Progesterone supplementation to reduce the risk of spontaneous preterm birth
- Errol R Norwitz, MD, PhD
Errol R Norwitz, MD, PhD
- Professor and Chair
- Department of Obstetrics and Gynecology
- Tufts Medical Center and Tufts University School of Medicine
Preterm birth (delivery prior to 37 weeks or 259 days of gestation) complicates 1 in 8 deliveries in the United States, but accounts for over 85 percent of all perinatal morbidity and mortality. Efforts to delay delivery in women presenting with acute preterm labor have been largely unsuccessful. For this reason, much attention has focused on preventative strategies.
ROLE OF PROGESTERONE IN PREGNANCY MAINTENANCE
Progesterone is a steroid hormone initially produced by the corpus luteum. In early pregnancy, progesterone is critical for pregnancy maintenance until the placenta takes over this function at 7 to 9 weeks of gestation, and its name is derived from this function: pro-gestational steroidal ketone. Indeed, removal of the source of progesterone (the corpus luteum)  or administration of a progesterone receptor antagonist  readily induces abortion before 7 weeks (49 days) of gestation.
Progesterone appears to be important in maintaining uterine quiescence in the latter half of pregnancy; however, the mechanism is unclear [3-5]. Functional withdrawal of progesterone activity at the level of the uterus appears to occur proximate to the onset of labor both at term and preterm, without a significant change in serum progesterone levels in the weeks preceding labor [3-10]. In addition, progesterone prevents apoptosis in fetal membrane explants, under both basal and pro-inflammatory conditions . This may help prevent preterm premature rupture of membranes, which is a common cause of preterm birth.
EFFICACY OF PROGESTERONE FOR PREVENTION OF PRETERM BIRTH
The efficacy of progesterone supplementation for prevention of preterm birth depends primarily on appropriate patient selection (table 1). In addition, in vitro and animal research suggest that the type of progestin, formulation, dose, and route of delivery have a significant impact on efficacy [12,13]. These factors likely played a role in the discordant findings reported in the trials discussed below.
Pregnancies likely to benefit from progesterone supplementation — Randomized trials have provided convincing evidence that progesterone supplementation reduces the rate of spontaneous singleton preterm birth in women who have had a previous spontaneous preterm singleton birth and in women with a short cervix on ultrasound examination in the current pregnancy . Neonatal morbidity and neonatal mortality are also reduced. This evidence is reviewed below.
- Csapo AI, Pulkkinen M. Indispensability of the human corpus luteum in the maintenance of early pregnancy. Luteectomy evidence. Obstet Gynecol Surv 1978; 33:69.
- Peyron R, Aubény E, Targosz V, et al. Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol. N Engl J Med 1993; 328:1509.
- Norwitz ER, Robinson JN, Challis JR. The control of labor. N Engl J Med 1999; 341:660.
- Matthews SG, Gibb W, Lye SJ. Endocrine and paracrine regulation of birth at term and preterm. Endocr Rev 2000; 21:514.
- Norwitz ER, Lye SJ. Biology of parturition. In: Creasy RK, Resnick R, Iams JD, et al, eds. Creasy & Resnick’s Maternal-Fetal Medicine, 6th ed. Philadelphia: Elsevier; 2009:69-85.
- Condon JC, Jeyasuria P, Faust JM, et al. A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition. Proc Natl Acad Sci U S A 2003; 100:9518.
- Oh SY, Kim CJ, Park I, et al. Progesterone receptor isoform (A/B) ratio of human fetal membranes increases during term parturition. Am J Obstet Gynecol 2005; 193:1156.
- Renthal NE, Chen CC, Williams KC, et al. miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor. Proc Natl Acad Sci U S A 2010; 107:20828.
- Mesiano S, Wang Y, Norwitz ER. Progesterone receptors in the human pregnancy uterus: do they hold the key to birth timing? Reprod Sci 2011; 18:6.
- Lockwood CJ, Stocco C, Murk W, et al. Human labor is associated with reduced decidual cell expression of progesterone, but not glucocorticoid, receptors. J Clin Endocrinol Metab 2010; 95:2271.
- Luo G, Abrahams VM, Tadesse S, Funai EF, Hodgson EJ, Gao J, Norwitz ER. Progesterone inhibits basal and TNF-induced apoptosis in fetal membranes: A novel mechanism to explain progesterone-mediated prevention of preterm birth. Reprod. Sci 2010; 17:532.
- Kuon RJ, Shi SQ, Maul H, et al. Pharmacologic actions of progestins to inhibit cervical ripening and prevent delivery depend on their properties, the route of administration, and the vehicle. Am J Obstet Gynecol 2010; 202:455.e1.
