Evaluation of ovarian reserve and the assisted reproductive technology (ART) cycles' outcome as well as the relapse rate within one year after ART in women with multiple sclerosis: a case-control study.

This case-control retrospective study was carried out following the approval of the research protocol by the scientific review board and the ethics committee of Royan Institute. The study included all patients diagnosed with multiple sclerosis (MS) who referred to Royan Institute for assessing and treatment of possible infertility from January 2011 to January 2022. Patients must have undergone at least one assisted reproduction technology (ART) treatment cycle during time period of study. Additionally, healthy women with tubal factor infertility, matched in age and date of ART cycle, were randomly selected from the registered patients list as the control group. The following items were considered as exclusion criteria: (1) previous ovarian surgery or bilateral tubal ligation, (2) addiction to smoking or alcohol, (3) history of treatment with toxic agents for the reproductive system, excluding mitoxantrone, (4) premature ovarian failure (POF) as well as endometriosis or hydrosalpinx diagnosis. Multiple Sclerosis diagnosis keyword was searched in Royan Institute’s patient information registration softwares in a certain time frame so that the files of all patients were checked and recorded. The patients’ files were reviewed by researchers and the information related to the baseline characteristics of the patients and the infertility treatment cycle was recorded. The MS clinical history included date of MS onset, MS type at ART cycle, the symptoms and severity of the MS at ART cycle time and post-ART cycle as well as the present time, and the relapse rate within 12 months after ART cycle were collected by the main researcher through telephone follow-up. The diagnosis of MS was based on two foundations: (1) diagnosis of spatial and temporal spread of focal neurological deficits and (2) exclusion of important differential diagnoses. The current revised McDonald’s 2017 diagnostic criteria are used, taking into account new data on magnetic resonance imaging (MRI) and introducing the role of cerebrospinal fluid diagnosis for the relapsing-remitting form [ 15 ]. MS relapse is defined as the reappearance or worsening of symptoms of neurological dysfunction for a period of at least 24 h, which cannot be explained by current infection or other reasons [ 16 ]. Disease modifying therapies (DMTs) were classified according to their assumed biological effects during FT. Patients were deemed to be on therapeutic DMT if they had been administered rituximab or ocrelizumab within the last 6 months; dimethyl fumarate, glatiramer acetate, or interferon treatment during the cycle. Natalizumab and S1P modulators were considered therapeutic only if they were maintained throughout the cycle to prevent rebound relapses. The control group was selected in a 1:1 proportion in patients who had been diagnosed with tubal factor infertility (either idiopathic or post-ectopic pregnancy). This group were matched for women’s age and the year of their IVF cycle.

Upon examination of the 60 cases documented with a diagnosis of MS, it was found that 27 MS patients had solely lodged cases without seeking treatment. Out of the total, 5 patients opted for IUI treatment, while 28 patients underwent IVF/ICSI cycle treatment. Out of the 5 patients who participated in the IUI cycle, one individual achieved pregnancy, resulting in a cycle success rate of 20%. The baseline characteristics of the patients in two groups were compared in Table  1 . It was found that two groups were similar in terms of the body mass index, menstrual status and duration of menstrual bleeding. However, the mean age of menarche in individuals with MS was notably lower than that of the control group (12.66 ± 1.17 vs. 13.69 ± 0.94, P  = 0.009). Additionally, the two groups were assessed for type and duration of infertility and no statistically significant variations were observed. Table 1 The comparison of the baseline characteristics and ovarian reserve markers between study groups Variable MS group ( n  = 28) Control group ( n  = 28) P -value* Menarche age (years) 