The course of myasthenia gravis during pregnancy is hard to predict. Myasthenia gravis is an autoimmune neuromuscular disease characterized by weakness and fatigue of the skeletal muscles of the face and extremities. It affects people of both sexes and all ages, but twice as many female patients are affected as male patients. Myasthenia gravis usually strikes in women in their third decade of life, but the elderly are increasingly affected.  Although the disease course is variable, pregnant patients face risks of exacerbation, respiratory failure, adverse drug response, crisis, and death. 
Because the severity of symptoms, as well as maternal mortality, is highest in the first 2 years following onset of myasthenia gravis, it is advisable for women to delay pregnancy for at least 2 years following diagnosis.  Severity of symptoms and risk of maternal mortality is lowest 7 years after onset of the disease. 
Myasthenia gravis can affect family planning in affected women. Data from a cross-sectional, anonymous survey of 1637 German women diagnosed with myasthenia gravis (801 of the questionnaires were eligible for analysis) revealed that higher age and personal experience of intensive-care treatment for this condition were independently associated with the decision to not have children, and a lower level of knowledge was independently associated with the likelihood of encouraging other women with myasthenia gravis to abstain from having children. 
Genetic studies have revealed a correlation between early-onset myasthenia gravis, which affects women of childbearing age, and the HLA-DR3 and B8 alleles.  Additionally, research suggests that certain non-HLA genes affect susceptibility to autoimmune disorders as a whole, thus increasing the risk of myasthenia gravis. 
The underlying pathology is the autoimmune production of immunoglobulin G (IgG) antibodies directed toward receptors on the postsynaptic membrane at neuromuscular junctions (NMJs).
Acetylcholine receptor (AChR) antibodies are detected in approximately 85% of patients with generalized myasthenia gravis, who are categorized as seropositive. [8, 9] Anti-AChR antibodies reduce the number of available AChR sites with which acetylcholine can interact to induce local depolarization and subsequent muscle fiber contraction. Muscular weakness, the primary symptom in patients with generalized myasthenia gravis, results.
Anti-AChR antibodies are not detected in patients with seronegative myasthenia gravis; however, other components of the postsynaptic membrane at the neuromuscular junctions may be the target of autoimmune attack in this class of patients.  The membrane protein muscle-specific tyrosine kinase (MuSK) has been identified as the target of antibody attack in approximately 40% of patients with seronegative myasthenia gravis. [1, 6] The MuSK protein functions at the cytoskeletal level of the endplate by anchoring clusters of AChRs to the postsynaptic neuromuscular junction membrane; therefore, autoimmune attack by anti-MuSK antibodies is another mechanism through which interaction with acetylcholine on the postsynaptic surface is reduced. 
The autoimmune responses that inhibit acetylcholine interaction on the postsynaptic membrane at neuromuscular junctions (NMJs), resulting in the inability of muscle fibers to contract, are often initiated and maintained by the thymus. Abnormalities of the thymus are observed in nearly 85% of patients with myasthenia gravis; however, thymectomies lead to a reduction of symptoms in nearly 85% of patients with myasthenia gravis without identifiable thymus abnormalities.  Thus, evidence supports a correlation between thymus activity and the incidence of myasthenia gravis.
Impact in Pregnancy
Myasthenia gravis typically affects females during their reproductive years. Difficulties specific to pregnant patients can be concerning, and the course of myasthenia gravis during pregnancy is hard to predict. Patients may have disease exacerbation, crisis, or, interestingly enough, remission. Although the disease course is variable, pregnant patients face risks of exacerbation, respiratory failure, adverse drug response, crisis, and death. 
In a large study, Plauche found that exacerbations occurred in approximately 41% of patients during pregnancy and in 29.8% of patients postpartum. Approximately 4% of patients died because of worsening of the disease or because of treatment complications. 
A study by Batocchi et al reported that the disease worsened in 10 (19%) of 54 patients. Approximately 60% of exacerbations occurred during the first trimester, and approximately 28% of patients deteriorated immediately after delivery. Premature delivery occurred in 4 (7.4%) of 54 patients. Cesarean delivery was performed in 16 pregnancies (30%). The study concluded that no correlation exists between myasthenia gravis severity before and during pregnancy. 
