Myasthenia gravis (MG) is an autoimmune disease caused by a decrease in nicotinic receptors in the neuronal transmission junction by the presence of anticholinergic receptors – IgG1-dominant antibodies to acetylcholine receptors (AChR), which block the transmission of acetylcholine in the junction or antibodies against muscle-specific protein kinase called MuSK. Thus, the impulse electricity is no longer transmitted to the muscles and they are no longer stimulated. Paralysis usually affects the small muscles, but all the body muscles are generally affected. Thymus tumors and thymic hyperplasia can cause the production of these antibodies. MG is a disease that occurs two times more often in women than in males and generally affects women in the second or third decade of life, which corresponds to the period when women want to conceive a child, the clinical onset of the disease being most common after the birth of the first child(1). MG’s possible triggers are extreme stress, infections, pregnancy, inhalation anesthetics, neuromuscular blockers, antibiotics (e.g., macrolides, aminoglycosides), antipsychotics, magnesium, corticosteroids and estrogens(2).
Among patients with MG, about 15% have a thymoma, and 60-80% have thymic hyperplasia that leads to the production of AChR antibodies.
Thymectomy can be performed before the pregnancy, thus improving the symptoms, or after the woman gives birth, preferably immediately after the onset of symptoms(3). Thymectomy increases the remission of the disease or reduces the dose of oral therapy, the benefits usually persisting for many years. Thymectomy during pregnancy and for MUSK-positive patients is contraindicated(4-7).
MG is clinically manifest in ocular or generalized form. The ocular form is found in about 50% of cases as a result of extraocular muscle damage and is manifested by eyelid ptosis and diplopia. However, the generalized form of the disease usually involves the bulbar muscle and is characterized by dysphagia and dysarthria. Uncommon forms of generalized MG involve damage to striated muscles in the upper limbs or respiratory muscles. Although MG is not a genetically transmitted disease, women with congenital MG or childhood symptoms can transmit the disease to the newborn(1,8).
In this review, we want to present the course of the disease in pregnancy, its effect on pregnancy and perinatal outcome, as well as the therapeutic methods, delivery and postpartum care.
2. The influence of pregnancy
on myasthenia gravis
The influence of pregnancy on the evolution of the disease is insignificant in the long-term outcomes. From a clinical point of view, pregnancy can usually be responsible for exacerbating fatigue and, possibly, neurological manifestations, which should lead to a change in the monitoring of the disease and to medication adjustment. These changes are dependent on the severity of the disease before conception, and with properly adjusted therapeutic doses, the disease will be stable(1).
The evolution of MG during pregnancy and from one pregnancy to another is unpredictable, and it is not possible to identify women at risk of aggravation of the disease. Of the patients, 30-41% have exacerbations of the symptoms, 30-45% have a stationary evolution, and about 19-29% may have diminished symptoms or even the remission of the disease(8-10).
Because MG may be exacerbated during the first trimester of pregnancy, the influence of physiological changes (vomiting, intestinal hypomotility, intestinal absorption, increase in blood volume) will lead to a correct adjustment of therapeutic doses. Exacerbation of the symptoms occurs both in the first trimester of pregnancy and in the postpartum period, being determined by hypoventilation secondary to respiratory muscle weakness and ascension of the diaphragm, medication, labor and to birth puerperal infections. Instead, in the second and third trimesters, improved symptoms or even complete remission of the disease have been frequently observed. This can be explained by the physiological immunosuppression encountered in pregnancy, with the decrease of adhesion and polymorphonuclear chemotaxis, which leads to a favorable evolution of autoimmune diseases in the last two trimesters of pregnancy. However, as the uterine volume increases, especially in the third trimester of pregnancy, respiratory dysfunction is observed by decreasing diaphragmatic excursions. In postpartum, the risk of symptoms is increased in the first three months. The risk of maternal complications is increased at the onset of the disease, which can be associated with increased morbidity and mortality, but pregnancy does not change the long-term outcome of MG(9,11-13).
During pregnancy, the risk of urinary tract infections increases, and the treatment with antibiotics such as aminoglycosides, fluoroquinolones and macrolides can aggravate the disease(14).
3. The influence of myasthenia gravis
on pregnancy outcomes
Fertility in women with MG is not affected. There has also been no evidence of an increased risk of miscarriage or pregnancy complications such as fetal restriction or preeclampsia. The risks are the same as in the general population. No increased incidence of birth defects was observed(1,15). In contrast, there is an increased frequency of premature rupture of amniotic membranes, especially in cases with symptomatic MG, possibly secondary to corticosteroid use(11).
