Vaginal progesterone vs intramuscular 17-hydroxyprogesterone caproate for prevention of recurrent preterm birth: a randomized controlled trial

Published:February 18, 2022DOI:


      Preterm birth is the leading cause of neonatal morbidity and mortality, and previous preterm birth is one of the strongest risk factors for preterm birth. National and international obstetrical societies have different recommendations regarding progesterone formulation for the prevention of recurrent preterm birth.


      This study aimed to determine whether vaginal progesterone is superior to 17-hydroxyprogesterone caproate in the prevention of recurrent preterm birth in patients with singleton pregnancies who had a previous spontaneous preterm birth.

      Study Design

      This was an open-label multicenter pragmatic randomized controlled trial at 5 US centers of patients with singleton pregnancies at <24 weeks of gestation who had a previous spontaneous preterm birth randomized 1:1 to either 200 mg vaginal progesterone suppository nightly or 250 mg intramuscular 17-hydroxyprogesterone caproate weekly from 16 to 36 weeks of gestation. Based on the estimated recurrent preterm birth rate of 36% with 17-hydroxyprogesterone caproate, 95 participants were needed in each arm to detect a 50% reduction in preterm birth rate with vaginal progesterone, with 80% power and 2-sided alpha of 0.05. The primary outcome was preterm birth at <37 weeks of gestation. Prespecified secondary outcomes included preterm birth at <34 and <28 weeks of gestation, mean gestational age at delivery, neonatal morbidity and mortality, and measures of adherence. Analysis was by intention to treat. The chi-square test and Student t test were used as appropriate. P<.05 was considered significant.


      Overall, 205 participants were randomized; 94 participants in the vaginal progesterone group and 94 participants in 17-hydroxyprogesterone caproate group were included. Although gestational age at enrollment was similar, those assigned to vaginal progesterone initiated therapy earlier (16.9±1.4 vs 17.8±2.5 weeks; P=.001). Overall continuation of assigned formulation until delivery was similar (73% vs 69%; P=.61). There was no significant difference in preterm birth at <37 (31% vs 38%; P=.28; relative risk, 0.81 [95% confidence interval, 0.54–1.20]), <34 (9.6% vs 14.9%; P=.26; relative risk, 0.64 [95% confidence interval, 0.29–1.41]), or <28 (1.1% vs 4.3%; P=.37; relative risk, 0.25 [95% confidence interval, 0.03–2.20]) weeks of gestation. Participants in the vaginal progesterone group had a later mean gestational age at delivery than participants in the 17-hydroxyprogesterone caproate group (37.36±2.72 vs 36.34±4.10 weeks; mean difference, 1.02 [95% confidence interval, 0.01–2.01]; P=.047).


