Choices and Challenges With Treatment of Myasthenia Gravis in Pregnancy: A Systematic Review

Myasthenia gravis (MG) is an autoimmune disease affecting young women in their second and third decades, coinciding with their reproductive years. We aim to explore the choices and challenges in the treatment of MG in pregnancy. Cochrane, PubMed, Google Scholar, and Embase were the four databases systematically searched for studies with patients reporting pregnancy outcomes for women with MG during pregnancy using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) technique. Quality assessment was done using the Joanna Briggs Institute critical tool (JBI, Adelaide, Australia) for methodological quality. From 2000 to 2023, 40 studies from database search results were considered. There is a substantial risk of complications with MG, especially if it appears during pregnancy. In particular, widespread weakness is a cause of severe, life-threatening disorders, but several treatment options are available.


Introduction And Background
Myasthenia gravis (MG) is one of the most commonly acquired neuromuscular disorders affecting almost one million globally [1,2].MG is a form of autoimmune illness affecting neuromuscular transmission frequently related to autoantibodies acting on the nicotinic acetylcholine receptor (AChR) [3][4][5].As a result of this event, there is a decrease in nerve impulse transmission to striated muscle fibers.Hyperplasia and thymic malignancies have been linked to aberrant autoantibody synthesis and secretion [4].The skeletal muscles, particularly those of the respiratory, ocular, leg, and eye muscles, frequently experience varying weakening in the affected people [1].The prevalence of MG is between one case per 100,000 people and one case per 50,000 people, with two-thirds of those affected being females [6].While MG can strike at any age or stage of life, women are more likely than males to experience it, with cases often peaking in the third decade [7].As a result, the reproductive stage of life is impacted, particularly during pregnancy [8].
The uncertain and unpredictable course of an episodic MG exacerbation necessitates more intensive medical attention [9,10].In order to regulate their symptoms as their muscle weakness or other symptoms develop, those suffering an exacerbation may need to take more medication or other forms of medicine [11].On the other hand, the myasthenic crisis is a potentially lethal illness characterized by the deterioration of the bulbar and respiratory muscles, which impairs breathing and necessitates a ventilator [12].The diagnosis of MG is made through clinical and physical tests, and the diagnosis is confirmed through serum immunoassays that measure autoantibody levels [4].The main goal of the available interventional MG treatments is to manage the disease's symptomatic stage by using anticholinesterase medications coupled with other immunosuppressive medications and steroids frequently used to treat other severe conditions [13,14].The management of myasthenic crises and other refractory cases has also been supported by alternative therapies such as intravenous immunoglobulin (IVIg) and plasmapheresis [15].
Pregnancy-related MG can manifest itself in a number of different ways [10,16].The aggravation of MG is known to occur throughout the first trimester of pregnancy and during the postpartum period, according to Tanacan et al. [17].Although the illness can develop at any point in a person's life, Tanacan et al. noted that this is the case for most MG cases [17].The high MG exacerbation rates have also been reported to be over 30% in pregnant women, whereas other investigations have found lower aggravation rates [18,19].It is crucial to note that MG has a substantial influence on newborns in addition to pregnant mothers [20].Both the mother and the newborn infant may have myasthenia symptoms in the case of maternal MG, such as varying degrees of weakness and skeletal muscle exhaustion [21].
In most cases, placentally transmitted antibodies to the AChR cause MG in the neonate (alias transient neonatal MG-TNMG), which impairs neuromuscular transmission [20,22,23].It affects 10-15% of infants born to mothers with MG [22].Following the dangers MG presents to women during pregnancy and consequential newborn issues, the current study systematically reviews the available literature to explore the effects of MG on women during pregnancy and the risks associated with pregnancy outcomes.

Design and Literature Sources
The current study is a systematic review that adhered strictly to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework's suggested reporting criteria [24].A thorough electronic database search was conducted to locate papers reporting on the impact of MG during pregnancy and the related effects on neonates.Google Scholar, Embase, Cochrane Library, and PubMed are among the databases that were searched for literature.

