Pregnancy In Multiple Sclerosis Research Articles

Eomesodermin-expressing CD4+ Th cells and association with pregnancy in multiple sclerosis.

Pregnancy in patients with multiple sclerosis (MS) is accompanied by a decline of relapse activity with increased risk of relapses 3 months post-partum, for unknown reasons. Eomesodermin+ T-helper cells (Eomes+ Th cells) are known to mediate neuroinflammation and disease progression in MS and are induced by prolactin-secreting cells. Here, investigated immune cell alterations and the pathophysiological role of Eomes+ Th cells for disease activity during pregnancy and post-partum in MS. We enrolled n = 81 pregnant patients with relapsing-remitting MS (RRMS), n = 27 post-partum RRMS and n = 26 female RRMS control patients under the umbrella of the German Multiple Sclerosis and Pregnancy Registry. Clinical data were collected and immune cell alterations were analysed using flow cytometry. While CD3+CD4+ Th cells were unaffected, CD3+CD8+ cytotoxic T-cells were elevated post-partum (p = 0.02) with reduced B-cell frequencies (p = 0.01) compared to non-pregnant RRMS patients. NK cells were elevated during first trimester (p = 0.02) compared to the third trimester. Frequencies of Eomes+ Th and Eomes+ Tc cells did not differ. There was no correlation of prolactin release and expression of Eomes+ Th cells. However, Eomes+ Th cells correlated with lower frequencies of regulatory T-cells during second (r = -0.42; p < 0.05) and third trimester (r = -0.37; p < 0.05). Moreover, Eomes+ Th cells correlated with frequencies of B-cells during third trimester (r = 0.54; p = 0.02). Frequencies of Eomes+ Th cells were not associated with the number of relapses before pregnancy, during pregnancy or post-partum. However, Eomes+ Th cells strongly correlated with disability post-partum as assessed using the EDSS (r = 0.52; p = 0.009). Pregnancy in MS is associated with robust immunological alterations. Eomes+ Th cells are capable of inducing immune cell alterations during the course of pregnancy, most evident during the second and third trimester as shown with a correlation of reduced Treg cells and a significant increase of B-cells. Importantly, Eomes+ Th cells correlate with disability post-partum. In summary, during late pregnancy in MS an inflammatory, cytotoxic and dysregulated immunological environment is primed gaining function post-delivery. This may be responsible for post-partum disability accumulation.

Cognitive Function During Pregnancy In Multiple Sclerosis: Is There A Decline In Processing Speed? (P9-3.004)

Cognitive Function During Pregnancy In Multiple Sclerosis: Is There A Decline In Processing Speed? (P9-3.004)

The protective role of breastfeeding in multiple sclerosis: Latest evidence and practical considerations.

The immunoprotective role of pregnancy in multiple sclerosis (MS) has been known for decades. Conversely, there has been rich debate on the topic of breastfeeding and disease activity in MS. In clinical practice, women are often offered to restart their disease-modifying drug (DMD) soon after delivery to maintain their relapse risk protection. Limited available information about peri-partum DMD safety can discourage women to choose breastfeeding, despite the World Health Organization's recommendation to breastfeed children for the first 6 months of life exclusively. New evidence is emerging about the protective role of exclusive breastfeeding on relapse rate. Research studies shed light on the hormonal and immunological mechanisms driving the risk of relapses during pregnancy and postpartum. Finally, case reports, real-world data, and clinical trials are increasing our knowledge of the safety of DMDs for the fetus and infant. While some DMDs must be avoided, others may be considered in highly active pregnant or lactating women with MS. This mini-review conveys recent evidence regarding the protective role of exclusive breastfeeding in MS and offers clinicians practical considerations for a patient-tailored approach.

