Highlight
– In a national multicenter cohort of 6,341 pregnancies in women with relapsing‑onset MS, DMT management during pregnancy increased relapse rates during gestation and postpartum.
– The highest excess relapse risk was seen after prolonged natalizumab interruption and with fingolimod exposure before pregnancy.
– Strategies that maintained B‑cell depletion with anti‑CD20 agents before conception were associated with the greatest reduction in relapse risk compared with stopping therapy.
Background
Pregnancy has long been recognized to alter the clinical course of multiple sclerosis (MS). Classical prospective data (PRIMS and follow‑ups) demonstrated a marked reduction in relapse rate during the third trimester followed by an increased risk in the postpartum months. Against this immunologic backdrop, modern disease‑modifying therapies (DMTs) for MS present clinicians and patients with complex decisions about timing, termination, or switching of therapy when pregnancy is planned or discovered.
Over the past two decades the therapeutic armamentarium for relapsing MS has expanded widely (interferon‑beta, glatiramer acetate, natalizumab, fingolimod, and anti‑CD20 monoclonal antibodies among others). These agents differ in efficacy, mechanism of action, pharmacokinetics, and teratogenic or fetal safety data, which complicates pregnancy planning. The net clinical effect of stopping, switching, or maintaining particular DMTs around pregnancy on maternal relapse risk has been incompletely quantified across a large, contemporary population.
Study design
The study by Gavoille et al. used the French OFSEP registry (January 1990–December 2023) to analyze pregnancies leading to childbirth among women with relapsing‑onset MS who had at least 18 months of preconception monitoring and 9 months of postpartum follow‑up. After exclusions, 6,341 pregnancies in 4,998 women were included.
Key exposure: DMT management strategy during pregnancy. Investigators compared several pragmatic strategies commonly used in clinical practice: interruption of DMT, switching to or maintaining interferon‑beta or glatiramer acetate, continuation or short interruption of natalizumab until late pregnancy, and strategies based on intravenous anti‑CD20 (eg, rituximab/ocrelizumab) given prior to conception with planned interruption ~3 months before conception.
Primary outcome: annualized relapse rate (ARR) across three time windows: preconception, gestation, and postpartum.
Analytic approach: causal inference methods were applied. The authors used longitudinal g‑computation to estimate counterfactual ARRs under different DMT management strategies, with a random forest algorithm for predicting DMT patterns and a mixed‑effects Poisson model for relapses. Mediation analysis estimated the proportion of pregnancy’s effect on relapse mediated by DMT management.
Key findings
Population: mean age at conception 31.5 (SD 4.5) years; 6,341 pregnancies analyzed.
Overall effect of DMT management: After accounting for confounding within the causal framework, DMT management during pregnancy significantly increased the ARR during both gestation (causal rate ratio [cRR] 1.13; 95% CI, 1.06–1.22) and the postpartum period (cRR 1.08; 95% CI, 1.01–1.16). In other words, choices made about DMTs around conception materially influenced maternal relapse rates.
High‑risk scenarios
– Natalizumab with prolonged interruption: Women taking natalizumab before pregnancy who had prolonged interruption (e.g., interruption before the second trimester or restarting more than 3 months after delivery) experienced a marked increase in relapse risk (cRR 2.18; 95% CI, 1.76–2.69). This indicates that stopping natalizumab early in pregnancy or significantly delaying postnatal reinitiation substantially raises relapse incidence.
– Fingolimod exposure: Pregnancies with fingolimod prior to conception had increased relapse risk (cRR 2.15; 95% CI, 1.60–2.93). These findings are consistent with recognized disease reactivation or rebound after fingolimod cessation.
Comparative effectiveness of strategies (referent = DMT interruption)
– Anti‑CD20 strategy (preconception dosing with interruption ~3 months before conception) was associated with the largest reduction in relapse risk compared with stopping therapy (cRR 0.38; 95% CI, 0.25–0.52).
– Natalizumab continued until the third trimester or with short interruption was protective versus complete interruption (cRR 0.80; 95% CI, 0.71–0.90).
– Interferon‑beta strategy (switching to or maintaining) had a modest protective effect (cRR 0.93; 95% CI, 0.86–0.99), as did glatiramer acetate (cRR 0.91; 95% CI, 0.84–0.99).
Interpretation of effect sizes: The magnitude of the anti‑CD20 association is substantial (≈60% reduction in ARR compared with stopping DMT) and clinically meaningful for women with active disease where relapse prevention is important to prevent disability accrual. The natalizumab short‑interruption strategy also meaningfully lowered risk, while first‑line injectable agents conferred modest benefit relative to stopping therapy.
Safety and fetal outcomes
This analysis focused on maternal relapse outcomes and did not primarily provide new data on fetal safety, congenital anomalies, or longer‑term child outcomes. Safety considerations remain central to the choice of strategy and must be individualized using available fetal safety data from other sources.
