure in providing safety data on drug exposure during pregnancy and lactation in combination with information on disease activity up to 6 years postpartum. This article will be the reference for describing the methods of future publications from the DMSKW.

Cladribine transfer into human milk: A case report.

BACKGROUND: Cladribine is an antimetabolite used for the treatment of relapsing-remitting multiple sclerosis. At present, there are no data available on its use in breastfeeding mothers and its transfer in human milk. OBJECTIVE: We present a case of a lactating mother who donated her milk samples to study the transfer of cladribine following a 20-mg oral dose. METHODS: Analysis was done using liquid chromatography-mass spectrometry. RESULTS: The relative infant dose calculated in this study was 3.06%. CONCLUSION: This is the first case report suggesting the transfer of cladribine in human milk in measurable quantities. However, caution should be advised during lactation.

Anti-CD20 therapies and pregnancy in neuroimmunologic disorders: A cohort study from Germany.

OBJECTIVE: To report pregnancy outcomes and disease activity (DA) in women with MS, neuromyelitis optica spectrum disorders (NMOSDs), and other neuroimmunologic diseases (ONID) after treatment with rituximab (RTX)/ocrelizumab (OCR) 12 months before or during pregnancy. METHODS: Data were collected in the German MS and pregnancy registry and centers from the Neuromyelitis Optica Study Group. Sixty-eight known outcomes of 88 pregnancies from 81 women (64 MS, 10 NMOSD, and 7 ONID) were included and stratified in 3 exposure groups: >6M-group = RTX/OCR >6 but ≤12 months before the last menstrual period (LMP) (n = 8); <6M group = RTX/OCR <6 months before the LMP (n = 47); preg group = RTX/OCR after the LMP (n = 13). RESULTS: Pregnancy outcomes were similar between groups, but significantly more preterm births (9.8% vs 45%) occurred after exposure during pregnancy. Overall, 2 major congenital abnormalities (3.3%), both in the preg group, were observed. Three women had severe infections during pregnancy. All women with MS (35) and 12/13 women with NMOSD, RTX/OCR exposure before the LMP and known pregnancy outcomes after gestational week 22 were relapse free during pregnancy. Five of 29 (17.2%) women with relapsing-remitting MS (RRMS) and 1 of 12 (8.3%) with NMOSD and at least 6 months postpartum follow-up experienced a relapse postpartum. Duration of RTX/OCR and early retreatment but not detection of B-cells were possible predictors for postpartum relapses in patients with RRMS/NMOSD. CONCLUSIONS: Although RTX/OCR might be an interesting option for women with RRMS/NMOSD who plan to become pregnant to control DA, more data on pregnancy outcomes and rare risks are needed.

Dimethyl fumarate transfer into human milk.

Dimethyl fumarate (DMF) is approved for the treatment of relapsing-remitting multiple sclerosis. It is unknown whether DMF or its primary metabolite monomethyl fumarate (MMF) are excreted into human milk. We present two cases of lactating patients who donated milk samples to study the transfer of MMF into human milk following a week of 2 × 240 mg daily oral dose. Samples were analyzed using liquid chromatography mass spectrometry. The calculated relative infant dose was 0.019% and 0.007%. This is the first study to demonstrate that MMF is transferred into human milk, with only limited exposure to an infant.

Gender issues of antibody-mediated diseases in neurology: (NMOSD/autoimmune encephalitis/MG).

Neuromyelitis optica spectrum disorder (NMOSD), autoimmune encephalitis (AE), myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are antibody-mediated neurological diseases. They have mostly female predominance, affecting many women during childbearing age. Interactions between the underlying disease (or necessary treatment) and pregnancy can occur in every of these illnesses. Herein, we present the characteristics of NMOSD, AE, MG and LEMS in general, and review published data regarding the influence of the different diseases on fertility, pregnancy, puerperium, treatment strategy during pregnancy and post-partum period, and menopause but also male factors. We summarise key elements that should be borne in mind when confronted with such cases.