Risk Factor: XM
Class: Hormones/ Progestogens
Fetal Risk Summary
Oral contraceptives contain a 19-nortestosterone progestin and a synthetic estrogen (see Mestranol, Norethindrone, Norethynodrel, Ethinyl Estradiol, Progesterone, Hydroxyprogesterone, Ethisterone). Because oral contraceptives are primarily combination products, it is difficult to separate entirely the fetal effects of progestogens and estrogens. Two groups of investigators have reviewed the effects of these hormones on the fetus (133 References) (1,2). Several potential problems were discussed: congenital heart defects, central nervous system defects, limb reduction malformations, general malformations, and modified development of sexual organs. Except for the latter category, no firm evidence has appeared that establishes a causal relationship between oral contraceptives and various congenital anomalies. The acronym VACTERL (Vertebral, Anal, Cardiac, Tracheal, Esophageal, Renal or Radial, and Limb) has been used to describe the fetal malformations produced by oral contraceptives or the related hormonal pregnancy test preparations (no longer available in the United States) (2,3). The use of this acronym should probably be abandoned in favor of more conventional terminology as a large variety of malformations have been reported with estrogen-progestogencontaining products (1,2,3,4,5,6,7,8,9,10 and 11). The Population Council estimates that, even if the study findings for VACTERL malformations are accurate, such abnormalities would occur in only 0.07% of the pregnancies exposed to oral contraceptives (12). Some reviewers have concluded that the risk to the fetus for nongenital malformations after in utero exposure to these agents is small, if indeed it exists at all (2).
In contrast to the above, the effect of estrogens and some synthetic progestogens on the development of the sexual organs is well established (2). Masculinization of the female infant has been associated with norethindrone, norethynodrel, hydroxyprogesterone, medroxyprogesterone, and diethylstilbestrol (2,13,14). The incidence of masculinization of female infants exposed to synthetic progestogens is reported to be approximately 0.3% (15). Pseudohermaphroditism in the male infant is not a problem, because of the low doses of estrogen employed in oral contraceptives (14).
Increased serum bilirubin in neonates of mothers taking oral contraceptives or progestogens before and after conception has been observed (16). Icterus occasionally reached clinically significant levels in infants whose mothers were exposed to the progestogens.
Concern that oral contraceptives may be a risk factor for preeclampsia has been suggested on the basis of the known effects of oral contraceptives on blood pressure (17). However, a retrospective controlled review of 341 patients found no association between this effect and the drugs (17).
Possible interactions between oral contraceptives and tetracycline, rifampin, ampicillin, or chloramphenicol resulting in pregnancy have been reported (18,19,20,21,22,23,24 and 25). The mechanism for this interaction may involve the interruption of the enterohepatic circulation of contraceptive steroids by inhibiting gut hydrolysis of steroid conjugates, resulting in lower concentrations of circulating steroids.
Breast Feeding Summary
Use of oral contraceptives during lactation has been associated with shortened duration of lactation, decreased infant weight gain, decreased milk production, and decreased composition of nitrogen and protein content of milk (26,27,28 and 29). The American Academy of Pediatrics has reviewed this subject (30) (37 References). Although the magnitude of these changes is low, the changes in milk production and composition may be of nutritional importance in malnourished mothers.
In general, progestin-only contraceptives demonstrate no consistent alteration of breast milk composition, volume, or duration of lactation (30). The composition and volume of breast milk will vary considerably even in the absence of steroidal contraceptives (29). Both estrogens and progestins cross into milk. An infant consuming 600 mL of breast milk daily from a mother using contraceptives containing 50 g of ethinyl estradiol will probably receive a daily dose in the range of 10 ng (30). This is in the same range as the amount of natural estradiol received by infants of mothers not using oral contraceptives. Progestins also pass into breast milk, although naturally occurring progestins have not been identified. One study estimated 0.03, 0.15, and 0.3 g of d-norgestrel/600 mL of milk from mothers receiving 30, 150, and 250 g of the drug, respectively (31). A milk:plasma ratio of 0.15 for norgestrel was calculated by the authors (31). A ratio of 0.16 has been calculated for lynestrenol (31,32).
Reports of adverse effects are lacking except for one child with mild breast tenderness and hypertrophy who was exposed to large doses of estrogen (30). If breast feeding is desired, the lowest effective dose of oral contraceptives should be chosen. Infant weight gain should be monitored, and the possible need for nutritional supplements should be considered. The American Academy of Pediatrics considers combination oral contraceptives to be compatible with breast feeding (33).
