You are here

Article Text

Article menu
Multiple sclerosis
Original research
Early postpartum treatment strategies and early postpartum relapses in women with active multiple sclerosis
  1. Sabrina Haben1,
  2. Andrea I Ciplea1,
  3. Marianne Tokic2,
  4. Nina Timmesfeld2,
  5. Sandra Thiel1,
  6. Ralf Gold1,
  7. Annette Magdalene Langer-Gould3,
  8. Kerstin Hellwig1
  1. 1 Department of Neurology, Katholisches Klinikum Bochum, Ruhr-Universität Bochum, Bochum, Germany
  2. 2 Medical Informatics, Biometry and Epidemiology, Ruhr-Universitat Bochum, Bochum, Germany
  3. 3 Research & Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
  1. Correspondence to Professor Kerstin Hellwig, Katholisches Klinikum Bochum Klinik für Neurologie, Bochum 44791, Germany; Kerstin.Hellwig{at}ruhr-uni-bochum.de

Abstract

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.

  • multiple sclerosis

Data availability statement

Data are available on reasonable request. Anonymised data that support the findings of this study will be shared, on reasonable request and if compatible with data protection policies.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jnnp-2023-331525

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Exclusive breast feeding has been shown in several studies to reduce the multiple sclerosis relapse risk post partum, however, as cohorts mainly composed of patients with low or moderate disease activity it is unknown whether protective effects are to be expected in women with highly active disease as well.

    WHAT THIS STUDY ADDS

    • We found that in women with active disease only restarting natalizumab or fingolimod within the first 6 weeks post partum significantly reduced relapse hazard as of month 3 after delivery, however, none of the different examined postpartum treatment strategies seemed to be able counteract the very early postpartum relapse risk.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Women with active multiple sclerosis need to be advised to restart highly and rapid effective disease-modifying treatment soon after delivery. Choosing breastfeeding compatible options might be preferred.

    Introduction

    During the first months after delivery, the relapse risk in women with multiple sclerosis (MS) is increased and dependent on disease activity before or during pregnancy and the withdrawal of higher efficient disease-modifying therapies (DMTs) such as natalizumab (NTZ) and fingolimod (FTY).1 2 Various publications suggest that exclusive breast feeding (exBF) might protect against postpartum (pp) relapses,3–8 but most studies did not stratify by disease activity. In our own previous publication, the majority of women had been on first-line treatments, only about 11% had received a second-line therapy (NTZ) before pregnancy.3 Meanwhile, second-line therapies are administered more often and earlier in the treatment of MS.9

    Studies on DMT-resumption show conflicting results and there is up to now no proof that early resumption of DMT after delivery reduces the early relapse risk pp.2 10 11 Whether women with active disease benefit from exBF or early resumption of DMTs is yet unknown. Therefore, the objective of this study was to assess associations of different early pp treatment strategies (exBF, early restart of: NTZ/FTY, other DMTs or no apparent strategy) with the pp relapse risk in a cohort of women with active MS.

    Methods

    Study population and data collection

    We included pregnancies, enrolled into the German Multiple Sclerosis and Pregnancy Registry (DMSKW)12—a nationwide prospective cohort study of pregnant women with MS, meting the following criteria: live birth between November 2007 and March 2020, active MS, enrolment during pregnancy, completed pp follow-up of ≥6 months and known breastfeeding status. ‘Active MS’ was defined as treatment with NTZ or FTY in the year preceding pregnancy or until the first trimester of pregnancy (because of the higher relapse risk after withdrawal of these drugs during pregnancy and pp)2 13 14 OR having had a relapse in the year before pregnancy regardless of DMT treatment (known to be associated with a higher pp relapse risk).1 15 Women treated with DMTs with long-lasting effect (alemtuzumab, cladribine, ocrelizumab or rituximab) before or during pregnancy, or who continued NTZ beyond the first trimester of pregnancy were excluded due to the small sample size at data cut-off. Data were collected during regular, standardised telephone interviews with the patients during pregnancy and the pp period as previously described.12

    This study contains data on 380 cases included and published also in preceding manuscripts/under review.3 10