12.66 ± 1.17 13.69 ± 0.94 0.009 Age of the women at the beginning of the treatment cycle 34.01 ± 4.10 34.01 ± 3.96 0.91 Body mass index (kg/m2) 24.20 ± 4.41 25.61 ± 4.58 0.25 Baseline FSH serum level (IU/L) 7.63 ± 2.35 6.78 ± 2.52 0.20 Baseline LH serum level (IU/L) 5.15 ± 3.30 5.70 ± 3.22 0.53 AMH serum level (ng/mL) 1.72 ± 1.15 (0.5–4.7) 1.90 ± 1.50 (0.5–5.5) 0.67 Serum TSH level (mIU/L) 1.87 ± 1.23 2.01 ± 1.24 0.67 Sonographic view of the ovary₤ Normal 21 (75%) 24 (85.7%) 0.55 Morphology of PCO 1 (3.6%) 0 DOR 6 (21.4%) 4 (14.3%) Duration of bleeding in the menstrual cycle (days) 6.83 ± 2.14 5.55 ± 1.50 0.10 Menstrual status Regular 27 (96.4%) 28 (100%) 0.94 Irregular 1 (3.6%) 0 Infertility duration (years) 6.01 ± 5.06 5.24 ± 3.60 0.51 Type of infertility Primary 25 (89.3%) 20 (71.4%) 0.17 Secondary 3(10.7%) 8 (28.6%) Previous history of the ART cycle Yes 6 (21.4%) 3(10.7%) 0.46 No 22 (78.6%) 25 (89.3%) ₤ Normal view of each ovary was defined as observing between 6 and 12 antral follicles in each ovary. Diminished ovarian reserve (DOR) was considered as detection less than 5 antral follicles in each ovary. Polycystic ovary syndrome (PCOS) was defined as observation more than 12 antral follicles in each ovary.MS: multiple sclerosis; ART: assisted reproductive technology; AMH: anti-Müllerian hormone; FSH: follicle-stimulating hormone; LH: luteinizing hormone; TSH: thyroid-stimulating hormone The comparison of the baseline characteristics and ovarian reserve markers between study groups 1.72 ± 1.15 (0.5–4.7) 1.90 ± 1.50 (0.5–5.5) ₤ Normal view of each ovary was defined as observing between 6 and 12 antral follicles in each ovary. Diminished ovarian reserve (DOR) was considered as detection less than 5 antral follicles in each ovary. Polycystic ovary syndrome (PCOS) was defined as observation more than 12 antral follicles in each ovary.MS: multiple sclerosis; ART: assisted reproductive technology; AMH: anti-Müllerian hormone; FSH: follicle-stimulating hormone; LH: luteinizing hormone; TSH: thyroid-stimulating hormone The analysis results indicated that there was no statistically significant difference in the mean serum levels of ovarian reserve markers including anti-Müllerian hormone (AMH) ( P  = 0.67), follicle-stimulating hormone (FSH) ( P  = 0.20) and luteinizing hormone (LH) ( P  = 0.53) between groups (Fig.  1 ). Moreover, the mean serum level of thyroid-stimulating hormone (TSH) was not statistically significantly different between the MS patients and the control group ( P  = 0.67). Fig. 1 The bar graph indicates that there was no statistically significant difference in the mean serum levels of ovarian reserve markers (anti-Müllerian hormone, follicle-stimulating hormone, and luteinizing hormone) between patients with MS and the control group prior to the commencement of assisted reproductive treatment The bar graph indicates that there was no statistically significant difference in the mean serum levels of ovarian reserve markers (anti-Müllerian hormone, follicle-stimulating hormone, and luteinizing hormone) between patients with MS and the control group prior to the commencement of assisted reproductive treatment Among the patients with MS, the reasons of infertility were as follows: 3.6% were diagnosed with polycystic ovary syndrome (PCOS) ( n  = 1), 10.7% with unexplained ( n  = 3), 53.7% with male factor ( n  = 15), 10.7% with repeated miscarriages, ( n  = 3), 7.1% with endometriosis ( n  = 2), and 14.2% with diminished ovarian reserve ( n  = 4). It is noteworthy that male infertility was the most prevalent cause of infertility among the MS patients (Fig.  2 ). The significant prevalence of male factor as the sole cause of infertility among MS patients in this study indicates that the majority of the patients were within the normal range in terms of ovarian reserve and fertility. Fig. 2 The pie chart presents the frequency of different cause of infertility in patients with multiple sclerosis diagnosis The pie chart presents the frequency of different cause of infertility in patients with multiple sclerosis diagnosis The outcomes of the ovarian stimulation and embryo transfer cycles were compared between groups in Table  2 . There was a statistically significant difference in the type