Search Strategy
The extensive database search was made possible thanks to the usage of the Boolean operators "AND" and "OR" along with keywords.The search was conducted using the terms "myasthenia gravis" OR "MG" OR "myasthenic crisis" AND "pregnancy" OR "pregnant women" OR "pregnancies" OR "obstetric delivery."Only English studies released between 2000 and 2023 were considered in the search.Recent research and quality of treatment after 2000 made it likely that a good quality of evidence was after that period.

Eligibility Criteria
Two independent reviewers were assigned to sort papers suitable to be considered for the current study based on predetermined eligibility criteria.The following inclusion criteria were used to acquire the included articles.Primary studies as well as review articles report the effect of MG in pregnancy and how pregnancy affects MG.Only free full-text papers available and done between 2000 and 2023 on MG in pregnancy were considered in the current study.Articles exploring MG without association with pregnancy, MG in men, other than women during pregnancy were ignored from inclusion.Similarly, papers in different languages done in 2000 were termed obsolete and excluded from the current study.

Data Extraction
Data extraction was then carried out by the two independent researchers using the population, intervention, control, and outcomes (PICO) framework [25] and the studies' established eligibility.The population was pregnant females, the intervention was pharmacotherapies and procedures, the comparison was standard of care, and outcome considerations were acute and chronic outcomes.Author information (name and year), study information (design, location, and period), participant information (sample size and characteristics), intervention information, and outcomes of interest were the information that was extracted.

Quality Appraisal
The quality of the included studies was evaluated using the Joanna Briggs Institute (JBI, Adelaide, Australia) tool for the methodological quality appraisal for retrospective case series [26].The JBI Critical Appraisal Checklist for Case Series is a tool offered by JBI for evaluating case series research's level of quality.This instrument comprises nine criteria to assess the study's quality and applicability.A score is assigned to each criterion, which can be "yes," "no," "unclear," or "not applicable."We can then estimate the overall quality of the study as per the checklist [27].

Results and findings
The thorough literature search across the four electronic databases indicated previously turned up 1735 relevant articles.The two reviewers in charge of completing the literature search found duplicates and eliminated the 466 articles.After carefully reviewing the remaining articles' titles and abstracts and content and conducting the eligibility assessment, only 40 studies met the requirements for the review [17,18,20,.The PRISMA literature search criteria are presented in Figure 1.

Characteristics of Included Studies
The data analyzed in the current study was obtained from 40 papers, as summarized in Tables 1-2.Of the 40 studies, 15 were retrospective case series and case reports, four were retrospective cohort studies, 16 were reviews, and the remaining a meta-analysis, protocol, research, and cross-sectional studies, one each.The studies were conducted across various countries, including Brazil, Turkey, Portugal, China, Spain, Mexico, Japan, Canada, Norway, the Netherlands, and Taiwan, constituting data of pregnant women with MG collected from 1967 to 2022.As reported in Table 1, there was a total of 1322 women with MG, with 1604 pregnancies recorded.The mean maternal age ranged from 25.8 to 48.1 years, while the gestational age ranged from 36.7 to 39.4 weeks (see Table 1).

Bibliographic details Patient characteristics
Author the conditions, while deteriorations were 35.05% with 8.753% improvement (Table 1).While most women delivered normally, through vaginal delivery, a significant number of cases required a caesarian section for delivery.Among the studies reporting complications for pregnant women, there was a 10.99% miscarriage rate, myasthenic crisis (6.67%), 11.4% spontaneous abortions [28], preterm deliveries, and pregnancies with preterm premature rupture of membranes (PPROM) reported.Infant-related outcomes reported include transient neonatal MG (TNMG), which were 17 (17.17%)cases of transient MG among the studies reporting the outcome with mortalities cases, Down syndrome, deformity, icterus, and erythroblastosis being reported among infants (see Table 2 for study characteristics) [29].