    Exposure and outcome

    We defined four early pp strategies: (1) intention to breastfed exclusively without DMT: breast feeding for ≥2 months without regular replacement of any meal by supplemental feeding.3 exBF stopped the day when at least one meal was fully replaced by any supplemental feeding. Women who initially breastfeed exclusively but replaced a meal or weaned within 2 weeks after a relapse in the first 2 months pp were also included into the exBF strategy, as we assumed the intention to breastfeed exclusively. Three other early treatment strategies included early (during the first 6 weeks pp and before a relapse) restart of DMTs with (2) NTZ or FTY (NTZ/FTY-strategy) or (3) any other DMTs (other DMT-strategy). Those who did not or only partially breastfed and did not restart DMTs early or only after a relapse in the first 6 weeks were grouped, in the last strategy and (4) no-DMT-no-exclusive-breastfeeding-strategy (no-DMT-no-exBF-strategy). Those who breastfed exclusively under a DMT were included into the respective DMT-strategy if treatment was started before the first relapse (even if started >6 weeks pp); if treatment started after a relapse, they were included into the exBF-strategy. MS relapse was defined using current criteria16; those occurring within the first 6 months pp were included into analyses.

    Statistical analysis

    Descriptive analyses were performed with analysis of variance, the Kruskal-Wallis or χ2 test where applicable. Mean cumulative functions were used to describe the accumulated number of relapses over time per strategy.

    To analyse the association of relapse hazard rates with the different strategies, adjusted HRs calculated by the Andersen-Gill extension of the cox proportional hazard model for recurrent events were used. Age, disease duration, relapses under second-line DMT before pregnancy as well as relapses during pregnancy were used as covariates to adjust for differing disease activities. Baseline hazards were stratified by inclusion criteria groups (NTZ/FTY vs relapse under other/no DMT in the year before pregnancy) to account for possible differing disease activities. To evaluate whether the strategies where stable in effect over time, three time intervals (each lasting 2 months) were included in the model as time-varying covariates. For each time interval, the difference between exBF and the other strategies was tested using Wald test and p values and CIs were adjusted for multiple testing via Bonferroni correction.

    To analyse a possible association between measures of disease characteristics and activity prior to delivery (age, disease duration, relapses before, relapse during pregnancy as well as a second-line DMT (NTZ or FTY) before the pregnancy) with pp strategy choice, a multinomial logistic regression model was applied. Statistical analyses were conducted using R V.4.1.2 with a two-sided significance level of .5% and 95% CI are reported.17

    Results

    Of 2507 pregnancies in the DMSKW database with live birth until March 2020, 911 fulfilled the inclusion criteria (figure 1). Forty-two women contributed two pregnancies and one contributed three pregnancies. Mean age at last menstrual period was 32.45 (SD 4.20) years and pregnancies had been diagnosed with MS for a median of 4.79 (IQR 1.91–8.66) years before pregnancy. Approximately half of the pregnancies met the criteria of active MS by having been treated with NTZ or FTY in the year before pregnancy (46.70%), the remaining cases were distributed almost evenly between those who relapsed under first line (28.7%) or no treatment (24.7%) in the year prior to pregnancy. Baseline characteristics of the four strategies are shown in table 1.

    View this table:
    Table 1

    Baseline characteristics of women with the four postpartum strategies

    Figure 1
    Figure 1

    Inclusion criteria and eligible pregnancies in the cohort. Depicted are the pregnancies fulfilling the inclusion criteria with the different strategies as well as the distribution of ‘active’ criteria in the year before pregnancy. Definition of strategies: exclusive breastfeeding strategy, women breast feeding for at least 2 months without regular replacement of any meal by supplemental feeding including those initially breast feeding exclusively but replacing a meal or weaning within 2 weeks after a relapse in the first 2 months pp; NTZ/FTY-strategy, women (re)starting NTZ or FTY-treatment within 6 weeks pp before a relapse; other-DMT-strategy, women (re)starting another DMT within 6 weeks pp before a relapse; no-DMT-no-exBF-strategy, women neither breast feeding exclusively nor (re)starting a DMT within first 6 weeks pp or restarting DMT within this time frame but after a relapse; women exclusively breast feeding under a DMT were included in respective DMT-strategy if treatment was started (not necessarily within 6 weeks pp) before a relapse; if afterwards they were included into the exclusive breastfeeding strategy. Cases were defined as prospective if they were enrolled into the registry during pregnancy. ALZ, alemtuzumab; CLAD, cladribine; DMT, disease-modifying therapy; exBF, exclusive breast feeding; FTY, fingolimod; MS, multiple sclerosis; NTZ, natalizumab; OCR, ocrelizumab; pp, post partum; RTX, rituximab.

