Myasthenia gravis and pregnancy

Abstract

Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular junction that has higher incidence in younger women than men, which could be related to differences in sex hormones physiology and immune system functioning between males and females. MG can first present during pregnancy and variably affect pregnancy, labor, and postpartum period. In this paper, we had an updated overview on our understanding about MG presentation and its effect on pregnancy and vice versa, therapeutic options for MG pregnant women, management of pregnancy or labor complications in MG patients, and finally fetal and neonatal considerations in MG pregnant women. A multidisciplinary approach, involving obstetricians/gynecologists, neurologists, and anes-thesiologists, plays a pivotal role in improving the clinical outcomes in both MG mothers and their infants during pregnancy, delivery and postpartum.

Key Words: Pregnancy, Myasthenia gravis, Delivery, Postpartum, Transient neonatal myasthenia gravis, Pyridostigmine

Core Tip: Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction that overall has higher incidence in women than men. This disease can variably affect pregnancy; and specific considerations need to be taken by a multidisciplinary team (including obstetricians/gynecologists, neurologists, and anesthesiologists) in pregnant women during their pregnancy, delivery, and post-partum period. We herein discuss about our understanding about MG presentation and its effect on pregnancy and vice versa, safe therapeutic approaches for MG as well as pregnancy/Labor complications, and finally specific fetal and neonatal considerations in MG pregnant women.

INTRODUCTION

Myasthenia gravis (MG) is one of the most common autoimmune neuromuscular junction disorders with a prevalence of about 200 per one million worldwide[1]. The characteristic clinical feature of MG is a fluctuating and fatigable skeletal muscle weakness. The most common initial presentation is ocular weakness with asymmetric ptosis and binocular diplopia, and less commonly early or isolated oropharyngeal or limb weakness[2]. The underlying pathophysiology is mostly related to production of autoantibodies against the acetylcholine receptors (AChRs) or other related protein complexes on the postsynaptic muscle membrane such as muscle specific tyrosine kinase (MuSK) and low-density lipoprotein receptor-related protein 4[1]. Additionally, pathologic thymic involvement including thymoma is present in 10%-20% of MG cases, particularly those with anti-AChR autoantibodies[2]. Women younger than 40 years old are more frequently affected than men with the same age range, with a female/male ratio of 3:1 for AChR MG and 9:1 for MuSK MG[3]. MG status during pregnancy is overall considered as unpredictable. Little is known about the underlying pathophysiology and etiology of unpredictable complications during pregnancy and the post-partum period, though some evidence suggests a role for sex hormones[4,5]. In this review, we discuss clinical presentation of MG during pregnancy, its effect on pregnant women and their children, pre-pregnancy planning in MG women, therapeutic options during pregnancy and breastfeeding, as well as considerations that need to be taken when managing pregnancy or delivery complications in MG patients.

HORMONAL EFFECTS ON MG

Sex hormones, especially estrogen but also progesterone as well as testosterone, are known to affect immune system[6]. MG which is one of the autoimmune diseases commonly affects women than men, especially childbearing age, indicating a role for sex hormones on MG.

Several previous studies have demonstrated that sex hormones have effects on modulating disease severity of MG[4,7], particularly during the menstrual period and pregnancy. MG symptoms are frequently exacerbated before and during the menstrual period[8] but opposite cases were also reported[9]. In addition, exacerbation of MG symptoms can occur during pregnancy[10,11]. Even though available studies indicate that sex hormones can influence immune system and modulate disease severity of MG, further studies are needed to confirm the underlying mechanisms.

MG AND PREGNANCY

MG symptoms can be first developed during the pregnancy or postpartum period[12,13]. In rare cases, myasthenic crisis can be the first symptoms to seek medical attention during pregnancy[14].

Appropriate diagnosis and treatment are important to avoid further exacerbation especially during pregnancy. Anti-AChR, -MuSK or - low-density lipoprotein receptor-related protein 4 antibodies can be tested to confirm the diagnosis of MG during pregnancy. If the results of these tests are negative, electrodiagnostic studies including repetitive nerve stimulation or single-fiber electromyography can be used as safe diagnostic tools during pregnancy. Chest computerized tomography (CT) to look for thymoma can be delayed until after the delivery to avoid unnecessary radiation exposure since there will be no expected benefit from thymectomy during pregnancy[15] and the incidence of thymoma in young MG patients under age 30 s is low[16,17]. If thymoma is strongly suspected, mediastinal magnetic resonance imaging will be preferred than chest CT.

