Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era
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Abstract
Objective To determine the rate of relapse occurrence during pregnancy and postpartum.
Methods In a cross-sectional study using the national multiple sclerosis (MS) registry, pregnant women with relapsing MS were identified. Data on demographics, clinical characteristics, and disease-modifying therapies (DMTs), including washout periods, were collected. Timings and durations of relapses were extracted. A multivariate logistic regression was used to assess the relationship between relapses and prior use of different DMTs.
Results Completed data were available for 99 pregnancies (87 patients). Mean age and mean age at onset were 31.8 ± 5 and 24.4 ± 5.6 years, respectively, while the mean disease duration was 7.4 ± 4.6 years. Most pregnancies (89.9%) occurred in patients who were on DMTs in the year preceding pregnancy with a mean treatment duration of 63.4 ± 29 months. The rates of occurrence of relapses during pregnancy and postpartum were 17.2% and 13.7%, respectively. Most of the relapses occurred during the first (n = 6) and third (n = 7) trimesters. Rate of relapse was highest among patients receiving natalizumab and fingolimod before pregnancy. A longer washout period was significantly associated with relapse occurrence.
Conclusion The relapse occurrence during pregnancy is higher than the previously published rates. The use of high-efficacy therapies with long washout periods before conception was associated with an increased risk of relapses during pregnancy. Postpartum relapse occurrence was similar to that in previous reports.
Glossary
- DMT=
- disease-modifying therapy;
- EDSS=
- Expanded Disability Status Scale;
- GA=
- glatiramer acetate;
- IFN-β=
- interferon beta;
- IVIG=
- IV immunoglobulin;
- IVMP=
- IV methyl prednisolone;
- MS=
- multiple sclerosis;
- PRIMS=
- Pregnancy in Multiple Sclerosis;
- Th=
- T-helper
Pregnancy is accepted to be a period in which relapses decrease significantly, especially in the third trimester. This was first shown in 1998 by the Pregnancy in Multiple Sclerosis (PRIMS) study, which prospectively assessed 254 women with MS during pregnancy and reported a 70% reduction in annualized relapse rate in the third trimester compared to the year before pregnancy.1 A meta-analysis that included 1,221 pregnancies in women with MS showed a significant decrease in the relapse rate during pregnancy (0.18 vs 0.44 before pregnancy, p < 0.0001).2
The pathophysiologic basis that accounts for the reduction in the relapse rate during pregnancy remains largely unknown. It is thought that the immune system is induced by estrogen and other sex hormones to switch the T-helper (Th) cell profile to predominantly Th2 (anti-inflammatory cytokines) rather than Th1 (proinflammatory cytokines).3,4 A significant increase in the percentage of circulating CD56 natural killer cells could be responsible for the reduction of disease activity during the third trimester, in addition to the downregulation of interferon gamma produced by peripheral blood lymphocytes that leads to an increased ratio of Th2 to Th1 during pregnancy.5
Most of the published studies included patients who were on either interferon beta (IFN-β) or glatiramer acetate (GA) before conception.6,–,9 The magnitude of reduction in relapse rate during pregnancy in patients with MS is different in patients who are on high-efficacy disease-modifying therapies (DMTs) that once discontinued can cause disease reactivation after several weeks or months.10,–,12 Therefore, we aimed to measure the relapse occurrence during pregnancy and postpartum in a population in whom different DMTs are used to assess the trends in disease activity in the new era of therapeutics.
Methods
This cross-sectional study was conducted with data from the Kuwait National MS Registry. Established in 2010, this registry accounted for nearly 95% of the patients with MS diagnosed in Kuwait.13 Once entered in the registry, patients are being followed up prospectively on a regular basis with at least 2 visits per year (every 6 months) in addition to unscheduled visits for suspected relapses or unexpected adverse events/laboratory abnormalities. The prospectively collected data include any events reported by the patients (adverse events, pregnancy, co-occurrence of other disorders) or any data reported by the treating neurologists (relapses, disability measures, MRI reports, and any change in therapies, including reasons for discontinuation/interruption). Using the revised 2010 McDonald diagnostic criteria,14 we classified patients as having relapsing-remitting, secondary progressive, or primary progressive MS.15 Pregnant women with relapsing-remitting MS were included, while women with progressive MS and clinically isolated syndrome were excluded because of the low likelihood of sustaining relapses. Demographic data (age) and clinical characteristics (age at onset, disease duration, number of relapses before and during the pregnancy and postpartum period, duration of pregnancy dichotomized by trimesters, prior/ongoing DMTs, including washout periods) were extracted from the registry database on May 31, 2017. Relapses were defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted for at least 24 hours and were accompanied by new neurologic signs.16 The main outcome of the study was to determine the rate of relapse occurrence during pregnancy and postpartum. In addition, the relationships between the relapse occurrence and prior use of different DMTs, length of washout period, age at MS onset, disease duration, and age were assessed.