of ovarian stimulation protocol between the two groups ( P  = 0.029), possibly attributed to the higher inclination towards the antagonist protocol among MS patients. The analysis demonstrated that the two groups were similar in terms of the duration of ovarian stimulation, total dosage of used gonadotropin, and the type of final oocyte trigger’s drug. Moreover, the data analysis revealed no significant differences in terms of type of ovarian response, total number of retrieved and MII oocytes as well as total number of obtained embryos, fertilization rate, clinical pregnancy and live birth rates between groups. Additionally, during the telephone follow-up with the MS patient group, it was discovered that three patients achieved spontaneous pregnancy and resulted in the birth of healthy babies. Table 2 The comparison of the ovarian stimulation and embryo transfer cycles outcomes between study groups Variable MS group ( n  = 28) Control group ( n  = 28) P -value* Total dose of gonadotropin ampoules (IU) 1943.70 ± 941.0 1877.60 ± 1102.3 0.81 Duration of ovarian stimulation (days) 10.28 ± 1.95 10.96 ± 2.25 0.23 Type of ovarian stimulation protocol Long GnRH-agonist 13 (46.4%) 21 (75%) 0.029 GnRH antagonist 15 (53.6%) 7 (25%) Type of medicine used for final oocyte triggering Recombinant hCG 10 (35.8%) 6 (21.3%) 0.48 Urinary hCG 16 (57.1%) 20 (71.8%) GnRH agonist (Buserlin) 2 (7.1%) 2 (7.1%) Type of ovarian response Normal 18(64.3%) 19(67.9%) 0.89 POR (number of retrieved oocytes less than 4) 7(25%) 7(25%) High response (number of retrieved oocytes more than 15) 3(10.7%) 2(7.1%) The total number of retrieved oocytes 8.28 ± 5.02 8.17 ± 6.07 0.93 The number of metaphase II (MII) oocytes 6.58 ± 4.02 6.78 ± 3.69 0.94 Fertilization rate 0.72 ± 0.27 0.76 ± 0.21 0.84 The number of obtained embryos 4.60 ± 3.42 5.32 ± 3.20 0.42 The number of transferred embryos 1.92 ± 0.84 2.70 ± 0.54 0.19 The number of cases of no embryo formation (No ET) 2 (7.1%) 0 (0) 0.15 Embryo stage on the day of transfer Cleavage 17(68%) 25(89.2%) 0.017 Blastocyst 8(32%) 3(10.7%) Type of ET Fresh 20 (80%) 18 (64.3%) 0.22 Frozen 5 (20%) 10 (35.7%) Implantation rate 0.61 ± 0.34 0.66 ± 0.32 0.74 Clinical pregnancy rate/ET 10/25 (40%) 12/28 (42.8%) 0.83 Live birth rate /ET 7/25 (28%) 11/28 (39.2%) 0.38 ET: embryos transfer; POR: poor ovarian response; HCG: human chorionic gonadotropins; GnRH: gonadotrophin-releasing hormone The comparison of the ovarian stimulation and embryo transfer cycles outcomes between study groups ET: embryos transfer; POR: poor ovarian response; HCG: human chorionic gonadotropins; GnRH: gonadotrophin-releasing hormone The data obtained from the telephone follow-up has reported in Table  3 . Among the 28 patients who underwent fertility treatment cycles, 7 patients failed to respond despite multiple attempts to contact them. 21 participants responded to the researcher’s telephone inquiries. According to the responses provided ( n  = 21), none of the participants reported a family history of MS among their first-degree relatives, nor did any of them have a history of other autoimmune conditions such as thyroiditis, systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, and so on. The average of disease duration was 10.40 ± 5.34 years. On the basis of the reports mentioned by the patients, there was no significant difference in the degree of disability before and after the ART cycle (Table  3 ). According to the neurologist’s assessment, the majority of patients (95.2%) were suffering from relapsing-remitting disease, whereas only one patient (4.8%) was diagnosed with progressive disease. Within a year before starting IVF treatment cycle, all patients confirmed that they had not experienced any attacks. Additionally, they ceased taking all of their DMTs approximately three months before commencing the IVF cycle. Out of the total patients, only two (9.5%) reported experiencing an attack or relapse within one year after ART. Table 3 The assessment of disability level and relapse rate in patients with multiple sclerosis (MS) before and after assisted reproductive technology (ART) cycles ( n  = 21) Age of patients at diagnosis of MS 24.04 ± 5.7 Time interval between treatment cycle and phone follow-up time (years) 