MG by itself does not have much influence on pregnancy including duration of pregnancy, risk of miscarriage or birth weight[18,19]. The course of MG disease during pregnancy is overall unpredictable. Exacerbation of MG symptoms can occur in about one third of pregnant women, especially in the first trimester and also postpartum period but the long-term course of MG is not worsened by pregnancy[10,11]. In addition, disease course of MG during pregnancy cannot be predicted by disease severity at the time of pregnancy and also previous course of pregnancy on MG[10]. For these reasons, pregnant women with MG should be seen by their obstetricians and neurologists relatively frequently throughout their pregnancy. They also need to be instructed to monitor fetal body movements carefully and get immediate medical advice if they feel reduced fetal movements. Pregnancy can change total blood volume, gastrointestinal absorption as well as renal clearance. Therefore, further medication dose adjustment may be needed during pregnancy. An overview of previous studies of MG in pregnancy are summarized in Table 1.

Table 1 Summary of previous studies of myasthenia gravis in pregnancy.

Ref.	Number of pregnancies/patients	Treatment	MG during pregnancy	Mode of birth	TNMG	MG after birth	Other findings
Plauché[60], 1991	322/255	NA	41.0% exacerbation, 31.7% no change, 28.6 % remission	5.6% C-sec before 1963; 15.4% forceps, 13.5% C-sec after 1963	14.9%	29.8% exacerbation, 4 % death	Large literature review
Batocchi et al[10], 1999	64/47	42 underwent thymectomy before conception 36% on no treatment, 47% on pyridostigmine alone, 17 % on multi-treatments (pyridostigmine, steroids, azathioprine, IVIG or plasmapheresis)	17% relapsed (no treatment); 19% relapsed, 42% unchanged, 39% improved (on treatment)	30% C-sec (most for obstetric reasons)	9%	28% worse	No correlation between TNMG and maternal disease severity
Djelmis et al[11], 2002	69/65	23.2% on no treatment, 43.5% on pyridostigmine alone, 33.3 % on pyridostigmine and steroids 9 received plasmapheresis	14.5% exacerbation, 22.3% unchanged, 24.6% improved	8.7% vacuum extraction, 17.4 % C-sec	30.0%	15.9% exacerbation	Inverse association between incidence of TNMG and maternal disease duration
Hoff et al[42], 2003	127/79	45 underwent thymectomy (16 before the first conception), No record before 1999; 54.5% on pyridostigmine alone since 1999	NA	17.3% C-sec, 8.7% forceps/vacuum extraction	3.9%	NA	Three times higher risk of preterm rupture of amniotic membranes in MG
Hoff et al[62], 2004	49/37	6 underwent thymectomy before conception	29.7% remission	14.6% C-sec, 8.2% forceps/vacuum	NA	NA	6.1% neonatal mortality. No correlation between TNMG and maternal disease severity
Hoff et al[12], 2007	135/73	50% on treatment at the time of conception (99% on pyridostigmine, 1% on steroids), then 45% continued throughout pregnancy, 3 received plasmapheresis	10% relapsed	19% protracted labor	19%	NA	A half risk of TNMG if mother had thymectomy
Wen et al[43], 2009	163/163	NA	NA	44.8% C-sec	NA	NA	No significant difference in the risk of preterm, low birth weight, small for gestational age and C-sec between women with and without MG
Almeida et al[14], 2010	17/17 (2 abortion)	23.5% on no treatment, 5.9% on pyridostigmine alone, 5.9% on steroids alone, 5.9% on IVIG alone, 47% on multi-treatments (pyridostigmine, steroids or IVIG)	23.5 % relapsed, 47.1% unchanged	47% C-sec (most for obstetric reasons)	NA	17.6% MG crisis	C-sec only carried out if there are obstetric reasons on women with controlled MG
Ducci et al[44], 2017	35/21 (4 abortion)	5 underwent thymectomy before conception, 8.6% on no treatment, 91.4% on treatment (22.9% on pyridostigmine alone, 68.6% on multi-treatments) at the time of first trimester, then most of them continued throughout pregnancy	50% relapsed, 20% unchanged, 30% improved	66.7% C-sec, 6.7% forceps/vacuum	12.9 %	NA	Severity and duration of MG, repetitive nerve stimulation and treatment influence MG and pregnancy
Gamez et al[63], 2017	5/5	100% on monthly IVIG (switched to IVIG prior to pregnancy)	100% unchanged	60% C-sec	0 %	100% unchanged	IVIG monotherapy during pregnancy in MG women could be a good option but bigger study is required
Santos et al[64], 2018	27/13 (All MuSK MG, 4/4 for pregnancy after MG onset)	77.8% on no treatment (74.1% who was pregnant before MG onset), 7.4% on pyridostigmine and steroids, 7.4% on multi-treatments including pyridostigmine and steroids with azathioprine or IVIG	3.7 % relapsed	22.2% C-sec	3.7%	0% relapse	Pregnancy does not precipitate MuSK MG

