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Does pregnancy alter the long-term course of multiple sclerosis?
Abstract
Purpose
The purpose was to examine the impact of pregnancy on the rates of relapses, progression to irreversible disability, and transition to secondary progressive multiple sclerosis (SPMS) in patients with relapsing-remitting multiple sclerosis (RRMS).
Methods
We retrospectively followed two subcohorts of women with RRMS: pregnant (n=254) and non-pregnant (n=423). We obtained data on demographic, life-style, and clinical characteristics from patient records. Poisson and logistic regressions estimated the rate ratios (RR) associated with pregnancy as a function of time. Confounding was controlled by propensity-score adjustment, and post-baseline selection bias was controlled by inverse probability weighting.
Results
In the pregnant and non-pregnant subcohorts, respectively, 300 and 787 relapses, 15 and 27 transitions to SPMS, and 11 and 34 progressions to irreversible disability were documented. Adjusted RRs (95% confidence intervals) shortly after baseline were 0.67 (0.49; 0.92) for relapses, 0.16 (0.03; 0.79) for irreversible disability, and 1.25 (0.39; 3.96) for SPMS. The corresponding estimates at 5 and 10 years were, respectively, 1.04 (0.72; 1.52), 0.82 (0.36; 1.88), and 2.33 (1.03; 5.26) and 1.62 (0.84; 3.14), 4.14 (0.89; 19.22), and 4.33 (1.10; 16.99).
Conclusions
Pregnancy likely ameliorates the short-term course of RRMS in terms of the rates of relapses and progression to irreversible disability. Over the long term it appears to have no material impact on these outcomes, and might in fact accelerate the rate of transition to SPMS.
... Symptoms of MS include vision disorders (nystagmus, diplopia, reduced vision, etc.), pain, fatigue, weakness, dizziness, numbness, neuromuscular disorders in various systems including ataxia and gait abnormalities, paralysis, tremors, spasms, muscle stiffness, speech problems, bladder dysfunction, bowel (constipation and diarrhea), memory loss, sexual problems, and mood swings. [8,9] With a typical age of onset in the third or fourth decades, [10] MS is two times more common in women than in men. [11] Most women with MS are diagnosed during their reproductive ages. ...
... However, in a cohort study by Karp et al.,55% of the studied population used oral contraceptives. [10] The results of the study showed that using oral contraceptive reduces the level of anti-Mullerian hormone, [31] and the use of this contraceptive method in women with MS has attracted lower attention than the general population (24%-28% vs. 50%). ...
... Other studies showed, in the third trimester, the highest reduction in recurrence and return of MS symptoms compared to before prenatal period. [10,12] Another study showed that pregnancy had a protective role against MS. Therefore, pregnancy had been associated with an 80% reduction in disease recurrence, especially in the third trimester of pregnancy. ...
BACKGROUND: Multiple sclerosis (MS) is a chronic disease of the central nervous system. Most women with MS are diagnosed during their reproductive ages. The aim of this study was to evaluate the interaction between fertility, pregnancy, and MS.
MATERIALS AND METHODS: A retrospective descriptive–analytic study was conducted on 110 women suffering from MS with a history of pregnancy (between 2007 and 2017 years) in Isfahan, Iran. Samples were selected in a census model. Women completed a researcher-constructed questionnaire by telephone. The questionnaire consisted of three parts: demographic information, MS and its symptoms and treatment, and reproductive system and the history of pregnancy associated with MS. The data were analyzed by SPSS software version 16 using Chi-square, ANOVA, and t-test.
RESULTS: The mean age of women was 32.4 years. In this population, the average number of pregnancies was 1.61, the number of deliveries was 1.35, the number of abortions was 0.24, the history of ectopic pregnancy was 0.01, the number of alive children was 1.36, and the number of dead children was 0.01. The average time of the last MS attack before the pregnancy was 21.36 months. Fatigue (24.5%) was the most common symptom exacerbated during pregnancy. MS symptoms improved in 55.0% of women in the second trimester.
CONCLUSIONS: MS had no effect on the pregnancy status, such as the number of abortions, ectopic pregnancy, alive and dead children, and the duration of pregnancy. Symptoms of the disease improved during pregnancy. Therefore, pregnancy has a protective role against MS.
... We found 23 longitudinal studies measuring the changes in the ARR ; 12 of them were prospective [15,[17][18][19][21][22][23][26][27][28]32] and 11 were retrospective [12][13][14]16,20,24,25,29,31,33,34]. In Table 1 are given the main characteristics of every study: number of patients, design, follow-up period and main outcomes. ...
... In other studies all patients had relapsing remitting (RR) forms [16,17,20,25,29,32]. With regard to DMT, most cohorts included women not under treatment during pregnancy. ...
... With regard to DMT, most cohorts included women not under treatment during pregnancy. In five cohorts the percentage of women exposed to DMT were: 1.2 [24], 3.7 [33], 15.3 [25], 17 [31] and 34% in a small cohort of 35 women [28]. Changes in the ARR In 16 studies, the ARR decreased significantly in pregnancy (see Table 1), especially in the third trimester. ...
Background: Although previous cohort studies of women with multiple sclerosis (MS) yielded a reduction in relapse rate during pregnancy, the effect size has not been quantified in a comprehensive manner. In addition, the effects on disability progression and peripartum outcomes have been controversial. The purpose of this work is to assess the effect of pregnancy on disease activity, and to assess the effects of MS on pregnancy as well. Materials & methods: We searched in PubMed, Cochrane Library and EMBASE for cohort studies dealing with the effects of pregnancy on relapse rates, disability progression and peripartum outcomes in women with MS. The evaluated outcomes were: changes in the annualized relapse rate (ARR) in pregnancy and puerperium, disability worsening compared with the year before pregnancy, and peripartum outcomes, which were compared with the ones of non-MS women. In the majority of cohorts included here, the women were not under disease modifying therapies during pregnancy. Results: We found 23 cohort studies measuring changes in the ARR during pregnancy and puerperium; 12 were prospective and 11 retrospective. In 17 cohorts there was significant reduction in the ARR during pregnancy compared with prepregnancy period. The pooled mean reduction in the ARR was -0.5 (95% CI: 0.67–0.38), p < 0.001, from 15 cohorts included in meta-analysis. In 18 cohorts the ARR increased in the 3-month puerperium relative to prepregnancy year period; the pooled mean increase in the ARR was 0.22 (95% CI: 0.11–0.33), p < 0.001, from 14 cohorts included in meta-analysis. Disability worsening was addressed in 18 cohorts, and in 14 of them there were no significant changes. Peripartum complications and obstetrical outcomes were assessed in 16 cohorts, of whom 13 were retrospective, without finding significant differences. Conclusion: Pregnancy is associated with lower disease activity, and puerperium with higher disease activity. Disability does not change significantly after pregnancy. The obstetrical outcomes are not very different from those of non-MS women in most cohorts.
... With a typical age of onset in the third or fourth decades (10), MS is two times more common in women than in men (11). Most women with MS are diagnosed during their reproductive ages (12). ...
... Despite the fact that studies show that hormonal methods are the most appropriate contraceptive method for this target group, just 7.3% of the subjects studied have had this method in the year before their pregnancy, which seems to be due to the low level of awareness of individuals and the inadequacy of receiving appropriate training from service providers. However, in a cohort study by Karp et al., 55% of the studied population used oral contraceptives (10). The results of the study showed that using oral contraceptive reduces the level of anti-mullerian hormone (31), and the use of this contraceptive method in women with MS has attracted lower attention than the general population (24-28% versus 50%). ...
... Other studies showed in third trimester, the highest reduction in recurrence and return of MS symptoms compared to before prenatal period (10,12). Another study showed that pregnancy had a protective role against MS and reduced 80% of recurrence, especially in the third trimester of pregnancy, which seems to increase the level of hormone, especially in the third trimester of pregnancy creates this protection (14). ...
Background Multiple sclerosis is a chronic disease of the central nervous System.Most women with MS are diagnosed during their reproductive ages.This study evaluated the effect of pregnancy on MS and the effect of MS disease on fertility and pregnancy health.
Material & methods: A retrospective descriptive-analytic study was conducted on 110 women suffering from MS with a history of pregnancy(between 2007 and 2017years) in Isfahan, Iran.Samples were selected in a census model.Women completed a researcher-constructed questionnaire by telephone.The questionnaire consisted of three parts: demographic information,MS and its symptoms and its treatment, and the third part was related to the reproductive system and the history of pregnancy associated with MS. Data were analyzed by SPSS software version 16 using Chi-square, ANOVA and t-test.
Results The mean age of women with MS was 32.4 years.The most common primary symptom was blurred vision(42.7%).In this population,the average number of pregnancies was 1.61,the number of deliveries was 1.35,the number of abortions was 0.24,the history of ectopic pregnancy was 0.01,the number of alive children was 1.36 and the number of dead children was 0.01.The average time of the last MS attack before the pregnancy was 21.36 months. Fatigue(24.5%) was the most common symptom exacerbated during pregnancy. MS symptoms improved in55.0% of subjects in the second trimester.
Discussion MS had no effect on the pregnancy status, such as the number of abortions,ectopic pregnancy, alive and dead children and the duration of pregnancy.The symptoms of the disease are improved during pregnancy.Therefore, pregnancy has a protective role against MS.
... There were three subsequent prospective studies in the 1990s that also showed no difference in MS disability between nulligravidae and gravidae post-MS women [46][47][48], although these studies had smaller sample sizes and shorter follow-up periods than the retrospective studies. More recent retrospective studies in the last decade have demonstrated similar findings [49][50][51][52], including two large population-based studies from Canada of over 2000 women with any MS phenotype [50] and 1000 women with RRMS respectively [51] ( Table 3). ...