Treatment with natalizumab during pregnancy in multiple sclerosis: The experience of implementing a clinical practice protocol (NAP-30)

BackgroundPregnancy planning in women with highly active multiple sclerosis (HAMS) who need a high-efficacy disease-modifying therapy (heDMT) currently requires a careful risk-benefit evaluation. This includes minimizing fetal drug toxicity and preventing MS reactivation. We describe our experience with natalizumab in women with HAMS and unplanned pregnancy by implementing a clinical practice protocol (NAP-30) designed to maintain the effectiveness of natalizumab during pregnancy, reduce fetal exposure and prevent complications. MethodsThis was an observational retrospective study including women with HAMS on active treatment with natalizumab who became unexpectedly pregnant in the period 2018–2021 and continued this treatment during pregnancy according to the NAP-30 protocol. MS clinical and radiological variables were analyzed before and during pregnancy and in the postpartum period, along with maternal and fetal toxicity during pregnancy and safety findings in newborns. We also describe the NAP-30 protocol, which includes the use of a bridging dose to adjust and maintain natalizumab infusions every 6 weeks during pregnancy up to week 30 and scheduled delivery at week 40. ResultsSix women (one in her first gestation) with a median age of 31.5 years at the onset of pregnancy (min-max: 24–37 years) were included. All were negative for anti-John Cunningham virus (JCV) antibodies and were on treatment with intravenous natalizumab 300 mg every 4 weeks. At the time of conception, three patients had received 12, 17 and 53 infusions of natalizumab, respectively, while for the remaining three patients natalizumab was their first DMT (two patients had received 6 infusions and one patient had received 3 infusions of natalizumab). All six patients received 6 doses of natalizumab during pregnancy according to the NAP-30 protocol. After delivery, all six patients restarted natalizumab every 4 weeks (median: 3 days; range: 2–4 days). No patients had relapses during pregnancy or at 6 months postpartum, nor did they develop any general health or laboratory abnormalities. The MRI scan performed at 4–6 months postpartum showed no new T2 lesions or gadolinium-enhancing lesions. No miscarriages or threatened miscarriages were reported. One of the patients underwent elective preterm delivery at week 35 after mild-to-moderate anemia was detected by fetal Doppler scan. The newborn had low birth weight (2080 g) and mild anemia, which resolved within two months with oral iron supplementation. The other infants were born with normal birth weight and showed no blood count abnormalities. After a median follow-up of 10 months, all six babies showed normal development with no complications detected. ConclusionsBased on our experience, the implementation of the NAP-30 protocol in women with HAMS and unplanned pregnancy undergoing treatment with natalizumab allows the continuation of natalizumab during pregnancy, with a very favorable clinical and radiological effectiveness and maternal-fetal safety profile during pregnancy and postpartum. Both in pregnancy with HAMS and in general, and particularly for successful implementation of the NAP-30 protocol, obstetric support and monitoring is essential for adequate pregnancy management.

Alterations of NK Cell Phenotype During Pregnancy in Multiple Sclerosis.

In multiple sclerosis (MS), relapse rate is decreased by 70-80% in the third trimester of pregnancy. However, the underlying mechanisms driving this effect are poorly understood. Evidence suggests that CD56bright NK cell frequencies increase during pregnancy. Here, we analyze pregnancy-related NK cell shifts in a large longitudinal cohort of pregnant women with and without MS, and provide in-depth phenotyping of NK cells. In healthy pregnancy and pregnancy in MS, peripheral blood NK cells showed significant frequency shifts, notably an increase of CD56bright NK cells and a decrease of CD56dim NK cells toward the third trimester, indicating a general rather than an MS-specific phenomenon of pregnancy. Additional follow-ups in women with MS showed a reversal of NK cell changes postpartum. Moreover, high-dimensional profiling revealed a specific CD56bright subset with receptor expression related to cytotoxicity and cell activity (e.g., CD16+ NKp46high NKG2Dhigh NKG2Ahigh phenotype) that may drive the expansion of CD56bright NK cells during pregnancy in MS. Our data confirm that pregnancy promotes pronounced shifts of NK cells toward the regulatory CD56bright population. Although exploratory results on in-depth CD56bright phenotype need to be confirmed in larger studies, our findings suggest an increased regulatory NK activity, thereby potentially contributing to disease amelioration of MS during pregnancy.