    The most common early pp strategy was exBF in n=416 (45.7%) of pregnancies, followed by no-DMT-no-exBF-strategy (n=290, 31.8%). 205/911 (22.5%) restarted DMTs early: n=93/205 (45.4%) with other-DMT-strategy, mainly injectables (n=77/93, 82.8%) and n=112/205 (54.6%) with NTZ/FTY-strategy. Only few, n=23/416 (5.5%) stopped exBF within the first 2 months pp due to a relapse.

    Only 38 of n=677 who breastfed did so while on DMT (n=25 exclusively and n=13 partially) mainly (76.3%) on injectables (15 on interferon-beta and 14 on glatiramer acetate) and 9 on monoclonal antibodies (NTZ n=7 and OCR n=2). For further details on those 25 pregnancies breast feeding exclusively while on DMT see online supplemental table 1.

    Supplemental material

    Disease activity before and during pregnancy and immunomodulatory treatment before pregnancy differed between the pp strategies (table 1). Pregnancies breast feeding exclusively were less likely to have been on second-line before conception (only 37.5%), whereas NTZ/FTY-strategy and no-DMT-no-exBF-strategy pregnancies had more often been treated with second-line treatments before conception (95.5% and 51.0%, respectively).

    Pregnancies with second-line treatment before conception and relapse during pregnancy were more likely to choose the NTZ/FTY-strategy (OR 32.6, 95% CI 12.1 to 87.9, p<0.001 and OR 2.35, 95% CI 1.45 to 3.83, p<0.001) instead of exBF strategy (see online supplemental table 2).

    pp disease activity

    Overall, 337/911 (37.0%) pregnancies relapsed at least once during the first 6 months pp (table 2). In the NTZ/FTY-strategy and other-DMT-strategy 76% of the cases remained relapse free during this time frame; in contrast for exBF-strategy and no-DMT-no-exBF-strategy this was the case in only 62% and 56% (table 2). When inspecting the mean cumulative function of the different strategies (figure 2), no-DMT-no-exBF-strategy had the highest overall number of cumulated relapses with a stable relapse risk. The exBF-strategy appears to remain stable in relapse risk throughout the 6-month pp period observed, whereas the NTZ/FTY-strategy shows a decline in relapse risk, most noticeable past the 4-month mark.

    View this table:
    Table 2

    Postpartum clinical characteristics in the four strategies

    Figure 2
    Figure 2

    Postpartum (pp) relapses—mean cumulative function. Average number of cumulated relapses in the first 6 months after delivery among women with the four pp strategies (no adjustment for confounders). Definition of strategies: exclusive breastfeeding strategy (depicted in red), women breast feeding for at least 2 months without regular replacement of any meal by supplemental feeding including those initially breast feeding exclusively but replacing a meal or weaning within 2 weeks after a relapse in the first 2 months pp; NTZ/FTY-strategy (depicted in green), women (re)starting NTZ or FTY-treatment within 6 weeks pp before a relapse; other-DMT-strategy (depicted in yellow), women (re)starting another DMT within 6 weeks pp before a relapse; no-DMT-no-exBF-strategy (depicted in blue), women neither breast feeding exclusively nor (re)starting a DMT within first 6 weeks pp or restarting DMT within this time frame but after a relapse; women exclusively breast feeding under a DMT were included in respective DMT-strategy if treatment was started (not necessarily within 6 weeks pp) before a relapse; if afterwards they were included into the exclusive breastfeeding strategy. DMT, disease-modifying therapy, exBF, exclusive breast feeding; FTY, fingolimod; NTZ, natalizumab.

    In the recurrent time-to-event analysis, pregnancies with no-DMT-no-exBF-strategy had the highest early pp relapse hazard (figure 3), although this finding was not statistically significant. Compared with exBF the NTZ/FTY-strategy showed a statistically significant reduction in relapse hazard rate from month 3 onwards (months 3–4: HR 0.31, 95% CI 0.12 to 0.82, p=0.008; months 5–6: HR 0.27, 95% CI 0.07 to 0.98, p=0.043; figure 3) but not during the first 2 months pp. For all other strategies, no significant differences were found compared with exBF-strategy for none of the three different time frames (figure 3).