Some rare problems may occur during pregnancy. In 2000, Ellison and colleagues reported a rare case of bone marrow suppression in a patient who experienced leukopenia and thrombocytopenia during all 3 of her pregnancies.  The patient's third pregnancy was the most serious. Her platelet count was 48 X 109/L, and her WBC count dropped to 1.5 X 109/L at 35 weeks' gestation.
The patient improved after receiving 65 mg of human immunoglobulin (1 mg/kg for 2 d). Labor was induced, and she delivered a boy. Interestingly, 1 day after each delivery, her platelet and white blood cell (WBC) counts increased. On the third postnatal day, her platelet count increased to 128 X 109/L from 82 X 109/L after immunoglobulin transfusion, and her WBC count increased to 2.5 X 109/L from 2.2 X 109/L. 
Bone marrow suppression has also been observed in other pregnant patients with myasthenia gravis. In 1992, Igarashi et al reported that suppression could be due to megakaryocyte colony-forming unit suppressive factor produced by autoimmune mechanisms. 
Some exacerbations can be linked to the anxiety and physiologic stress of pregnancy. Hypoventilation is a risk during pregnancy, because respiratory muscles are weakened from myasthenia gravis. Also, the lungs do not become fully inflated, because the diaphragm is elevated during pregnancy. Approximately 20% of patients experience respiratory crises that require mechanical ventilation. This is one of most severe complications.
Infections due to decreased immunity play a very important role in the exacerbation of myasthenia gravis during pregnancy.
Labor may be complicated. Although smooth muscle is not affected by autoantibodies and the uterus is not compromised, the second stage of labor involves striated muscle. The patient may become exhausted during labor and may require assistance. Operative vaginal delivery has been recommended.
In 1979, Duff described an association between myasthenia gravis and preeclampsia.  He observed preeclampsia in 3 patients and reasoned that altered immune status could be an etiologic factor in preeclampsia. Preeclampsia may also be problematic from a pharmacologic standpoint, because magnesium sulfate is contraindicated in myasthenic patients. In the event that eclampsia does present in the pregnant patient with myasthenia gravis, phenytoin is the currently accepted method of treatment. 
Not only is the mother at risk, her baby also faces significant risks, including neonatal myasthenia gravis, prematurity, severe malformation, and death.
Rates of neonatal myasthenia gravis are as high as 10-20%. Affected babies show respiratory distress and inadequate suck. Babies are affected by transient myasthenia, which is self-limited and lasts approximately 3 weeks. This is due to the transplacental transfer of antibodies. This is puzzling because no close correlation exists between maternal disease severity and neonatal myasthenia, and no correlation exists between the occurrence of neonatal myasthenia gravis and maternal anti-AChR antibody titers. These unpredictable results could be due to the protective role of alpha-fetoprotein in neonatal myasthenia gravis. Alpha-fetoprotein has been shown to inhibit the binding of myasthenia gravis antibody to its receptor.
More severe neonatal problems have been reported, including death from malformations attributable to myasthenia gravis. Carr and colleagues reported that the most common fetal abnormalities are pulmonary hypoplasia and arthrogryposis. [19, 20] Prematurity is also a concern. In 1991, Plauche compiled the results from various studies and found that premature delivery occurred in approximately 36.5% of cases. 
Breastfeeding by the mother with myasthenia gravis is safe if she is following a treatment course that utilizes pyridostigmine or corticosteroids; however, mothers with myasthenia gravis being treated with azathioprine, methotrexate, mycophenolate mofetil, or cyclophosphamide, as well as mothers of newborns with myasthenia gravis, should not breastfeed. 
Recent estimations suggest 20 cases of generalized myasthenia gravis per 100,000 persons in the United States.  Estimations of worldwide prevalence of myasthenia gravis vary greatly due to regional discrepancies. Worldwide incidence is recorded as ranging from 20-100 per million, with the higher prevalence observed in those nations with greater access to modernized diagnostic resources and treatments, which correlates with increasing longevity as well.