... There were three subsequent prospective studies in the 1990s that also showed no difference in MS disability between nulligravidae and gravidae post-MS women [46][47][48], although these studies had smaller sample sizes and shorter follow-up periods than the retrospective studies. More recent retrospective studies in the last decade have demonstrated similar findings [49][50][51][52], including two large population-based studies from Canada of over 2000 women with any MS phenotype [50] and 1000 women with RRMS respectively [51] ( Table 3). ...
... In terms of outcome measure for disability, the most commonly used outcome was time to EDSS 4.0 and/or 6.0, with time to SPMS or EDSS score being some of the other outcomes used. The mean disease duration or follow-up in these studies ranged from 5 to 17 years [43][44][45][46][47][48][49][50][51][52][53][54][55]. ...
Multiple sclerosis (MS) is commonly diagnosed in women of childbearing age. Having a greater understanding of the effects of pregnancy on the course of MS will lead to improved family-planning counselling for women. We found well-established evidence for a protective effect of pregnancy on relapse occurrence in historical cohorts. More recent studies suggest that the protective effect of pregnancy against relapse may be lost in those women with more active disease treated with high efficacy therapies. Furthermore, a strong body of evidence suggests that gravidity after diagnosis of MS does not lead to worse long-term outcomes. More contentious however, is whether pregnancy can delay a first episode of demyelination or a confirmed diagnosis of MS. This review provides a detailed analysis of the literature relating to the clinical effects of pregnancy on MS outcomes across a woman's reproductive lifespan.
... The prevalence of MS is twice higher in women than men (8), with the rate gradually increasing in women (6.9). The majority of MS patients experience the onset of the symptoms in the second and third decade of their life (10). Therefore, MS is most commonly diagnosed in the women of reproductive age (11). ...
... According to a research, the recurrence of MS reduces by 80% during Iranian Journal of Neonatology 2018; 9 (3) pregnancy, particularly in the third trimester (12), while the disease may be exacerbated in the patients during the postpartum period as opposed to before pregnancy (11). On the other hand, Karp et al. claimed that the rate of relapse in a group of pregnant women with MS was lower compared to non-pregnant women within the first years after pregnancy (10). ...
... In addition, women with gestational diabetes could probably experience stable, long-lasting protective effects on MS analogs (13). Some studies have denoted that the risk of the recurrence of MS symptoms is lower by half in breastfeeding women compared to those with no breastfeeding (10). The results of another study indicated that prolonged breastfeeding (more than four months) exerts protective effects against MS (23). ...
Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system, which is more prevalent in women than men. Considering the onset of MS in the women of reproductive age, the present study aimed to investigate the reciprocal effects of MS, childbirth, and postpartum. Methods: This retrospective, descriptive-analytical study was conducted on 110 women diagnosed with MS during pregnancy in Isfahan, Iran during 2016-2017. The subjects had become pregnant within the recent decade and were selected via random sampling. Data on the demographic characteristics, pregnancy and postpartum profile, medicinal changes, symptoms, severity, and attack rates of MS were collected. Data analysis was performed in SPSS version 16. Results: Mean age at the completion of pregnancy was 38.13 weeks. In total, 63.9% of the deliveries were accomplished via caesarean and 35.1% of the women had natural vaginal delivery. Mean pain intensity at childbirth was 7.11. No symptoms of MS attacks were reported in 86.7% of the subjects during delivery and 90.7% of the women within the first six weeks of childbirth. All the neonates were healthy, and 66.3% of the mothers had no psychological and emotional postpartum complications. In addition, 40.3% of the women started their MS medication within the first six months after childbirth. Conclusion: According to the results, MS was not associated with the increased risk of preterm or post-term delivery. Moreover, it did not increase the severity of labor pain in the mothers. On the other hand, the rate of elective cesarean section was higher in MS patients compared to the general population, especially in the cases with disabilities. According to the Friedman curve, MS caused no substantial changes in the progression of delivery, and most of the neonates were healthy males with an Apgar score of 10. However, the severity of limb numbness and blurred vision increased in the women with MS in the postpartum period. © 2018 Mashhad University of Medical Sciences. All Rights Reserved.
... This change in relapse activity is thought to be estrogen-mediated, but studies investigating the effect of pregnancy on long-term MS disability accumulation have mostly failed to find an association [4][5][6][7][8][9][10] although a few studies did show some long-term protective effects of pregnancy [11][12][13]. In contrast to studies of MS in pregnancy, there is less evidence for disease flares during other stages of a woman's reproductive lifespan, including menopause, although some evidence for disability worsening during menopause exists, reviewed in Ysrraelit and Correale [14]. ...
... . Median (5th-95th percentiles) follow-up was 8 years(2)(3)(4)(5)(6)(7)(8). The only notable differences among women ever on HT versus those never on HT during follow-up were calendar year of diagnosis and cohort entry. ...
Background:
Sex differences in multiple sclerosis (MS) prevalence and disease course are thought to be driven by hormones. Exogenous exposure to estrogens may affect MS disease course. Thus, our aim was to investigate the association between hormone therapy (HT) and disease activity and disability accrual among women with MS.
Methods:
Register-based cohort study with prospectively enrolled cases from the Danish MS registry. Information on hormone exposure was retrieved from The National Prescription Registry. Outcomes were relapse rate, relapse rate ratio, recurrent relapses, 6-month confirmed and sustained Expanded Disability Status Scale (EDSS) milestone 4 and 6, and recurrent EDSS worsening.
Results:
In all, 3,325 women were eligible for analyses of whom 333 (10%) ever were on HT sometime during follow-up. We found no association between HT and disability accrual, although a trend for increasing risk with increasing length of use was seen: The risk of reaching 6-month confirmed and sustained EDSS 4 among users was 0.6 (95% CI 0.3-1.2) after less than one year of use and 1.4 (95% CI 0.9-2.2) after more than five years of HT compared to never use. The risk of recurrent relapse was increased by 20% (95% CI 1.0-1.4) among current users of HT compared to non-users. However, the risk of recurrent relapses was driven by the first calendar period (1996-2005) before the introduction of high efficacy DMTs.
Conclusions:
Our findings from this nationwide MS population suggest that HT does not affect disability accrual in women with MS, especially if used for less than five years.
... 6,8 Due to the observed effect of pregnancy on relapse activity during pregnancy, its potential effect on longterm disability accumulation has been investigated in real-world studies with contradictive findings during the past decades. No effect of parity was found in some studies, [10][11][12][13][14][15] whereas others demonstrated a beneficial effect on several outcomes: time to reach Expanded Disability Status Scale (EDSS) score of 6, 16-18 a milder disease course in terms of relapses and irreversible disability over several initial years, 10 and that having at least one pregnancy was 4 times more effective in preventing EDSS progression than firstline therapy within the first 10 years. 19 In this study, nationwide Danish registries were used to cross-link 20 years of follow-up data, enabling us to investigate whether pregnancy has a protective effect on long-term disability accrual. ...
... 6,8 Due to the observed effect of pregnancy on relapse activity during pregnancy, its potential effect on longterm disability accumulation has been investigated in real-world studies with contradictive findings during the past decades. No effect of parity was found in some studies, [10][11][12][13][14][15] whereas others demonstrated a beneficial effect on several outcomes: time to reach Expanded Disability Status Scale (EDSS) score of 6, 16-18 a milder disease course in terms of relapses and irreversible disability over several initial years, 10 and that having at least one pregnancy was 4 times more effective in preventing EDSS progression than firstline therapy within the first 10 years. 19 In this study, nationwide Danish registries were used to cross-link 20 years of follow-up data, enabling us to investigate whether pregnancy has a protective effect on long-term disability accrual. ...
Background
Pregnancy is considered to influence the disease course in women with multiple sclerosis (MS).
Objective
The aim of this study was to investigate the effect of pregnancy on long-term disability accrual in women with MS.
Methods
The Danish Multiple Sclerosis Registry (DMSR) was used to identify women diagnosed with clinically isolated syndrome or relapsing-remitting MS. Cox models with pregnancy as a time-dependent exposure and propensity score (PS) models were used to evaluate time to reach confirmed Expanded Disability Status Scale (EDSS) score of 4 and 6.
Results
A total of 425 women became parous and 840 remained nulliparous. When including pregnancy as a time-dependent exposure, a non-significant association with time to reach EDSS 4 (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.61–1.20) and EDSS 6 (HR 0.70, 95% CI 0.40–1.20) was found. Correspondingly, the PS model showed no association with pregnancy on time to reach EDSS 4 (HR 0.85, 95% CI 0.56–1.28).
Conclusion
This study concludes that pregnancy does not affect long-term disability accumulation.
... There was no change in the average EDSS years after pregnancy [39]. Similarly, the findings of 2 large cohort studies by Karp et al. [40] indicated no relationship between pregnancy and long-term disability [40,41]. A prospective study investigating 577 women who had carried one or more full-term pregnancies found no negative long-term effects of pregnancy [42]. ...
... There was no change in the average EDSS years after pregnancy [39]. Similarly, the findings of 2 large cohort studies by Karp et al. [40] indicated no relationship between pregnancy and long-term disability [40,41]. A prospective study investigating 577 women who had carried one or more full-term pregnancies found no negative long-term effects of pregnancy [42]. ...
Background:
Multiple sclerosis (MS) is an inflammatory demyelinating chronic neurological disease that affects the central nervous system of young adults and their quality of life. Several studies have investigated the effects of pregnancy and breastfeeding on MS. However, the evidence regarding the influence of pregnancy and breastfeeding on MS is still accumulating. This review aimed to summarize the current evidence regarding the effects of pregnancy and breastfeeding on MS.
Summary:
A systematic electronic literature search of the PubMed and Embase databases was conducted to determine relevant published articles. The eligible studies were summarized and evaluated in tables. Key Messages: The majority of the studies indicated that pregnancy appears to lower the rate of MS relapses, particularly in the third trimester. The evidence regarding the effect of breastfeeding on MS remains inconsistent. Despite reports of negative obstetric outcomes in some pregnant women with MS, pregnancies in women with MS should not be categorized as high-risk pregnancies.