Natalizumab treatment and pregnancy in multiple sclerosis: A reappraisal of maternal and infant outcomes after 6 years

Objectives: To assess the impact of timing of natalizumab cessation/redosing on long-term maternal and infant outcomes in 72 out of the original 74 pregnancies of the Italian Pregnancy Dataset in multiple sclerosis (MS). Methods: Maternal outcomes in patients who received natalizumab until conception and restarted the drug within 1 month after delivery (“treatment approach,” (TA)) and patients who stopped natalizumab before conception and/or restarted the drug later than 1 month after delivery (“conservative approach,” (CA)) were compared through multivariable Cox regression analyses. Pediatric outcomes were assessed through a semi-structured questionnaire. Results: After a mean follow-up of 6.1 years, CA (hazard ratio (HR) = 4.1, 95% CI 1.6–10.6, p = 0.003) was the only predictor of relapse occurrence. Worsening on the Expanded Disability Status Scale (EDSS) was associated with higher annualized relapse-rate during the follow-up (HR = 3.3, 95% CI 1.4–7.9 p = 0.007). We found no major development abnormalities in children. Discussion: Our data confirm that TA reduces the risk of disease activity; we did not observe an increase in major development abnormalities in the child.

Short-chain fatty acids during pregnancy in multiple sclerosis: A prospective cohort study.

Short-chain fatty acids (SCFAs) can have pro- or anti-inflammatory properties, but their relationship with multiple sclerosis (MS) relapses during pregnancy remains unknown. This study aimed to explore SCFA profiles in MS patients during pregnancy and to assess their association with the appearance of relapses during pregnancy and postpartum. We prospectively included 53 pregnant MS patients and 21 healthy control women. Patients were evaluated during pregnancy and puerperium. SCFAs were measured by liquid chromatography-mass spectrometry. Sixteen patients (32%) had relapses during pregnancy or puerperium, and 37 (68%) did not. All MS patients showed significant increases in acetate levels during pregnancy and the postpartum period compared to non-MS women. However, propionate and butyrate values were associated with disease activity. Their values were higher in nonrelapsing patients and remained similar to the control group in relapsing patients. The variable that best identified active patients was the propionate/acetate ratio. Ratios of <0.36 during the first trimester were associated with higher inflammatory activity (odds ratio =165, 95% confidence interval = 10.2-239.4, p<0.01). Most nonrelapsing patients showed values of >0.36, which were similar to those in healthy pregnant women. Low propionate/acetate ratio values during the first trimester of gestation identified MS patients at risk of relapses during pregnancy and the postpartum period.

Pregnancy in multiple sclerosis: from scientific aspects to practical

Background: Multiple sclerosis (MS) is a disease that affects young people of reproductive age (20-40 years old), predominantly women. Therefore, almost every patient has questions about pregnancy and breastfeeding. Family planning is one of the key issues in the choice of treatment tactics. Despite the growing number of therapeutic options for individualized treatment, it is still a question how to manage women with MS who become pregnant while taking disease-modifying drugs or want to become pregnant after starting this treatment. Conclusions: Women with MS should not be discouraged from pregnancy due to their illness. It is necessary to proactively discuss pregnancy planning with all women with MS of childbearing age. Based on available data, interferon beta and glatiramer acetate appear to be most suitable for use up until the time of confirmed pregnancy. A large amount of data (more than 1000 cases) obtained from registries shows that use of interferon beta before conception and during pregnancy suggests no evidence of increase in the rate of congenital anomalies or spontaneous abortions. For women with persistent high disease activity, pulsed immune reconstitution therapy gives additional opportunity for family planning after the last dose. The choice between available options for pulsed immune reconstitution therapy should be based on efficacy balanced against the risks.