    Figure 3
    Figure 3

    HRs per postpartum (pp) time frame compared with exclusive breastfeeding (exBF) strategy. Definition of strategies: exBF strategy, women breast feeding for at least 2 months without regular replacement of any meal by supplemental feeding including those initially breast feeding exclusively but replacing a meal or weaning within 2 weeks after a relapse in the first 2 months pp; NTZ/FTY-strategy, women (re)starting NTZ or FTY-treatment within 6 weeks pp before a relapse; other-DMT-strategy, women (re)starting another DMT within 6 weeks pp before a relapse; no-DMT-no-exBF-strategy, women neither breast feeding exclusively nor (re)starting a DMT within first 6 weeks pp or restarting DMT within this time frame but after a relapse; women exclusively breast feeding under a DMT were included in respective DMT-strategy if treatment was started (not necessarily within 6 weeks pp) before a relapse; if afterwards they were included into the exBF strategy. HRs adjusted for age, disease duration, relapses under second-line DMT before pregnancy and relapse during pregnancy. aWith reference strategy exBF. DMT, disease-modifying therapy; FTY, fingolimod; NTZ, natalizumab.

    Discussion

    The findings of our large prospective cohort study of women with active MS in the year prior to pregnancy or at high risk of disease activity due to recent cessation of NTZ or FTY suggest that the pp relapse risk is high. No-DMT-no-exBF-strategy appeared as the worst approach. This underscores the importance of counselling patients prior to delivery and again in the very early pp period to resume a DMT (preferably NTZ or FTY), to breastfeed exclusively or both. In the first 2 months following delivery, none of the two drug treatment strategies reduced the relapse hazard significantly compared with exBF, however, recurrent time-to-event analysis did show a statistically significant beneficial effect of early NTZ/FTY (re)start after delivery in mid and late first half of the pp year, demonstrating that over time DMT-effects become apparent.

    Overall, 37% in our cohort experienced one or more relapse in the first 6 months pp, which is in the higher range of other published modern cohorts where about 30%–39% relapsed only during the entire first pp year.4 15 18 This variation in relapse occurrence could be explained by lower disease severity in these cohorts as only 3%,4 6%18 and 11%3 were treated with highly effective DMTs or only 39% were reported to have been exposed to any DMT at all in the year before pregnancy.15 Cohorts from our registry comprising of the most active MS cases treated with FTY or NTZ before pregnancy report that almost half experience at least one relapse during this time frame (NTZ: 49%,10 FTY: 45% (NEURIMMINFL accepted); data overlap with present analysis). These women are especially vulnerable, as relapse activity can be associated with relevant persistent disability.10 Although severe rebound relapses seem to be more common during pregnancy, relapse risk is highest in the first few months after delivery, why effective and modifiable strategies are of interest.

    If exBF is regarded as a treatment, it seems to be an attractive early strategy with multiple health benefits for mother and child. Some modern cohorts, including ours,3 found a reduction in the pp relapse risk compared with no-exBF or non-exBF, with relapses ranging between 9%4 and 25%3 19 consistent with the results of a recent meta-analysis.5 In our present cohort, relapse risk was higher (38%) compared with other studies in those breast feeding exclusively reflecting our selection of pregnancies with active disease.

    The ability to prevent very early pp relapses by rapid restart of fast-acting DMT after delivery seems restricted considering their immunological background. As a decline of circulating CD4+ interferon-gamma producing cells—which starts already in the third trimester of pregnancy—might sensitise for these relapses,20 it might be too late to try to counter this process starting a treatment only after delivery. Pregnancy has been shown to not be a continuous immunosuppressed phase, but dynamic and consisting of different stages.17 Of note, the third trimester is characterised by an inflammatory immune state necessary to induce delivery and labour.17