... After multiple sclerosis onset, studies reported either no negative effect (Weinshenker et al., 1989b;Confavreux et al., 1998;Koch et al., 2009;Ramagopalan et al., 2012) or even a positive effect of pregnancy on accrual of disability (Verdru et al., 1994;Runmarker and Andersen, 1995;D'Hooghe et al., 2012;Keyhanian et al., 2012;Karp et al., 2014). However, women who were diagnosed with multiple sclerosis and who had a more severe disease course tend to have fewer or no children (Runmarker and Andersen, 1995;Koch et al., 2009). ...
... We found a clear association with number of pregnancies and a delay in onset of progressive multiple sclerosis. Although most of the studies focussed on the impact of pregnancy on disability worsening in multiple sclerosis (Weinshenker et al., 1989b;Verdru et al., 1994;Runmarker and Andersen, 1995;Confavreux et al., 1998;Koch et al., 2009;D'Hooghe et al., 2012;Keyhanian et al., 2012;Ramagopalan et al., 2012;Karp et al., 2014), only two prior studies investigated the impact of pregnancy on progressive multiple sclerosis onset. One study found a lower risk of developing SPMS in patients with higher parity (Runmarker and Andersen, 1995), whereas another study found no association (Koch et al., 2009). ...
Being a woman is one of the strongest risk factors for multiple sclerosis. The natural reproductive period from menarche to natural menopause corresponds to the active inflammatory disease period in multiple sclerosis. The fifth decade marks both the peri-menopausal transition in the reproductive aging and a transition from the relapsing-remitting to the progressive phase in multiple sclerosis. A short reproductive period with premature/early menopause and/or low number of pregnancies may be associated with an earlier onset of the progressive multiple sclerosis phase. A cross-sectional study of survey-based reproductive history in a multiple sclerosis clinical series enriched for patients with progressive disease, and a case–control study of multiple sclerosis and age/sex matched controls from a population-based cohort were conducted. Menarche age, number of complete/incomplete pregnancies, menopause type and menopause age were compared between 137 cases and 396 control females. Onset of relapsing-remitting phase of multiple sclerosis, progressive disease onset and reaching severe disability (expanded disability status scale 6) were studied as multiple sclerosis-related outcomes (n = 233). Menarche age was similar between multiple sclerosis and control females (P = 0.306). Females with multiple sclerosis had fewer full-term pregnancies than the controls (P < 0.001). Non-natural menopause was more common in multiple sclerosis (40.7%) than in controls (30.1%) (P = 0.030). Age at natural menopause was similar between multiple sclerosis (median, interquartile range: 50 years, 48–52) and controls (median, interquartile range: 51 years, 49–53) (P = 0.476). Nulliparous females had earlier age at progressive multiple sclerosis onset (mean ± standard deviation: 41.9 ± 12.5 years) than females with ≥1 full-term pregnancies (mean ± standard deviation: 47.1 ± 9.7 years) (P = 0.069) with a pregnancy-dose effect [para 0 (mean ± standard deviation: 41.9 ± 12.5 years), para 1–3 (mean ± standard deviation: 46.4 ± 9.2 years), para ≥4 (mean ± standard deviation: 52.6 ± 12.9 years) (P = 0.005)]. Menopause age was associated with progressive multiple sclerosis onset age (R2 = 0.359, P < 0.001). Duration from onset of relapses to onset of progressive multiple sclerosis was shorter for females with premature/early menopause (n = 26; mean ± standard deviation: 12.9 ± 9.0 years) than for females with normal menopause age (n = 39; mean ± standard deviation: 17.8 ± 10.3 years) but was longer than for males (mean ±standard deviation: 10.0 ± 9.4 years) (P = 0.005). There was a pregnancy-dose effect of age at expanded disability status scale 6 (para 0: 43.0 ± 13.2 years, para 1–3: 51.7 ± 11.3 years, para ≥4: 53.5 ± 4.9 years) (P = 0.013). Age at menopause was associated with age at expanded disability status scale 6 (R2 = 0.229, P < 0.003). Premature/early menopause or nulliparity was associated with earlier onset of progressive multiple sclerosis with a ‘dose effect’ of pregnancies on delaying progressive multiple sclerosis and severe disability. Although causality remains uncertain, our results suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis. If confirmed in prospective studies, our findings have implications for counselling women with multiple sclerosis about pregnancy, surgical menopause and menopausal hormone therapy.
... The study showed a significant decrease in relapse rates during pregnancy, especially during the third trimester compared to the rates of the previous year, however, relapses increased the first three months after the increase in new levels before pregnancy, although Only 28% of the cohort experienced them (Figure 1), Other key findings of the study that deserve to be highlighted were the absence of related differences when comparing the relapse rates of the nine months of pregnancy plus the three months postpartum with the rates of the year prior to pregnancy, and the absence of disability progression during the study period. Posterior cohort studies confirmed the same results with decreased rate of relapses in pregnancy and increased in postpartum [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. ...
... According to cohort studies the relapse rate decreases significantly in pregnancy [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. In contrast to the protective effect of pregnancy, the postpartum period carries a higher risk of relapse [10,[12][13][14][15][16][17][18][19][20][23][24][25][26][27][28], which could be due to the abrupt elimination of the protective factors of pregnancy after childbirth or to unique harmful factors inherent in this period [5,36]. ...
Multiple sclerosis is an autoimmune disorder that affects the central nervous system, more common in women of childbearing age, so pregnancy can affect the disease. In these patients, the relapse rate decreases during pregnancy, especially in the third trimester, however, there seems to be an increased risk of exacerbations during the first three months postpartum, before returning to the pre-pregnancy rate.
Although the evidence is not conclusive and there is no certainty that pregnancy can protect a genetically susceptible patient, it seems that the risk of disease is lower in women with a previous pregnancy than in nulliparous women, as well as women with exclusively breastfeeding.
Among these patients, there seems to be a greater number of small newborns for gestational age, as well as higher figures for instrumented deliveries or caesarean section, although without other complications, so it is not considered a "high risk" pregnancy. However, the possible interaction between drugs and the course of the disease make essential a good family planning, with proper advice.
Formerly it was recommended to stop the treatment since no drug was approved for its use. Nowadays, although the data is still limited, the therapeutic strategy has evolved remarkably; some drugs may require suspension, even six months before conception, however, others are safe, including during pregnancy. Hence the great importance of preconceptional consultation, in which each case will be assessed individually in order to obtain the best solution for each patient in particular.
... Nerveless, the impact of pregnancy on the long-term course of the disease and disability in MS is still unclear. In this regard, several studies have suggested that pregnancy has no effect on long-term outcome in MS, whereas others indicated that pregnancy is potentially beneficial [34,[36][37][38][39][40][41][42]. Benefits include reduced risk of excessive gestational weight gain, gestational diabetes and preeclampsia [43]. ...
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that affects 2.3 million people worldwide, mostly young adults, with a high female prevalence (70% to 75%). Therefore, most individuals who get diagnosed with MS are women of childbearing age. However, disease activity is greatly reduced during the last trimester of pregnancy, although an increased relapse rate is observed in the three months after delivery. Despite several studies point to pregnancy as a period of stabilization in the clinical course of MS, pregnancy in MS remains a controversial issue, mainly in relation to discontinuation of disease-modifying treatment, which is recommended from the time pregnancy is established and, to date, remains confirmed. Therefore, this is a very sensitive issue to consider given the importance of, on the one hand, ensuring the health of the fetus and, on the other hand, the health of the woman about both the accumulation and progression of the disease.
... The issues of pregnancy outcomes, delivery, and breastfeeding in MS have received renewed interest in recent years; however, most studies have focused on how reproduction affects the disease and not how reproduction occurs in these patients (Karp et al., 2014;Jesus-Ribeiro et al., 2017;Dobson et al., 2019;Rosa-Garrido et al., 2023). ...
... In our study, we concluded that pregnancy did not affect the disability status of our patients. While some studies supported our findings (14,15), there are studies that have reached different results. Jokubaitis et al., in a study in which they followed 1,830 MS patients for 10 years, showed that patients who gave birth after MS diagnosis had lower disability scores than patients who did not give birth (16). ...
INTRODUCTION: In this study, it was aimed to investigate how pregnancy and postpartum processes affect the course of MS disease, the effects of breast feeding on the frequency of attacks, and the fetal development in pregnant patients using MS treatment (disease modifying treatment (DMT) METHODS: Our pregnant relapsing remitting MS (RRMS) patients who were followed up in our MS outpatient clinic were included in the study. Our patients were followed up during pregnancy and postpartum 1 year. Annualized relapse rate (ARR) was calculated in the year preceding pregnancy, during pregnancy, and in the first year of postpartum. The duration of DMT use while pregnant, pregnancies resulting in miscarriage, low birth weight babies, preterm babies, and breastfeeding times were recorded and evaluated. RESULTS: The number of pregnancies followed was 102 pregnancies, including 89 deliveries and 13 abortions. Twenty nine patients used DMT in some part of their pregnancy due to unplanned pregnancy. The disability condition evaluated before and 12 months after pregnancy progressed in 12 patients. Interestingly, 70 patients remained stable, while seven patients regressed. No relation was found between the use of DMT during pregnancy and miscarriage, preterm baby, and low birth weight baby. Mothers who were not breastfeeding or breastfeeding for less than 3 months experienced more attacks than mothers who breastfed for 3 months or more. DISCUSSION AND CONCLUSION: Disease activity and disability status during pregnancy and the postpartum period did not change in RRMS patients compared to pre-pregnancy. DMTs used during pregnancy did not affect fetal development and abortion status.