Influence of Pregnancy in Multiple Sclerosis and Impact of Disease-Modifying Therapies.

Purpose of this Review: This article is a systematic review on the influence pregnancy has on multiple sclerosis and the resulting impact of disease-modifying therapies.Findings: Multiple sclerosis predominantly affects young women with a clinical onset most often during the child-bearing age. The impact of multiple sclerosis and disease-modifying therapies on fertility, pregnancy, fetal outcome, and breastfeeding is a pivotal topic when it comes to clinical practice. The introduction of disease-modifying therapies has changed not only the natural history of the disease but also the perspective of pregnancy in women with multiple sclerosis. Family planning requires careful consideration, especially because many disease-modifying drugs are contraindicated during pregnancy. In this article, we review current evidence collected from published literature and drug-specific pregnancy registers on the use of disease-modifying therapies. Additionally, we discuss safety profiles for each drug and correlate them to both risk for the exposed fetus and risk for the mothers interrupting treatments when seeking pregnancy.

Pregnancy in multiple sclerosis: A reflection on the importance of individualizing management

AbstractIntroductionThe management of multiple sclerosis during pregnancy has changed in recent years; it is no longer viewed as hindering the evolution of the disease. Lower relapse rates are expected during gestation, while the early puerperium may be more critical.Case reportWe present two cases of active relapse‐remitting multiple sclerosis in pregnant women with different clinical courses, mirroring the disease heterogeneity and unpredictability. The first one, despite the ongoing activity, had two uneventful pregnancies. The second woman, previously controlled, experienced an increase in the disease activity during pregnancy.DiscussionsThe decision of maintaining disease‐modifying therapy throughout gestation could be a strategy to reduce postpartum relapses.

Circulating endothelial progenitor cells during pregnancy in multiple sclerosis

BackgroundEndothelial progenitor cells (EPCs) have been shown to increase during physiological pregnancy and are believed to play a fundamental role in the process of placentation. Reduced levels of EPCs during pregnancy have been associated with preeclampsia and miscarriage. Women with multiple sclerosis (MS) are not at increased risk of preeclampsia nor of general adverse obstetric outcome, in contrast with some other autoimmune diseases.ObjectiveThe aim of this study was to evaluate circulating EPCs levels in pregnant patients with MS.MethodsCD34+ and CD133+ were longitudinally detected by flow cytometry in the maternal plasma of 29 healthy controls and 9 MS patients and in the cord blood of their newborns.ResultsEPCs were affected by pregnancy with the same trend in both groups (CD34+ p = 0.0342; CD133+ p = 0.0347). EPCs during pregnancy were increased in MS (mean ± SD: CD34+ cells 0.038 ± 0.010; CD133+ 0.024 ± 0.009) with respect to healthy controls (mean ± SD: CD34+ cells 0.022 ± 0.006; CD133+ 0.016 ± 0.004), CD34+ p = 0.0004; CD133+ p = 0.0109. EPCs levels of the cord blood of MS patients' newborns mild correlated with maternal EPC levels at delivery (CD34+: spearman’s Rho 0.658, p = 0.054; CD133+: spearman’s Rho 0.758, p = 0.018).ConclusionsThis work identified increased circulating EPC levels during pregnancy, following the same trend both in MS patients and healthy controls. Despite the similar trend, the levels of circulating EPCs were significantly higher in MS patients with respect to the control population. A correlation was also found in MS patients between cord blood EPCs and circulating EPCs at delivery.

