Abstract & Commentary
Commentary by Michael Rubin, MD, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, and Assistant Editor of Neurology Alert.
Synopsis: In 15%, and without correlation to maternal disease severity or antibody level, neonatal MG due to the transplacental transfer of maternal antibodies results in transient weakness of the newborn that resolves within 12 weeks.
Source: Stafford IP, et al. Myasthenia Gravis and Pregnancy. Clin Obstet Gynecol. 2005;48;48-56.
Pregnancy has a variable effect on the course of myasthenia gravis (MG). During pregnancy, approximately 40% of patients experience an exacerbation, occurring equally in each trimester, whereas 30% each undergo no change or enter remission. Alpha-fetoprotein may partly explain the variable clinical course, as it appears to have a protective effect in MG by blocking acetylcholine receptor antibody binding to the nicotinic receptor. Postpartum, 30% will experience an exacerbation, usually in the first 3 weeks, but no long-term effects on MG are appreciated following pregnancy.
Maternal mortality from MG during pregnancy is inversely related to the pre-partum duration of disease, with the greatest risk appearing in the first year following diagnosis. Prospective mothers newly diagnosed with MG are advised to delay pregnancy for 1-2 years to avoid this hazard. Prior course of disease during pregnancy does not predict how a subsequent pregnancy will evolve. Therapeutic abortion is not indicated and may precipitate disease flare, whereas spontaneous abortion is usually followed by remission. No increase in spontaneous abortion in seen in MG.
Emesis gravidarum, weight gain, and changes in blood volume, renal clearance, and gastrointestinal absorption may require dosage modification. Otherwise, management of a pregnant myasthenic requires the same consideration of risk-benefit ratios as for any patient. Steroids, azathioprine, and cyclosporine A, when administered at therapeutic doses, do not increase fetal malformations, although premature labor and spontaneous abortion are more common with the last. At high dosage, azathioprine is teratogenic and may result in low birth weight, bone marrow and immunologic suppression, and chromosomal abnormalities. Breast feeding is contraindicated with all the above medications, including anticholinesterase agents if given in high doses, as all are secreted in breast milk. Plasma exchange and intravenous immunoglobulin may be used during pregnancy, but are best reserved for crisis management or the refractory patient. Thymectomy is best left for the post partum period, as its beneficial effect is in any event usually delayed.
Pre-eclampsia is not more common in MG, but its management is complex, as magnesium interferes with neuromuscular transmission and may exacerbate weakness. Preterm delivery may occur more commonly in MG, but this remains uncertain. Labor and delivery may require forceps or vacuum extraction due to maternal fatigue but are usually routine. Arthrogryposis and polyhydramnios are reported in severe MG. Should C-section be required, regional anesthesia is preferred for the mild to moderate myasthenic, but intubation and airway protection are recommended for patients with bulbar involvement. In 15%, and without correlation to maternal disease severity or antibody level, neonatal MG due to the transplacental transfer of maternal antibodies results in transient weakness of the newborn that resolves within 12 weeks.
Commentary
IgG antibodies of the G1 and G3 subclasses form the majority of acetylcholine receptor antibodies in MG. Other antibodies reported in MG include striational antibodies, of which anti-titin and anti-RyR (ryanodine receptor) are the best defined. These bind in a cross-striational pattern to heart and skeletal muscle, occur in 30% of myasthenics, mainly those with late onset MG and with thymoma, and may presage an unsatisfactory outcome following thymectomy. Titin, the third most abundant sarcomeric protein in cardiac and skeletal muscle, is a giant protein (3000 kDa), of which 90% is composed of a repetitive structure of hundreds of copies of 2 different 100-residue repeats (Arch Neurol. 2005;62;442-446). Mechanical stability and tension of the sarcomere is enhanced by titin. RyR1 (skeletal) and RyR2 (cardiac), both located in the sarcoplasmic reticulum, are calcium release channels. MG RyR antibodies react with both, and both RyR and titin antibodies can activate complement (Acta Neurol Scand. 2005;111;134-141). Other striational antibodies include antibodies to human myosin, alpha actinin, and actin. Antibodies to rapsyn, a post-synaptic protein crucial for acetylcholine receptor anchoring and clustering, are also reported in MG but are non-specific, having also been reported in lupus and procainamide myopathy.
Of the 15% seronegative generalized MG population, 40% to 70% have MuSK (muscle-specific tyrosine kinase) antibody, but its clinical role in MG remains undefined. Anti-myosin and anti-actomyosin antibodies are higher in MG with thymoma than without, but their diagnostic value remains negligible when thoracic magnetic resonance imaging or computerized tomography are available.
In 15%, and without correlation to maternal disease severity or antibody level, neonatal MG due to the transplacental transfer of maternal antibodies results in transient weakness of the newborn that resolves within 12 weeks.
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