      Vaginal progesterone did not reduce the risk of recurrent preterm birth by 50% compared with 17-OHPC; however, vaginal progesterone may lead to increased latency to delivery. This trial was underpowered to detect a smaller, but still clinically significant, difference in the efficacy of preterm birth prevention. Patient factors that impact adherence and ability to obtain medication in a timely fashion should be included in counseling on progesterone selection.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Martin J.A.
        • Osterman M.J.K.
        Describing the increase in preterm births in the United States, 2014-2016.
        NCHS Data Brief. 2018; : 1-8
        • Martin J.A.
        • Hamilton B.E.
        • Osterman M.J.K.
        • Driscoll A.K.
        Births: final data for 2019.
        Natl Vital Stat Rep. 2021; 70: 1-51
        • Csapo A.I.
        • Pinto-Dantas C.A.
        The effect of progesterone on the human uterus.
        Proc Natl Acad Sci U S A. 1965; 54: 1069-1076
        • Larsen B.
        • Hwang J.
        Progesterone interactions with the cervix: translational implications for term and preterm birth.
        Infect Dis Obstet Gynecol. 2011; 2011: 353297
        • Yellon S.M.
        • Dobyns A.E.
        • Beck H.L.
        • Kurtzman J.T.
        • Garfield R.E.
        • Kirby M.A.
        Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth.
        PLoS One. 2013; 8e81340
        • Kirby M.A.
        • Heuerman A.C.
        • Custer M.
        • et al.
        Progesterone receptor-mediated actions regulate remodeling of the cervix in preparation for preterm parturition.
        Reprod Sci. 2016; 23: 1473-1483
        • Wagner G.P.
        • Nnamani M.C.
        • Chavan A.R.
        • et al.
        Evolution of gene expression in the uterine cervix related to steroid signaling: conserved features in the regulation of cervical ripening.
        Sci Rep. 2017; 7: 4439
        • Lockwood C.J.
        • Kayisli U.A.
        • Stocco C.
        • et al.
        Abruption-induced preterm delivery is associated with thrombin-mediated functional progesterone withdrawal in decidual cells.
        Am J Pathol. 2012; 181: 2138-2148
        • Guzeloglu-Kayisli O.
        • Kayisli U.A.
        • Semerci N.
        • et al.
        Mechanisms of chorioamnionitis-associated preterm birth: interleukin-1β inhibits progesterone receptor expression in decidual cells.
        J Pathol. 2015; 237: 423-434
        • Guzeloglu-Kayisli O.
        • Semerci N.
        • Guo X.
        • et al.
        Decidual cell FKBP51-progesterone receptor binding mediates maternal stress-induced preterm birth.
        Proc Natl Acad Sci U S A. 2021; 118e2010282118
        • Caritis S.N.
        • Feghali M.N.
        • Grobman W.A.
        • Rouse D.J.
        • Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network
        What we have learned about the role of 17-alpha-hydroxyprogesterone caproate in the prevention of preterm birth.
        Semin Perinatol. 2016; 40: 273-280
        • O’Brien J.M.
        • Lewis D.F.
        Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety.
        Am J Obstet Gynecol. 2016; 214: 45-56
        • Kumar D.
        • Springel E.
        • Moore R.M.
        • et al.
        Progesterone inhibits in vitro fetal membrane weakening.
        Am J Obstet Gynecol. 2015; 213: 520.e1-520.e9
        • Kumar D.
        • Moore R.M.
        • Mercer B.M.
        • et al.
        In an in-vitro model using human fetal membranes, 17-α hydroxyprogesterone caproate is not an optimal progestogen for inhibition of fetal membrane weakening.
        Am J Obstet Gynecol. 2017; 217: 695.e1-695.e14
        • Meis P.J.
        • Klebanoff M.
        • Thom E.
        • et al.
        Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
        N Engl J Med. 2003; 348: 2379-2385
        • Blackwell S.C.
        • Gyamfi-Bannerman C.
        • Biggio J.R.
        • et al.
        17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): a multicenter, international, randomized double-blind trial.
        Am J Perinatol. 2020; 37: 127-136
        • EPPPIC Group
        Evaluating Progestogens for Preventing preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials.
        Lancet. 2021; 397: 1183-1194
        • da Fonseca E.B.
        • Bittar R.E.
        • Carvalho M.H.
        • 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: 419-424
        • O’Brien J.M.
        • Adair C.D.
        • Lewis D.F.
        • 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: 687-696
        • Saccone G.
        • Khalifeh A.
        • Elimian A.
        • et al.
        Vaginal progesterone vs intramuscular 17α-hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations: systematic review and meta-analysis of randomized controlled trials.
        Ultrasound Obstet Gynecol. 2017; 49: 315-321
        • Jarde A.
        • Lutsiv O.
        • Beyene J.
        • McDonald S.D.
        Vaginal progesterone, oral progesterone, 17-OHPC, cerclage, and pessary for preventing preterm birth in at-risk singleton pregnancies: an updated systematic review and network meta-analysis.
        BJOG. 2019; 126: 556-567
        • American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics
        Prediction and prevention of spontaneous preterm birth: ACOG Practice Bulletin, Number 234.
        Obstet Gynecol. 2021; 138: e65-e90
        • Society for Maternal-Fetal Medicine (SMFM) Publications Committee