MG: Myasthenia gravis; IVIG: Intravenous immunoglobulins; MuSK: Muscle specific tyrosine kinase; TNMG: Transient neonatal myasthenia gravis.

PRE-PREGNANCY COUNSELLING IN MG WOMEN

Women with MG who are in childbearing age should be encouraged to discuss their plan for pregnancy with their neurologists in advance. Optimizing the treatment before and during pregnancy is the key for the safe pregnancy and a multidisciplinary team approach consisting of the patient, her partner and family, a neurologist as well as an obstetrician is required in this condition[15,20]. If the patient is recently diagnosed with MG, delaying her pregnancy at least one to two years may be recommended to estimate her disease severity and optimize the individual therapy.

The treatment of MG includes medications for symptomatic relief such as cholinesterase inhibitors and immunosuppressants such as steroids, azathioprine, cyclosporine, mycophenolate, cyclophosphamide, methotrexate as well as intravenous immunoglobulins (IVIG) and plasmapheresis. Some of the medications can be continued safely during pregnancy and breastfeeding. Among those, oral pyridostigmine is considered as the first-line treatment[12,19]; however, intravenous cholinesterase inhibitors should not be used during pregnancy since they can induce uterine contractions[15]. Patients with insufficient control of MG symptoms with pyridostigmine require immunosuppressants. Among immunomodulatory medications, steroids are the treatment of choice in pregnancy as their adverse effects to myasthenic mother or fetus are minimal except for slightly increased risk of cleft palate, infection, weight gain, gestational diabetes and preterm delivery[21-23]. Immunosuppressants other than steroids are mostly avoided during pregnancy, but azathioprine and cyclosporine can be used as steroid-sparing agents if required. Even though a number of studies have reported increased risk of intrauterine growth retardation, prematurity and low birth weight, there is no association between fetal malformations and azathioprine or cyclosporine exposure during pregnancy[24,25]. Mycophenolate, cyclophosphamide and methotrexate are considered as teratogens and they are contraindicated during pregnancy[26-28]. There is limited data on rituximab and eculizumab use in pregnancy. Rituximab can decrease B-cell and CD19⁺-cell counts in newborns transiently[29] and increase the risk of prematurity as well as low birth weight[30], but the recent report has shown healthy baby deliveries from myasthenic mothers who were on rituximab[31]. Eculizumab was approved by food and drug administration for treatment of MG recently, thus its effect on pregnant women with MG is still elusive. Notably, there are several previous studies which have shown safe use of eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome[32-34]. Table 2 summaries current treatment options in MG during pregnancy.

Table 2 Treatment options in myasthenia gravis during pregnancy.

Medication	FDA category	Effects on pregnancy	Breastfeeding
Treatment of choice
Pyridostigmine	B	None reported	No limitation (Excreted in breast milk)
Steroid	C	Cleft lip or palate (rare), low birth weight	No limitation (Excreted in breast milk)
Treatment of choice for steroid-sparing agents if indicated
Azathioprine	D	Intrauterine growth retardation, prematurity, low birth weight, hematological toxicities (lymphopenia, pancytopenia) in newborn	Limited but can be considered (Excreted in breast milk)
Cyclosporine	C	Intrauterine growth retardation, prematurity, low birth weight	Limited but can be considered (Excreted in breast milk)
Contraindicated
Mycophenolate	D	Congenital anomalies	Contraindicated
Cyclophosphamide	D	Congenital anomalies	Contraindicated
Methotrexate	X	Fetal death, congenital anomalies	Contraindicated
Insufficient data
Rituximab	C	Transient B- and CD19+-cell depletion in newborns, prematurity, low birth weight	Limited data (minimally detected in breast milk)
Eculizumab	C	Limited data (prematurity)	Limited data (not detected in breast milk)
Treatment of choice for exacerbation of MG or myasthenic crisis
IVIG	C	None reported	No limitation
Plasmapheresis	N/A	Small for gestational age	No limitation