    Whereas rapid DMT-reintroduction after delivery did not show superiority in very early relapse reduction in our cohort we observed a plausible temporal dynamic in relapse reduction over the course of first 6 months pp with the NTZ/FTY-strategy. In contrast to our cut-off of 6 weeks pp, the definition of ‘early’ DMT resumption differs between studies, ranging from a few days after delivery,21 2 weeks11 to 1 (1, 10, 22), 2 (4) and 3 (23) months and includes highly effective therapies1 10 21–23 or injectables.4 11 Our findings are in line with several studies showing that ‘early’ DMT-resumption reduces relapses at least during the entire pp year1 10 11 but contrasts with those not detecting any4 or a case series which at least descriptively showed immediate effect.21 Considering the mechanisms of action of the various drugs this may not be surprising—even for the fastest drugs as NTZ where gadolinium enhancing lesions were reduced already as of 1 month after treatment, most DMTs require up to several months to reduce relapse rate.

    Or study shows that effective reduction of (very) early pp relapses remains challenging in women with active disease.

    Given the numerous health benefits of exBF for mothers and their infants including a reduced risk of developing diabetes/breast or ovarian cancer in the mothers, reduced risk of obesity/diabetes, higher intelligence quotients in children and reduction of infant mortality also in high income settings,24–26 women with chronic diseases such as MS should be able to combine both. In our study, DMT and breast feeding were basically mutually exclusive with only 4% breast feeding under DMTs. Whether a combined strategy may be effective is unclear and has to be investigated in the future. Currently, breast feeding under DMTs on label in the European Union is restricted to interferon-beta,27 very recently glatiramer acetate28 and ofatumumab.29 However, there is emerging evidence that monoclonal antibodies only enter the breastmilk in small amounts30–32 and off-label breast feeding under monoclonal antibodies in MS seems to be safe for breastfed infants30 31 33 as they might not be absorbed by the child and thus not pharmacologically effective. Owing to their higher oral bioavailability and molecular properties favouring excretion into breastmilk, oral administered DMTs are currently not considered compatible with breast feeding.34 Interestingly, two recently published case reports on cladribine35 and dimethyl fumarate36 show relatively low concentrations in breastmilk with a relative infant dose of below the acceptable threshold of 10%. Given that breast feeding under oral drugs is considered compatible in epilepsy with a partially reversal of prenatal valproic acid induced cognitive teratogenicity through exposed breast feeding37–39 and breast feeding is recommended for example, under azathioprine, we need to get more and timely information of the content of oral drugs in the breastmilk.

    Our study has several limitations. The sample size for the following subgroup analysis was too small to analyse and draw firm conclusions: (1) women who breastfed under DMTs, (2) women treated with DMTs with long-lasting effect (alemtuzumab, cladribine, ocrelizumab or rituximab) before or during pregnancy, (3) women who restarted DMTs with long-lasting effect pp and (4) women who restarted NTZ pp. We did not have EDSS values for the entire cohort, so we cannot postulate an effect in the severity of relapses in the strategies. Currently, it is scientifically discussed if prolactin can promote remyelinisation40 and future studies should investigate its effect on severity of relapses. Also, the lacking analyses of MRI results preclude statements on effects on subclinical disease activity. We did not inquire the strategy during the interviews; therefore, it is possible that our strategy-definition differentially misclassified those in the no-DMT-no-exBF-strategy and worsened this group. exBF-strategy was not evenly distributed between the most severe cases and the rest of the cohort and although statistical analyses accounted for this imbalance residual confounding is still possible. Finally, being a registry study there may have been a selection bias, so extrapolations to community-based populations need to be made with caution.

    Strengths of our study include the unique patient population and large sample size, prospective follow-up and detailed information on breastfeeding status.

    Conclusion

    In this cohort, the early NTZ/FTY restart during the first 6 weeks pp reduced pp relapse hazard significantly from month 3, compared with the exBF-strategy. Appropriate counselling should be provided to every woman before or latest during pregnancy. In the future, more data on breast feeding under DMTs are needed.

    Data availability statement

    Data are available on reasonable request. Anonymised data that support the findings of this study will be shared, on reasonable request and if compatible with data protection policies.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by Institutional review board of the Ruhr-University Bochum;Reg-Nr.: 18-6474-BR. Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    The authors would like to thank all the patients for their participation, as well as all referring neurologists and nurses.