7.95 ± 3.15 The time interval between the diagnosis of the disease and the start of the ART cycle (years) 10.40 ± 5.34 Types of symptoms at the time of MS diagnosis Weakness and fatigue 5 (23%) Sensory disorders 10 (47.6%) Visual disorders 10 (47.6%) Disturbance of balance 3 (14.2%) Movement disorders 5 (23%) Degree of disability before ART She has no disability and is normal 18 (85.8%) A little weak but no problem 1 (4.7%) She moves with help 2 (9.5%) Degree of disability one year after ART She has no disability and is normal 16 (76.2%) A little weak but no problem 3 (14.3%) She moves with help 2 (9.5%) Degree of disability at time of telephone follow-up She has no disability and is normal 14 (66.6%) A little weak but no problem 5 (24%) She moves with help 1 (4.7%) She walks with a walker 1 (4.7%) The assessment of disability level and relapse rate in patients with multiple sclerosis (MS) before and after assisted reproductive technology (ART) cycles ( n  = 21)

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, the peak incidence of which is around the age of 30, and the ratio of female to male is 3:1 [ 1 ]. The incidence of MS in women of reproductive age is higher than in any other age group [ 2 ], making family planning a common concern for many MS patients [ 3 ].There is limited data regarding the fertility rate of women with MS (wMS) [ 4 , 5 ]. For years, women with MS have been discouraged from becoming pregnant for fear of not being able to care for their children due to fatigue or infirmity, or because of concerns about passing on a genetic predisposition to an autoimmune disease to their children [ 6 , 7 ]. Despite the fact that up to one-third of wMS have children after being diagnosed with the disease, MS has been found to have a notable impact on reproductive decisions and this often leads to a decrease in the number of children and a delay in the first childbirth when compared to the general population [ 8 ]. Hence, the topic of fertility in women diagnosed with MS remains a subject of debate, with potential impacts on fertility due to decreased ovarian function [ 9 – 11 ]. The exact reasons behind these effects on female reproduction are still uncertain, as they could be attributed to the underlying pathology of MS, the influence of certain MS treatments on the endocrine system and ovarian function, or the choices made by these women to postpone pregnancy [ 5 ]. Researches have shown that serum level of anti-Müllerian hormone (AMH) in reproductive age women with autoimmune diseases is lower than normal women (9). Based on the search conducted so far, 4 studies have been published on ovarian reserve in MS patients [ 4 , 5 , 11 , 12 ]. At first, Cil et al. have reported that ovarian volume and follicular reserve were reduced in MS patients using immunomodulatory drugs compared to age-matched healthy controls [ 4 ]. Elsewhere, Sepúlveda et al. have concluded that serum AMH levels, total number of antral follicles, and ovarian volume were significantly lower in those with active disease [ 11 ]. Recently, in contrast to these studies, Sadeghpour et al. found no statistically significant difference in mean serum AMH levels between patients with relapsing-remitting MS and patients with neuromyelitis optica spectrum disorder compared to normal women in the control group [ 12 ]. Therefore, due to the contradictory data, more studies are required in this field. The number of women with MS who seek infertility treatment and assisted reproduction technology (ART) cycles is increasing over time. A number of case reports and small studies with different ART protocols have shown an increase in MS activity after ART [ 13 ]; however, the impact of ART on the immune system in wMS remains to be elucidated [ 14 ]. In spite of the fact that accessible information appear that the live birth rate has not diminished in wMS experiencing ART cycles, some relevant data are still needed to be investigated [ 3 ]. Considering the conflicting results of prior research in this area and the need for further studies on this intriguing topic, this retrospective study was designed to investigate ovarian reserve and treatment results in infertile wMS compared to healthy women with tubal factor infertility.