Recommended Medications for Women With MG
The majority of women across the studies were administered with treatments mainly comprising of drugs such as prednisone, corticosteroid, pyridostigmine, rituximab, cyclosporine, azathioprine, methotrexate, and IVIg (see Table 2).The percentage of women who underwent a thymectomy before becoming pregnant ranged from 16% to 100% [31].Most pregnant women were treated with anticholinesterase drugs across studies, although a sizable proportion also required prednisone, IVIg, and azathioprine [18,19,28,30].Table 3 below summarizes the common medications for pregnant women with MG [14].

Quality and Risk of Bias Assessment
Based on the JBI critical tool for methodological quality of retrospective case series, 10 were of low risk of bias, while the remaining five were of moderate quality [27].There was no case study of poor quality.The JBI tool for retrospective cohort studies gave four studies of high quality and five of moderate quality (Figures 2-5).Prior studies also showed consistent results, with a sizeable portion of women (29%) experiencing improvement.Contrarily, there was no change, or MG stabilized in 31% of cases, with 40% of pregnant women experiencing deteriorating conditions [65].Ferrero et al. reiterated that symptoms worsened for 41% of pregnant women with MG, compared to 30% who exhibited no change and 29% who went into remission.
Similarly, the percentage of MG exacerbations during pregnancy can range from 0% to 60% in an individual series [31,66].The 30.4% of MG symptoms exacerbation in the present study falls in range with the overall cited risk of between 30% and 45%, consistent with a previous systematic review whose symptoms worsening was recorded at 33.8% [19,34,49].The majority of this worsening, according to two of the included studies, mainly occurred during the postpartum period (43.3% to 46.4%) and in the third trimester (5.4% to 38.9%) in pregnant women [18,40].However, Chaudhry et al. observed that typical immunosuppressive changes in late pregnancy have been linked to symptoms improving in the second and third trimesters.In contrast, symptoms will likely worsen in the first trimester or the days following delivery [10].
Following the course of MG in pregnancy, the likelihood of maternal mortality likely happening in the first year of the diagnosis of MG, and the fact that is less likely to happen seven years later [19], several previous studies have recommended pregnancy delay for at least two years.By doing so, especially in women with unstable MG, the risk of MG exacerbation lessens, thus lowering the associated risks to the fetus [19,33].On the other hand, the present study observed that myasthenic crises were a critical and potentially fatal MG complication occurring at a rate of 6.67% and were reported in one pregnant woman [30].Likewise, Banner et al. found that myasthenic crisis occurred in 6.4% of pregnant women during pregnancy and 8.2% during postpartum [49].Other reported complications include preterm deliveries, spontaneous abortions, and PPROM.Abortions were reported among 11.4% of pregnant women with MG [17,18,32,45,46].In contrast to the 3% risk in the general population, PPROM appears more common in women with MG, which affects 6.7% of all pregnancies [17,28,67].
There were reported instances of the impact of MG on infants born to mothers with MG.Incidences of babies with fetal growth restriction (FGR) and TNMG were common among these mothers [39,42].The odds ratio of low birth weight (LBW) and FGR among the neonates were higher than 1 [42].Similarly, Banner et al. observed that 14.1% of infants born to women with MG have LBW less than the gestational age [49].Our study reports a 17.17% rate of TNMG among infants born to mothers with MG.Our findings align with earlier studies that noted the potential for TNMG to manifest in babies.TNMG can be explained as since immunoglobulin G antibodies are delivered through the placenta in the second and third trimesters, TNMG in newborns born to MG moms happens in 10% to 20% of cases [68].Close monitoring is, therefore, necessary because the baby frequently displays indications of TNMG two to four days after birth, including respiratory problems, muscle weakness, a feeble scream, poor sucking, and ptosis [5,19].Eventually, the condition reverses as the mother's antibodies deteriorate of their volition after two to three weeks [19].