Race-, sex-, and age-related demographics
A study conducted on 220 patients diagnosed with myasthenia gravis between 2003 and 2008 suggested that there is a similar incidence of anti-AChR antibody in Caucasians in the United States and African Americans but that there is a greater incidence of anti-MuSK antibodies in African Americans. 
Both sexes are affected by myasthenia gravis, and the overall female-to-male ratio is 2:1. The prevalence of early onset (< 40 y) myasthenia gravis is nearly 3 times higher in females than in males, while the prevalence of late-onset myasthenia gravis (>50 y) is more prevalent in males than in females.  During puberty and the fifth decade of life, the rate of incidence appears to be similar in males and females. Persons of any age are affected, but myasthenia gravis usually affects women in their third decade of life.
Patient History and Physical Examination
Patients with myasthenia gravis present with symptoms such as ptosis, diplopia, breathing and swallowing difficulties, and weak limbs. Intermittent ptosis and diplopia are usually the initial reported symptoms, presenting in about 85% of patients with myasthenia gravis.  Symptoms fluctuate in severity; they worsen with exertion and are relieved with rest. Fatigue upon exertion is essential to making the diagnosis.
Symptoms are often exacerbated by periods of emotional stress, infection, pregnancy, thyroid disorders, and other conditions, and usually are most severe within 2 years. Despite these common presenting symptoms, some patients have atypical presentations.
Upon physical examination, muscle strength should be assessed by having the patient squeeze the examiner's hand repeatedly or having the patient flex her arm against resistance. Facial weakness can be evaluated by asking the patient to smile. A snarling expression may be evident when the patient attempts to smile. Although muscles are weak, deep tendon reflexes are preserved. Diplopia and ptosis should also be addressed.
The differential diagnosis of myasthenia gravis includes conditions associated with weakness of muscles, such as the following:
Lambert-Eaton myasthenic syndrome
Intracranial mass lesion
Progressive external ophthalmoplegia
Drug-induced myasthenia gravis
Anti-AChR and anti-MuSK antibody titration is usually performed by radioimmunoassay. This is the most specific test for myasthenia gravis.
Current literature suggests that anti-AChR titers do not correlate reliably with the severity of weakness in patients with myasthenia gravis. Additionally, at early stages of the disease, as well as during periods of immunosuppression, anti-AChR antibodies can remain undetected in the serum of seropositive patients with myasthenia gravis, leading to a false seronegative diagnosis. 
Low-rate repetitive nerve stimulation is used to demonstrate problems with neuromuscular transmission. A decremental pattern (>10% difference in compound muscle action potential amplitude between the first and fourth or fifth stimulus) is the usual finding. Single-fiber electromyography produces the most sensitive data to support the diagnosis. Findings are abnormal in more than 90% of patients. This test shows abnormalities in neuromuscular transmission as increased jitter and blocking.
Intravenous injection of edrophonium (Tensilon) is a routine test when symptoms and signs suggest myasthenia gravis. This cholinesterase inhibitor increases the amount of acetylcholine available, which increases the probability of acetylcholine binding to the receptor. It is the test of choice because it is fast and inexpensive. Initially, the patient is injected with 1-2 mg of edrophonium. If this dose does not yield expected results and no adverse effects are observed, another 4-5 mg is administered. Clinical improvement occurs in 10-60 seconds and lasts for approximately 10 minutes. Muscles that do not require patient cooperation should be tested so that results are more reliable. Edrophonium test results are positive in approximately 90% of myasthenic patients.
Myasthenia gravis is associated with many other autoimmune disorders. Patients must be checked for the following conditions:
Systemic lupus erythematosus
Autoimmune hemolytic anemia
Thymic abnormalities are also associated with myasthenia gravis. As many as 50-60% of patients have lymphofollicular hyperplasia, and 10-20% have a thymoma.
Additional Diagnostic Considerations
Obtain computed tomography (CT) scans to study the thymus, or obtain magnetic resonance imaging (MRI) scans to evaluate the mediastinum. The pregnant patient with myasthenia gravis should undergo routine ultrasonography to assess the amniotic fluid index; screen for signs of neonatal myasthenia gravis.  Diagnosis is based on clinical history and signs, improvement with anticholinesterase injection, serum anti-AChR antibody titers, serum anti-MuSK antibody titers, and electromyographic signs of impaired neuromuscular transmission. The combination of test results helps the physician to confirm the diagnosis.
