Abstract
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. To determine the association of early natalizumab withdrawal before or during pregnancy with risk of severe relapses and relapse-related disability. 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. Cessation of natalizumab before pregnancy or until the first trimester. 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. 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. 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.
Highlights
Natalizumab is a highly effective and well-tolerated treatment for relapsing-remitting multiple sclerosis (MS), but if treatment is discontinued, clinical disease activity returns in 9% to 80% of patients after 4 to 7 months.[1]
Neither exclusive breastfeeding nor restarting natalizumab within 4 weeks post partum were associated with a reduced risk of early postpartum relapses 6 months after delivery
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. 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
Summary
Natalizumab is a highly effective and well-tolerated treatment for relapsing-remitting multiple sclerosis (MS), but if treatment is discontinued, clinical disease activity returns in 9% to 80% of patients after 4 to 7 months.[1] Pregnancy is thought to be an effective natural treatment and is associated with a reduced relapse risk in the third trimester.[2,3] smaller cohort studies show that relapse and disability progression risk during pregnancy and post partum is higher in women who received natalizumab before pregnancy.[4,5,6,7] Case reports of severe disease reactivation and rebound up to death in the context of pregnancy planning have been reported.[8,9,10,11,12] These cases are concerning, yet the magnitude of this risk is still unknown. Counting any relapse or sustained disability progression, as is typical of MS randomized clinical trials and MS and pregnancy studies,[4,5,6,7] doesn’t reflect the disabling relapses patients fear, where the most valuable function for MS patients seems to be lower limb function.[13]
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