Based on the findings, the ovarian reserve, ovarian stimulation cycle outcomes, and pregnancy rates post-ART cycle in MS patients were comparable to those of the age-matched control group. After conducting telephone follow-up, it was found that proceeding with ART cycle in MS patients with well-managed disease before infertility treatment did not result in a higher risk of relapse. Merely 9.5% of patients experienced a relapse within the first year following the ART cycle. It is advised that upcoming research should investigate the factors influencing regional differences in yearly recurrence rates following ART, along with the effects of different type of DMTs on natural conception and pregnancies resulting from ART.

The findings of the current research indicated that there was no significant difference in ovarian reserve between patients with MS and normal women with tubal infertility. Moreover, the success rate of infertility treatment in these patients was deemed satisfactory and acceptable when compared to the control group. It was also observed that undergoing an ART cycle did not lead to a higher risk of MS relapse, with only 9.5% of patients reporting a relapse within one year after ART. The results of our research, which compared serum AMH levels in patients with MS, align with the results of Sadeghpour et al. in 2020. Sadeghpour’s study examined the ovarian reserve in 23 women with relapsing-remitting MS and compared it to that of 23 normal women. The study found no significant difference between the two groups [ 12 ]. Another pilot study investigated the pituitary-ovarian axis and ovarian reserve, including AMH levels and ultrasound imaging of the ovaries. It revealed that women with relapsing MS and more active disease had significantly lower AMH levels, as well as fewer antral follicles and smaller ovarian volumes. These women also had fewer ovaries compared to those with less disease activity [ 11 ]. As a result, women experiencing elevated disease activity, who may choose to postpone pregnancy in order to manage their health, may also encounter an increased likelihood of diminished ovarian reserve. Consequently, an increasing number of women with MS are now seeking pregnancy [ 3 ]. Meanwhile, the significant lower average age of menarche in women with MS in the current study has validated findings from prior research in this field [ 17 – 19 ]. Recently, the result of a systematic review demonstrated that the risk of MS decreases by increasing age at menarche [ 20 ]. Moreover, the outcomes of our research were in agreement with two recent studies, indicating that the pregnancy and live birth rates after ART cycles in women with MS were comparable to those in the control group. In 2020, Houtchens et al., [ 3 ] conducted a study comparing live birth rates, infertility diagnoses, and infertility treatments between women with MS and those without. The study involved a retrospective review of US administrative claims databases. Patients aged 18 to 55 years with MS were matched with non -MS patients in a 1:1 ratio. Live birth rates, infertility diagnoses, and infertility treatments were compared between the two groups. The findings revealed that, overall, women with MS ( n  = 96,937) had a lower live birth rate compared to women without MS ( n  = 96,937) (5% vs. 7% ( P  < 0.0001). A higher percentage of women with MS received an infertility diagnosis compared to those without MS (8.5% vs. 8.1%; p  = 0.0006). However, among women with or without MS who underwent infertility treatment, there was no significant difference in live birth rates following infertility treatments [ 3 ]. Furthermore, in a distinct study carried out by Jølving and colleagues [ 21 ] in 2020, the Danish Health Organization examined the live birth rate after ART cycles in women with MS over a period of 22 years (1995–2017) in comparison to a control group. The findings of this study revealed that the likelihood of live birth was similar in women with MS who undergo ART remains compared to women without MS. Additionally, the utilization of corticosteroids three months prior to embryo transfer in these patients did not impact the outcomes [ 21 ]. The implementation