    References

    1. ↵
      2. Bsteh G ,
      3. Algrang L ,
      4. Hegen H , et al
      . Pregnancy and multiple sclerosis in the DMT era: a cohort study in Western Austria. Mult Scler 2020;26:69–78. doi:10.1177/1352458518816614
      OpenUrl
    2. ↵
      2. Yeh WZ ,
      3. Widyastuti PA ,
      4. Van der Walt A , et al
      . Natalizumab, fingolimod and dimethyl fumarate use and pregnancy-related relapse and disability in women with multiple sclerosis. Neurology 2021;96:e2989–3002. doi:10.1212/WNL.0000000000012084
      OpenUrlCrossRef
    3. ↵
      2. Hellwig K ,
      3. Rockhoff M ,
      4. Herbstritt S , et al
      . Exclusive breastfeeding and the effect on postpartum multiple sclerosis relapses. JAMA Neurol 2015;72:1132–8. doi:10.1001/jamaneurol.2015.1806
      OpenUrl
    4. ↵
      2. Langer-Gould A ,
      3. Smith JB ,
      4. Albers KB , et al
      . Pregnancy-related relapses and breastfeeding in a contemporary multiple sclerosis cohort. Neurology 2020;94:e1939–49. doi:10.1212/WNL.0000000000009374
      OpenUrl
    5. ↵
      2. Krysko KM ,
      3. Rutatangwa A ,
      4. Graves J , et al
      . Association between breastfeeding and postpartum multiple sclerosis relapses: a systematic review and meta-analysis. JAMA Neurol 2020;77:327–38. doi:10.1001/jamaneurol.2019.4173
      OpenUrl
    6. ↵
      2. Pakpoor J ,
      3. Disanto G ,
      4. Lacey MV , et al
      . Breastfeeding and multiple sclerosis relapses: a meta-analysis. J Neurol 2012;259:2246–8. doi:10.1007/s00415-012-6553-z
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      2. Langer-Gould A ,
      3. Huang SM ,
      4. Gupta R , et al
      . Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. Arch Neurol 2009;66:958–63. doi:10.1001/archneurol.2009.132
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      2. Hellwig K ,
      3. Haghikia A ,
      4. Agne H , et al
      . Protective effect of breastfeeding in postpartum relapse rate of mothers with multiple sclerosis. Arch Neurol 2009;66:1580–1; doi:10.1001/archneurol.2009.281
      OpenUrlCrossRefPubMed
    9. ↵
      2. Simpson A ,
      3. Mowry EM ,
      4. Newsome SD
      . Early aggressive treatment approaches for multiple sclerosis. Curr Treat Options Neurol 2021;23:19. doi:10.1007/s11940-021-00677-1
    10. ↵
      2. Hellwig K ,
      3. Tokic M ,
      4. Thiel S , et al
      . Multiple sclerosis disease activity and disability following discontinuation of natalizumab for pregnancy. JAMA Netw Open 2022;5:e2144750. doi:10.1001/jamanetworkopen.2021.44750
    11. ↵
      2. Beaber BE ,
      3. Chi MD ,
      4. Brara SM , et al
      . Immunomodulatory agents and risk of postpartum multiple sclerosis relapses. Perm J 2014;18:9–13. doi:10.7812/TPP/13-090
      OpenUrl
    12. ↵
      2. Thiel S ,
      3. Ciplea AI ,
      4. Gold R , et al
      . The German multiple sclerosis and pregnancy registry: rationale, objective, design, and first results. Ther Adv Neurol Disord 2021;14:17562864211054956. doi:10.1177/17562864211054956
    13. ↵
      2. Alroughani R ,
      3. Alowayesh MS ,
      4. Ahmed SF , et al
      . Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era. Neurology 2018;90:e840–6. doi:10.1212/WNL.0000000000005065
      OpenUrlCrossRefPubMed
    14. ↵
      2. Prosperini L ,
      3. Kinkel RP ,
      4. Miravalle AA , et al
      . Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis. Ther Adv Neurol Disord 2019;12:1756286419837809. doi:10.1177/1756286419837809
    15. ↵
      2. Hughes SE ,
      3. Spelman T ,
      4. Gray OM , et al
      . Predictors and dynamics of postpartum relapses in women with multiple sclerosis. Mult Scler 2014;20:739–46. doi:10.1177/1352458513507816
      OpenUrlCrossRefPubMed
    16. ↵
      2. Thompson AJ ,
      3. Banwell BL ,
      4. Barkhof F , et al
      . Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018;17:162–73. doi:10.1016/S1474-4422(17)30470-2
      OpenUrlCrossRefPubMed
    17. ↵
      2. Mor G ,
      3. Aldo P ,
      4. Alvero AB
      . The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol 2017;17:469–82. doi:10.1038/nri.2017.64
      OpenUrlCrossRefPubMed
    18. ↵
      2. Jesus-Ribeiro J ,
      3. Correia I ,
      4. Martins AI , et al
      . Pregnancy in multiple sclerosis: a Portuguese cohort study. Mult Scler Relat Disord 2017;17:63–8. doi:10.1016/j.msard.2017.07.002
      OpenUrlPubMed
    19. ↵
      2. Gulick EE ,
      3. Halper J
      . Influence of infant feeding method on postpartum relapse of mothers with MS. Int J MS Care 2002;4:183–91. doi:10.7224/1537-2073-4.4.183
      OpenUrl
    20. ↵
      2. Langer-Gould A ,
      3. Gupta R ,
      4. Huang S , et al
      . Interferon-gamma-producing T cells, pregnancy, and postpartum relapses of multiple sclerosis. Arch Neurol 2010;67:51–7. doi:10.1001/archneurol.2009.304
