There is a significant risk of relapse-related disability in patients with multiple sclerosis (MS) who stop taking the drug natalizumab (Tysabri) during pregnancy, new research suggests.
In a prospective cohort study of 255 pregnant women with MS who stopped taking natalizumab, almost 11% had significant relapse-related disability 1 year after delivery. Relapses during pregnancy and in the postpartum period were also common.
"The results of our study add relevant information on different maternal risks and may inform a distinct risk–benefit discussion between every neurologist and women on natalizumab who plan a pregnancy," investigators led by Kerstin Hellwig, MD, Katholisches Klinikum, Bochum, Germany, write.
The findings were published online January 24 in JAMA Network Open.
Pregnancy has a benign effect on MS and data suggest a reduced relapse risk in the third trimester. However, in small cohort studies, women who received natalizumab before pregnancy and stopped taking it while pregnant were at increased risk for relapse and disability progression during pregnancy and in the postpartum period.
However, the full implications of natalizumab treatment before pregnancy are still unclear, the investigators note.
To investigate, they analyzed data from the German Multiple Sclerosis and Pregnancy Registry. Patients eligible for this analysis had a documented last menstrual period (LMP) and delivery date, had discontinued natalizumab within 2 years before or up to 84 days after the LMP, had a pregnancy duration of at least 22 weeks, and received no bridging therapy.
Participants provided data during standardized phone interviews at enrollment, during each remaining trimester, and at 1, 3, 6, and 12 months postpartum. Information about Expanded Disability Status Scale (EDSS) scores and relapses was obtained from medical records.
The researchers defined severe relapses until the end of pregnancy or 1 year postpartum as new or worsening walking impairment.
They also created the Severe Relapse Disability Composite Score, which they defined as any relapse during pregnancy or postpartum leading to a change of two EDSS points, new walking impairment without significant prepregnancy walking impairment, or significant worsening walking impairment with at least some preexisting ambulatory impairment.
The mean age of the 255 study participants was 31.2 years and the population had 274 successful pregnancies. In 85 cases, women stopped natalizumab prior to becoming pregnant. For the other 189 pregnancies, natalizumab was halted during the first trimester.
High Relapse Risk
Results showed relapses occurred in 183 pregnancies (66.8%), and at least one severe relapse occurred in 44 pregnancies (16.1%). At 1 year postpartum, significant relapse-related disability was accumulated in 29 pregnancies (10.6%).
In addition, the investigators recorded 135 relapses (49.3%) during the first postpartum year.
Median duration of natalizumab treatment before pregnancy was shorter for women with nonsevere relapses (2.5 years) and those with severe relapses (2.25 years) compared with women with no relapses (4.1 years). Severe relapses during pregnancy or postpartum accounted for most of the population's disability worsening.
The proportion of women with at least one relapse was higher among those who discontinued natalizumab before pregnancy (48.2%) than among those who discontinued treatment during the first trimester (36%). The latter group had a significantly lower risk for relapse throughout pregnancy compared with the former group.
Pregnancy, considered as a time-dependent variable, was not associated with a reduced risk for relapse (adjusted hazard ratio [HR], 0.9).
In addition, exclusive breastfeeding (adjusted HR, 1.34) and restarting natalizumab within 4 weeks postpartum (adjusted HR, 1.06) were not associated with a reduced risk of early postpartum relapses at 6 months after delivery.
Nevertheless, the relapse rate ratio during the first postpartum year was lower (0.49) when the mother restarted natalizumab during the first 4 weeks after delivery.
Catastrophic relapses rendered three women bedbound. Two of these cases occurred during pregnancy and one occurred postpartum. Risk for catastrophic relapse was 1.09% per pregnancy, which is greater than the risk for progressive multifocal leukoencephalopathy that is associated with natalizumab, the researchers note.
"This risk of experiencing catastrophic relapse after cessation of disease-modifying treatment was likely never a clinical challenge until natalizumab and fingolimod [Gilenya] were introduced," they write.
"A Problem No Matter When You Stop"
Commenting on the findings for Medscape Medical News, Jennifer Graves, MD, PhD, director of neuroimmunology research and associate professor of neurosciences, University of California San Diego, said the investigators' treatment of pregnancy as a time-dependent covariate was unique.
Previous studies have suggested that continuing natalizumab into the first trimester may reduce risk for relapse during pregnancy compared with discontinuation before conception, she noted.
"This is showing that when you do a more rigorous statistical analysis, it looks like it's a problem no matter when you stop it. We need to better understand how to protect women coming off of natalizumab for pregnancy," said Graves, who was not involved with the research.
However, she noted that women with more severe relapses entered the study at a later point during peripregnancy than women without relapses and those with milder relapses. This discrepancy could have introduced bias and is the study's most notable limitation, Graves said.
Out of concern for the fetus, neurologists tend to be conservative regarding medication use before and during pregnancy, she noted.
"But we need to push the limits more on research in the peripregnancy period so that we can give women better information about the risks to the baby vs the risks to themselves with decisions like stopping natalizumab," she said.
Researchers should also study the safety of administering natalizumab in breastfeeding women. The balance of risks may show it is safe and advisable, Graves concluded.
The German Multiple Sclerosis and Pregnancy Registry receives funding from the Innovation Fund of the Federal Joint Committee, Almirall, Biogen, Merck, Novartis, Roche, and Teva Pharmaceuticals. Hellwig has received speaker honoraria and research support from and served on scientific advisory boards for Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Her participation in congresses has been supported by the same with the exception of Novartis. Graves has disclosed no relevant financial relationships.
JAMA Netw Open. Published online January 24, 2022. Full text
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Cite this: Stopping MS Med in Pregnancy Tied to High Disability Risk - Medscape - Feb 07, 2022.