of novel DMTs has revolutionized the approach to family planning for women with MS [ 22 ]. As the utilization of ART continues to rise, it becomes imperative to comprehend its implications for women with MS [ 14 ]. A case-series study has highlighted that the suppression of the pituitary-hypothalamic axis using GnRH agonists, which bind to pituitary GnRH receptors, diminishes the GnRH pulse and results in a hypoestrogenic phase [ 23 – 26 ]. This has been associated with a specific risk of MS relapses, prompting a shift towards the utilization of GnRH antagonists in the protocol [ 14 ]. There are three potential mechanisms contributing to this heightened risk: the initial one involves direct impacts via the GnRH receptor on immune cells, resulting in the proliferation of CD + 4 T cells and autoreactive myelin T cells, as well as an increased production of cytokines such as interleukin 8 and 12, and interferon alfa. The second mechanism entails significant estrogenic fluctuations, particularly following the use of GnRH agonists, which can modify immune profiles, including the number of cells secreting anti-MOG antibodies, levels of B-cell survival factor BAFF, and anti-apoptotic protein cl-2B. These alterations in the immune system can heighten the likelihood of disease relapses. Finally, the ART cycle could enhance the migration of immune cells through the blood-brain barrier by triggering three specific molecules: IL-8, EGFV, and CXCL-12 [ 26 ]. To the best of our knowledge, there have been eight studies published regarding ART treatment cycles in patients with MS (15, 25, 28–33). Consistently, in early studies from 2007 to 2012, the Relapse risk (RR) increased following ART cycles (Table  4 ). In 2019, Bove et al. conducted a study with the objective of assessing the likelihood of relapse following ART in an independent case series. Additionally, they performed a meta-analysis by pooling the existing data [ 14 ]. The meta-analysis revealed that although the pre-ART relapse figures were comparable, the participants in the case series of Boston study exhibited a lower number of relapses after ART compared to the other studiess. However, the pooled data analysis indicated an elevated risk of relapse even after employing GnRH antagonists, implying the likelihood of additional mechanisms contributing to recurrence [ 14 ]. Two additional studies [ 27 , 28 ] have been carried out in this domain subsequent to the release of the meta-analysis in 2020. These studies, however, contradicted the findings of the aforementioned meta-analysis. The relapse rates reported in these studies were 7.3% and 6.1% respectively, aligning with the outcomes of our own study. Our research indicates that the absence of a higher relapse rate risk could be attributed to the fact that most patients had stable disease under control with DMT drugs before starting the treatment cycle. It appears that the initial studies have indicated a rise in the likelihood of relapse, along with a greater understanding of the factors that contribute to relapse in MS patients undergoing infertility treatment. As a result, medical professionals are now focusing on the existing risk factors when managing patients and prescribing DMT drugs. Patients with a higher risk are advised to take these medications during infertility treatment. Ultimately, this approach aims to prevent the relapse of the disease following the completion of the infertility treatment cycle. In our study which is the ten-year experiences at an infertility treatment center, only two patients reported relapses. Upon further investigation, it was found that both patients had a higher severity of MS prior to undergoing infertility treatment and despite following the standard protocols, both patients experienced relapse within a year after the ART cycle. Table 4 Previous studies conducted in the field of ART in MS patients Authors’ name Country/year of publication Study design Sample size/ART cycle Main results Secondary outcomes RR in the 3 months after ART Relapse Rate GnRH agonist GnRH antagonist Laplaud et al. [ 23 ]. France 2007 Retrospective 6/10 RR:40% Increased Not increased Not reported Hellwig et al. [ 24 ]. Germany 2008 