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      2. Vukusic S ,
      3. Durand-Dubief F ,
      4. Benoit A , et al
      . Natalizumab for the prevention of post-partum relapses in women with multiple sclerosis. Mult Scler 2015;21:953–5. doi:10.1177/1352458514554056
      OpenUrlCrossRefPubMed
    22. ↵
      2. Portaccio E ,
      3. Amato MP
      . Author response: pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: fetal risks. Neurology 2018;91:851. doi:10.1212/WNL.0000000000006430
    23. ↵
      2. Razaz N ,
      3. Piehl F ,
      4. Frisell T , et al
      . Disease activity in pregnancy and postpartum in women with MS who suspended rituximab and natalizumab. Neurol Neuroimmunol Neuroinflamm 2020;7:e903. doi:10.1212/NXI.0000000000000903
    24. ↵
      2. Victora CG ,
      3. Bahl R ,
      4. Barros AJD , et al
      . Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet 2016;387:475–90. doi:10.1016/S0140-6736(15)01024-7
      OpenUrlCrossRefPubMed
    25. ↵
      2. Evenhouse E ,
      3. Reilly S
      . Improved estimates of the benefits of breastfeeding using Sibling comparisons to reduce selection bias. Health Serv Res 2005;40:1781–802. doi:10.1111/j.1475-6773.2005.00453.x
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      2. Chowdhury R ,
      3. Sinha B ,
      4. Sankar MJ , et al
      . Breastfeeding and maternal health outcomes: a systematic review and meta-analysis. Acta Paediatr 2015;104:96–113. doi:10.1111/apa.13102
      OpenUrlCrossRefPubMed
    27. ↵
      1. EMA
      . Betaferon (interferon beta 1B) EPAR summary of product characteristics. 2021. Available: https://www.ema.europa.eu/en/documents/product-information/betaferon-epar-product-information_en.pdf
    28. ↵
      Copaxone 40 mg/ml solution for injection in pre-filled syringe electroninic medicines compendium (emc). 2022. Available: https://www.medicines.org.uk/emc/product/7046/smpc#gref
    29. ↵
      1. EMA
      . Kesimpta® (Ofatumumab) - EPAR summary of product Charcteristics. 2021. Available: https://www.ema.europa.eu/en/documents/product-information/kesimpta-epar-product-information_en.pdf
    30. ↵
      2. Krysko KM ,
      3. LaHue SC ,
      4. Anderson A , et al
      . Minimal breast milk transfer of rituximab, a monoclonal antibody used in neurological conditions. Neurol Neuroimmunol Neuroinflamm 2020;7:e637. doi:10.1212/NXI.0000000000000637
    31. ↵
      2. Anderson A ,
      3. Jacobs D ,
      4. LaHue SC , et al
      . Ocrelizumab in postpartum women with multiple sclerosis: low transfer into breast milk and reassuring infant development in a multicenter cohort. Actrims 2022 Forum; Florida, U.S.2022
    32. ↵
      2. Proschmann U ,
      3. Haase R ,
      4. Inojosa H , et al
      . Drug and neurofilament levels in serum and breastmilk of women with multiple sclerosis exposed to natalizumab during pregnancy and lactation. Front Immunol 2021;12:715195. doi:10.3389/fimmu.2021.715195
    33. ↵
      2. Ciplea AI ,
      3. Langer-Gould A ,
      4. de Vries A , et al
      . Monoclonal antibody treatment during pregnancy and/or lactation in women with MS or neuromyelitis optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm 2020;7:e723. doi:10.1212/NXI.0000000000000723
    34. ↵
      2. Krysko KM ,
      3. Graves JS ,
      4. Dobson R , et al
      . Sex effects across the lifespan in women with multiple sclerosis. Ther Adv Neurol Disord 2020;13:1756286420936166. doi:10.1177/1756286420936166
    35. ↵
      2. Datta P ,
      3. Ciplea AI ,
      4. Rewers-Felkins K , et al
      . Cladribine transfer into human milk: a case report. Mult Scler 2021;27:799–801. doi:10.1177/1352458520912173
      OpenUrl
    36. ↵
      2. Ciplea AI ,
      3. Datta P ,
      4. Rewers-Felkins K , et al
      . Dimethyl fumarate transfer into human milk. Ther Adv Neurol Disord 2020;13:1756286420968414. doi:10.1177/1756286420968414
    37. ↵
      2. Veiby G ,
      3. Engelsen BA ,
      4. Gilhus NE
      . Early child development and exposure to antiepileptic drugs prenatally and through breastfeeding: a prospective cohort study on children of women with epilepsy. JAMA Neurol 2013;70:1367–74. doi:10.1001/jamaneurol.2013.4290
      OpenUrl
    38. ↵
      2. Meador KJ ,
      3. Baker GA ,
      4. Browning N , et al
      . Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years. JAMA Pediatr 2014;168:729–36. doi:10.1001/jamapediatrics.2014.118
      OpenUrl
    39. ↵
      2. Veiby G ,
      3. Bjørk M ,
      4. Engelsen BA , et al
      . Epilepsy and recommendations for breastfeeding. Seizure 2015;28:57–65. doi:10.1016/j.seizure.2015.02.013
      OpenUrlCrossRef
    40. ↵
      2. Costanza M ,
      3. Pedotti R
      . Prolactin: friend or foe in central nervous system autoimmune inflammation? Int J Mol Sci 2016;17:2026. doi:10.3390/ijms17122026

