17 alpha-hydroxyprogesterone caproate (17OHP-C, Delalutin®)

17OHPC is a synthetic progesterone similar in structure  to medroxyprogesterone acetate (MPA). Molecular weight: 428.62 [1].

17OHPC is used to decrease the chance of recurrent preterm birth.

In 1956 17 alpha-hydroxyprogesterone caproate (17 OHP-C) was approved under the trade name Delalutin® (NDA 10-347) for use in pregnant women for the treatment of habitual and recurrent abortion, threatened abortion, and post-partum “after pains”.  In 2000 the Food and Drug Administration (FDA) withdrew approval for Delalutin®  at the request of the holder of the New Drug Application (NDA), Bristol-Myers Squibb Co, because the company was no longer marketing the drug.

In 2003 a large randomized placebo-controlled trial conducted by the National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network found a significant reduction in recurrent preterm birth before 37 weeks for women who received 17OHP-C versus a control group receiving placebo (36.3% versus 54.9%) [14].

Treatment with 17-OHPC seems to be most effective in prolonging pregnancy in women with a history of previous spontaneous singleton delivery before 34 weeks gestation [5,6]. 17-OHPC appears to be ineffective in preventing preterm birth in multiple gestation in the regimens  used to date [7,17].

Shortly after the NIHCD study was published an opinion issued by the American College of Obstetricians and Gynecologists (ACOG) Committee on Obstetric Practice supported the treatment of a select group of women (i.e., those with a prior spontaneous birth at < 37 weeks of gestation) with a derivative of the hormone progesterone . The ACOG Committee opinion cautioned that further studies are needed to evaluate the use of progesterone in patients with other high-risk obstetric factors, such as multiple gestations, short cervical length, or positive test results for cervicovaginal fetal fibronectin and the optimal route of drug delivery[3].

A Cochrane Database of Systematic Review found intramuscular progesterone to be associated with a reduction in the risk of preterm birth less than 37 weeks' gestation, and infant birthweight less than 2500 grams. The Cochrane review also stated  "It is unclear if the prolongation of gestation translates into improved maternal and longer-term infant health outcomes. Similarly, information regarding the potential harms of progesterone therapy to prevent preterm birth is limited." [4].

Currently there is no drug product approved in the United States for prevention of preterm birth. Adeza Biomedical has submitted NDA 21-945 for 17OHP-C injection for the proposed indication: “Prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth” [2].

17OHP-C is presently being compounded by pharmacists and is being used widely for prevention of preterm birth in women at high risk. The proposed dosing regimen is a weekly intramuscular injection of 250 mg of 17OHP-C in 1 mL castor oil with 46% benzyl benzoate and 2% benzyl alcohol beginning at 16 weeks 0 days to 20 weeks 6 days gestation and used through 36 weeks 6 days gestation or birth [2]. However, 17OHP-C may be effective if initiated as late as 27 weeks gestation [18].

In the past the FDA labeled the therapeutic exposure of progestational drugs and contraceptives in pregnant women as a risk factor for limb-reduction defects (LRDs) and congenital heart defects (CHDs). In 1999 the FDA published new wording for package inserts that removed warnings for nongenital malformations for all progestational agents [8].

Although there is considerable evidence that 17OHPC does not cause birth defects [9-13] some have questioned the importance of the small, statistically nonsignificant, increase in the rate of miscarriages and stillbirths before 24 weeks associated with the use of 17 OHPC [13-15].

Follow up of the children of the women who participated in the 2003 NIHCD study found no significant difference in the frequency of genital malformations between children who had been exposed in utero to 17 OHPC and children whose mothers had been given placebo. In addition at a mean age at follow up of 48 months height, weight, head circumference, blood pressure, neurodevelopment,  and scores for gender specific roles were comparable between the two groups [16].

Reported side effects in the mother have included edema and local reactions at the site of injection [19], hypersensitivity reactions, cough, dyspnea [20], and an increased risk of developing gestational diabetes [21].

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REFERENCES

1. Canada JR, editor. USAN 1998. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1997. p. 364, 417, 445, 447, 519, 520, 606.
2. 17α-Alpha Hydroxyprogesterone Caproate for Prevention of Preterm Birth. Overview of FDA Background Document. http://www.fda.gov/ohrms/dockets/AC/06/briefing/2006-4227B1-02-01-FDA-Background.pdf
3. ACOG Committee Opinion. Use of progesterone to reduce preterm birth. Obstet Gynecol.2003 ;102(5 Pt 1):1115-6. PMID:14672496
4.Dodd JM, et al., Prenatal administration of progesterone for preventing preterm birth. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004947. Review. PMID:16437505 5. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, et al Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003 Jun 12;348(24):2379-85. Erratum in: N Engl J Med. 2003 ;349(13):1299. PMID:12802023
6.Spong CY, et al. Progesterone for prevention of recurrent preterm birth: impact of gestational age at previous delivery.Am J Obstet Gynecol. 2005;193:1127-31. PMID:16157124
7. Hartikainen-Sorri AL, et. al. Inefficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of prematurity in twin pregnancy.Obstet Gynecol.1980;56(6):692-5. PMID:7443111
8. Progestational drug products for human use; requirements for labeling directed to the patient. Food and Drug Administration, HHS. Final rule.Fed Regist.1999 Nov 16;64(220):62110-2. PMID:11010691
9. Raman-Wilms L, Tseng AL, Wighardt S, Einarson TR, Koren G. Fetal genital effects of first-trimester sex hormone exposure: a meta-analysis. Obstet Gynecol 1995;85:141-149 PMID:7800312
10. Katz Z , et al., Teratogenicity of progestogens given during the first trimester of pregnancy.Obstet Gynecol. 1985 Jun;65(6):775-80. PMID:3158848
11.Resequie LJ et al. Congenital malformations among offspring exposed in utero to progestins, Olmsted County, Minnesota, 1936-1974.Fertil Steril. 1985 ;43(4):514-9.PMID:3987922
12. Dudas I. et al. Population-based case-control teratogenic study of hydroxyprogesterone treatment during pregnancy.Congenit Anom (Kyoto). 2006 ;46(4):194-8. PMID:17096820
13. Christian MS, Brent RL, Calda P. Embryo-fetal toxicity signals for 17alpha-hydroxyprogesterone caproate in high-risk pregnancies: a review of the non-clinical literature for embryo-fetal toxicity with progestins. J Matern Fetal Neonatal Med.2007;20(2):89-112. PMID:17437208
14. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, et al Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003 12;348(24):2379-85.  PMID:12802023
15. Keirse MJ.Progestogen administration in pregnancy may prevent preterm delivery.Br J Obstet Gynaecol. 1990 ;97(2):149-54. PMID:2138496
16. Northen AT, et al. Follow-up of Children Exposed In Utero to 17 {alpha}-Hydroxyprogesterone Caproate Compared With Placebo.Obstet Gynecol. 2007 ;110:865-872. PMID:17906021

17. Rouse DJ, et al., A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.N Engl J Med. 2007;357:454-61. PMID:17671253

18. How HY et al. ,Prophylaxis with 17 alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery: does gestational age at initiation of treatment matter?Am J Obstet Gynecol. 2007;197:260.e1-4.PMID:17826411

19. American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977., p. 1142

20. Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 923

21. Rebarber A, et. al.,Increased incidence of gestational diabetes in women receiving prophylactic 17alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery.Diabetes Care. 2007;30(9):2277-80.PMID:17563346

Created: 9/25/2007
Updated : 9/26/07
Updated 10/2/07
Updated 10/18/07

Reviewed by Mark Curran, M.D,FACOG