Descriptive statistics (mean and SD) were used to describe the numeric values of the sample. Analysis of variance was used to compare pregnancies with a relapse and pregnancies without a relapse in terms of age, age at MS onset, disease duration, and length of washout period. If one of these was significantly different, then analysis of covariance was used to compare this significant relationship after adjustment for age and type of prior medication. To compare type of medications used before pregnancy between pregnancies with relapse and pregnancies without a relapse, the Fisher exact test was used because of the low occurrence of relapses in each individual therapy. Lastly, a multivariate logistic regression was used to explore the effect of age, age at MS onset, disease duration, length of washout period, and type of medication before pregnancy on the probability of getting a relapse.
Standard protocol approvals, registrations, and patient consents
On the establishment of the national MS registry, a generic informed consent was given to the patient before data entry to grant his/her approval before data entry. A specific informed consent was created for each substudy, and specific information about the study was discussed with the patient. The institutional ethics committee approved the study, and informed consent forms were obtained from all patients.
Results
A total of 107 pregnancies were identified from the national registry. Patients with clinically isolated syndrome (n = 3) and secondary progressive MS (n = 2) were excluded. Completed data were available for 99 pregnancies (87 patients), which were subsequently analyzed. Baseline demographics and clinical characteristics are outlined in table 1. The mean age and mean age at onset were 31.8 ± 5 and 24.4 ± 5.6 years, respectively. The mean disease duration was 7.4 ± 4.6 years. When dichotomized according to treatment, women who were on fingolimod and natalizumab had longer disease duration, while natalizumab-treated women had higher EDSS score at baseline (table 2). Four relapses were reported in the year preceding pregnancy, while 17 and 13 relapses occurred during pregnancy and the postpartum period in 15 and 13 patients, respectively. Spontaneous abortion occurred in 4 pregnancies. All relapses during pregnancy except 1 were treated with IV methyl prednisolone (IVMP) 1 g for 3 to 5 days, depending on severity. One patient received an additional 5-day course of IVMP 2 weeks after the initial course because of a lack of response and her reluctance to receive IV immunoglobulin (IVIG) or plasmapheresis. No DMTs were prescribed after any of the relapses. The rates of relapse occurrence during pregnancy and postpartum were 17.2% (17 of 99) and 13.7% (13 of 95), respectively. Two patients sustained relapses during both pregnancy and the postpartum period. Most relapses were clustered around 5 to 7, 10 to 12, and 34 to 37 weeks of gestation (figure). There was no significant difference in the distribution of relapses according to patients' EDSS scores. The mean duration of relapses that occurred during pregnancy was 18 ± 9.1 days. Full recovery was observed in 11 relapses. In relapses that resulted in sustained residual disabilities (n = 6), the EDSS score was increased by 1.0 point in 3 patients, by 1.5 points in 2 patients, and by 3 points in 1 patient. It was noted that patients with an EDSS score >3 tended to have residual disabilities after relapses. Most pregnancies (89.9%) occurred in patients who were on DMTs in the year preceding pregnancy, as outlined in table 3. The mean treatment duration before pregnancy was 63.4 ± 29 months. Two patients were not on DMTs before their first pregnancies, but later DMTs were prescribed before their second pregnancies. Natalizumab and fingolimod were the most commonly prescribed DMTs in patients who sustained relapses during pregnancy and the postpartum period (table 3).
Baseline demographics and clinical characteristics of the studied cohort (n = 87)
Baseline characteristics according to DMTs
Each diamond represents 1 relapse.
Characteristics of relapses during pregnancy and postpartum
The mean washout period was 5.04 ± 5.3 weeks in pregnancies that were preceded by the use of DMTs. In patients who received natalizumab, the mean washout period before conception was 5.5 ± 4.4 weeks. However, it should be noted that the mean washout period was 9.5 ± 2.8 weeks in pregnancies that occurred before September 2014 compared to 2.8 ± 2.9 weeks afterward when patients were advised to continue natalizumab until pregnancy confirmation (p < 0.001). Moreover, 3 patients continued natalizumab until the end of the second trimester on the basis of the physician decision and patients' agreement given their highly active disease in the preceding year. Of 24 patients who were on natalizumab, 6 of 7 relapses occurred before the implementation of the recommendation to continue natalizumab until pregnancy is confirmed. With respect to fingolimod, the mean washout period was 10.8 ± 2.7 weeks. For IFN-β, there was no washout period for most patients except 1 patient who stopped subcutaneous IFN-β-1b for 7 months before conception because of nonadherence. Incidental pregnancy occurred in 1 patient who was prescribed teriflunomide, and an accelerated clearance procedure was carried out on pregnancy confirmation. Labor was induced in 3 pregnancies between the 37th and 39th weeks for obstetric reasons (n = 2) and a severe relapse (n = 1). After adjustment for age, age at MS onset, disease duration, and type of prior medication, the multivariate logistic regression showed a higher probability of having a relapse with longer treatment washout periods (odds ratio 3.9, 95% confidence interval 1.4–10.6, p = 0.008), as shown in table 4. Specific treatment per se was not associated with a relapse occurrence (p = 0.578), likely because of the low number of events once DMTs were dichotomized into specific variables.