Plasmapheresis and Intravenous Immunoglobulin Therapy
Plasmapheresis is an expensive procedure used in patients in myasthenic crisis. Together with steroids, plasmapheresis is a very effective treatment. It consists of 3-6 exchanges of 2-3 L over 1-2 weeks. It is safe during pregnancy and has even saved patients during fulminant crises. As the etiology of preterm delivery is unknown, plasmapheresis is (or may be) associated with preterm delivery. Other complications can occur from hypovolemic reactions or allergies. Large hormone shifts may cause preterm delivery. Patients undergoing plasmapheresis should be monitored.
Intravenous immunoglobulin is also useful in patients in myasthenic crisis. It is thought to interfere with anti-AChR antibodies. It is infused at 0.4 g/kg/d for 5 consecutive days. Improvement is noticeable in 3-21 days and lasts as long as 3 months.
Thymectomy is recommended for most young patients. It improves the disease course and can improve remission. Thymectomy is thought to remove an antigen source and reduce an anti-AChR antibody source. A thymoma, which is a potentially invasive tumor that must be removed, is found in few cases. In 1999, Batocchi et al reported that 4 of 44 patients had thymomas. 
To avoid any postoperative problems, thymectomy is performed when the disease is in control. Plasmapheresis can be used for disease control. In 1986, Ip et al used thymectomy as a treatment for myasthenic crisis during pregnancy.  The patient improved, and although she had to receive large doses of pyridostigmine, she delivered her baby at 39 weeks' gestation.
Findings from a study by Mitchell and Bebbington, however, contradict those of studies that have concluded that thymectomy leads to fewer exacerbations. The investigators reviewed the course of patients with myasthenia gravis during pregnancy at the Vancouver Salvation Army Grace Hospital. Four of 9 patients experienced antepartum exacerbations ranging from muscle weakness to respiratory failure. Three of the 4 patients had undergone previous thymectomy, including the patient with the worst symptoms (respiratory failure). 
Hoff et al reviewed the pregnancy, delivery, and newborn records of 135 births to mothers with myasthenia gravis that occurred between 1967 and 2004 in Norway, and statistical analysis of the obstetrical records showed no significant differences in the progression of myasthenia gravis during pregnancy between the thymectomized and nonthymectomized mothers. Forty-one mothers were thymectomized, accounting for 72 thymectomized births. Of the 41 thymectomized mothers, 25 had undergone thymectomy prior to their first delivery, while 2 women had undergone thymectomy during their pregnancy.
Interestingly, the medical records of the neonates born in the 135 births evaluated in this study indicated an increased prevalence of neonatal myasthenia gravis in neonates born to nonthymectomized mothers compared with those born to thymectomized mothers. 
Other Treatment Considerations
Monitoring patients for infection is important, especially those on steroids. Serial ultrasonography, nonstress tests, and biophysical profiles should be used for pregnancies at risk as per the usual obstetrical management protocol.
Many patients develop depression or comorbid depressive episodes. Bupropion (Wellbutrin XL) has been studied extensively and may be a good addition for these patients.
Brenner et al elucidated the impact of alpha-fetoprotein in the remission of myasthenia gravis during pregnancy as well as the remission of other autoimmune disease during gestation. The study demonstrated a potential positive impact of alpha-fetoprotein on inducing significant clinical remission during pregnancy. 
Diet and activity
Pregnant patients with myasthenia gravis should maintain a well-balanced, potassium rich, diet.  Rest is very important to restore muscle strength, especially during pregnancy. Pregnant patients with myasthenia gravis should be cautious not to compromise sleep.
Follow-up consists of evaluating patients for adverse effects of pharmaceuticals and preventing infection. Observing the patient for signs of respiratory deterioration is necessary. The postanesthetic period is very important, because postpartum exacerbation is common. Arterial blood gases should be checked often; thus, a surgical intensive care unit (ICU) is the best place for postoperative patients with myasthenia gravis.