... The results of other observational studies investigating long-term effects of pregnancy on disability are discordant depending on the methodology used. [1][2][3][9][10][11][12][13][14][15][16][17][18][19] A majority of them used a Cox survival model and considered the time to reach a level of EDSS of 4 or 6 or the time to SP transition as outcome. The age at MS onset is a major confounder in the relationship between pregnancy and disability: while in the study of Ramagopalan et al. 2 including more than 2,000 patients, the beneficial effect of pregnancy shown in univariate analyses was no longer significant after adjustment on the age at MS onset, other studies have found a protective effect of pregnancies despite adjustment for age. ...
Background and objectives
The question of the long-term safety of pregnancy is a major concern in multiple sclerosis (MS) patients, but its study is biased by reverse causation (women with higher disability are less likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in MS patients, and secondarily the short-term effects (during the per-partum and post-partum years) and delayed effects (occurring beyond one year after delivery).
Methods
We conducted an observational cohort study with data from MS patients followed in the OFSEP registry between 1990 and 2020. We included MS female patients aged 18-45 years at MS onset, clinically followed-up for more than 2 years and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least one pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first three years of follow-up).
Results
We included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least one pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS at 9 years (causal mean difference [95% CI] = 0.00 [-0.16; 0.15]), nor on the annual probability of relapse (causal risk ratio [95% CI] = 0.95 [0.93; 1.38]). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the per-partum year and significantly increased it during the post-partum year, but no significant delayed effect was found on EDSS and relapse rate.
Discussion
Using a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias.
... 90,94,100 The Impact of Pregnancy on the Long-Term Course of MS There is no evidence that pregnancy has a negative impact on the long-term course or progression of MS disability. 11,95,101,102 In contrast, there is some evidence that pregnancy after MS onset could have a favorable long-term effect on the course of MS, as women who deliver one or more children after MS onset appear to have a slower disability progression than nulliparous women with MS. 103,104 In a recent population-based cohort study, nulliparous women had an earlier age at progressive MS onset, and a pregnancy-dose effect on delaying progressive MS and severe disability was observed. 105 Whether pregnancy has a true protective effect on the MS course due to transient immunosuppression, or whether it represents a bias derived from female patients with milder MS being more inclined towards childbearing and causing those with more aggressive MS to avoid pregnancy, warrants further investigation. ...
Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, and degenerative disease that is up to three times more frequent in young women. MS does not alter fertility and has no impact on fetal development, the course of pregnancy, or childbirth. The Pregnancy in Multiple Sclerosis Study in 1998 showed that pregnancy, mostly in untreated women, did not adversely affect MS, as disease activity decreased during pregnancy (although it significantly increased in the first trimester postpartum). These findings, together with the limited information available on the potential risks of fetal exposure to disease modifying treatments (DMTs), meant that women were advised to delay the onset of DMTs, stop them prior to conception, or, in case of unplanned pregnancy, discontinue them when pregnancy was confirmed. Now, many women with MS receive DMTs before pregnancy and, despite being considered a period of MS stability, up to 30% of patients could relapse in the first trimester postpartum. Factors associated with an increased risk of relapse and disability during pregnancy and postpartum include relapses before and during pregnancy, a greater disability at the time of conception, the occurrence of relapses after DMT cessation before conception, and the use of high-efficacy DMTs before conception, especially natalizumab or fingolimod. Strategies to prevent postpartum activity are needed in some patients, but consensus is lacking regarding the therapeutic strategies for women with MS of a fertile age. This, along with the increasing number of DMTs, means that the decision-making processes in aspects related to family planning and therapeutic strategies before, during, and after pregnancy are increasingly more complex. The purpose of this review is to provide an update on pregnancy-related issues in women with MS, including recommendations for counseling, general management, use of DMTs in pre-pregnancy, pregnancy, and postpartum periods, and breastfeeding-related aspects of DMTs.
... The confirmation that pregnancy is protective of relapse with a rebound phenomenon after delivery has been known for some time (Confavreux et al., 1988). Further trials have generally shown, that pregnancy had no negative impact on long term disease course in MS patients or progression to irreversible disability (Masera et al., 2015;Ramagopalan et al., 2012;Thompson et al., 1986;Weinshenker et al., 1989;Roullet et al., 1993;Worthington et al., 1994;Koch et al., 2009;Karp et al., 2014;Ponsonby et al., 2012). The PRISMS (Pregnancy in Multiple Sclerosis) study showed decreased annualized relapse rate (ARR) during the third trimester of pregnancy comparing to the year before pregnancy, increased ARR within first 3 months after delivery and similar overall ARR in the pregnancy year (9 months of pregnancy and 3 months of postpartum period) compared to the ante partum year. ...
Background: A special care of MS women planning a pregnancy is highly demanding especially in the terms of disease modifying treatment (DMD) decisions and counselling regarding periods of conception, pregnancy and postpartum period.
Objective: To provide data about impact of pregnancy, delivery or miscarriage/artificial abortion on MS disease course in Czech women with MS based on analysis of retrospective data from the Czech national registry ReMuS.
Methods: The analysis focused on women with MS with at least one record of pregnancy in the registry. Clinical data (EDSS, relapses) were collected prior to conception, during pregnancy and after delivery or miscarriage/artificial abortion. These data were analysed according to baseline characteristics of DMD treatment prior to conception and according to breastfeeding status.
Results: A total of 1 533 pregnancies were analysed from the period of 2013 until 31st December 2019. The occurrence of relapses and worse EDSS was significantly related to the treatment with escalation therapy prior to conception. Relapses were significantly more frequent in women who breastfed less than 3 months than in women who breastfed more than 3 months or did not breastfeed at all. Patients treated with either fingolimod or natalizumab prior to pregnancy were significantly more likely to develop relapses during pregnancy.
Conclusion: Pregnancy and postpartum period were generally safe for Czech women with MS. Better disease outcomes were observed in those who had been treated with first line injectable DMDs prior to conception and those who either breastfed more than 3 months or did not breastfeed at all. We confirmed the assumption of rebound phenomenon of MS after discontinuation of treatment due to planned pregnancy both for fingolimod and natalizumab.
... Patients who did not have a recorded last date of prescription of interferon-beta-1a or a recorded reason for discontinuation of interferon-beta-1a were considered under treament. 17 ...
Purpose
Describing patterns of use, including changes in dose and interruptions is challenging. Group-based trajectory modelling (GBTM) can be used to identify individuals with similar dose patterns. We provide an intuitive graphical representation of dose patterns in groups identified using GBTM. We illustrate our approach using two drugs with different combinations of available dosages.
Methods
We drew data on patients with MS followed from 1977 to 2014 in Montréal using two sub-cohorts of subjects. A sub-cohort of patients taking interferon-beta-1a and another of patients taking amitriptyline were identified from the initial cohort. We use GBTM to identify groups of patients with homogeneous dose patterns for each of the two drugs. We compared the graphical representation obtained from the fitted values of GBTM with our proposed approach, which consisted of using step functions whose values corresponded to the mode. Differences in characteristics across groups were identified using chi-squares and analysis of variance, both weighted by the posterior probability of group membership.
Results
Seven patterns of dose were identified for interferon-beta-1a and five for amitriptyline. The graphical representations of the patterns of dose from GBTM included values outside of the prescribed doses and did not capture changes in dose as clearly as the proposed representation using step functions.
Conclusion
Our proposed approach which is based on the mode at each visit in each pattern provides an intuitive and realistic representation of dose patterns in groups identified with GBTM.
... Historical studies of women treated with no or lowefficacy platform therapies demonstrated a fall in relapse activity during pregnancy, reaching a trough in the third trimester followed by an increase in early postpartum. [2][3][4] There has been a substantial increase in the number of DMTs over the past decade. 5 Several recent studies included pregnancies of women treated with newer DMTs, although these are limited by small sample size. ...
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.
... A marked resurgence of relapses is, in contrast, reported within the first 3 months after delivery (82,132). Conversely, the long-term progression of MS is probably not influenced by pregnancy, since parous women with MS show no signs of increased disability over their lifetime compared with nulliparous women (132,(211)(212)(213). Pregnancy, however, may accelerate the rate of transition to SPMS (213), although a different study suggested that parous women with RRMS may be less likely to develop a progressive course of the disease (214). ...
Multiple sclerosis (MS) is the most common chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). An interesting feature that this debilitating disease shares with many other inflammatory disorders is that susceptibility is higher in females than in males, with the risk of MS being three times higher in women compared to men. Nonetheless, while men have a decreased risk of developing MS, many studies suggest that males have a worse clinical outcome. MS exhibits an apparent sexual dimorphism in both the immune response and the pathophysiology of the CNS damage, ultimately affecting disease susceptibility and progression differently. Overall, women are predisposed to higher rates of inflammatory relapses than men, but men are more likely to manifest signs of disease progression and worse CNS damage. The observed sexual dimorphism in MS may be due to sex hormones and sex chromosomes, acting in parallel or combination. In this review, we outline current knowledge on the sexual dimorphism in MS and discuss the interplay of sex chromosomes, sex hormones, and the immune system in driving MS disease susceptibility and progression.
... [228][229][230] One notable exception found weak evidence for increased risk of converting to SPMS over 10-years in a parous cohort (on injectable or no DMT). 231 More recently, a protective effect of pregnancy on long-term outcomes was reported in a large real-world cohort (MSBase). Females with at least one pregnancy had lower EDSS scores over 10 years, after adjustment for relapse rate, therapy use, and other covariates. ...
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.
... Term pregnancies prove to have no effect on the time to reach a given disability level, which was predicted only by a progressive course and older age at MS onset 41 . Overall, there is no evidence to conclude that pregnancy or the number of pregnancies has a negative impact on the long-term course or progression to irreversible disability [40][41][42][43][44][45][46][47][48] . With regard to whether pregnancy has an impact on the risk for developing MS in patients with clinically isolated syndrome, an Australian study revealed that increasing gravidity and parity was associated with a lower risk of developing MS. ...
Objective: To review the current evidence regarding pregnancy-related issues in multiple sclerosis (MS) and to provide recommendations specific for each of them.
Research design and methods: A systematic review was performed based on a comprehensive literature search.