- O'Sullivan MD, Hehir MP, O'Brien YM, Morrison JJ. 17 alpha-hydroxyprogesterone caproate vehicle, castor oil, enhances the contractile effect of oxytocin in human myometrium in pregnancy. Am J Obstet Gynecol 2010; 202:453.e1.
- Likis FE, Andrews JC, Woodworth AL, et al. Progestogens for Prevention of Preterm Birth. Comparative Effectiveness Review No. 74. (Prepared by the Vanderbilt Evidence-based Practice Center under Contract No. 290-2007-10065-I). AHRQ Publication No. 12-EHC105-EF. Rockville, MD: Agency for Healthcare Research and Quality. September 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm.
- Likis FE, Edwards DR, Andrews JC, et al. Progestogens for preterm birth prevention: a systematic review and meta-analysis. Obstet Gynecol 2012; 120:897.
- Dodd JM, Jones L, Flenady V, et al. Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database Syst Rev 2013; 7:CD004947.
- Rode L, Langhoff-Roos J, Andersson C, et al. Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies. Acta Obstet Gynecol Scand 2009; 88:1180.
- Petrini JR, Callaghan WM, Klebanoff M, et al. Estimated effect of 17 alpha-hydroxyprogesterone caproate on preterm birth in the United States. Obstet Gynecol 2005; 105:267.
- da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003; 188:419.
- Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003; 348:2379.
- Spong CY, Meis PJ, Thom EA, et al. Progesterone for prevention of recurrent preterm birth: impact of gestational age at previous delivery. Am J Obstet Gynecol 2005; 193:1127.
- O'Brien JM, Adair CD, Lewis DF, et al. Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2007; 30:687.
- Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012; 206:124.e1.
- Grobman WA, Thom EA, Spong CY, et al. 17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm. Am J Obstet Gynecol 2012; 207:390.e1.
- Winer N, Bretelle F, Senat MV, et al. 17 alpha-hydroxyprogesterone caproate does not prolong pregnancy or reduce the rate of preterm birth in women at high risk for preterm delivery and a short cervix: a randomized controlled trial. Am J Obstet Gynecol 2015; 212:485.e1.
- Briery CM, Veillon EW, Klauser CK, et al. Women with preterm premature rupture of the membranes do not benefit from weekly progesterone. Am J Obstet Gynecol 2011; 204:54.e1.
- Su LL, Samuel M, Chong YS. Progestational agents for treating threatened or established preterm labour. Cochrane Database Syst Rev 2014; 1:CD006770.
- Saccone G, Suhag A, Berghella V. 17-alpha-hydroxyprogesterone caproate for maintenance tocolysis: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol 2015; 213:16.
- Schaaf JM, Hof MH, Mol BW, et al. Recurrence risk of preterm birth in subsequent twin pregnancy after preterm singleton delivery. BJOG 2012; 119:1624.
- Rafael TJ, Hoffman MK, Leiby BE, Berghella V. Gestational age of previous twin preterm birth as a predictor for subsequent singleton preterm birth. Am J Obstet Gynecol 2012; 206:156.e1.
- Schaaf JM, Hof MH, Mol BW, et al. Recurrence risk of preterm birth in subsequent singleton pregnancy after preterm twin delivery. Am J Obstet Gynecol 2012; 207:279.e1.
- Facco FL, Nash K, Grobman WA. Are women who have had a preterm twin delivery at greater risk of preterm birth in a subsequent singleton pregnancy? Am J Obstet Gynecol 2007; 197:253.e1.
- Lei K, Chen L, Cryar BJ, et al. Uterine stretch and progesterone action. J Clin Endocrinol Metab 2011; 96:E1013.
- Schuit E, Stock S, Rode L, et al. Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis. BJOG 2015; 122:27.
- Serra V, Perales A, Meseguer J, et al. Increased doses of vaginal progesterone for the prevention of preterm birth in twin pregnancies: a randomised controlled double-blind multicentre trial. BJOG 2013; 120:50.
- Ananth CV, Kirby RS, Vintzileos AM. Recurrence of preterm birth in twin pregnancies in the presence of a prior singleton preterm birth. J Matern Fetal Neonatal Med 2008; 21:289.
- Durnwald CP. 17 OHPC for prevention of preterm birth in twins: back to the drawing board? Am J Obstet Gynecol 2013; 208:167.
- Senat MV, Porcher R, Winer N, et al. Prevention of preterm delivery by 17 alpha-hydroxyprogesterone caproate in asymptomatic twin pregnancies with a short cervix: a randomized controlled trial. Am J Obstet Gynecol 2013; 208:194.e1.
- Romero R, Conde-Agudelo A. Is 17α-hydroxyprogesterone caproate contraindicated in twin gestations? BJOG 2015; 122:6.
- Caritis SN, Rouse DJ, Peaceman AM, et al. Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Obstet Gynecol 2009; 113:285.
