Parasympathomimetic (Cholinergic)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Pyridostigmine is a quaternary ammonium compound with anticholinesterase activity used in the treatment of myasthenia gravis. Most reports have described no fetal harm and the animal data suggest low risk.
FETAL RISK SUMMARY
Pyridostigmine 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 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 (2–16). However, a case report published in 2000 described microcephaly and 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 (1500–3000 mg/day) throughout gestation to control her diplopia and ptosis. In comparison, the average recommended daily dose is 600 mg, with daily doses ≤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-restricted (1880 g, <2nd percentile), hypotonic male infant with Apgar scores of 3 and 8 at 1 and 5 minutes, respectively. Shortly after birth, neonatal myasthenia gravis was diagnosed, two exchange transfusions were used to lower his acetylcholine receptor antibody titer, and IV immunoglobulin was administered. The infant required immediate intubation because of poor respiratory effort and was continued on the respirator until age 3.5 months. Mild finger and wrist contractures and bilateral cryptorchidism were noted at birth, but he had no abnormal ocular findings (17). The head circumference was 33.5 cm at birth and 37 cm (<5th percentile) at 3 months of age. By about 5 months of age, a number of dysmorphic features were noted, including a broad nasal bridge with a prominent nose, slight downslanting palpebral fissures, high arched palate, short neck, broad chest, campylodactyly, and hammer toes (17). He continued to do poorly, requiring additional hospitalizations and mechanical ventilation. At 4.5 months, he was discharged home but readmitted 1 week later because of prolonged apnea and cyanosis. His weight (5.1 kg, 10th percentile) and head circumference (38 cm, <2nd percentile) were still restricted and he remained hypotonic. A cranial ultrasound, karyotyping, and TORCH titers (i.e., toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex) were normal or negative and there was no evidence of craniosynostosis. A brain magnetic resonance imaging scan at 5 months revealed apparent brachycephaly and mild ventriculomegaly. At 9 months of age, he still required nasal oxygen, tone was normal, and the joint contractures had resolved, but his reflexes were brisk and ankle clonus was evident. Because no other cause could be identified, the authors attributed the microcephaly and CNS injury to pyridostigmine (17).
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 anti-acetylcholine 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).
BREASTFEEDING SUMMARY
Pyridostigmine is excreted into breast milk. Levels in two women receiving 120–300 mg/day were 2–25 ng/mL, representing milk:plasma ratios of 0.36–1.13 (15). 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 classifies pyridostigmine as compatible with breastfeeding (20).
References
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17.Niesen CE, Shah NS. Pyridostigmine-induced microcephaly. Neurology 2000;54:1873–4.
18.Product information. Mestinon. ICN Pharmaceuticals, 2000.
19.Gilchrist JM. Muscle disease in the pregnant woman. Adv Neurol 1994;64:193–208.
20.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.