Pregnancy in multiple sclerosis: influence on disease trajectory

Pregnancy in multiple sclerosis: influence on disease trajectory

T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis

Identifying Tcell clones associated with human autoimmunity has remained challenging. Intriguingly, many autoimmune diseases, including multiple sclerosis (MS), show strongly diminished activity during pregnancy, providing a unique research paradigm to explore dynamics of immune repertoire changes during active and inactive disease. Here, we characterize immunomodulation at the single-clone level by sequencing the Tcell repertoire in healthy women and female MS patients over the course of pregnancy. Clonality is significantly reduced from the first to third trimester in MS patients, indicating that the Tcell repertoire becomes less dominated by expanded clones. However, only a few Tcell clones are substantially modulated during pregnancy in each patient. Moreover, relapse-associated Tcell clones identified in an individual patient contract during pregnancy and expand during a postpartum relapse. Our data provide evidence that profiling the Tcell repertoire during pregnancy could serve as a tool to discover and track "private" Tcell clones associated with disease activity in autoimmunity.

The Short and Long-Term Effects of Pregnancy on Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.

The role of pregnancy in multiple sclerosis (MS) is of importance because many patients with MS are young women in the childbearing age who require information to inform their reproductive decisions. Pregnancy is now well-known to be associated with fewer relapses of MS and reduced activity of autoimmune encephalomyelitis (EAE). However, in women with multiple sclerosis, this benefit is not always sufficient to protect against a rebound of disease activity if disease-modulating therapy is ceased for pregnancy. There is concern that use of assisted reproductive therapies can be associated with relapses of MS, but more data are required. It is thought that the beneficial effects of pregnancy are due to the pregnancy-associated changes in the maternal immune system. There is some evidence of this in human studies and studies of EAE. There is also evidence that having been pregnant leads to better long-term outcome of MS. The mechanism for this is not fully understood but it could result from epigenetic changes resulting from pregnancy or parenthood. Further studies of the mechanisms of the beneficial effects of pregnancy could provide information that might be used to produce new therapies.

Neuraxial analgesia is not associated with an increased risk of post-partum relapses in MS

Background: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses. Objective: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy. Methods: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992–1995 and 2005–2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis. Results: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78). Conclusion: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.

Humoral response to John Cunningham virus during pregnancy in multiple sclerosis

BackgroundPregnancy induces an immunosuppressive state in the mother to ensure immunological acceptance of the foetus. Impairment of cell-mediated immune responses may render the mother susceptible to intracellular pathogens. It is not presently known whether pregnancy alters the immunosurveillance for John Cunningham virus (JCV), an opportunistic pathogen associated with natalizumab treatment for multiple sclerosis (MS). ObjectiveTo evaluate whether the humoral immune response to JCV is altered during pregnancy among MS patients and healthy controls to get insight to potential pregnancy-induced alterations related to immune response to JCV during pregnancy. MethodsSerum anti-JCV-antibody-indices (JCV-Ab-index) were determined by a two-step second–generation enzyme-linked immunosorbent assay in 49 MS patients during and after pregnancy and in 49 healthy controls during pregnancy. For comparison, total IgG levels and antibodies against Epstein-Barr, cytomegalo and measles viruses were similarly measured. ResultsThe JCV-Ab-indices of MS patients were not altered during the pregnancy (1st vs. 3rd trimester, 0.62 vs. 0.77, p = 0.99). Contrary to this, in the healthy controls JCV-Ab-indices (p = 0.005), antibody levels to the other viruses, and total IgG levels (p < 0.0001) decreased significantly during pregnancy. ConclusionsJCV-Ab levels remain unaltered during MS pregnancy, while the total IgG concentration is reduced/diluted due to increasing plasma volumes during the course of pregnancy. This may imply a biologically significant alteration in the immune response to JCV during MS pregnancy.

