How stable is Multiple Sclerosis during pregnancy?
Nearly 25 years have passed since the Pregnancy in Multiple Sclerosis (PRIMS) study demonstrated that women with multiple sclerosis have a reduction in relapse rates during pregnancy.1 Although these data suggest that pregnancy is a time of clinical stability, 15–30% of patients do experience relapse and disability progression continues to occur.1,2 Additionally, since the release of PRIMS, numerous disease modifying therapies (DMTs) have become available, altering the clinical course of Multiple Sclerosis (MS).3 So, how stable is MS during pregnancy in the current era?
The PRIMS study
PRIMS was a prospective, observational study, performed in 12 European countries, that investigated the impact of pregnancy on the course of MS.1 Although earlier studies had reported on MS during pregnancy, this was the first large, prospective analysis.1 Recruitment to the study began in 1993 and the final birth took place in 1996, with a total of 269 pregnancies studied in 254 women. All but eight patients had relapsing-remitting MS (RRMS) at the time of enrolment.1 Relapse rates during the first two trimesters of pregnancy were lower than those reported in the year before conception, then fell further in the third trimester. Despite this, disability progression remained constant, with a steady increase in Expanded Disability Status Scale (EDSS) score over the time of the study.1 A meta-analysis including PRIMS and 21 other studies published up to 2009 provided robust support for the finding that relapse rate decreases during pregnancy.4 When considering how applicable these data are to the present day, it should be considered that even first-line injectable agents were still in development at the time of the PRIMS study, and most of the high-efficacy DMTs in use today were not introduced until after the meta-analysis was performed.3
What do more recent data show?
A population-based study performed at two US centres included data from 466 pregnancies in 375 women between 2008 and 2016.5 As seen in the PRIMS study, the number of relapses reported was substantially lower during pregnancy than in the time before conception; relapses occurred during 9% of pregnancies.5 Unlike the patients in PRIMS, however, the majority (70%) of this cohort had received a DMT for their MS; in the year before conception, first-line injectable agents were predominantly used (94%).5 The German MS and Pregnancy Registry has been prospectively collecting data on MS in pregnancy since 2006, with a dataset including 2579 pregnancies up to the end of 2020.6 At the time of conception, 76% of women had been receiving a DMT. Similar to previous data, there was a large decrease in the proportion of women experiencing a relapse during their pregnancy, but 19% of women experienced at least one relapse in this period.6 These more contemporary data suggest that the general trend of MS clinical stability during pregnancy holds true in the modern era of DMTs. But how do DMT treatment patterns impact MS stability?
The impact of DMTs
Although the availability of high-efficacy DMTs for MS has enabled a high level of control to be achieved over the disease,7 pregnancy can present a problem, with many patients advised to stop therapy before conception to reduce foetal risk.8 More recently, the accumulation of safety data has led to the European Medicines Agency relaxing its restrictions on the use of first-line injectable agents during pregnancy.8 However, some DMTs are not recommended in pregnant women and must be discontinued,9 leading to the possibility of loss of disease control.8 The impact of DMT treatment patterns on relapse during pregnancy was investigated in a systemic review that analysed data from 4739 pregnancies in 28 publications.8 The risk of relapse during pregnancy was found to be higher in women who had used high-efficacy DMTs (such as α4-integrin monoclonal antibodies or sphingosine-1-phosphate receptor modulators) before conception than in those who were untreated or had used first-line injectable agents, with relapses being reported in 29–37% of women who had received high-efficacy DMTs.8 Longer washout periods were associated with a significant increase in the likelihood of experiencing relapse.8 Data were mixed on the effect of continuing DMTs into early pregnancy: five studies suggested that this reduced the risk of relapse, while five found no effect on relapse activity. This may depend on the type of agent used, as those studies reporting on high-efficacy DMTs were more likely to report an effect than those investigating moderate-efficacy agents.8 Similar to the effects on relapse rates, use of high-efficacy DMTs and longer washout periods were also associated with increased risk of disability progression.8
Other factors influencing the clinical stability of MS during pregnancy
In an Austrian real-world cohort, 17% of 239 women with RRMS had a relapse during pregnancy, the majority during the first trimester.10 The use of high-efficacy DMTs and a longer wash-out period were both associated with an increased risk of relapse and disability progression during pregnancy.10 The number of relapses in the year before conception impacted on both relapse risk and disability progression, while EDSS score at the time of conception was only associated with the latter.10
Conclusions
Despite the quarter century that has elapsed since the publication of the PRIMS data and the progress that has been made in MS therapy since then, it remains the case that pregnancy is a time when most women can expect a period of clinical stabilisation. However, a proportion of women with MS do experience relapse and an increased rate of disability progression when pregnant, with an increased likelihood in those who discontinue high-efficacy agents or have poor disease control prior to conception, highlighting the continued need for careful management of MS both before and during pregnancy.
Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T, and the Pregnancy in Multiple Sclerosis Group. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998;339:285.
Villaverde-González R. Updated perspectives on the challenges of managing multiple sclerosis during pregnancy. Degener Neurol Neuromuscul Dis 2022;12:1.
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Finkelsztejn A, Brooks JBB, Paschoal Jr FM, Fragoso YD. What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature. BJOG 2011;118:790.
Langer-Gould A, Smith JB, Albers KB, et al. Pregnancy-related relapses and breastfeeding in a contemporary multiple sclerosis cohort. Neurology 2020;94:e1939.
Thiel S, Ciplea AI, Gold R, Hellwig K. The German Multiple Sclerosis and Pregnancy Registry: rationale, objective, design, and first results. Ther Adv Neurol Disord 2021;14:17562864211054956.
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Hellwig K, Verdun di Cantogno E, Sabidó M. A systematic review of relapse rates during pregnancy and postpartum in patients with relapsing multiple sclerosis. Ther Adv Neurol Disord 2021;14:1.
Bsteh G, Hegen H, Riedl K, et al. Estimating risk of multiple sclerosis disease reactivation in pregnancy and postpartum: the VIPRiMS score. Front Neurol 2022;12:766956.
Bsteh G, Algrang L, Hegen H, et al. Pregnancy and multiple sclerosis in the DMT era: A cohort study in Western Austria. Mult Scler 2020;26:69.
