Highlights
- DMT management during pregnancy increases relapse risk in women with multiple sclerosis, especially with natalizumab interruption or prior fingolimod use.
- Anti-CD20 monoclonal antibody therapy administered prior to conception offers the greatest protection against pregnancy- and postpartum-related relapses.
- Natalizumab with short interruption is more effective than interferon β or glatiramer acetate for relapse prevention during pregnancy.
- Real-world registry data provide robust comparative effectiveness for DMT strategies across pregnancy stages.
Study Background and Disease Burden
Multiple sclerosis (MS) is a chronic, immune-mediated neurological disease that disproportionately affects women of reproductive age. The management of MS during pregnancy is complex due to the need to balance maternal disease control with fetal safety. Disease-modifying therapies (DMTs) are the cornerstone of relapse prevention in relapsing-remitting MS, but many have uncertain safety profiles during gestation and lactation. Historically, pregnancy was considered a protective factor for MS relapses; however, recent evidence suggests that the interruption or modification of DMTs around conception and throughout pregnancy may increase the risk of disease reactivation. Understanding the comparative effectiveness of contemporary DMT strategies in the context of pregnancy is critical for optimizing outcomes for both mother and child.
Study Design
This retrospective multicenter cohort study analyzed data from the French MS registry (OFSEP) spanning January 1990 to December 2023. Among 52,955 women in the registry, 6,341 pregnancies in 4,998 women with relapsing-onset MS were included based on stringent eligibility criteria: monitoring for at least 18 months before delivery and 9 months after, with exclusion of closely spaced or incomplete pregnancies. The study employed mediation analysis to estimate direct and indirect effects of pregnancy on relapse risk, focusing on DMT management as a potential mediator.
Therapeutic strategies compared included:
- DMT interruption (cessation prior to or at conception)
- Switching to or maintaining interferon β or glatiramer acetate
- Switching to or maintaining natalizumab until the third trimester (with distinction between short and prolonged interruption)
- Switching to or maintaining intravenous anti-CD20 monoclonal antibodies (with interruption 3 months before conception)
The primary endpoint was annualized relapse rate (ARR) across the preconception, gestational, and postpartum periods. Counterfactual ARRs were estimated using longitudinal g-computation, integrating a random forest algorithm for therapeutic prediction and a mixed-effects Poisson model for relapse events.
Key Findings
In this large cohort (mean age at conception, 31.5 years), the management of DMTs during pregnancy had a significant impact on relapse risk. The main results are as follows:
- Relapse Risk Associated With DMT Management: DMT adjustment or interruption during pregnancy led to a modest but statistically significant increase in ARR during gestation (causal rate ratio [cRR], 1.13; 95% CI, 1.06-1.22) and postpartum (cRR, 1.08; 95% CI, 1.01-1.16) compared to preconception rates.
- High-Risk Scenarios: The deleterious effect on relapse risk was most pronounced in two groups:
- Women receiving natalizumab prior to pregnancy who had prolonged interruption (e.g., stopped before the second trimester or delayed resumption postpartum) showed a marked increase in ARR (cRR, 2.18; 95% CI, 1.76-2.69).
- Women on fingolimod prior to conception also faced a significantly elevated relapse risk (cRR, 2.15; 95% CI, 1.60-2.93).
- Comparative Effectiveness of DMT Strategies: When benchmarked against DMT interruption:
- Anti-CD20 monoclonal antibodies administered before conception and interrupted 3 months prior demonstrated the greatest reduction in relapse risk (cRR, 0.38; 95% CI, 0.25-0.52).
- Natalizumab with short interruption (until third trimester or resumed soon after delivery) was also protective (cRR, 0.80; 95% CI, 0.71-0.90).
- Maintenance of interferon β (cRR, 0.93; 95% CI, 0.86-0.99) or glatiramer acetate (cRR, 0.91; 95% CI, 0.84-0.99) were less effective but still favorable compared to complete DMT cessation.
- Safety Considerations: While the study focused on ARR, it did not directly address fetal or maternal safety outcomes, which are a critical aspect of DMT selection during pregnancy. The use of anti-CD20 agents and natalizumab, though effective for relapse prevention, require careful risk-benefit analysis, particularly in the context of emerging safety data.
Expert Commentary
These findings provide robust, real-world evidence to guide DMT decision-making for women with MS planning pregnancy or currently pregnant. The pronounced relapse risk associated with prolonged natalizumab interruption and fingolimod discontinuation underscores the need for proactive preconception counseling and individualized therapeutic planning. The superior performance of anti-CD20 therapies (such as ocrelizumab or rituximab) aligns with their known long-lasting immunomodulatory effects, which may extend protection through gestation and the high-risk postpartum period.
Current guidelines (e.g., ECTRIMS/EAN, AAN) increasingly support the use of anti-CD20 agents in women planning pregnancy, provided that dosing schedules are carefully timed to minimize fetal exposure. The data also reinforce the role of natalizumab as a bridging therapy for women with highly active disease, while highlighting the risks of prolonged interruption. Interferon β and glatiramer acetate remain viable options for women with lower disease activity or those prioritizing fetal safety; however, their efficacy in preventing relapses during this vulnerable period is comparatively modest.
Limitations of the study include its retrospective design, potential for residual confounding, and lack of direct safety data for the fetus or mother. Nevertheless, the large sample size, robust analytical framework, and comprehensive registry data enhance the generalizability and clinical relevance of the findings.
Conclusion
This large registry-based study demonstrates that management of DMTs during pregnancy in women with MS is a critical determinant of relapse risk. Strategies based on anti-CD20 monoclonal antibodies administered before conception offer the most robust protection against peripartum relapses, with short-interruption natalizumab as a secondary option for those with highly active disease. Interferon β and glatiramer acetate are less effective but may be appropriate where safety is paramount. These results emphasize the importance of individualized, multidisciplinary approaches to MS management in women of childbearing age and highlight persistent gaps in knowledge regarding optimal safety and efficacy profiles for both mother and child.
References
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