Mechanistic and clinical rationale
Pregnancy leads to immune adaptation — particularly in the third trimester — that historically reduces relapse frequency. However, abrupt withdrawal of potent immune‑modifying therapies can remove pharmacologic disease suppression and, depending on pharmacodynamics, lead to disease reactivation or rebound (well described for fingolimod and reported for natalizumab). Anti‑CD20 therapies produce durable B‑cell depletion that can extend across conception and pregnancy when timed appropriately, providing ongoing disease suppression without continuous dosing.
Strengths and limitations
Strengths
– Large, contemporary, multicenter national registry with many pregnancies and extended follow‑up spanning 1990–2023.
– Use of causal inference methods (g‑computation, mediation analysis) to estimate counterfactual outcomes and to quantify the role of DMT management as a mediator.
– Evaluation of real‑world therapeutic strategies that reflect clinical decision pathways.
Limitations
– Observational and retrospective design — residual confounding and indication bias are possible despite advanced statistical adjustment.
– Treatment practices, available therapies, and pregnancy counseling evolved across the study period (1990–2023), which may affect generalizability to current practice and newer agents.
– Precise perinatal safety data for fetus and neonate were not the principal outcome here, so therapeutic recommendations must still balance maternal benefit and fetal risk using separate safety evidence.
– Some strategies may include fewer pregnancies (limited power for certain subgroups), and rare but severe outcomes may not be fully captured in registry data.
Clinical implications and practical guidance
1. Preconception planning is critical. Women with relapsing MS benefit from individualized counseling about the timing of pregnancy relative to DMT dosing and the comparative relapse risks of different strategies.
2. Anti‑CD20 strategy for selected patients. When feasible and clinically appropriate, scheduling anti‑CD20 dosing prior to conception appears to offer strong protection against relapse during gestation and postpartum, as suggested by this large registry analysis. This approach requires coordination with reproductive plans and informed discussion about fetal exposure and available safety data.
3. Natalizumab continuation into pregnancy for high‑activity disease. For patients on natalizumab with aggressive disease, continuation or short interruption (eg, up to the third trimester) may limit relapse risk. Prolonged interruption is associated with substantially increased relapse rates and should be approached cautiously.
4. Caution with fingolimod. Fingolimod cessation carries a recognized risk of disease reactivation; avoid stopping fingolimod without a clear bridging or alternative immunosuppressive strategy when pregnancy is desired, and counsel patients about increased relapse risk.
5. Injectable DMTs (interferon‑beta, glatiramer acetate) may be reasonable bridging options for some patients with lower disease activity, offering modest relapse protection and generally favorable pregnancy safety profiles compared with complete interruption.
6. Shared decision‑making. Decisions should integrate individual relapse history, MRI activity, disability status, fetal safety evidence, patient preferences, and family planning timelines.
Expert commentary and guideline context
This study provides large‑scale, real‑world evidence quantifying the impact of common DMT management strategies on relapse risk across pregnancy and postpartum windows. These findings align with mechanistic expectations and prior smaller studies highlighting rebound risks after fingolimod or natalizumab cessation and the potential benefit of maintained immune suppression. Clinical guideline committees and specialists should incorporate such data when updating pregnancy management recommendations, emphasizing preconception planning and individualized risk‑benefit balancing.
Conclusion
Management of DMTs around pregnancy meaningfully influences relapse risk in women with relapsing‑onset MS. Prolonged natalizumab interruption and fingolimod exposure prior to conception are associated with the highest relapse risks. In contrast, a preconception anti‑CD20 strategy conferred the greatest reduction in relapse incidence compared with stopping therapy, and continuing natalizumab into late pregnancy or using injectable agents offered intermediate benefits. These data support careful preconception planning and individualized therapeutic strategies to minimize maternal disease activity while accounting for fetal safety considerations.
Recommendations for clinicians
– Engage in early preconception counseling for women of childbearing potential on DMTs.
– For women with high disease activity, discuss options that preserve disease suppression during pregnancy (anti‑CD20 timing or continued natalizumab with short interruption) and outline known fetal safety evidence.
– Avoid unplanned cessation of high‑efficacy agents without a clear bridging plan; document the rationale and monitoring strategy when therapy is modified for pregnancy.
– Coordinate multidisciplinary care (neurology, obstetrics, neonatology) and monitor closely during pregnancy and the postpartum period.
Funding and trial registration
The cited study used data from the French OFSEP registry. For funding details and registry identifiers, refer to Gavoille et al., JAMA Neurol. 2025.
References
1. Gavoille A, Rollot F, Casey R, et al; OFSEP Investigators. Therapeutic Management During Pregnancy and Relapse Risk in Women With Multiple Sclerosis. JAMA Neurol. 2025 Oct 1;82(10):994–1003. doi: 10.1001/jamaneurol.2025.2550 .
2. Confavreux C, Hutchinson M, Hours M, Cortinovis‑Tourniaire P, Moreau T. Rate of pregnancy‑related relapse in multiple sclerosis. N Engl J Med. 1998;339(5):285–291.