Among deliveries, some studies find that less than 50% were done via vaginal deliveries among pregnant women with MG, while the rest were cesarean sections [29,35,37,[40][41][42]64]. Contrary, another review found that vaginal delivery was the most common mode, with 56.3% of pregnant women giving birth through spontaneous vaginal deliveries [49].Nonetheless, there is some worry that for mothers experiencing symptoms of MG at the time of delivery, the voluntary striated muscles required for vigorous pushing may be reduced by MG exacerbation and further damaged by excessive maternal effort, leading to the myasthenic crisis [68].An aided second stage of labor may reduce the requirement for maternal action and mitigate this risk in women experiencing exacerbation symptoms at birth.Since the uterus is formed of smooth muscle and is unaffected by ACh receptor antibodies, vaginal delivery is advised for MG patients [68].However, due to the involvement of striated muscles during the second stage and the potential impact of the ACh receptor antibody on these muscles, assisted or vacuum extraction may be necessary for VD [68,69].In the event of cesarean section, epidural anesthesia is recommended for use during labor and delivery since opioids and neuromuscular drugs can amplify the effects of ACh receptor antibodies on the neuromuscular junction [68].The mode of delivery is an important consideration.Vaginal delivery is possible if the mother's respiratory muscles are strong enough to tolerate the increased effort of labor.However, in cases of severe myasthenia or respiratory compromise, a cesarean section may be recommended to avoid excessive stress on the respiratory system.The decision is based on the mother's clinical condition, fetal well-being, and obstetric factors [29,35,37,[40][41][42]64].
Pharmacologic therapy concentrates on raising ACh levels and lowering the production of autoantibodies and is the mainstay of MG treatment and management [14].However, the pharmacologic course of treatment during pregnancy may need to be modified depending on the severity or escalation of the condition [69].Acetylcholine esterase inhibitors such as pyridostigmine, IVIg, azathioprine, steroids, and prednisolone are often used in the therapy interventions documented in this study [14].Although there is limited data and information on acetylcholine esterase inhibitors during pregnancy, none indicates an increased risk of deformity or other unfavorable pregnancy outcomes [2,14].Watching for a myasthenic crisis is very important.Pregnancy places additional stress on the body, and myasthenic mothers may experience myasthenic crises during pregnancy or postpartum.As the crisis can cause severe muscle weakness, respiratory failure, and bulbar weakness, prompt recognition and treatment are crucial.Management involves ensuring adequate respiratory support and administering IVIg or plasmapheresis to stabilize the condition [35,37,[40][41][42]64].The role of thymectomy is debatable but it is a definitive treatment for MG.Thymectomy can be performed before or during pregnancy, and the decision should be individualized based on the patient's condition.Studies suggest that thymectomy can lead to disease remission or improvement in a significant number of patients, potentially reducing the need for long-term immunosuppressive medications during pregnancy.However, the timing of thymectomy should be carefully considered to optimize the benefits and minimize risks to both the mother and the fetus [39].
treatment plans must consider the MG severity, the distribution of weakness, any concurrent disorders, and the welfare of the fetus 2023 Kumar et al.Cureus 15(7): e42772.DOI 10.7759/cureus., and anesthesiologists should support MG patients during pregnancy and postpartum.Newborns of MG mothers are at risk of TNM.Pregnancy outcome is favorable in MG women who receive treatment

FIGURE 2 :
FIGURE 2: Traffic light plot for 15 case series studiesStudies[17, 18, 20, 28, 30-33, 36, 39, 43, 57, 59, 63]  .D1: clear criteria for inclusion in the case series, D2: condition measured in a standard reliable way for all participants, D3: valid methods used for identification of the condition of all participants, D4: consecutive inclusion, D5: complete inclusion, D6: clear reporting of demographics of the participants, D7: clear reporting of clinical information, D8: outcomes or follow-up results clearly recorded, D9: clear reporting of presenting site demographic information

FIGURE 3 :FIGURE 4 :
FIGURE 3: Risk of bias summary for case series

FIGURE 5 :
FIGURE 5: Risk of bias summary for cohort studies

TABLE 3 : Summary of recommended medication for MG during pregnancy
IVIg: intravenous immunoglobulin, AEs: adverse effects