Multivariate logistic regression of the variables that may predispose to relapses in pregnancy
No major fetal anomalies or congenital malformations were observed. One newborn had a low birth weight, and another had jaundice for 48 hours that resolved spontaneously.
Discussion
Women with MS usually plan their pregnancies when they have been stable without any disease activity and tend to consider pregnancy early in their disease course while they have no or minimal neurologic disabilities. In addition, pregnancy is an important stratification factor in the decision to initiate or switch DMTs, especially for therapies requiring strict washout periods such as fingolimod.
At baseline, heterogeneity of the studied women receiving different DMTs was observed, especially with respect to the clinical characteristics (disease duration, relapse, and EDSS score), which might have affected the findings. There was a 4-fold increase in the relapse occurrence in our cohort, driven mostly by patients who were on natalizumab and fingolimod before conception. We expected to find quiescent disease in interferon-treated patients and possible reactivation of disease in natalizumab-treated patients. This was a potential source of bias because most natalizumab-treated patients were escalated after having breakthrough disease while on first-line therapies such as interferons or had an initial highly active course necessitating initiation of natalizumab as a first-line therapy. On the other hand, the effect of the washout period in the fingolimod group and to a lesser extent in the natalizumab group was unexpected given the faster disease reactivation in the first trimester.
Most of the previous reports did not assess the effect of treatment or evaluated the effects of only IFN-β/GA because of the unavailability of high-efficacy DMTs or because of the lack of data on pregnancies in patients using second-line therapies. Most of the available reports were driven by retrospective, observational, and open-label studies or were extracted from postmarketing pharmacovigilance data collected by registries or pharmaceutical companies.6,–,9,17 A retrospective study evaluated 152 pregnancies, of which 61 pregnancies were exposed to immunomodulators (41 to GA, 17 to IFN-β, 2 to IVIG, 2 to IVMP) with a mean period of 18.4 ± 13.2 weeks.8 The largest study was performed with an international MS registry (MSBase) that included 893 pregnancies (674 women). DMTs were used by 39.0% of women in the 2-year period before conception. Discontinuation of DMT occurred at a median of 7.1 months before the onset of pregnancy. The 3 period epochs examined were 1967 to 2002, 2002 to 2006, and 2006 to 2010, which mostly did not include any second-line or new DMTs. The authors acknowledged the potential bias in that women who have milder disease were more likely to stop a DMT to become pregnant.17 In a prospective cohort study from the German Multiple Sclerosis and Pregnancy Registry, 445 pregnancies in women with MS were exposed to IFN-β (n = 251), and 194 patients had no exposure to DMTs.9
The interval between diminished/no treatment effect and the beginning of pregnancy is difficult to assess without proper pharmacokinetics studies. The serum concentration of a drug does not reflect its sustained effects. However, there are no established blood levels to determine the cessation of treatment effects. Some of the practical decisions with respect to determination of cessation of treatment effect were based on clinical or laboratory observations. For example, the normalization of lymphopenia in fingolimod-treated patients may indicate the diminution of effect, whereas a rebound/reactivation phenomenon might be seen in natalizumab-treated patients after 12 weeks of treatment cessation, suggestive of a possible lack of effect. Teriflunomide is the only drug for which the serum level can be measured after the accelerated clearance procedure is performed; however, it would be difficult to definitely determine that the treatment has no clinical effect.
