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 [17,18,19]. 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 [23,24,25,26]. 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.
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.
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