Rest periods should be emphasized in the months after delivery. Caring for a newborn is difficult, and maternal exhaustion may occur. The disease course is variable and unpredictable during pregnancy and after delivery. One pregnancy without exacerbations does not necessarily mean that future pregnancies carry no risk.
Pharmacologic and Therapeutic Precautions
Because many medications can adversely affect patients with myasthenia gravis, the following drugs should be avoided:
Inhalation anesthetics (ie, halothane, trichloroethylene, ether)
Magnesium and lithium salts
Therapy should be individualized, and each patient must be monitored closely by a neurologist and an obstetrician/gynecologist during pregnancy. Although medical therapy is effective, the patient's condition may worsen. Crisis can occur as a result of a worsening disease processes, reduced effects of anticholinesterase drugs, or overdose of anticholinesterase medication. Management of myasthenic crisis requires careful monitoring. Arterial blood gas values must be monitored in patients with increasing weakness.
Precautions in Cesarean Delivery
Surgery is very stressful; therefore, cesarean delivery is reserved only for necessary cases. Also, the hazards of anesthesia must be kept in mind, because patients are sensitive to sedatives and narcotics. Not depressing respiration is important.
In 1978, Rolbin and colleagues reported on their evaluation of the safety of anesthesia for patients with myasthenia gravis.  They concluded that regional anesthesia is good for abdominal delivery. They stated that epidural anesthesia could be used to decrease the requirements of systemic medications and provide anesthesia for outlet forceps. Amide-type local anesthetics are thought to be safe when large doses of drugs are needed. The group recommended general endotracheal anesthesia for cesarean delivery in patients with respiratory problems. Depolarizing anesthetics must always be avoided. 
Planning for pregnancy should be instituted well in advance to allow time for optimization of myasthenic clinical status and to minimize risks to the fetus.
Multidisciplinary communication among relevant specialists should occur throughout pregnancy, during delivery, and in the postpartum period.
Provided that their myasthenia is under good control before pregnancy, the majority of women can be reassured that they will remain stable throughout pregnancy. If worsening occurs, it may be more likely during the first few months after delivery.
Oral pyridostigmine is the first-line treatment during pregnancy. IV cholinesterase inhibitors may produce uterine contractions and should not be used during pregnancy.
Thymectomy should be postponed until after pregnancy as benefit is unlikely to occur during pregnancy.
Chest CT without contrast can be performed safely during pregnancy, although the risks of radiation to the fetus need to be carefully considered. Unless there is a compelling indication, postponement of diagnostic CT until after delivery is preferable.
Prednisone is the IS agent of choice during pregnancy.
Current information indicates that azathioprine and cyclosporine are relatively safe in expectant mothers who are not satisfactorily controlled with or cannot tolerate corticosteroids. Current evidence indicates that mycophenolate mofetil and methotrexate increase the risk of teratogenicity and are contraindicated during pregnancy. Although this statement achieved consensus, there was a strong minority opinion against the use of azathioprine in pregnancy. Azathioprine is the nonsteroidal IS of choice for MG in pregnancy in Europe but is considered high risk in the United States. This difference is based on a small number of animal studies and case reports.
PLEX or IVIg are useful when a prompt, although temporary, response is required during pregnancy. Careful consideration of both maternal and fetal issues, weighing the risks of these treatments against the requirement for use during pregnancy and their potential benefits, is required.
Spontaneous vaginal delivery should be the objective and is actively encouraged.
Magnesium sulfate is not recommended for management of eclampsia in MG because of its neuromuscular blocking effects; barbiturates or phenytoin usually provide adequate treatment.
All babies born to myasthenic mothers should be examined for evidence of transient myasthenic weakness, even if the mother’s myasthenia is well-controlled, and should have rapid access to neonatal critical care support.
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- Impact in Pregnancy
- Neonatal Impact
- Patient History and Physical Examination
- Differential Diagnosis
- Diagnostic Testing
- Associated Disorders
- Additional Diagnostic Considerations
- Plasmapheresis and Intravenous Immunoglobulin Therapy
- Other Treatment Considerations
- Pharmacologic and Therapeutic Precautions
- Precautions in Cesarean Delivery
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