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Contributors Conception, design, acquisition or interpretation of the data: all authors. Statistical analysis: SH, MT, NT and KH. Drafting the work or revising it critically for important intellectual content: all authors. Final approval of the version to be published: all authors. Guarantor: KH.

    • Funding The German Multiple Sclerosis and Pregnancy Registry (DMSKW) is partly supported by the Innovation Fund of the Federal Joint Committee (Grant: 01VSF17022), Almirall, Biogen, Hexal, Merck, Novartis, Roche, Sanofi Genzyme and Teva Pharma.

    • Competing interests AIC: received speaker honoraria from Bayer Healthcare, Biogen and Teva and sponsorship for congress participation and travel grants from Teva; MT: is employed in a project funded by a grant from the Innovation Fund of the Federal Joint Committee, NT: has received a grant from the Innovation Fund of the Federal Joint Committee; ST: received speakers honoraria from Bayer Healthcare and Biogen as well as payment for manuscript writing from HEXAL AG; RG: has received speaker honoraria and research support from Bayer-Schering Healthcare, Biogen-Idec Germany, Chugai, Eisai, Merck Serono, Nikkiso Pharma, Novartis, Roche, Sanofi-Genzyme, and TEVA, has received consulting honoraria from CSL Behring, Baxter, Janssen and Talecris and has stock options in Bayer, Merck and Roche; KH: has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Roche and Teva, has received support for congress participation from Bayer, Biogen, Merck, Roche, Sanofi Genzyme and Teva, and has served on scientific advisory boards for Bayer, Biogen, Sanofi, Teva, Roche, Novartis, Merck.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.