FDA: Food and Drug Administration; MG: Myasthenia gravis; IVIG: Intravenous immunoglobulins.

Thymectomy can improve clinical outcomes and reduce use of immuno-suppressants in MG patients[15]. While it is recommended for patients especially who have thymic hyperplasia or thymoma, it should be delayed until after delivery if patients are pregnant since expected benefits from thymectomy during pregnancy is very low[15,35].

MANAGEMENT OF COMPLICATIONS DURING PREGNANCY IN MG PATIENTS

It is important to monitor and treat exacerbation of MG or myasthenic crisis during pregnancy. Hypoventilation related to elevation of diaphragm, infections, fatigue and stress are major causes of exacerbation of MG during pregnancy. IVIG or plasmapheresis along with supportive care may be used safely in pregnancy and they are generally well-tolerated[36,37].

Preeclampsia, eclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelet counts) are potentially life-threatening complications of pregnancy which require prompt therapy urgently. MG does not have any effect on these pregnancy complications; however, there are some important considerations in management of these complications in MG women. Certain medications (β-blockers and calcium channel blockers) should be avoided for blood pressure control since they have the potential to exacerbate MG symptoms or crisis. Methyldopa or hydralazine are considered as drugs of choice[38]. For seizure prophylaxis, magnesium sulfate should be avoided since it can block acetylcholine release and interfere neuromuscular transmission[15,39]. Barbiturates or phenytoin can be considered as alternative therapy instead of magnesium[15]. If β-blockers, calcium channel blockers or magnesium sulfate are needed, close monitoring is essential for the patient care. For HELLP syndrome, heparin, aspirin, plasmapheresis or IVIG can be used in addition to proper blood pressure management and seizure prophylaxis[40,41].

CONSIDERATIONS DURING LABOR AND BIRTH

Maternal MG has an increased risk for birth complications, most commonly preterm rupture of membranes, even though MG by itself does not increase the risk for pregnancy complications including spontaneous abortion or premature birth[42-44]. Vaginal delivery should be always encouraged in women with MG and cesarean delivery should only be performed for standard obstetric indications[15]. MG does not affect the first stage of labor since the uterus which is composed of smooth muscle is not affected by the disease due to lack of the postsynaptic AChRs. However, the second stage of labor may get affected since the striated muscle is involved during expulsive efforts and it can result in maternal fatigue. Forceps or vacuum extraction may be required to ease this stage of labor[11,39] and an increased cesarean delivery rate was also reported due to maternal fatigue during the labor[42]. Parenteral cholinesterase inhibitors can be used to strengthen muscles during labor and stress dose of intravenous hydrocortisone (100 mg) is recommended to patients who are on chronic oral steroids (at dose larger than the equivalent of 7.5 mg/d prednisone) during the intrapartum period[20,43,44].

Epidural analgesia is the most preferable method during labor and regional anesthesia is recommended for cesarean delivery[14,45]. General anesthesia and neuromuscular blocking agents should be avoided if possible. Sedatives and opioids should be avoided as well since they can possibly induce respiratory depression. If they are unavoidable, patients should be monitored carefully with a peripheral nerve stimulator[20].

FETAL AND NEONATAL CONSIDERATIONS

Maternal AChR antibodies can be transferred to the fetus, which can cause transient neonatal myasthenia gravis (TNMG) in about 20% of infants who are born to myasthenic mothers[46]. Symptoms are noticeable with general muscle weakness, poor sucking, weak cry, swallowing difficulty, lethargy and breathing difficulty. In most cases, these symptoms present within few hours to three days after birth. Therefore, all infants from myasthenic mothers should be monitored closely, especially in the first few days[47]. Most infants with TNMG have myasthenic mothers with active disease; however, some mothers may be in remission or may not have any evidence of MG. In addition, there is no clear correlation between maternal disease severity as well as maternal antibody titers and existence of TNMG[48,49].