Retrospective 6/14 RR: 35.7% Increased Increased Not reported Hellwig et al. [ 16 ]. Germany 2009 Retrospective and Prospective 23/78 RR:52.1% Increased Increased RR following the administration of the ART increased regardless of the time gap between the stimulation. Michel et al. [ 25 ]. France 2012 Retrospective 32/70 RR:59.3% Increased Not increased RR increased in the event of ART failure. Correale et al. [ 26 ]. Argentina 2012 Prospective 16/26 RR:58% Increased Not included in this study There has been a ninefold rise in the risk of MRI activity. A higher number of cells producing IL-8, IL-12, IFNc, TGFβ, VEGF, CXCL-12 plasma levels, anti-MOG antibody titers, BAFF, and Bcl-2 levels were observed in correlation with the elevated RR. Bove et al. [ 14 ] USA 2020 Retrospective 12/22 RR:18% Not increased Not increased Not reported Mainguy et al. [ 27 ]. France 2022 Retrospective 225/338 RR:7.7% Not increased Not increased There was a decrease in the RR following ART cycle among individuals who were taking DMT. Graham et al. [ 28 ]. USA 2023 Retrospective 65/124 RR:6.1% Not increased Not increased RR increased in instances where two or more COH cycles were performed. The use of DMT during COH was linked to a decreased RR. The table has been extracted from the publication by Sparaco and colleagues [ 29 ]. ART: assisted reproduction technology; BAFF: Blood B Cell-Activating Factor; COH: controlled ovarian hyperstimulation; DMTs: Disease Modifying Therapies; IL-8: interleukin 8; IL-12: interleukin 12; IFNc: interferon-c; MOG: myelin oligodendrocyte glycoprotein; RR: relapse rate TGFβ: Transforming growth factor-beta; VEGF: vascular endothelial growth factor Previous studies conducted in the field of ART in MS patients France 2007 6/10 RR:40% Germany 2008 6/14 RR: 35.7% Germany 2009 23/78 RR:52.1% France 2012 32/70 RR:59.3% Argentina 2012 16/26 RR:58% There has been a ninefold rise in the risk of MRI activity. A higher number of cells producing IL-8, IL-12, IFNc, TGFβ, VEGF, CXCL-12 plasma levels, anti-MOG antibody titers, BAFF, and Bcl-2 levels were observed in correlation with the elevated RR. USA 2020 12/22 RR:18% France 2022 225/338 RR:7.7% USA 2023 65/124 RR:6.1% The table has been extracted from the publication by Sparaco and colleagues [ 29 ]. ART: assisted reproduction technology; BAFF: Blood B Cell-Activating Factor; COH: controlled ovarian hyperstimulation; DMTs: Disease Modifying Therapies; IL-8: interleukin 8; IL-12: interleukin 12; IFNc: interferon-c; MOG: myelin oligodendrocyte glycoprotein; RR: relapse rate TGFβ: Transforming growth factor-beta; VEGF: vascular endothelial growth factor A recent study conducted by Sparaco and colleagues in 2023 examined the efficacy of infertility treatment protocols and strategies for managing women with MS who are experiencing infertility [ 29 ]. The immune system’s response to sex hormones makes it challenging to understand why ART could potentially affect disease activity in MS, according to the researchers’ findings. It is plausible that the fluctuation of estrogen levels during and after COS could have a negative impact on the immune system, similar to what happens after ART failure. Although current data do not clearly indicate an increased risk of relapse with a specific ART protocol, the evidence suggests that opting for an antagonist protocol is relatively safe. It is recommended to undergo a maximum of three cycles of ovarian stimulation [ 29 ]. Unfortunately, there is no available information regarding the types and doses of gonadotropins used [ 29 ]. According to this recent review article, the suggested guidelines for individuals with MS who are undergoing fertility treatment are provided as follows: the first recommendation: There is limited information available regarding the utilization of additional therapy (letrozole or clomiphene) to regulate the hypothalamic-pituitary axis for treating infertility in women with MS, and there is no direct evidence connecting these medications to the risk of MS relapse. Hence, the decision to use them should be based on the individual infertility concerns of the patient [ 29 ]. Second recommendation: It is advisable to refrain from concurrently using