Results: MS has no effect on fertility, pregnancy or fetal outcomes, and pregnancies do not affect the long-term disease course and accumulation of disability. There is a potential risk for relapse after use of gonadotropin-releasing hormone agonists during assisted reproduction techniques. At short-term, pregnancy leads to a reduction of relapses during the third trimester, followed by an increased risk of relapses during the first three months postpartum. Pregnancies in MS are not per se high risk pregnancies, and MS does not influence the mode of delivery or anesthesia unless in the presence of significant disability. MRI is not contraindicated during pregnancy; however, gadolinium contrast media should be avoided whenever possible. It is safe to use pulse dose methylprednisolone infusions to manage acute disabling relapses during pregnancy and breastfeeding. However, its use during the first trimester of pregnancy is still controversial. Women with MS should be encouraged to breastfeed with a possible favorable effect of exclusive breastfeeding.
Disease-modifying drugs can be classified according to their potential for pregnancy-associated risk and impact on fetal outcome. Interferon beta (IFNβ) and glatiramer acetate (GA) may be continued until pregnancy is confirmed and, after consideration of the individual risk-benefit if continued, during pregnancy. The benefit of continuing natalizumab during the entire pregnancy may outweigh the risk of recurring disease activity, particularly in women with highly active MS. GA and IFNβ are considered safe during breastfeeding. The use of natalizumab during pregnancy or lactation requires monitoring of the newborn.
Conclusions: This review provides current evidence and recommendations for counseling and management of women with MS preconception, during pregnancy and postpartum.
... There is strong evidence that pregnancy does not worsen long-term prognosis, [157][158][159] despite an increased risk of relapses in the early postpartum period. 160 It is unclear if pregnancy improves MS outcome. ...
Recent findings have provided a molecular basis for the combined contributions of multifaceted risk factors for the onset of multiple sclerosis (MS). MS appears to start as a chronic dysregulation of immune homeostasis resulting from complex interactions between genetic predispositions, infectious exposures, and factors that lead to pro‐inflammatory states, including smoking, obesity, and low sun exposure. This is supported by the discovery of gene–environment (GxE) interactions and epigenetic alterations triggered by environmental exposures in individuals with particular genetic make‐ups. It is notable that several of these pro‐inflammatory factors have not emerged as strong prognostic indicators. Biological processes at play during the relapsing phase of the disease may result from initial inflammatory‐mediated injury, while risk factors for the later phase of MS, which is weighted toward neurodegeneration, are not yet well defined. This integrated review of current evidence guides recommendations for clinical practice and highlights research gaps.
... This approach has been performed in other previous studies. 35 However, in our study we have considered not only clinical variables for the multivariate analysis but biological (oligoclonal bands) and MRI data, and both factors are known to be important at the time to predict the course of MS. 4 The results of this study provide us with useful information for women with MS regarding reproductive counseling. The main message is that the prognosis of MS will not be significantly affected by pregnancy once all other variables are considered. ...
Objective:
To investigate the effect of menarche, pregnancies, and breastfeeding on the risk of developing multiple sclerosis (MS) and disability accrual using a multivariate approach based on a large prospective cohort of patients with clinically isolated syndrome (CIS).
Methods:
A cross-sectional survey of the reproductive information of female participants in a CIS cohort was performed. We examined the relationship of age at menarche with the risk of clinically definite MS (CDMS), McDonald 2010 MS, and Expanded Disability Status Scale (EDSS) 3.0 and 6.0. The effect of pregnancy (before and after CIS) and breastfeeding in the risk of CDMS, McDonald 2010 MS, and EDSS 3.0 was also examined. Univariate and multivariate analyses were performed and findings were confirmed using sensitivity analyses and a propensity score model.
Results:
The data of 501 female participants were collected. Age at menarche did not correlate with age at CIS and was not associated with the risk of CDMS or EDSS 3.0 or 6.0. Pregnancy before CIS was protective for CDMS in the univariate analysis, but the effect was lost in the multivariate model and did not modify the risk of EDSS 3.0. Pregnancy after CIS was protective for both outcomes in univariate and multivariate analyses when pregnancy was considered a baseline variable, but the protective effect disappeared when analyzed as a time-dependent event. Breastfeeding did not modify the risk for the 3 outcomes.
Conclusions:
These results demonstrate that menarche, pregnancies, and breastfeeding did not substantially modify the risk of CDMS or disability accrual using a multivariable and time-dependent approach.
... Both nulliparity and delayed pregnancy appear to increase the risk of MS. [35,46] After MS onset, experiencing a pregnancy reportedly has either a neutral [47][48][49], or a protective effect [43,[50][51][52][53][54][55] on maternal MS progression and disability. Confounders which have been overlooked in some studies include reverse causation, whereby women with more severe disease are less likely to have children [50], and older age at MS onset. ...
Purpose of review:
Caring for women with multiple sclerosis (MS), whose first symptoms typically begin during the childbearing years, requires a comprehensive approach to management across a range of reproductive exposures, and beyond through menopause.
Recent findings:
This article summarizes what is known about the disease course in women with MS, how it differs from men, and the current state of knowledge regarding effects of reproductive exposures (menarche, childbearing, menopause) on MS-related inflammation and neurodegeneration. Recent findings regarding pregnancy-associated relapses in the treatment era, protective effects of breastfeeding, and care for women during the menopausal transition are reviewed. Then, updated recommendations to guiding women during childbearing-including pre-conception counseling, discontinuation of MS therapies, and management of postpartum relapses-are provided. Whenever possible, areas of uncertainty and avenues for future research are highlighted. From childhood through the postreproductive life stages, gender and hormonal exposures appear to shape an individual's risk for MS, as well as the experience of living with MS.
... This study provided documentation that the relapse rate declined during pregnancy, particularly in the third trimester, and increased in the post-partum period, particularly in the first [5]. Further studies followed over the two decades since then, which have included (i) follow-up surveys [6], (ii) recent observational studies that either excluded a long-term effect [7] or observed a protective effect of pregnancy on maternal MS [8,9] and (iii) systematic reviews [10]. In addition, the availability of an increasing number of therapies with specific effects on pregnancy and understanding of the impact of treatment discontinuation because of improved knowledge about the disease in general [1] and pregnancy in particular [11] has contributed to a significant change in the management of MS patients who consider becoming pregnant. ...
Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system (CNS), most probably autoimmune in origin, usually occurring in young adults with a female/male prevalence of approximately 3:1. Women with MS in the reproductive age may face challenging issues in reconciling the desire for parenthood with their condition, owing to the possible influence both on the ongoing or planned treatment with the possible consequences on the disease course and on the potential negative effects of treatments on foetal and pregnancy outcomes. At MS diagnosis, timely counselling should promote informed parenthood, while disease evolution should be assessed before making therapeutic decisions. Current guidelines advise the discontinuation of any treatment during pregnancy, with possible exceptions for some treatments in patients with very active disease. Relapses decline during pregnancy but are more frequent during puerperium, when MS therapy should be promptly resumed in most of the cases. First-line immunomodulatory agents, such as interferon-β (IFN-β) and glatiramer acetate (GA), significantly reduce the post-partum risk of relapse. Due to substantial evidence of safety with the use of GA during pregnancy, a recent change in European marketing authorization removed the pregnancy contraindication for GA. This paper reports a consensus of Italian experts involved in MS management, including neurologists, gynaecologists and psychologists. This consensus, based on a review of the available scientific evidence, promoted an interdisciplinary approach to the management of pregnancy in MS women.
... W badaniach potwierdzono, że w krótkim okresie ciąża wpływa korzystnie na przebieg MS. Nie odnotowano natomiast pozytywnego wpływu na długotrwały przebieg choroby, a nawet zauważono, że ciąża może przyspieszać konwersję RRMS do SPMS (Karp et al., 2014). Wzrost liczby rzutów po rozwiązaniu koreluje ze wzrostem aktywności radiologicznej choroby. ...
Stwardnienie rozsiane jest postępującą chorobą ośrodkowego układu nerwowego o złożonej immunopatogenezie, w której
występują zapalenie, uszkodzenie mieliny i utrata aksonów. W badaniach doświadczalnych nad patofizjologią stwardnienia
rozsianego istotną rolę odgrywa model zwierzęcy – eksperymentalne autoimmunologiczne zapalenie mózgu i rdzenia.
Badania kliniczne i doświadczalne wskazują na autoimmunologiczne tło zapalenia w tej chorobie. Niestety, przyczyny rozwoju stwardnienia rozsianego nie zostały dotąd w pełni poznane, a dostępne leki tylko hamują progresję objawów
neurologicznych. Z badań epidemiologicznych jednoznacznie wynika, że płeć istotnie wpływa na zachorowalność, a także
na przebieg stwardnienia rozsianego. Liczne dane wskazujące na ważną rolę zarówno płci, jak i ciąży były bodźcem do
rozwoju badań nad rolą hormonów płciowych w tej chorobie oraz do poszukiwania nowych form terapii. W niniejszej
publikacji dokonano przeglądu literatury omawiającej wpływ żeńskich hormonów płciowych, ze szczególnym
uwzględnieniem estrogenów i progestagenów, na przebieg stwardnienia rozsianego. Pod uwagę wzięto dane z badań
klinicznych i eksperymentalnych. Estrogeny i progestageny należą do najważniejszych żeńskich hormonów steroidowych.
Są niezbędne do prawidłowego rozwoju i różnicowania narządów rozrodczych, a także do utrzymania płodności i ciąży.
Od dawna znany jest wpływ tych hormonów na regulację odpowiedzi immunologicznej. W niniejszym opracowaniu
szczególną uwagę poświęcono nie tylko działaniu immunomodulacyjnemu, ale również neuroprotekcyjnemu
i neuroregeneracyjnemu żeńskich hormonów płciowych. Omówiono też nowe możliwości terapeutyczne związane z terapią
hormonalną.