TNMG should be suspected in the symptomatic infants born to mothers with history of MG. Diagnosis can be made with elevated levels of anti-AChR or anti-MuSK antibodies, decremental response in repetitive nerve stimulation or clinical improvement after administration of cholinesterase inhibitors in symptomatic infants. Neostigmine is the most commonly used cholinesterase inhibitors as a diagnostic bedside test[49]. Treatment usually depends on severity of TNMG. For mild symptoms, supportive care with small amount of feeding or nasogastric feeding, ventilatory support and/or cholinesterase inhibitors are sufficient. For more severe cases, IVIG or plasmapheresis needs to be considered[20,49]. Overall, TNMG has good prognosis if it is early identified and properly treated. Symptoms usually resolve in the first two months but can last as long as 4 mo[50].

There is rare but more severe manifestation reported in infants born to myasthenic mothers including arthrogryposis multiplex congenita[51]. Arthrogryposis multiplex congenita can be a potentially fatal condition resulting from decreased limb movements, for which pregnant women with MG should be advised and encouraged to monitor their fetal movements and get fetal scan at 13 and 20 wk of pregnancy[20,51].

BREASTFEEDING

Breastfeeding after delivery is not a contraindication in women with MG, if their disease is well-controlled[20]. On the other hand, breastfeeding should not be considered if their disease is poorly-controlled since increased fatigue associated with nursing may increase the likelihood of disease exacerbation. Breastfeeding does not increase the risk of myasthenic symptoms in newborns, even though maternal IgG are known to present in breast milk[52].

In terms of therapy, there are few relatively safe therapies during breastfeeding including cholinesterase inhibitors, steroids and IVIGs[15,20,52]. Although cholinesterase inhibitors are detected in the breast milk, they are considered safe since their levels are relatively low in the breast milk unless patients require high doses[53]. Azathioprine and cyclosporine are acceptable during breastfeeding[54,55], whereas mycophenolate, cyclophosphamide or methotrexate should be avoided since they are excreted in breast milk and affect the newborns[56,57]. There are very few studies available for the effects of monoclonal antibodies including rituximab and eculizumab on breastfeeding, which have shown very minimal effects without any significant harm[58,59].

CONCLUSION

MG may first manifest during pregnancy and can variably affect pregnancy and labor period in an unpredictable manner. Overall, worsening of MG symptoms (i.e., MG crisis) occurs more commonly in the first trimester or in the first month postpartum. Even, effects of pregnancy on MG may vary in subsequent pregnancies in a patient with MG[60-64]. Therefore, close monitoring of MG women during their childbearing age is crucial. On the other hand, given the unpredictability of MG course during pregnancy, we would recommend that the MG patients to be frequently evaluated during and before pregnancy because this can help physicians to timely and appropriately modify the MG therapy based on alterations in the disease severity. It is also noteworthy that the treatment options for MG are limited in pregnant or breastfeeding women compared to other MG patient population. Based on our clinical experience and previous studies, a considerable number of MG patients can safely benefit from oral pyridostigmine alone or in combination with steroid therapy (e.g., oral prednisone) during pregnancy. However, if more aggressive immunosuppressive therapy is needed (e.g., due to intolerance or insufficient response to pyridostigmine or steroid therapy), azathioprine and cyclosporine can be considered as steroid-sparing medications. Knowing the side effect profile of immunosuppressive medications in pregnant women and their fetus is essential, as some of these medications such as mycophenolate, cyclophosphamide and methotrexate are contraindicated in these patients due to teratogenicity. Overall, we preferably discontinue immuno-suppressants 4 to 6 mo before conceiving. Additionally, IVIG, plasmapheresis, and corticosteroids are usually preserved for myasthenic crisis when more immediate therapy is needed to stabilize patients’ symptoms during pregnancy or postpartum. An individualized and multidisciplinary approach involving neurologists, obstetricians, and anesthesiologists is an important consideration when monitoring these patients during pregnancy, delivery and postpartum, as this can improve the clinical outcomes in both MG mothers and their infants.