Fetal Risk Summary
Norethindrone is a progestogen derived from 19-nortestosterone. It is used in oral contraceptives and hormonal pregnancy tests (no longer available in the United States). Masculinization of the female fetus has been associated with norethindrone (1,2 and 3). One researcher observed an 18% incidence of masculinization of female infants born to mothers given norethindrone (2). A more conservative estimate for the incidence of masculinization caused by synthetic progestogens has been reported as 0.3% (4).
The Collaborative Perinatal Project monitored 866 mother-child pairs with 1st trimester exposure to progestational agents (including 132 with exposure to norethindrone) (5, pp. 389, 391). Evidence of an increased risk of malformation was found for norethindrone. An increase in the expected frequency of cardiovascular defects and hypospadias was also observed for progestational agents as a group (5, p. 394; 6). 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 (7). An earlier study also failed to find any relationship with nongenital malformations (3). One investigator observed two infants with malformations who were exposed to norethindrone (8). The congenital defects included spina bifida and hydrocephalus. The relationship between norethindrone and the anomalies is unknown.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 238 newborns had been exposed to norethindrone (see also Oral Contraceptives) shortly before or after conception (F. Rosa, personal communication, FDA, 1993). A total of 20 (8.4%) major birth defects were observed (10 expected). Specific data were available for six defect categories, including (observed/expected) 2/2 cardiovascular defects, 1/0.5 oral clefts, 0/0 spina bifida, 0/1 polydactyly, 0/0.5 limb reduction defects, and 1/1 hypospadias. The total number of congenital malformations suggests a moderate association between the drug and the incidence of congenital defects, but the study could not determine the percentage of women who presumably stopped the hormone before conception or the number of anomalies as a result of prematurity (F. Rosa, personal communication, FDA, 1993).
Breast Feeding Summary
Norethindrone exhibits a dose-dependent suppression of lactation (9). Lower infant weight gain, decreased milk production, and decreased composition of nitrogen and protein content of human milk have been associated with norethindrone and estrogenic agents (10,11,12 and 13). The magnitude of these changes is low. However, the changes in milk production and composition may be of nutritional importance in malnourished mothers. If breast feeding is desired, the lowest dose of oral contraceptives should be chosen. Monitoring of infant weight gain and the possible need for nutritional supplementation should be considered. The American Academy of Pediatrics considers norethindrone to be compatible with breast feeding (14).
- Hagler S, Schultz A, Hankin H, Kunstadter RN. Fetal effects of steroid therapy during pregnancy. Am J Dis Child 1963;106:58690.
- Jacobson BD. Hazards of norethindrone therapy during pregnancy. Am J Obstet Gynecol 1962;84:9628.
- Wilson JG, Brent RL. Are female sex hormones teratogenic? Am J Obstet Gynecol 1981;141:56780.
- Bongiovanni AM, McFadden AJ. Steroids during pregnancy and possible fetal consequences. Fertil Steril 1960;11:1814.
- Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
- 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;296:6770.
- Wiseman RA, Dodds-Smith IC. Cardiovascular birth defects and antenatal exposure to female sex hormones: a reevaluation of some base data. Teratology 1984;30:35970.
- Dillon S. Congenital malformations and hormones in pregnancy. Br Med J 1976;2:1446.
- Guiloff E, Ibarra-Polo A, Zanartu J, Toscanini C, Mischler TW, Gomez-Rogers C. Effect of contraception on lactation. Am J Obstet Gynecol 1974;118:425.
- Karim M, Ammarr R, El-Mahgoubh S, El-Ganzoury B, Fikri F, Abdou I. Injected progestogen and lactation. Br Med J 1971;1:2003.
- Kora SJ. Effect of oral contraceptives on lactation. Fertil Steril 1969;20:41923.
- Miller GH, Hughes LR. Lactation and genital involution effects of a new low-dose oral contraceptive on breast-feeding mothers and their infants. Obstet Gynecol 1970;35:4450.
- Lonnerdal B, Forsum E, Hambraeus L. Effect of oral contraceptives on composition and volume of breast milk. Am J Clin Nutr 1980;33:81624.
Committee on Drugs, American Academy of Pediatrics. Transfer of drugs and other chemicals into human milk. Pediatrics 1989;84:92436.