... This turned out to be untrue. Some studies suggest pregnancy conveys a long-term benefit [Keyhanian et al. 2012;Masera et al. 2015;Runmarker and Andersen 1995;Verdru et al. 1994], while others find no long-term impact [Karp et al. 2014;Ramagopalan et al. 2012]. The most accurate current counseling would be to inform patients that pregnancy has no negative effect on long-term prognosis. ...
Multiple sclerosis (MS) is a major acquired neurologic disease of young adults. The prototypic patient is a young woman of reproductive age. Gender preference is becoming more pronounced, since MS is increasing specifically among women. Any healthcare provider who deals with MS must be prepared to discuss pregnancy issues, and provide appropriate counseling. This is now complicated by the availability of multiple treatment options. There is growing literature on which to base recommendations, particularly regarding washout periods. After a brief background introduction, this review will discuss state-of-the-art family planning counseling in the treatment era, divided into prepregnancy, pregnancy, and postpartum MS issues.
... Multiple sclerosis presenting for the first time during pregnancy has also been reported. 29 Pituitary Apoplexy-Sheehan's Syndrome Pituitary apoplexy is pituitary gland enlargement due to sudden infarct or hemorrhage in pituitary adenomas. Pregnancy is one of the risk factors for this condition, and occurs as a result of serious postpartum hemorrhage. ...
Pregnancy causes significant changes in all systems of the body. Although most of them are physiological, they may also lead to
pathological consequences. The resulting pathological changes may occur for the first time or existing diseases affected by pregnancy can
become more serious or change course. Diseases specific only to pregnancy may arise. Like all systems of the body, the visual system is
also affected by pregnancy, developing a wide range of physiological and pathological changes. Knowing the ocular physiological changes
and diagnosing eye diseases that may develop during pregnancy, and preventing and treating these diseases is crucial to ensure the baby’s
healthy development. Therefore, we have reviewed the conditions that an ophthalmologist should recognize, follow-up, and pay attention
to during treatment and summarized them under the topic “pregnancy and the eye”. (Turk J Ophthalmol 2015; 45: 213-219)
... Elsewhere, a retrospective analysis of pregnant (n = 254) and non-pregnant (n = 423) cohorts of women with relapsingÀremitting MS indicated that, over the long term (up to 10 years), pregnancy had no material impact on rates of relapse and progression to irreversible disability [22]. ...
Although pregnancy in women with multiple sclerosis (MS) is not generally considered high risk, there are some associated therapeutic challenges. The pregnancy-associated reduction in the relapse rate, especially in the third trimester, is followed by a sharp increase in the first few months postpartum. Nevertheless, retrospective evidence for pregnant women with and without MS followed for up to 10 years indicates that pregnancy has no perceptible effect on long-term disease course or disability progression. Likewise, MS has no apparent effects on the pregnancy course or fetal outcomes. All disease-modifying therapies (DMTs) have potential adverse effects on fertility and pregnancy outcomes, but the level of risk varies amongst agents. There is some support for continued use of interferon-β and glatiramer acetate throughout pregnancy to reduce the risk of relapse. Use of DMTs during breastfeeding is best avoided if possible. Close evaluation of drug safety information is imperative when managing women with MS who are pregnant or wish to become pregnant. Decision-making should be a shared experience between patient and physician, and the approach must be individualized for each patient.
... 28,34 Pregnancy reportedly has either no adverse effects on maternal MS progression and disability [35][36][37] or a beneficial effect. [38][39][40][41][42][43][44] Important confounders often overlooked in studies include reverse causation, whereby women with more severe disease are less likely to have children, 38 and age at MS onset. Maternal age appeared to fully explain delay in disability progression in one large study 39 but not in three others. ...
To examine the evidence guiding management of multiple sclerosis (MS) in reproductive-aged women.
We conducted an electronic literature search using PubMed, ClinicalTrials.gov, and other available resources. The following keywords were used: "multiple sclerosis" and "pregnancy." We manually searched the reference lists of identified studies.
Two reviewers categorized all studies identified in the search by management topic, including effect of pregnancy on MS course, fetal risks associated with disease-modifying treatments during pregnancy, and management of patients off disease-modifying treatment. We categorized studies by strength of evidence and included prior meta-analyses and systematic studies. These studies were then summarized and discussed by an expert multidisciplinary team.
The risk of MS relapses is decreased during pregnancy and increased postpartum. Data are lacking regarding the risks of disease-modifying treatments during pregnancy. There may be an increased risk of MS relapses after use of assisted reproductive techniques. There does not appear to be a major increase in adverse outcomes in newborns of mothers with MS.
Although there are many unmet research needs, the reviewed data support the conclusion that in the majority of cases, women with MS can safely choose to become pregnant, give birth, and breastfeed children. Clinical management should be individualized to optimize both the mother's reproductive outcomes and MS course.
... We have reported that pregnancy may hasten transition to secondary progression. 2 Family planning for a woman with MS must consider the following: a 3-5% risk of MS transmission to the child, treatment cessation, a post-partum relapse rate of around 30%, resumption of disease-modifying therapies (DMT), and the possibility of a lessened capacity to take care of the child. The only demonstrated effects of standard DMTs on pregnancy outcomes are a slightly decreased child birth weight and length, and an increased rate of spontaneous abortions with interferons. ...
1Women with multiple sclerosis (MS) want to enjoy life to the full, including giving birth to and raising children. MS, in itself, has little impact on the course of pregnancy. It is well established that disease activity is considerably reduced during the last two trimesters of pregnancy. 1 Breast-feeding has a neutral effect on MS course. We have reported that pregnancy may hasten transition to secondary progression. 2 Family planning for a woman with MS must consider the following: a 3–5% risk of MS transmission to the child, treatment cessation, a post-partum relapse rate of around 30%, resumption of disease-modifying therapies (DMT), and the possibility of a lessened capacity to take care of the child. The only demonstrated effects of standard DMTs on pregnancy outcomes are a slightly decreased child birth weight and length, and an increased rate of spontaneous abortions with interferons. 3 Uncertainty remains over some possible long-term effects of treatments on the child. Women are generally unwilling to take any DMT during pregnancy, so that treatment is almost always deferred. DMT interruption carries the risk of disease reactivation, so that it is now advised to continue DMTs until a pregnancy test is positive. There is still, though, a high percentage of unplanned pregnancies. Natalizumab (NZB) is highly effective in reducing clinical and magnetic resonance imaging (MRI) manifestations of MS. Its use as a 4-weekly IV infusion is convenient, and is well tolerated in the short term. Alpha4-integrin, which is the target of NZB, plays an active role in fertilization, implantation, placental and cardiac development. When antagonized with NZB in pregnant animals, severe birth defects have been reported. Risks associated with NZB exposures during pregnancy and potential adverse effects on the developing fetus have therefore been expected.
Multiple sclerosis (MS) is an autoimmune, demyelinating disease with the highest incidence in women of childbearing age. The effect of pregnancy on disease activity and progression is a primary concern for women with MS and their clinical teams. It is well established that inflammatory disease activity is naturally suppressed during pregnancy, followed by an increase postpartum. However, the long-term effect of pregnancy on disease progression is less understood. Having had a pregnancy before MS onset has been associated with an older age at first demyelinating event, an average delay of 3.4 years. After MS onset, there is conflicting evidence about the impact of pregnancy on long-term outcomes. The study with the longest follow-up to date showed that pregnancy was associated with a 0.36-point lower disability score after 10-years of disease in 1830 women. Understanding the biological mechanism by which pregnancy induces long-term beneficial effects on MS outcomes could provide mechanistic insights into the elusive determinants of secondary progression. Here, we review potential biological processes underlying this effect, including evidence that acute sex hormone exposure induces lasting changes to neurobiological and DNA methylation patterns, and how sustained methylation changes in immune cells can alter immune composition and function long-term.
Background
Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS.
Results
We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5–44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women; together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4⁺ and eight in CD8⁺ T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women.
Conclusion
Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential ‘CNS signature’ of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.
Many neurologic diseases in women are influenced by the physiologic and hormonal changes of pregnancy, and pregnancy itself poses challenges in both treatment and evaluation of these conditions. Some diseases, such as epilepsy and multiple sclerosis, have a high enough prevalence in the young female population to support robust epidemiologic data while many other neurologic diseases, such as specific myopathies and muscular dystrophies, have a low prevalence, with data limited to case reports and small case series. This chapter features epidemiologic information regarding a breadth of neurologic conditions, including stroke, epilepsy, demyelinating disease, peripheral neuropathies, migraine, sleep-disordered breathing, and meningioma, in women in the preconception, pregnancy, and postpartum stages.
Background:
The relapse is character of relapsing-remitting multiple sclerosis. The therapeutic goal is to reduce the risk of relapse. Factors associated with relapses can help to manage and prevent relapses. In addition, patients and doctors all pay attention to it. However, there are differences between studies. Our aim is to summarize factors associated with relapses in relapsing-remitting multiple sclerosis (RRMS).
Methods:
PubMed, EMBASE, Web of science, Cochrane library, CNKI, Wanfang, SinoMed, and VIP were searched to identify risk factors about relapses in RRMS, which should be in cohort or case-control studies. This article was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The quality of studies was evaluated by the Newcastle-Ottawa Scale (NOS). Meta-analysis, subgroup and sensitivity analyses, and publication bias were all performed with Stata. This research has been registered on the international prospective register of systematic reviews (PROSPERO, CRD42019120502).
Results:
43 articles were included. Infection, postpartum period, risk gene, stress, and vitamin D were risk factors for relapses in RRMS. Pregnancy period was the protective factor. Among those, infection increased the risk of relapses in infection period (relative risk [RR], 2.07 [confidence interval (CI), 1.64 to 2.60]). Women in the postpartum period increased the risk of relapses compared with women before pregnancy (RR, 1.43 [CI, 1.19 to 1.72]), or women in pregnancy period (RR, 2.07 [CI, 1.49 to 2.88]). Women in the pregnancy period decreased the risk of relapses (RR, 0.56 [CI, 0.37 to 0.84]) compared with women before pregnancy. However, fewer studies, heterogeneity, and sample size were the limitations.
