Risk Factor: C
Class: Autonomics/ Parasympathomimetics (cholinergics)
Fetal Risk Summary
Pyridostigmine is a quaternary ammonium compound with anticholinesterase activity used in the treatment of myasthenia gravis. The agent was not teratogenic in rats at doses up to 30 mg/kg/day, but maternal and fetal toxicity (reduced weight) were observed at the highest dose (1).
Although it is ionized at physiologic pH, the low molecular weight of pyridostigmine (about 261) allows the nonionized fraction to cross to the fetus. Pyridostigmine concentrations have been determined at birth in maternal plasma, cord blood, and amniotic fluid (2). Two women with long-term myasthenia gravis were treated throughout gestation with pyridostigmine, 360 mg and 420 mg per day, respectively. The latter woman was also treated with neostigmine (105 mg/day) and ambenonium (60 mg/day). In the first case, the maternal plasma, cord blood, and amniotic drug concentrations were 77, 65, and 290 ng/mL, respectively, and in the second, 53, 39, and 300 ng/mL, respectively. Thus, the cord blood:maternal plasma ratios were 0.84 and 0.74, respectively, whereas the amniotic fluid:maternal plasma ratios were 3.8 and 5.7 respectively (2).
Caution has been advised against the use in pregnancy of IV anticholinesterases because they may cause premature labor (3,4). This effect on the pregnant uterus increases near term.
A number of reports have described the apparent safe use of pyridostigmine during human gestation (2,3,4,5,6,7,8,9,10,11,12,13,14,15 and 16). However, a case report published in 2000 described microcephaly and central nervous system (CNS) injury in a newborn that was attributed to high-dose pyridostigmine (17). The infant’s mother was a 24-year-old primigravida with a 14-year history of myasthenia gravis. She required high-dose pyridostigmine (15003000 mg/day) throughout gestation to control her diplopia and ptosis. In comparison, the average recommended daily dose is 600 mg, with daily doses up to 1500 mg required in severe cases (18). The mother denied smoking and the use of other drugs during pregnancy. At 36 weeks’ gestation, an emergency cesarean section for fetal bradycardia was conducted, delivering a severely growth retarded (1880-g,
Both antenatal and neonatal myasthenia gravis have been reported and either may result in perinatal death. Both forms of the disorder are caused by transplacental passage of antiacetylcholine receptor immunoglobulin G antibodies (11,19). The inhibited fetal skeletal muscle movement and development may result in pulmonary hypoplasia, arthrogryposis multiplex, and polyhydramnios (19).
Transient muscular weakness has been observed in about 20% of newborns of mothers with myasthenia gravis (11,19).
Breast Feeding Summary
Pyridostigmine is excreted into breast milk (15). Levels in two women receiving 120300 mg/day were 225 ng/mL, representing milk:plasma ratios of 0.361.13. Although pyridostigmine is an ionized quaternary ammonium compound, these values indicate that the nonionized fraction crosses easily into breast milk. The drug was not detected in the infants nor were any adverse effects noted. The authors estimated that the two infants were ingesting 0.1% or less of the maternal doses (15). The American Academy of Pediatrics considers pyridostigmine to be compatible with breast feeding (20).
- Levine BS, Parker RM. Reproductive and developmental toxicity studies of pyridostigmine bromide in rats. Toxicology 1991;69:291300.
- Lefvert AK, Osterman PO. Newborn infants to myasthenic mothers: a clinical study and an investigation of acetylcholine receptor antibodies in 17 children. Neurology 1983;33:1338.
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- Blackhall MI, Buckley GA, Roberts DV, Roberts JB, Thomas BH, Wilson A. Drug-induced neonatal myasthenia. J Obstet Gynaecol Br Commonw 1969;76:15762.
- Rolbin SH, Levinson G, Shnider SM, Wright RG. Anesthetic considerations for myasthenia gravis and pregnancy. Anesth Analg (Cleve) 1978;57:4417.
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- Cohen BA, London RS, Goldstein PJ. Myasthenia gravis and preeclampsia. Obstet Gynecol 1976;48(Suppl):35S7S.
- Catanzarite VA, McHargue AM, Sandberg EC, Dyson DC. Respiratory arrest during therapy for premature labor in a patient with myasthenia gravis. Obstet Gynecol 1984;64:81922.
- Hardell LI, Lindstrom B, Lonnerholm G, Osterman PO. Pyridostigmine in human breast milk. Br J Clin Pharmacol 1982;14:5657.
- Carr SR, Gilchrist JM, Abuelo DN, Clark D. Treatment of antenatal myasthenia gravis. Obstet Gynecol 1991;78:4859.
- Niesen CE, Shah NS. Pyridostigmine-induced microcephaly. Neurology 2000;54:18734.
- Product information. Mestinon. ICN Pharmaceuticals, 2000.
- Gilchrist JM. Muscle disease in the pregnant woman. Adv Neurol 1994;64:193208.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.