- Combs CA, Garite T, Maurel K, et al. Failure of 17-hydroxyprogesterone to reduce neonatal morbidity or prolong triplet pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol 2010; 203:248.e1.
- Sotiriadis A, Papatheodorou S, Makrydimas G. Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis. Ultrasound Obstet Gynecol 2012; 40:257.
- Caritis SN, Venkataramanan R, Thom E, et al. Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth. Am J Obstet Gynecol 2014; 210:128.e1.
- Statement on Makena [press release]. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; March 30, 2011. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm249025.htm (accessed on May 9, 2011).
- Updated FDA Statement on Compounded Versions of hydroxyprogesterone caproate (the active ingredient in Makena) http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm308546.htm (Accessed on January 06, 2014).
- Chang J, Zhao Y, Zhao W, et al. Quality assessment of compounded 17-hydroxyprogesterone caproate. Am J Obstet Gynecol 2014; 210:47.e1.
- Schardein JL. Congenital abnormalities and hormones during pregnancy: a clinical review. Teratology 1980; 22:251.
- Resseguie LJ, Hick JF, Bruen JA, et al. Congenital malformations among offspring exposed in utero to progestins, Olmsted County, Minnesota, 1936-1974. Fertil Steril 1985; 43:514.
- Raman-Wilms L, Tseng AL, Wighardt S, et al. Fetal genital effects of first-trimester sex hormone exposure: a meta-analysis. Obstet Gynecol 1995; 85:141.
- Northen AT, Norman GS, Anderson K, et al. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. Obstet Gynecol 2007; 110:865.
- Rouse DJ, Caritis SN, Peaceman AM, et al. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med 2007; 357:454.
- Norman JE, Mackenzie F, Owen P, et al. Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis. Lancet 2009; 373:2034.
- Combs CA, Garite T, Maurel K, et al. 17-hydroxyprogesterone caproate for twin pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol 2011; 204:221.e1.
- Berghella V, Figueroa D, Szychowski JM, et al. 17-alpha-hydroxyprogesterone caproate for the prevention of preterm birth in women with prior preterm birth and a short cervical length. Am J Obstet Gynecol 2010; 202:351.e1.
- US Food and Drug Administration, Center for Drug Evaluation and Research. Summary minutes of the Advisory Committee for Reproductive Health Drugs, August 29, 2006. http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4227M1.pdf (accessed June 30, 2011).
- Manuck TA, Lai Y, Meis PJ, et al. Progesterone receptor polymorphisms and clinical response to 17-alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol 2011; 205:135.e1.
- Silver RI, Rodriguez R, Chang TS, Gearhart JP. In vitro fertilization is associated with an increased risk of hypospadias. J Urol 1999; 161:1954.
- Carmichael SL, Shaw GM, Laurent C, et al. Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med 2005; 159:957.
- Waters TP, Schultz BA, Mercer BM, Catalano PM. Effect of 17alpha-hydroxyprogesterone caproate on glucose intolerance in pregnancy. Obstet Gynecol 2009; 114:45.
- Rebarber A, Istwan NB, Russo-Stieglitz K, et al. Increased incidence of gestational diabetes in women receiving prophylactic 17alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery. Diabetes Care 2007; 30:2277.
- Gyamfi C, Horton AL, Momirova V, et al. The effect of 17-alpha hydroxyprogesterone caproate on the risk of gestational diabetes in singleton or twin pregnancies. Am J Obstet Gynecol 2009; 201:392.e1.
- Background Document for Meeting of Advisory Committee for Reproductive Health Drugs. January 20, 2012. NDA 22-139. Progesterone gel (8%) http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM287987.pdf.
- Fonseca EB, Celik E, Parra M, et al. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007; 357:462.
- Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011; 38:18.
- Thornton JG. Progesterone and preterm labor--still no definite answers. N Engl J Med 2007; 357:499.
- ROLE OF PROGESTERONE IN PREGNANCY MAINTENANCE
- EFFICACY OF PROGESTERONE FOR PREVENTION OF PRETERM BIRTH
- Pregnancies likely to benefit from progesterone supplementation
- - Spontaneous singleton preterm birth in prior pregnancy
- Seminal trials
- - Short cervix in current pregnancy
- Pregnancies where the benefit of progesterone supplementation is unclear
- - Positive fetal fibronectin test
- - Cerclage
- - Preterm premature rupture of membranes
- - Threatened preterm labor
- - After threatened preterm labor
- - Spontaneous twin preterm birth in prior pregnancy
- - Multiple gestations
- Twin pregnancy
- Triplet pregnancy
- Uterine anomaly or ART
- SIDE EFFECTS AND ADVERSE EFFECTS
- PROGESTERONE PREPARATIONS, ROUTES, AND DOSES
- Hydroxyprogesterone caproate
- Vaginal progesterone preparations
- Oral progesterone
- SUMMARY AND RECOMMENDATIONS