In case of pregnancy-induced hypertension or preeclampsia, methyldopa or intravenous hydralazine is indicated, along with avoiding beta-blockers and calcium channel blockers, as they may aggravate the symptoms of MG. Levetiracetam and valproic acid are recommended to prevent seizures in severe preeclampsia, and in refractory cases phenytoin may be given with the risk of potentiating muscle weakness. Benzodiazepines also have a relaxing muscle effect and should be used with caution. Neuroprotection with magnesium sulfate is not recommended in these patients because it inhibits the influx of calcium at the neuromuscular junction and may worsen the symptoms of MG, increasing the risk of intubating the patient(16-19).
In the intrauterine period, the transplacental transfer of AChR antibodies into the fetal circulation leads to the appearance of multiplex congenital arthrogryposis, which is associated with decreased fetal active movements(20).
The birth must occur in a hospital with an intensive neonatal care unit. AChR antibodies or specific muscle kinase passively cross the placental barrier and can cause transient MG syndrome in 10-20% of newborns. This transfer of antibodies is independent of the severity of MG in the mother, and even asymptomatic pregnant women may have children with transient MG. It usually appears in the first 2-4 days of life and manifests with respiratory problems, muscle weakness, difficulty feeding, weight in sucking, weak crying, laziness, eyelid ptosis and ophthalmoparesis. These newborns need to be closely monitored. Symptoms usually go away in about two months, and the newborns do not have persistent muscle weakness or motor disabilities. The diagnosis is confirmed based on the symptoms of the newborn, and the detection of pathogenic antibodies is not necessary. Treatment consists in supportive measures, the administration of cholinesterase inhibitors, plasmapheresis or immunoglobulins being reserved for severe cases(8,15,20-22).
Extremely rare, as a result of the production of maternal antibodies against fetal AChR, cases of arthrogryposis and fetal AChR inactivation syndrome have been reported(23,24).
4. Therapeutic features in myasthenia
gravis during pregnancy
The Food and Drug Administration previous drug classification system was replaced in 2015 by the PLLR system – pregnancy and lactation labeling rule, which provides data on fetal risks of drugs for the fetus during pregnancy, childbirth and breastfeeding.
A multidisciplinary team composed of obstetricians and neurologists performs the optimal management of pregnant women with MG. Drug therapy used in patients with MG includes pyridostigmine, corticosteroids (prednisone) and immunosuppressive drugs(1).
Pyridostigmine is an anticholinesterase agent used in the first line of treatment. It does not cause teratogenicity in animal models, with no adverse effects on the fetus reported(24). As pregnancy alters intestinal absorption and renal clearance, the level of pyridostigmine should be adjusted. The clinical symptoms are improved and the maximum recommended dose is less than 600 mg/day, avoiding the intravenous administration because it can cause uterine contractions(25).
Corticosteroids (prednisone/prednisolone) are also recommended during pregnancy, especially if the patient used them before pregnancy. Studies have shown that they may increase the cleft lip/palate risk by less than 1% when using them in the first trimester. They are administered in the minimum effective dose and are inactivated by the placenta with low plasma concentrations. There is an increased risk of pregnancy complications, such as gestational diabetes, maternal hypertension, preterm delivery and urinary tract infections(8).
As for azathioprine, it is contraindicated during pregnancy because it has a transplacental passage and has a teratogenic potential of 0-11.8%, with the risk of fetal malformations (e.g., cardiac septal defects). It is also associated with low birth weight and premature birth(9,26). However, there are conflicting studies; in Europe, it is considered safe because the fetal liver does not convert the drug into active metabolites, so the risks are low(9,11).
Mycophenolate mofetil easily crosses the placenta and is associated with an increased incidence of miscarriage and birth defects. EMFO tetrad has been reported to include ear malformations (microtia/atresia of the ear canal), mouth (cleft lip/palate), fingers (brachydactyly, hypoplastic toenail) and other organs malformations (major heart, kidney, CNS, eye, diaphragmatic malformations). Thus, it is recommended to discontinue mycophenolate at least six weeks before pregnancy to prevent these effects(9,27,28).
Calcineurin inhibitors – cyclosporine and tacrolimus – can only be used during pregnancy if the maternal benefits outweigh the fetal risks. Cyclosporine is associated with premature birth, low birth weight, gestational diabetes and gestational hypertension. Tacrolimus is also associated with premature birth weight and low birth weight, with rare congenital malformations, such as cleft palate, being reported, especially if associated with corticosteroids(29-31).