Conclusion:
It is reliable to adopt results about infection, pregnancy period, and postpartum period.
For the fi rst time in Ukraine, was explored the eff ect of pregnancy, childbirth and the postpartum period on the further course of multiple sclerosis (MS) in sporadic and family forms of women giving birth at the preclinical stage (group 1) and against the background of the disease (group 2). Through the use of questioning method and clinical and neurological examination the following phenomena were studied. Namely, premonitory history; features of the course of the disease; the duration between labor and development of the onset of the illness in women of the 1st group and between the onset and labor in women of the 2nd group; obstetric and gynecological history; the eff ect of pregnancy and childbirth on the further course of MS. A total of 82 women were examined, 51 of them were giving birth at preclinical stage (group 1) and 31 — against the background of MS (group 2). In the 1st group with remitting course (RC), 26 women had a sporadic form and 5 — a family form; with progressive course (PC) — in 14 — sporadic and in 6 — family form. In the 2nd group with RC, 23 women had sporadic and 1 family form; with PC — 6 had sporadic and 1 family. Research has shown, the disease of majority of women from the first group has been developed after childbirth. Women from the second group with RC were giving birth most often after 5—10 years of the disease onset; with PC — after more than 10 years. According to the obstetric and gynecological history, differences were obtained during pregnancy, childbirth and the postpartum period between two groups of women with different types of course. An assessment of the effects of pregnancy, childbirth and the postpartum period of women from the 2nd group made it possible to identify criteria for various options for the further course of MS (such as improvement, stabilization, improvement through worsening, worsening), which are closely interrelated with the types of course of the disease. To sum up, an integrated analysis of the above mentioned outcome shows a positive eff ect of pregnancy and childbirth in the vast majority of women with RC and a high incidence of decline of women with PC. Key words: multiple sclerosis, types of course, sporadic and familial form, pregnancy and childbirth, obstetric and gynecological history, complications during pregnancy and childbirth
Background
Persons with multiple sclerosis (MS) have many pregnancy‐related doubts and fears. Careful counselling is thus important. Mitoxantrone (MITO) is used in patients with aggressive MS and may affect reproductive capacity.
Aim
To investigate pregnancy planning and outcomes in MS patients treated with MITO, both before and after the treatment.
Materials
Patients with MS previously treated with MITO were recruited. Clinical, demographic, and treatment data were recorded. A questionnaire regarding the planning and outcomes of all pregnancies was administered. Parametric and non‐parametric tests were performed using SPSS‐22 software.
Results
We included 238 patients (F/M=158/80). One hundred and six subjects planned a pregnancy before MITO, and 40 after MITO. Respectively, 102 (97%) and 35 (85%) resulted in conception, 19 (19%) and 7 (18%) in miscarriage, 6 (6%) and 1 (3%) in abortion, and 98 (96%) and 32 (91%) were at term pregnancies. Ninety‐six patients (40%) planned a pregnancy only before MITO, while 30 (13%) only after (p<0.01). One hundred and three patients did not plan a pregnancy before MITO and 198 after. The reasons included: lack of interest or a partner, fear of MS, and infertility. All of the babies born were healthy until the end of the follow‐up.
Conclusions
MITO does not affect the ability to conceive or the pregnancy outcomes. We found no differences in pregnancies, abortions, or miscarriages before versus after MITO. The tendency to plan pregnancies decreased significantly after MITO. Our findings may be useful for improving the quality of life of patients and the neurologists approach.
This article is protected by copyright. All rights reserved.
Women at childbearing age more often present with relapsing–remitting MS. This phenotype is associated with longer times to disability landmarks compared to primary progressive MS. When planning a family, women with MS need information about conception, pregnancy, postpartum, breastfeeding, and long-term outcomes.
Although the reduced relapse risk during pregnancy is followed by a threefold increase in the 3-month postpartum period, the majority of women do not suffer such relapses. Exclusive breastfeeding has been associated with a reduction of disease activity. Increased social support during the postpartum period may help mothers with MS by minimizing the impact of MS-related symptoms.
The disease itself is not associated with an increased risk to the fetus. There is some evidence to suggest that childbirth could lessen the risk of developing MS and ameliorate the course of MS in terms of relapse rates and progression to irreversible disability. As it is virtually impossible to fully control for the heterogeneity of disease activity in MS, reverse causality cannot be ruled out.
Objective:
To identify predictors of ten year expanded disability status scale (EDSS) change after treatment initiation in patients with relapse-onset MS.
Methods:
Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for one day and were monitored on any approved disease modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.
Results:
We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range 0-2) at 10 years post-baseline. Annualised relapse rate was highly predictive of increases in median EDSS over 10 years (coeff 1.14, p=1.9x10(-22) ). On therapy relapses carried greater burden than off therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff -0.86, p=1.3x10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10 year observation period (coeff -0.36, p=0.009).
Interpretation:
We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high-annualised relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. This article is protected by copyright. All rights reserved.
Introduction:
Multiple sclerosis (MS) is a disease that mainly affects young adults who are of reproductive age. MS can lead to severe disability and is associated with worse prognosis in untreated patients. Although MS is not negatively affected by pregnancy itself, it may be a high-risk decision to leave a woman without treatment because she may get pregnant.
Areas covered:
This paper reviews the literature on pregnancies where the mother was exposed to glatiramer acetate . Few data are available on paternal exposure, but this does not seem to pose a problem due to the pharmacological characteristics of the drug. Only a limited amount of data from individual groups in the world is available in the literature.
Expert opinion:
TEVA Pharmaceuticals would need to open the database on pregnancy exposure to glatiramer acetate to allow for proper conclusions. Glatiramer acetate is a drug of low risk in pregnancy (category B in the FDA classification) and may be a safe option for the treatment of women of fertile age with MS.
The propensity score is the conditional probability of assignment to a particular treatment given a vector of observed covariates. Both large and small sample theory show that adjustment for the scalar propensity score is sufficient to remove bias due to all observed covariates. Applications include: (i) matched sampling on the univariate propensity score, which is a generalization of discriminant matching, (ii) multivariate adjustment by subclassification on the propensity score where the same subclasses are used to estimate treatment effects for all outcome variables and in all subpopulations, and (iii) visual representation of multivariate covariance adjustment by a two- dimensional plot.
A growing body of literature indicates that the natural course of multiple sclerosis can be influenced by a number of factors. Strong evidence suggests that relapses can be triggered by infections, the postpartum period and stressful life events. Vaccinations against influenza, hepatitis B and tetanus appear to be safe. Surgery, general and epidural anaesthesia, and physical trauma are not associated with an increased risk of relapses. Factors that have been associated with a reduced relapse rate are pregnancy, exclusive breastfeeding, sunlight exposure and higher vitamin D levels. A number of medications, including hormonal fertility treatment, seem to be able to trigger relapses. Factors that may worsen progression of disability include stressful life events, radiotherapy to the head, low levels of physical activity and low vitamin D levels. Strong evidence suggests that smoking promotes disease progression, both clinically and on brain magnetic resonance imaging. There is no evidence for an increased progression of disability following childbirth in women with multiple sclerosis. Moderate alcohol intake and exercise might have a neuroprotective effect, but this needs to be confirmed.
Positivity, or the experimental treatment assignment assumption, requires that there be both exposed and unexposed participants at every combination of the values of the observed confounders in the population under study. Positivity is essential for inference but is often overlooked in practice by epidemiologists. This issue of the Journal includes 2 articles featuring discussions related to positivity. Here the authors define positivity, distinguish between deterministic and random positivity, and discuss the 2 relevant papers in this issue. In addition, the commentators illustrate positivity in simple 2 x 2 tables, as well as detail some ways in which epidemiologists may examine their data for nonpositivity and deal with violations of positivity in practice.
The uncertainty about long-term effects of childbirth presents MS patients with dilemmas.
Based on clinical data of 330 female MS patients, the long-term effects of childbirth were analysed, using a cross-sectional study design. Four groups of patients were distinguished: (1) without children (n = 80), (2) with children born before MS onset (n = 170), (3) with children born after MS onset (n = 61) and (4) with children born before and after MS onset (n = 19). A time-to-event analysis and Cox proportional hazard regression were performed with time from onset to EDSS 6 and age at EDSS 6 as outcome measure.
After a mean disease duration of 18 years, 55% had reached EDSS 6. Survival curves show a distinct shift in the time to EDSS 6 between patients with no children after MS onset and patients with children after MS onset in favour of the latter. Cox regression analysis correcting for age at onset shows that patients with children only after MS onset had a reduced risk compared with patients without children (HR 0.61; 95% CI 0.37 to 0.99, p = 0.049). Also, patients who gave birth at any point in time had a reduced risk compared with patients without children (HR 0.66; 95% CI 0.47 to 0.95, p = 0.023). A similar pattern was seen for age at EDSS 6 (HR 0.57, p = 0.027 and HR 0.68, p = 0.032 respectively)
Although a bias cannot fully be excluded, these results seem to support a possible favourable long-term effect of childbirth on the course of MS.
A standard analysis of the Framingham Heart Study data is a generalized person-years approach in which risk factors or covariates are measured every two years with a follow-up between these measurement times to observe the occurrence of events such as cardiovascular disease. Observations over multiple intervals are pooled into a single sample and a logistic regression is employed to relate the risk factors to the occurrence of the event. We show that this pooled logistic regression is close to the time dependent covariate Cox regression analysis. Numerical examples covering a variety of sample sizes and proportions of events display the closeness of this relationship in situations typical of the Framingham Study. A proof of the relationship and the necessary conditions are given in the Appendix.