- Ambani LM, Joshi NJ, Vaidya RA, Devi PK. Are hormonal contraceptives teratogenic? Fertil Steril 1977;28:7917.
- Wilson JG, Brent RL. Are female sex hormones teratogenic? Am J Obstet Gynecol 1981;141:56780.
- Corcoran R, Entwistle GC. VACTERL congenital malformations and the male fetus. Lancet 1975;2:9812.
- Nora JJ, Nora AH. Can the pill cause birth defects? N Engl J Med 1974;294:7312.
- Kasan PN, Andrews J. Oral contraceptives and congenital abnormalities. Br J Obstet Gynaecol 1980;87:54551.
- Kullander S, Kallen B. A prospective study of drugs and pregnancy. Acta Obstet Gynecol Scand 1976;55:2214.
- Oakley GP, Flynt JW. Hormonal pregnancy test and congenital malformations. Lancet 1973;2:2567.
- Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am J Obstet Gynecol 1981;140:5214.
- Frost O. Tracheo-oesophageal fistula associated with hormonal contraception during pregnancy. Br Med J 1976;3:978.
- Redline RW, Abramowsky CR. Transposition of the great vessels in an infant exposed to massive doses of oral contraceptives. Am J Obstet Gynecol 1981;141:4689.
- Farb HF, Thomason J, Carandang FS, Sampson MB, Spellacy WH. Anencephaly twins and HLA-B27. J Reprod Med 1980;25:1669.
- Department of Medical and Public Affairs. Population Reports. Washington, D.C.: George Washington University Medical Center, 1975;2:A2951.
- Bongiovanni AM, DiGeorge AM, Grumbach MM. Masculinization of the female infant associated with estrogenic therapy alone during gestation: four cases. J Clin Endocrinol Metab 1959;19:100411.
- Hagler S, Schultz A, Hankin H, Kunstadter RH. Fetal effects of steroid therapy during pregnancy. Am J Dis Child 1963;106:58690.
- Bongiovanni AM, McFadden AJ. Steroids during pregnancy and possible fetal consequences. Fertil Steril 1960;11:1814.
- McConnell JB, Glasgow JF, McNair R. Effect on neonatal jaundice of oestrogens and progestogens taken before and after conception. Br Med J 1973;3:6057.
- Bracken MB, Srisuphan W. Oral contraception as a risk factor for preeclampsia. Am J Obstet Gynecol 1982;142:1916.
- Bacon JF, Shenfield GM. Pregnancy attributable to interaction between tetracycline and oral contraceptives. Br Med J 1980;1:283.
- Stockley I. Interactions with oral contraceptives. Pharm J 1976;216:140.
- Reiners D, Nockefinck L, Breurer H. Rifampin and the pill do not go well together. JAMA 1974;227:608.
- Dosseter EJ. Drug interactions with oral contraceptives. Br Med J 1975;1:1967.
- Pullskinnen MO, Williams K. Reduced maternal plasma and urinary estriol during ampicillin treatment. Am J Obstet Gynecol 1971;109:8956.
- Friedman GI, Huneke AL, Kim MH, Powell J. The effect of ampicillin on oral contraceptive effectiveness. Obstet Gynecol 1980;55:337.
- Back DJ, Breckenridge AM. Drug interactions with oral contraceptives. IPFF Med Bull 1978;12:12.
- Orme ML, Back DJ. Therapy with oral contraceptive steroids and antibiotics J Antimicrob Chemother 1979;5:1246.
- 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.
- Kora SJ. Effect of oral contraceptives on lactation. Fertil Steril 1969;20:41923.
- Guiloff E, Ibarra-Polo A, Zanartu J, Tuscanini C, Mischler TW, Gomez-Rodgers C. Effect of contraception on lactation. Am J Obstet Gynecol 1974;118:425.
- Lonnerdal B, Forsum E, Hambraeus L. Effect of oral contraceptives on consumption and volume of breast milk. Am J Clin Nutr 1980;33:81624.
- Committee on Drugs, American Academy of Pediatrics. Breast-feeding and contraception. Pediatrics 1981;68:13840.
- Nilsson S, Nygren KC, Johansson EDB. D-Norgestrel concentrations in maternal plasma, milk, and child plasma during administration of oral contraceptives to nursing women. Am J Obstet Gynecol 1977;129:17883.
- van der Molen HJ, Hart PG, Wijmenga HG. Studies with 4-14C-lynestrol in normal and lactating women. Acta Endocrinol 1969;61:25574.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.