Methotrexate is strictly forbidden during pregnancy and lactation. This is because it can be associated with an increased risk of miscarriage and with the occurrence of neural tube defects, heart and facial and limb malformations. It is recommended that the treatment be stopped at least three months before pregnancy(11,32).
Cyclophosphamide is associated with craniofacial and distal limb malformations and should be stopped one year before pregnancy(11,15).
Rituximab is a monoclonal antibody used to treat refractory MG or in MUSK-positive patients. Only fetal hematological abnormalities, such as decreased B cell count, and no congenital fetal malformations have been reported. However, its use in pregnancy is limited, as published studies are a few, therefore it is recommended to administer only if the maternal benefits outweigh the fetal risks(11,15,33). The same is true for eculizumab, which is the newest drug indicated in patients with the nonresponsive refractory disease to other therapeutic lines, with no clear data available for use in pregnant patients(34,35).
During pregnancy, the symptoms of MG can worsen, which leads to the use of rescue treatments without any causation regarding the incidence of these crises. Exacerbations of MG can occur in pregnancy and postpartum in 19-50% of patients(21). Identifying these crises and treating them properly can significantly reduce the impact on the mother and the fetus, respectively. During the crisis, acute respiratory failure increases the risk of complications, even maternal death, in extremely severe forms. It is necessary to stabilize the respiratory and cardiac function, as well as the administration of intravenous immunoglobulins or plasmapheresis. In these situations, renal function, coagulation and hydroelectrolyte balance should be monitored, as there is a risk of renal failure, hypercoagulability, hypocalcemia and fluid overload. In addition, when using plasmapheresis, it is necessary to adjust the plasma volume so that the blood volume does not decrease by more than 10%, and due to the increased risk of hypotension, the blood pressure will be monitored(36-38).
5. Labor, delivery and postpartum care
The uterus is made up of smooth muscle fibers with muscarinic AChR and, thus, is not affected by MG autoantibodies. The delivery route must consider the obstetric indications, MG not being a contraindication for vaginal birth. However, other parameters must be evaluated in addition to the obstetric indication, such as the severity of GM symptoms, the mother’s respiratory function and the degree of muscle and/or bulbar weakness during labor. There is an increased risk of instrumental birth due to maternal exhaustion in the second part of labor. The mode of birth does not influence the evolution of MG in the postpartum period(39,40).
The anesthetic management of adequate pain control in the second stage of labor may be beneficial, without significantly influencing the mode of delivery. Thus, it is recommended to use local, spinal, epidural and nitrous oxide anesthesia to reduce maternal fatigue. General anesthesia should be avoided, as it is reserved for cases of maximum urgency due to possible respiratory depression secondary to the use of neuromuscular blockers(39). Caesarean section performed under general anesthesia is recommended in pregnant women with severe forms of MG (severe bulbar and respiratory weakness). The induction and maintenance of anesthesia should be performed with inhalation agents (sevoflurane, isoflurane) or propofol and fentanyl intravenously. Postpartum analgesia should be based on non-opioid drugs, such as acetaminophen or nonsteroidal anti-inflammatory drugs. Opioid or narcotic painkillers are not recommended as they can cause respiratory depression(11).
Breastfeeding should be encouraged in women with MG, with maternal IgG AChR being only 2% of those in serum. But it does consider the therapeutic regimen and the long-term benefits of breastfeeding. Thus, it is not contraindicated in patients undergoing treatment with corticosteroids, azathioprine, tacrolimus, anticholinesterase inhibitors (e.g., pyridostigmine) or with monoclonal antibodies, because the excretion in breast milk is minimal. In contrast, breastfeeding is not recommended for women treated with mycophenolate, cyclophosphamide, cyclosporine or methotrexate, because they are excreted in milk and have teratogenic potential. Although, in the first three months of the postpartum period, a worsening of MG symptoms was demonstrated, the contribution of breastfeeding was not highlighted, on the contrary, having a potential protective role(1,15,20).
During pregnancy, the symptoms of myasthenia gravis are unpredictable. Several patients may show a worsening of the clinical manifestations, especially in the case the duration of the disease is below two years. MG continues to cause problems for both the mother and the newborn, which requires special attention from a team of specialists. Prenatal thymectomy has an improved prognosis, while neonatal transient myasthenia gravis has a low incidence. Proper counseling and monitoring of these patients will result in a reduced number of complications and in a favorable prognosis for these pregnancies.
Conflict of interests: The authors declare no conflict of interests.