medications that alter SP1, such as fingolimod, siponimod, ozanimod, and ponesimod, along with GnRH agonists [ 29 ]. The third recommendation: ideally, women with MS should receive ART during periods of stabilization or remission, as there is limited data available on pregnancy through ART in this population. It is important to conduct preoperative clinical and radiological monitoring of the disease to effectively plan the timing of ART and reduce the potential risks of postoperative and postpartum relapses [ 29 ]. The fourth recommendation: it is not advisable to discontinue treatment before ART in women with MS, especially if they are on pregnancy-incompatible DMTs or GnRH agonists. Switching to compatible therapies is recommended to ensure continued treatment with Glatiramer acetate and Interferons during pregnancy resulting from ART. The decision to continue Natalizumab during pregnancy should be based on individual risk and benefit assessment, although it can be considered. Anti-CD20 therapies administered shortly before pregnancy have reassuring data, but ideally should not be used during pregnancy [ 29 ]. The fifth recommendation: Standardized protocols for monitoring MS during ART have not yet been established. However, careful clinical and radiological monitoring, especially after hormonal stimulation and in case of pregnancy failure, is reasonably recommended [ 29 ]. The Sixth recommendation: It is advised that women with MS do not stop DMTs before ART, however, if they are on DMTs that are not compatible with pregnancy, they should switch to compatible treatments before undergoing ART. If switching treatments is not feasible, then the suspension of DMT should be carefully considered based on clinical and radiological characteristics, as well as the type of treatment being received. Ideally, the suspension should occur less than 3 months before ART to minimize the risk of relapse. Research has shown that not receiving any treatment before ART or suspending DMTs more than 3 months prior significantly increases the risk of relapse after ART [ 29 ]. The seventh recommendation: it is strongly suggested to provide multidisciplinary counseling prior to ART and to continue with multidisciplinary follow-up during and after ART, including discussions about childbirth and abortion. It is strongly advised to establish a close collaboration between neurologists and reproductive medicine specialists to effectively manage the treatment of women with MS during ART. Furthermore, it has been suggested to closely monitor patients after hormonal stimulation, particularly within the first 3 months, and in cases of repeated ART failure [ 29 ]. Based on the frequency of multiple sclerosis in various populations, there are variations observed. In the majority of research conducted within this area, the sample size typically consisted of fewer than 100 patients. Given the continuous evolution of ART protocols and treatment strategies for women with MS who desire to conceive, it is imperative to conduct multicenter prospective studies. These studies should focus on evaluating the risk of relapse associated with GnRH agonist and antagonist therapy, as well as investigating the impact of adjuvant therapies on ART outcomes and relapse risk. Furthermore, these studies should aim to identify the most effective and safest ART protocol for women with MS. The present study was the first study in Iran that investigated patients with MS referred for infertility treatment and ART cycle therapy. However, it is important to note that this study is retrospective, which suggests the need for future prospective studies in this area. From one perspective, our study holds the potential for innovation as it compared ovarian reserve tests, ovarian stimulation outcomes, and live birth rates with a cohort of age-matched infertile patients. Further research on ovarian reserve and infertility causes in women with multiple sclerosis is imperative, given the significance of this disease in women of childbearing age, more studies, regardless of sample size, can serve as valuable resources for healthcare professionals specializing in the counseling and management of these individuals.