CYPROHEPTADINE

Fetal Risk Summary

Cyproheptadine has been used as a serotonin antagonist to prevent habitual abortion in patients with increased serotonin production (1,2). No congenital defects were observed when the drug was used for this purpose.

Reproductive studies in mice, rats, and rabbits with oral or SC doses up to 32 times the maximum recommended human dose found no evidence of impaired fertility or fetal harm (3,4). In contrast, Shepard cited a 1982 study that observed dose-related fetotoxicity characterized by skeletal retardation, hydronephrosis, liver and brain toxicity, and increased mortality in fetuses of rats administered 2–50 mg/kg/day intraperitoneally during organogenesis (5).

Two patients, who were being treated with cyproheptadine for Cushing's syndrome, conceived while taking the drug (6,7). Therapy was stopped at 3 months in one patient, but continued throughout gestation in the second. Apparently healthy infants were delivered prematurely (33–34 weeks and 36 weeks) from both mothers. Fatal gastroenteritis developed at 4 months of age in the 33–34 week gestational infant who was exposed throughout pregnancy to the drug (6). The use of cyproheptadine to treat a pregnant woman with Cushing's syndrome secondary to bilateral adrenal hyperplasia was described in a 1990 Reference (8). Specific details were not provided on the case, except that the fetus was delivered prematurely at 33 weeks' gestation. In a separate case, a woman with Cushing's was successfully treated with cyproheptadine; 2 years after stopping the drug, she conceived and eventually delivered a healthy male infant (9).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 285 newborns had been exposed to cyproheptadine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 12 (4.2%) major birth defects were observed (12 expected), including (observed/expected) 2/3 cardiovascular defects, 2/0.6 oral clefts, and 2/0.7 hypospadias. Only with the latter two defects is there a suggestion of an association, but other factors, including the mother's disease, concurrent drug use, and chance may be involved. No anomalies were observed in three other categories of anomalies (spina bifida, polydactyly, and limb reduction defects) for which specific data were available.

Breast Feeding Summary

No reports describing the use of cyproheptadine during lactation have been located. Chronic use of cyproheptadine will lower serum prolactin levels and it has been used in the management of galactorrhea (10). No studies have been found, however, that evaluated its potential to interfere with the normal lactation process. Because of the increased sensitivity of newborns to antihistamines and the potential for adverse reactions, the manufacturer considers cyproheptadine to be contraindicated in nursing mothers (3).

References

1. Sadovsky E, Pfeifer Y, Polishuk WZ, Sulman FG. A trial of cyproheptadine in habitual abortion. Isr J Med Sci 1972;8:623–5.
2. Sadovsky E, Pfeifer Y, Sadovsky A, Sulman FG. Prevention of hypothalamic habitual abortion by Periactin. Harefuah 1970;78:332–4. As cited in Anonymous. References and reviews. JAMA 1970;212:1253.
3. Product information. Periactin. Merck & Co., 1997.
4. Pfeifer Y, Sadovsky E, Sulman FG. Prevention of serotonin abortion in pregnant rats by five serotonin antagonists. Obstet Gynecol 1969;33:709–14.
5. Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD:Johns Hopkins University Press, 1995:121–2.
6. Kasperlik-Zaluska A, Migdalska B, Hartwig W, Wilczynska J, Marianowski L, Stopinska-Gluszak U, Lozinska D. Two pregnancies in a woman with Cushing's syndrome treated with cyproheptadine. Br J Obstet Gynaecol 1980;87:1171–3.
7. Khir ASM, How J, Bewsher PD. Successful pregnancy after cyproheptadine treatment for Cushing's disease. Eur J Obstet Gynecol Reprod Biol 1982;13:343–7.
8. Aron DC, Schnall AM, Sheeler LR. Cushing's syndrome and pregnancy. Am J Obstet Gynecol 1990;162:244–52.
9. Griffith DN, Ross EJ. Pregnancy after cyproheptadine treatment for Cushing's disease. N Engl J Med 1981;305:893–4.
10. Wortsman J, Soler NG, Hirschowitz J. Cyproheptadine in the management of the galactorrhea-amenorrhea syndrome. Ann Intern Med 1979;90:923–5.