Time to Pregnancy in Multiple Sclerosis: A Case-Control Study

Time to Pregnancy in Multiple Sclerosis: A Case-Control Study

Pregnancy in Multiple Sclerosis: A Portuguese cohort study

BackgroundPregnancy in Multiple Sclerosis (MS) has been a controversial issue, without international standardized treatment recommendations. The goal of our study was to evaluate the clinical course of MS during pregnancy and the respective therapeutic options, obstetrical outcomes and breastfeeding data. MethodsThis was a retrospective study including women with a diagnosis of relapsing-remitting MS at least one year before pregnancy. Three periods were evaluated: one year prior to pregnancy, pregnancy and one year postpartum. Information acquired included demographic and disease activity data, treatment options, and obstetrical and breastfeeding data. ResultsFrom a cohort of 1134 patients and 777 women, we included 127 pregnancies in 97 women (111 deliveries of a live infant, 11 spontaneous abortions, 3 fetal deaths and 2 voluntary abortions). The annualized relapse rate (ARR) decreased during pregnancy, mainly in the third trimester (prior to pregnancy 0.6 ± 0.8 vs. during pregnancy 0.3 ± 0.6, p = 0.006). There were no significant changes in the ARR in the year after delivery compared to baseline (0.6 ± 0.8 vs. 0.6 ± 0.8, p = 0.895). Patients with relapses in the postpartum period had a shorter disease duration at conception (5.4 ± 3.9 vs. 7.4 ± 4.7; p = 0.029) and breastfed less (53.5% vs. 72.1%, p = 0.046). In the multivariate analysis, relapses during pregnancy predicted postpartum relapses (OR = 4.9, p < 0.005). Neither the previous use of disease modifying therapy (DMT), given to 80.2% of women, nor breastfeeding, caesarean delivery (CD) or epidural analgesia (EA) had an impact on the presence of postpartum relapses. Compared to baseline, the Expanded Disability Status Scale (EDSS) increased in pregnancy and the postpartum period (1.6 ± 0.7 vs. 1.7 ± 0.9 vs. 2.1 ± 1.0, p < 0.001). CD was performed in 43.3% of patients, mainly because of fetal-pelvic incompatibility (35.7%) and EA was performed in 63.9%. The most frequent complications were restriction of fetal growth (4.5%) and gestational diabetes mellitus (3.6%). Concerning newborns, 6.4% had birth asphyxia and 6.1% low birth weight. No malformations were registered. ConclusionDespite a reduction in the relapse rate during pregnancy, the presence of relapses during pregnancy predicted postpartum relapses, with impact on disability. DMT appeared to have no influence on clinical or obstetrical outcome. MS did not have a deleterious effect on the pregnancy course. CD and EA were safe procedures, with a tendency towards CD in MS patients, compared to Portuguese women in general. Breastfeeding did not influence MS activity.

The effect of postpartum intravenous immunoglobulins on the relapse rate among patients with multiple sclerosis

ObjectiveTo evaluate the effect of intravenous immunoglobulins (IVIGs) on the expected increase in postpartum relapse rate (RR) among patients with multiple sclerosis (MS). MethodsIn a retrospective study, data were analyzed from patients with relapsing remitting MS who received postpartum IVIG at the Academic MS Center Limburg, Sittard-Geleen, Netherlands, between April 2005 and January 2015. Patients received 10g IVIG (Nanogam) for 3 consecutive days after childbirth, and then once monthly until 5months after delivery. Data were compared with results from the Pregnancy in Multiple Sclerosis (PRIMS) I and II studies, which followed the natural outcomes of patients with MS with no intervention. ResultsOverall, 42 pregnancies were evaluated. The RR in the first 3months after delivery was 0.48±1.31, as compared with 1.2 in the PRIMS studies. The RR also remained low at 3–6, 6–9, and 9–12months after delivery for patients who received IVIG. ConclusionPostpartum administration of IVIG could be beneficial in preventing childbirth-associated relapses among patients with MS. It led to a substantial decrease in RR.

Family planning, pregnancy and breastfeeding in multiple sclerosis.

Multiple sclerosis often affects women of childbearing age. The availability of more effective immunomodulatory therapy may increase the number of afflicted women wanting to fulfil their desire to have children. The purpose of this article is to provide an up-to-date review of medical issues and dilemmas related to family planning and pregnancy in multiple sclerosis.