Disease reactivation on discontinuation of DMTs played a significant role in our study. This was evident when the relapse occurrence decreased in women who continued natalizumab after implementation of the practice recommendation. The effect of washout duration was more pronounced in patients who were on fingolimod given the unpredictability of pregnancy after fingolimod discontinuation. Concerns regarding a risk of reactivation after DMT discontinuation have increased with the advent of recent drugs.18 Disease reactivation after natalizumab discontinuation is an established phenomenon, especially when natalizumab is stopped in patients with highly active MS because of concerns about progressive multifocal leukoencephalopathy.10,19 Even in what it was presumed to be a protective period, clinical and radiologic disease activity reappeared after natalizumab withdrawal for pregnancy planning with rare consequences of accumulation of disabilities after a relapse during pregnancy.11,20 Similarly, disease reactivation during pregnancy was observed several weeks after cessation of fingolimod.12
We have confirmed that, as shown previously, the postpartum period was associated with a high risk of relapses. A higher relapse rate in the prepregnancy year is believed to be a predictor of a higher relapse rate in the postpartum period.1,3,8,17 Pregnant women who were exposed to immunomodulators were less likely to have postpartum relapses than women who were not exposed to any DMT during the pregnancy or in the 3 months before conception.8 Similarly, the use of DMTs in the 2 years preceding conception was independently associated with a decreased postpartum relapse rate.17 It is unclear how DMTs may attenuate the relapse rate several months after discontinuation, yet this observation could be an argument for maintaining DMTs until conception whenever it is safe.20 Most treating physicians tend to advise the resumption of DMTs after delivery, although the optimal time to restart DMTs is unclear.21
Several reports addressed possible measures to prevent relapse occurrence in the postpartum period. The administration of different doses of IVIG was evaluated by 2 prospective studies, and there were no statistical differences between the dose regimens in reducing postpartum relapses.22,23 A recent retrospective study that evaluated 134 pregnancies (47 in women who received IVIG after delivery) in women with MS did not find any beneficial effect of the use of IVIG on relapse rates.24 In a nonrandomized study of monthly IVMP in 20 patients, the authors suggested a modest beneficial effect in reducing the risk of postpartum relapses. However, the results were not replicated.25 Breastfeeding has also been evaluated for possible protective effects in the postpartum period, but the results were conflicting in that 1 study that included 32 patients showed beneficial effects while another with a larger cohort of 298 women showed the opposite.26,27
In view of our findings, there are few practical points that need to be discussed. Women who are in remission or actively using DMT for at least 2 years have a significantly decreased risk for postpartum attacks but not necessarily during pregnancy.17 Women contemplating pregnancy should be counseled on several issues. First, a woman might have discontinued treatment for a long period of time before conception, resulting in a prolonged washout period. Hence, it might be possible for the woman to continue her DMTs such as IFN-β and GA until conception on the basis of systematic evidence of postmarketing studies.18,28 Second, an extended washout period before conception in patients with highly active disease might be associated with an increased risk of relapse especially beyond several weeks/months. Thus, continuing natalizumab until conception and possibly during the first trimester could decrease this risk because the teratogenic effects are low except in the third trimester when there is a risk of thrombocytopenia in the fetus.29,30 It was shown that treatment with natalizumab in women with highly active MS during their third trimester of pregnancy was associated with the suppression of disease activity.31 Fingolimod is associated with teratogenic effects, and it is recommended to withdraw the drug 2 months before pregnancy planning. Similar issues could be raised with alemtuzumab and teriflunomide because the former requires at least a 4-month washout period while the latter needs to be washed out with an elimination procedure. A definitive washout period for dimethyl fumarate is yet to be established but is ≈2 weeks because of its short half-life.30 The possibility of switching to a safer drug such as IFN-β/GA until pregnancy begins can be discussed in a case-specific manner.18 Third, the appropriate measure to prevent postpartum relapse remains controversial. In a woman who had a relapse during pregnancy or had highly active disease before pregnancy, it is recommended to resume her maintenance therapy after delivery. The decision regarding the potential benefits of breastfeeding vs treatment reinitiation to reduce the risk of postpartum relapse should be individualized.3
Our study has several limitations. Apart from the retrospective nature of the study, the population of women was relatively young at the onset of MS. Second, the prepregnancy relapse rate was low because the majority of patients were on DMTs and half of women were on high-efficacy therapies. Furthermore, a subgroup analysis could not be performed given the low number of relapses in the interferon group. On the other hand, the study was conducted with a registry, eliminating the bias of it being conducted in a tertiary center. In addition, this is the first study to be conducted with a high proportion of pregnant women who were previously on natalizumab/fingolimod.
In this study, the risk of relapse in women who were on fingolimod and natalizumab was high during the first and third trimesters. Pregnancy in women contemplating conception should be carefully planned with an emphasis on shortening washout periods.
Author contributions
Raed Alroughani: study concept and design, acquisition of data, analysis and interpretation of data, writing manuscript, study supervision. Maryam Alowayesh: statistical analysis, manuscript revision and editing. Samar Ahmed: acquisition of data, analysis and interpretation of data, manuscript revision. Raed Behbehani: data collection, analysis, manuscript revision and editing. Jasem Al-Hashel: data collection, manuscript revision and editing.
Study funding
No targeted funding was reported.
Disclosure
R. Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, Novartis, Sanofi-Genzyme, Roche, and Merck. M. Alowayesh, S. Ahmed, R. Behbehani, and J. Al-Hashel report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.
Acknowledgment
The authors thank the administrative assistants at Amiri and Ibn Sina Hospitals for their continuous support.
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Podcast: NPub.org/vsx0bb
- Received July 21, 2017.
- Accepted in final form December 4, 2017.
- © 2018 American Academy of Neurology
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