NEOSTIGMINE

Fetal Risk Summary

Neostigmine is a quaternary ammonium compound with anticholinesterase activity used in the diagnosis and treatment of myasthenia gravis and to reverse muscle relaxation from competitive (nondepolarizing) muscle relaxants.

Although neostigmine is ionized at physiologic pH, the low molecular weight (about 223) is low enough that transfer of the nonionized fraction to the fetus should be expected. Circumstantial evidence for neostigmine placental transfer was presented in a 1996 case report (1). A woman at 31 weeks' gestation, undergoing surgery for a fractured elbow, was given IV neostigmine (5 mg) and glycopyrrolate (1 mg) to reverse muscle paralysis at the end of the procedure. The fetal heart rate immediately decreased from 115–130 beats/minute to 90–110 beats/minute and then gradually returned to 130 beats/minute within 1 hour. Four days later, surgical repair of the elbow was again required. At the end of this surgery, neostigmine (5 mg) and atropine (0.4 mg) were given IV and no change in the fetal heart rate was observed. The authors attributed the different effects on the fetal heart rate to the greater placental transfer of atropine in comparison to glycopyrrolate (see also Glycopyrrolate), that resulted in blocking the transplacental muscarinic effects of neostigmine (1).

The safe use of neostigmine in the treatment of maternal myasthenia gravis or other conditions has been reported (2,3,4,5,6,7,8,9,10,11 and 12). One study described 22 exposures to neostigmine in the 1st trimester (2). No relationship to congenital defects was found. A 1973 study reported the use of IM neostigmine (0.5 mg/day) for 3 days as a pregnancy test in 27 women with “uncertain pregnancies” at 5–14 weeks' gestation (3). Although vaginal bleeding occurred in seven (26%) patients, only one aborted and the remaining 26 went to term without complications. In a 1983 report, two women with myasthenia gravis were treated throughout gestation with neostigmine, 105 mg/day (combined with pyridostigmine and ambenonium) and 300 mg/day (combined with pyridostigmine), respectively, without apparent fetal harm (12).

One investigator considers neostigmine to be one of the drugs of choice for pregnant patients with myasthenia gravis (4). This author also cautioned that IV anticholinesterases should not be used in pregnancy because of the potential for inducing premature labor and suggested that IM neostigmine be used in place of IV edrophonium for diagnostic purposes (4). This recommendation, however, should be approached with caution in view of the high rate of vaginal bleeding following IM neostigmine described above.

Transient muscular weakness has been observed in about 20% of newborns of mothers with myasthenia gravis (10). The neonatal myasthenia is caused by transplacental passage of anti–acetylcholine receptor immunoglobulin G antibodies (10).

Breast Feeding Summary

No reports describing the use of neostigmine, a quaternary ammonium compound, during lactation have been located. Two publications have stated that the drug is not excreted into breast milk (11,13). However, pyridostigmine, another quaternary ammonium compound, is found in breast milk (see Pyridostigmine). Thus, although neostigmine is ionized at physiologic pH, the low molecular weight (about 223) is low enough that the nonionized fraction should be excreted into milk. The effects, if any, on a nursing infant from exposure to neostigmine in milk are unknown.

References

1. Clark RB, Brown MA, Lattin DL. Neostigmine, atropine, and glycopyrrolate: does neostigmine cross the placenta? Anesthesiology 1996;84:450–2.
2. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:345–56.
3. Brunclik V, Hauser GA. Short-term therapy in secondary amenorrhea. Ther Umsch 1973;30:496–502.
4. McNall PG, Jafarnia MR. Management of myasthenia gravis in the obstetrical patient. Am J Obstet Gynecol 1965;92:518–25.
5. Foldes FF, McNall PG. Myasthenia gravis: a guide for anesthesiologists. Anesthesiology 1962;23:837–72.
6. Chambers DC, Hall JE, Boyce J. Myasthenia gravis and pregnancy. Obstet Gynecol 1967;29:597–603.
7. Hay DM. Myasthenia gravis and pregnancy. J Obstet Gynaecol Br Commonw 1969;76:323–9.
8. Blackhall MI, Buckley GA, Roberts DV, Roberts JB, Thomas BH, Wilson A. Drug-induced neonatal myasthenia. J Obstet Gynaecol Br Commonw 1969;76:157–62.
9. Eden RD, Gall SA. Myasthenia gravis and pregnancy: a reappraisal of thymectomy. Obstet Gynecol 1983;62:328–33.
10. Plauche WC. Myasthenia gravis in pregnancy: an update. Am J Obstet Gynecol 1979;135:691–7.
11. Fraser D, Turner JWA. Myasthenia gravis and pregnancy. Proc R Soc Med 1963;56:379–81.
12. Lefvert AK, Osterman PO. Newborn infants to myasthenic mothers: a clinical study and an investigation of acetylcholine receptor antibodies in 17 children. Neurology 1983;33:133–8.
13. Wilson JT. Pharmacokinetics of drug excretion. In Wilson JT, ed. Drugs in Breast Milk. Balgowlah, Australia: ADIS Press, 1981:17.