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The Safety of 17alpha Hydroxyprogesterone Caproate Use in Pregnancy
The evidence for the safety of the use of 17alpha Hydroxyprogesterone Caproate, (17OHP-C), in pregnancy exists in three categories: 1. Theoretical considerations, 2. Animal studies, and 3. Clinical studies.
1. Theoretical. 17Hydroxyprogesterone is a naturally occurring metabolite of progesterone. Progesterone and 17hydroxyprogesterone are produced in large amounts in human pregnancy (1). The quantities produced in pregnancy, mainly by the placenta, exceed pharmacologic doses employed in clinical use. 17OHP-C has no androgenic activity in contrast to some other progestins, especially 19 nor compounds, which are used in oral contraceptives, and are known to possess androgenic actions. Logically, it is not reasonable to expect ill effects of a non-androgenic progestin, naturally found in large quantities, upon human gestation.
2. Animal studies. Junkmann (2) studied 17OHP-C and found no androgenic or anabolic effects in rats. Kessler and Borman (3) studied the effect of 17OHP-C in rabbits and rats and found esterification to amplify the progestational effects of hydroxyprogesterone and found no evidence of androgen or glucocorticoid activity. Johnstone and Franklin (4) studied virilizing effects of several steroid compounds in the fetal mouse model. In contrast to 19 nortestosterone, 17OHP-C demonstrated no virilizing effect compared to control mouse fetuses. Suchowsky and Junkmann (5) examined a number of progestogens for 1. virilizing activity upon the female fetus of the rat, 2. Androgenic activity on the spayed rat seminal vesicle weight and on the chick comb, and 3. Progestational effect on the rabbit uterus. Several of the compounds studied exhibited virilizing and/or androgenic properties. 17OHP-C, even at very high doses, showed no virilizing effects and no androgenic properties. Courtney and Valerio (6) examined effects of various compounds on the monkey fetus, (Macaca Mulatta). They found no effects of 17OHP-C on the developing monkey fetus. Carbone and Brent (7) treated pregnant mice throughout gestation with doses of 17OHP-C of up to 70 times the equivalent human dose and found no effects on embryonic or fetal development, cleft palate or endochondrial ossification. Seegmiller (8) administered 17OHP-C at 200 times the human dose on a per weight basis and found no increase in congenital anomalies. Thus, animal studies of 17)HP-C have failed to show any harmful or teratogenic effects on the fetus of a number of species even when the drug was administered at very high doses.
3. Clinical studies. A number of authors have reported the results of well-controlled clinical studies to examine the safety of 17hydroxyprogesterone in human pregnancy. Varman and Horsman (9) examined the outcome of 150 pregnancies treated with hydroxyprogesterone because of threatened abortion, and compared them with 150 patients who experienced early pregnancy bleeding but were not treated with the drug. No evidence was found that the drug had any adverse effect on the fetus or the outcome of the pregnancy. Michaelis et al (10) in a cohort study of 13,643 pregnancies in West Germany found no increase in malformation in infants exposed in utero to 17OHP-C compared with controls. Resseguie et al (11) examined a cohort of 24,000 pregnancies delivered in Olmstead County, Minnesota 1936-1974 and found that the 649 offspring exposed to 17OHP-C showed no increase in congenital anomalies or other ill effects compared with controls. A notable feature of this study was the long period of follow-up of the children, with a mean of 11.5 years. Check et al (12) performed a follow-up study by questionnaire of 382 women treated with progestins during pregnancy and found no increase in anomalies compared with control offspring. Katz et al (13) studied 1608 infants exposed to progestins in utero and compared them to 1146 control infants. No difference was found in rates of all malformations, (120/1000 and 123.9/1000 respectively), or in rates of major malformations, (63.4/1000 and 71.5/1000 respectively). Kester (14) examined a group of adolescent males who were exposed in utero to 17OHP-C and performed a battery of psychological tests on the subjects and on matched control subjects. They found no significant differences between the groups in psychological testing.
Several extensive reviews of the literature have been published regarding the safety of the use of progestins in pregnancy. Schardein (15) in a very extensive review found "no justification (exists) for undue concern over the induction of nongenital malformations through hormone use in pregnancy." This review found masculinazation of the female fetus, progesterone and 17OHP-C have no such potential. Ramon-Wilms et al (16) performed a meta-analysis of the literature after review of 186 published articles. The meta-analysis showed no association between the first trimester exposure to sex hormones and external genital malformations. In the current REPROTOX (17) computer database, supported by Micomedix, the review of Hydroxyprogesterone concludes that "There is no available evidence that the administration of this agent, (17OHP-C) during pregancy is harmful."
In summary, the safety of 17OHP-C administration in pregnancy is well documented by animal and clinical studies. Reviews of this topic by knowledgeable authors have uniformly concluded that no evidence exists that administration of 17OHP-C in pregnancy represents a significant risk to mother, fetus or newborn.
REFERENCES
1. Tulchinsky D and Simmer H. Sources of plasma 17aHydroxyprogesterone in human pregnancy. J Clin Enocrinol Metab. 1972;35:799
2. Junkmann K. Prolonged-acting progestogens. Arch Exper Path u Pharmskol. 1954;23:244
3. Kessler W and Borman A. Some biological activities of certain progestogens. Ann N Y Acad Sci. 1958;71:486
4. Johnstone EE and Franklin RR. Assay of progestins for fetal virilizing properties using the mouse. Obstet Gynecol. 1964;23:359
5. Suchowsky GK and Junkmann K. Endocrinology. 1961;68:341
6. Courtney KD and Valerio DA. Teratology in the Macaca Mulatta. Teratology. 1968; 1:163
7. Carbone JP and Brent RL. Genital and nongenital teratogenesis of prenatal progesterone therapy: The effects of 17alpha Hydroxyprogesterone Caproate on embryonic and fetal development and endochondrial ossification in the C57B1/6L mouse. Am J Obstet Gynecol. 1993;169:1292
8. Seegmiller RE et al. Evaluation of teratogenic potential of Delalutin, (17alpha Hydroxyprogesterone Caproate), in mice. Teratology 1983;28:201
9. Varma T and Morsman J. Evaluation of the use of Proluton-Depot (Hydroxyprogesterone Hexanate) in early pregnancy. Int J Gynecol Obstet. 1982;20:13
10. Michaelis J, Michaelis H, Gluck E and Keller S. Prospective studies of suspected association between certain drugs administered in early pregnancy and congenital malformations. Teratology 1983;27:57
11. Resequie LJ et al. Congenital malformations among offspring exposed in utero to progestins, Olmstead County, Minnesota 1936-1974. Fertility and sterility. 1985;43:514
12. Check JH, Rankin A and Teichman M. The risk of fetal anomalies as a result of progesterone therapy during pregnancy. Fertility and Sterility 1986;45:575
13. Katz et al. Teratogenicity of progestogens given during the first trimester of pregnancy. Obstet Gynecol 1985;65:775
14. Castro PA. Effects of prenatally administered 17alpha Hydroxyprogesterone Caproate in Adolescent Males. Archives of Sexual Behavior 1984;13:441
15. Schardein AL. Congenital abnormalities and hormones during pregnancy: a clinical review. Teratology 1980;22:251
16. Raman-Wilms L et al. Fetal genital effects of first trimester sex hormone exposure: a meta-analysis. Obstet Gynecol 1995;85:141
17. Anonymous. Reprotox 1997 Vol. 92, Micomedix Inc.
