Natalizumab, Fingolimod and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis

Abstract

Objective: To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort.

Methods: Using data from the MSBase Registry, we included pregnancies conceived after 31 Dec 2010 from women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse, and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses.

Results: We included 1998 pregnancies from 1619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% CI 0.27-0.32), fell to 0.19 (0.14-0.24) in third trimester, and increased to 0.59 (0.51-0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28-0.49) and 0.29 (0.22-0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 [0.04-0.32], p<0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41-0.91], p=0.016). 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum.

Conclusion: Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation, with early re-initiation after delivery is an effective option to minimize relapse risks. Strategies of DMT use have to be balanced against potential fetal/neonatal complications.

Figure 1. Flowchart of Pregnancy and Patient Inclusion/Exclusion

MS = multiple sclerosis.

Figure 2. ARRs Before Conception, During Pregnancy, and Postpartum Across Epochs for Term/Preterm Pregnancies

Bars represent 95% confidence intervals. ARR = annualized relapse rate.

Figure 3. ARRs Before Conception, During Pregnancy, and Postpregnancy for Abortions/Miscarriages/Stillbirths in the Modern Epoch

Bars represent 95% confidence intervals. ARR = annualized relapse rate.

Figure 4. Annualized Relapse Rates (ARRs) Before Conception, During Pregnancy, and Postpartum for Term/Preterm Pregnancies in the Modern Epoch

By disease-modifying therapy (DMT) used before conception (A), of pregnancies associated with preconception natalizumab (NAT) use (B), of pregnancies associated with preconception dimethyl fumarate (DMF) use (C), and of pregnancies associated with preconception fingolimod (FIN) use (D). In panel A, pregnancies associated with preconception NAT, FIN, or DMF use are compared to those with low-efficacy or no DMT use. In panels B, C, and D, pregnancies associated with NAT, DMF, or FIN use are grouped according to whether the drug was continued into pregnancy or stopped (i.e., washout) before conception. Bars represent 95% confidence intervals.