A prospective study of the level of disability, severity and distribution of relapses in 15 women with multiple sclerosis prior to, during and up to 3 years following pregnancy was undertaken. The pregnant group was compared with 22 nulliparous women attending the same clinic and matched for age and severity and duration of disease. In the pregnant group, relapses were more frequent and severe than expected values during the first 6 months post partum, but were below expected values 6–24 months post partum. Over the total study period, therefore, there were no significant differences in relapse number, Expanded Disability Status Score or functional scores between the two groups. Babies born during the study showed normal distributions of weight and head circumference.
In observational studies with exposures or treatments that vary over time, standard approaches for adjustment of confounding are biased when there exist time-dependent confounders that are also affected by previous treatment. This paper introduces marginal structural models, a new class of causal models that allow for improved adjustment of confounding in those situations. The parameters of a marginal structural model can be consistently estimated using a new class of estimators, the inverse-probability-of-treatment weighted estimators.
Although several papers report on pregnancy and multiple sclerosis (MS), no systematic review of the literature has been carried out. Neurologists and obstetricians need to have proper information to discuss with women presenting with MS who consider pregnancy.
Literature review and meta-analysis of data on pregnancy in women with MS.
The present work followed the recommendations of the PRISMA Statement. Using the PICO framework, the authors independently searched for the terms 'pregnancy' OR 'gestation' OR 'pregnant' AND 'multiple sclerosis' OR 'MS' in the following databases: EMBASE/Excerpta Medica, Medline, Pubmed, Scopus, Index Medicus, Biomed Central, Ebsco Fulltext, LILACS, Scielo and the Cochrane Database of Systematic Reviews. Selection criteria: only papers presenting original work with analysis of at least one of the outcomes among pregnant women with MS were included.
Two independent workers performed the literature review. All the authors selected and read the relevant papers. Two other authors summarised data for analysis.
Twenty-two papers reporting on 13,144 women with MS and their pregnancies were analysed. A significant decrease in relapse rate was observed during pregnancy, followed by a significant increase after delivery. Miscarriages, low birthweight, prematurity, neonatal death and malformations were assessed among these women and their offspring. There seems to be a regional influence on the rates of caesarean sections and abortions among women with MS. Neonatal death and malformation rates did not seem to be particularly high.
The present work provides evidence-based data that can be discussed with women with MS and their relatives when pregnancy is considered by these families.
The hazard ratio (HR) is the main, and often the only, effect measure reported in many epidemiologic studies. For dichotomous, non–time-varying exposures, the HR is defined as the hazard in the exposed groups divided by the hazard in the unexposed groups. For all practical purposes, hazards can be thought of as incidence rates and thus the HR can be roughly interpreted as the incidence rate ratio. The HR is commonly and conveniently estimated via a Cox proportional hazards model, which can include potential confounders as covariates.
Pregnancy has a well-documented effect on relapses in multiple sclerosis (MS), whereas little is known about the impact of pregnancy and childbirth on the risk of secondary progression.
To investigate the association of parity and secondary progression in women with MS.
The association of the number of births and secondary progression was studied in a hospital-based cohort of 277 women with MS. Data were analysed in a multivariable logistic regression model, with adjustment for possible confounders.
Parity was not independently associated with secondary progression, while the factors disease duration (OR per year increase: 1.05, 95% CI 1.03 to 1.09) and use of immunomodulatory treatments (OR 0.23, 95% CI 0.08 to 0.65) were independently associated with secondary progression.
We found no evidence that parity influences the risk of secondary progression in MS. Further population-based studies on the association of pregnancy and childbirth on the long-term prognosis of MS are needed.
The Women's Health Initiative randomized trial found greater coronary heart disease (CHD) risk in women assigned to estrogen/progestin therapy than in those assigned to placebo. Observational studies had previously suggested reduced CHD risk in hormone users.
Using data from the observational Nurses' Health Study, we emulated the design and intention-to-treat (ITT) analysis of the randomized trial. The observational study was conceptualized as a sequence of "trials," in which eligible women were classified as initiators or noninitiators of estrogen/progestin therapy.
The ITT hazard ratios (HRs) (95% confidence intervals) of CHD for initiators versus noninitiators were 1.42 (0.92-2.20) for the first 2 years, and 0.96 (0.78-1.18) for the entire follow-up. The ITT HRs were 0.84 (0.61-1.14) in women within 10 years of menopause, and 1.12 (0.84-1.48) in the others (P value for interaction = 0.08). These ITT estimates are similar to those from the Women's Health Initiative. Because the ITT approach causes severe treatment misclassification, we also estimated adherence-adjusted effects by inverse probability weighting. The HRs were 1.61 (0.97-2.66) for the first 2 years, and 0.98 (0.66-1.49) for the entire follow-up. The HRs were 0.54 (0.19-1.51) in women within 10 years after menopause, and 1.20 (0.78-1.84) in others (P value for interaction = 0.01). We also present comparisons between these estimates and previously reported Nurses' Health Study estimates.
Our findings suggest that the discrepancies between the Women's Health Initiative and Nurses' Health Study ITT estimates could be largely explained by differences in the distribution of time since menopause and length of follow-up.
The method of inverse probability weighting (henceforth, weighting) can be used to adjust for measured confounding and selection bias under the four assumptions of consistency, exchangeability, positivity, and no misspecification of the model used to estimate weights. In recent years, several published estimates of the effect of time-varying exposures have been based on weighted estimation of the parameters of marginal structural models because, unlike standard statistical methods, weighting can appropriately adjust for measured time-varying confounders affected by prior exposure. As an example, the authors describe the last three assumptions using the change in viral load due to initiation of antiretroviral therapy among 918 human immunodeficiency virus-infected US men and women followed for a median of 5.8 years between 1996 and 2005. The authors describe possible tradeoffs that an epidemiologist may encounter when attempting to make inferences. For instance, a tradeoff between bias and precision is illustrated as a function of the extent to which confounding is controlled. Weight truncation is presented as an informal and easily implemented method to deal with these tradeoffs. Inverse probability weighting provides a powerful methodological tool that may uncover causal effects of exposures that are otherwise obscured. However, as with all methods, diagnostics and sensitivity analyses are essential for proper use.
Retrospective studies strongly suggest that pregnancy is an example of a naturally occurring human condition that consistently and predictably affects the course of multiple sclerosis (MS). Pregnancy seems to be associated with clinical MS stability or improvement, while the postpartum period seems to be one of high risk for clinical flares of the disease symptoms. Similarly, pregnancy protects animals from developing experimental allergic encephalomyelitis. Immune system changes in pregnancy and MS are reviewed, as they may be involved in the observed clinical effects of pregnancy on MS. Important questions of the patient with MS in the childbearing age group are addressed.
The purpose of this paper is to indicate how repeated measures on risk factors have been employed in the prediction of the development of disease in the Framingham Heart Study. Since these measures vary over time, the method accounts for time dependent covariates. The technique is a generalized person-years approach in that it treats each observation interval (of equal length) as a mini-follow-up study in which the current risk factor measurements are employed to predict an event in the interval. Observations over multiple intervals are pooled into a single sample to predict the short term risk of an event. This approach is compared to the long-term prediction of disease which utilizes only the baseline measurements and ignores subsequent repeated measures on the risk factors.
The purpose of the study was to evaluate the effect of pregnancy and childbirth on the longterm prognosis for women with multiple sclerosis (MS).
A cohort of 39 women with definite MS were identified on 1.1.1986 using a reproducible selection method. The investigation was initiated in 1986 when handicap was evaluated by Kurtzke Disability Status Score (DSS). At a 5-year follow up 4 had died and 6 could not participate. There were 29 women in the investigation of whom 7 were childless, 10 had onset of MS at least 6 months after last childbirth, and 12 had onset of MS before or in connection with childbirth. Age and disease duration of the group was uniform.
At follow up the DSS significantly deteriorated (p = 0.008). The deterioration was seen particularly for childless women (p = 0.03) and women with onset of MS before or in connection with childbirth (p = 0.005).
On the basis of this prospective investigation and the literature, it may be concluded that it is unlikely that pregnancy and childbirth have an influence on the longterm prognosis for MS. However, the conclusion must be interpreted with caution as the number of patients is small.
The effects of pregnancy were studied in a multiple sclerosis incidence cohort. In order to eliminate interaction bias between the disease and pregnancy, analysis of the risk of relapse during pregnancy and the puerperium was limited to the onset bout, using fecundity figures for Sweden. The risk of onset bout was significantly reduced during pregnancy while the risk of onset bout in the post-partum period did not differ significantly from the risk during non-pregnancy periods. We also found a decreased risk of multiple sclerosis onset in parous compared with nulliparous women. The association between nulliparity and multiple sclerosis tended to increase with age. Furthermore, the effect of pregnancy on the long-term prognosis in established multiple sclerosis was analysed by comparing the risk of change from a relapsing-remitting to a chronic progressive course and the risk of reaching level 6 of the Disability Status Scale in women with pregnancy after multiple sclerosis onset with that in non-pregnant control patients, matched for neurological deficit, disease duration and age. There was a significantly decreased risk of a progressive course in women who were pregnant after multiple sclerosis onset.
We studied 200 female patients with multiple sclerosis (MS) to investigate whether pregnancy after the onset of disease influences long term disability. As an index of progression, we used the time between disease onset and wheelchair dependence. Patients who had at least one pregnancy after onset were wheelchair dependent after 18.6 years, versus 12.5 years for the other women (P < 0.0001). This difference remains statistically significant after correction for age at onset of disease.
Correlated response data are common in biomedical studies. Regression analysis based on the generalized estimating equations (GEE) is an increasingly important method for such data. However, there seem to be few model-selection criteria available in GEE. The well-known Akaike Information Criterion (AIC) cannot be directly applied since AIC is based on maximum likelihood estimation while GEE is nonlikelihood based. We propose a modification to AIC, where the likelihood is replaced by the quasi-likelihood and a proper adjustment is made for the penalty term. Its performance is investigated through simulation studies. For illustration, the method is applied to a real data set.