MEDROXYPROGESTERONE

Fetal Risk Summary

The FDA mandated deletion of pregnancy-related indications from all progestins because of a possible association with congenital anomalies. Fourteen cases of ambiguous genitalia of the fetus have been reported to the FDA, although the literature is more supportive of the 19-nortestosterone derivatives (see Norethindrone, Norethynodrel) (1).

The Collaborative Perinatal Project monitored 866 mother-child pairs with 1st trimester exposure to progestational agents, including 130 with exposure to medroxyprogesterone (2, p. 389). An increase in the expected frequency of cardiovascular defects (also see FDA data below) and hypospadias was observed for the progestational agents as a group (2, p. 394). The cardiovascular defects included a ventricular septal defect and tricuspid atresia (3). Re-evaluation of these data in terms of timing of exposure, vaginal bleeding in early pregnancy, and previous maternal obstetric history, however, failed to support an association between female sex hormones and cardiac malformations (4). Other studies have also failed to find any relationship with nongenital malformations (5,6).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 407 newborns had been exposed to medroxyprogesterone during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 15 (3.7%) major birth defects were observed (13 expected), including (observed/expected) 7/4 cardiovascular defects and 1/1 oral clefts. No malformations were observed in four other defect categories (spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available. Only the number of cardiovascular defects is suggestive of an association, but other factors, including the mother's disease, concurrent drug use, and chance, may be involved.

A 1985 study described 2,754 infants born to mothers who had vaginal bleeding during the 1st trimester (7). Of the total group, 1,608 of the newborns were delivered from mothers treated during the 1st trimester with either oral medroxyprogesterone (20–30 mg/day), 17-hydroxyprogesterone (500 mg/week by injection), or a combination of the two. Medroxyprogesterone was used exclusively in 1,274 (79.2%) of the study group. The control group consisted of 1,146 infants delivered from mothers who bled during the 1st trimester but who were not treated. There were no differences between the study and control groups in the overall rate of malformations (120 vs. 123.9/1,000, respectively) or in the rate of major malformations (63.4 vs. 71.5/1,000, respectively). Another 1985 study compared 988 infants exposed in utero to various progesterones with a matched cohort of 1,976 unexposed controls (8). Only 60 infants were exposed to medroxyprogesterone. No association between progestins, primarily progesterone and 17-hydroxyprogesterone, and fetal malformations was discovered.

Breast Feeding Summary

Medroxyprogesterone has not been shown to affect lactation adversely (9,10). A 1981 review concluded that use of the drug by the mother would not have a significant effect on the nursing infant (11). Milk production and duration of lactation may be increased if the drug is given in the puerperium. If breast feeding is desired, medroxyprogesterone may be used safely. The American Academy of Pediatrics considers medroxyprogesterone to be compatible with breast feeding (12).

References

1. Dayan E, Rosa FW. Fetal ambiguous genitalia associated with sex hormones use early in pregnancy. Food and Drug Administration, Division of Drug Experience. ADR Highlights 1981:1–14.
2. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
3. Heinonen OP, Slone D, Monson RR, Hook EB, Shapiro S. Cardiovascular birth defects and antenatal exposure to female sex hormones. N Engl J Med 1977;296:67–70.
4. Wiseman RA, Dodds-Smith IC. Cardiovascular birth defects and antenatal exposure to female sex hormones: a reevaluation of some base data. Teratology 1984;30:359–70.
5. Wilson JG, Brent RL. Are female sex hormones teratogenic? Am J Obstet Gynecol 1981;141:567–80.
6. Dahlberg K. Some effects of depo-medroxyprogesterone acetate (DMPA): observations in the nursing infant and in the long-term user. Int J Gynaecol Obstet 1982;20:43–8.
7. Katz Z, Lancet M, Skornik J, Chemke J, Mogilner BM, Klinberg M. Teratogenicity of progestogens given during the first trimester of pregnancy. Obstet Gynecol 1985;65:775–80.
8. Resseguie LJ, Hick JF, Bruen JA, Noller KL, O'Fallon WM, Kurland LT. Congenital malformations among offspring exposed in utero to progestins, Olmsted County, Minnesota, 1936–74. Fertil Steril 1985;43:514–9.
9. Guiloff E, Ibarra-Polo A, Zanartu J, Toscanini C, Mischler TW, Gomez-Rogers C. Effect of contraception on lactation. Am J Obstet Gynecol 1974;118:42–5.
10. Karim M, Ammar R, El Mahgoub S, El Ganzoury B, Fikri F, Abdou Z. Injected progesterone and lactation. Br Med J 1971;1:200–3.
11. Schwallie PC. The effect of depot-medroxyprogesterone acetate on the fetus and nursing infant: a review. Contraception 1981;23:375–86.
12. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.