        The choice of progestogen for the prevention of preterm birth in women with singleton pregnancy and prior preterm birth.
        Am J Obstet Gynecol. 2017; 216: B11-B13
        • National Institute for Health and Care Excellence
        Preterm labour and birth.
        (Available at:) (Accessed February 2, 2022)
        • Harris P.A.
        • Taylor R.
        • Thielke R.
        • Payne J.
        • Gonzalez N.
        • Conde J.G.
        Research Electronic Data Capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support.
        J Biomed Inform. 2009; 42: 377-381
        • Harris P.A.
        • Taylor R.
        • Minor B.L.
        • et al.
        The REDCap consortium: building an international community of software partners.
        J Biomed Inform. 2019; 95: 103208
        • Schulz K.F.
        • Altman D.G.
        • Moher D.
        • CONSORT Group
        CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials.
        Ann Intern Med. 2010; 152: 726-732
        • Kianersi S.
        • Luetke M.
        • Ludema C.
        • et al.
        Use of research electronic data capture (REDCap) in a COVID-19 randomized controlled trial: a practical example.
        BMC Med Res Methodol. 2021; 21: 175
        • Boelig R.C.
        • Berghella V.
        Current options for mechanical prevention of preterm birth.
        Semin Perinatol. 2017; 41: 452-460
      1. ACOG Practice Bulletin No.142: cerclage for the management of cervical insufficiency.
        Obstet Gynecol. 2014; 123: 372-379
        • Romero R.
        • Conde-Agudelo A.
        • da Fonseca E.
        • et al.
        Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data.
        Am J Obstet Gynecol. 2018; 218: 161-180
        • Krosnick J.A.
        • Presser S.
        ”Question and Questionnaire Design.” Chapter 9 in Handbook of Survey Research. 2nd Edition.
        Emerald Group Publishing. 2010;
        • Pocock S.J.
        When (not) to stop a clinical trial for benefit.
        JAMA. 2005; 294: 2228-2230
        • Schulz K.F.
        • Grimes D.A.
        Multiplicity in randomised trials II: subgroup and interim analyses.
        Lancet. 2005; 365: 1657-1661
        • Ning A.
        • Vladutiu C.J.
        • Dotters-Katz S.K.
        • Goodnight W.H.
        • Manuck T.A.
        Gestational age at initiation of 17-alpha hydroxyprogesterone caproate and recurrent preterm birth.
        Am J Obstet Gynecol. 2017; 217: 371.e1-371.e7
        • Elimian A.
        • Smith K.
        • Williams M.
        • Knudtson E.
        • Goodman J.R.
        • Escobedo M.B.
        A randomized controlled trial of intramuscular versus vaginal progesterone for the prevention of recurrent preterm birth.
        Int J Gynaecol Obstet. 2016; 134: 169-172
        • Iams J.D.
        • Applegate M.S.
        • Marcotte M.P.
        • et al.
        A statewide progestogen promotion program in Ohio.
        Obstet Gynecol. 2017; 129: 337-346
        • Orsulak M.K.
        • Block-Abraham D.
        • Gee R.E.
        17α-Hydroxyprogesterone caproate access in the Louisiana Medicaid population.
        Clin Ther. 2015; 37: 727-732
        • Boelig R.C.
        • Jiang E.
        • Scheidemantle B.
        • Villani M.
        • Berghella V.
        Utilization of progesterone and cervical length screening for prevention of recurrent preterm birth.
        J Matern Fetal Neonatal Med. 2019; 32: 4146-4153
        • Garcia S.M.
        • Kellom K.S.
        • Boelig R.C.
        • Wang X.
        • Matone M.
        Patient and provider perspectives on acceptability, access, and adherence to 17-alpha-hydroxyprogesterone caproate for preterm birth prevention.
        Womens Health Rep (New Rochelle). 2021; 2: 295-304
        • Boelig R.C.
        • Zuppa A.F.
        • Kraft W.K.
        • Caritis S.
        Pharmacokinetics of vaginal progesterone in pregnancy.
        Am J Obstet Gynecol. 2019; 221: 263.e1-263.e7
        • Sharma S.
        • Caritis S.
        • Hankins G.
        • et al.
        Population pharmacokinetics of 17α-hydroxyprogesterone caproate in singleton gestation.
        Br J Clin Pharmacol. 2016; 82: 1084-1093
        • Manuck T.A.
        Pharmacogenomics of preterm birth prevention and treatment.
        BJOG. 2016; 123: 368-375
        • Manuck T.A.
        • Watkins W.S.
        • Moore B.
        • et al.
        Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth prevention.
        Am J Obstet Gynecol. 2014; 210: 321.e1-321.e21
        • Manuck T.A.
        • Watkins W.S.
        • Esplin M.S.
        • et al.
        Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: a case-control study.
        BJOG. 2018; 125: 343-350
        • Boelig R.C.
        • Naert M.N.
        • Fox N.S.
        • et al.
        Predictors of early preterm birth despite vaginal progesterone therapy in singletons with short cervix.
        Am J Perinatol. 2020; 37: 1289-1295
        • Society for Maternal-Fetal Medicine (SMFM) Publications Committee
        SMFM statement: use of 17-alpha hydroxyprogesterone caproate for prevention of recurrent preterm birth.
        Am J Obstet Gynecol. 2020; 223: B16-B18
        • Wheeler S.M.
        • Massengale K.E.C.
        • Blanchard K.P.
        • et al.
        Improving uptake and adherence to 17-hydroxyprogesterone caproate in non-Hispanic Black women: a mixed methods study of potential interventions from the patient perspective.
        Biores Open Access. 2019; 8: 155-161
        • Choi S.J.
        • Kwak D.W.
        • Kil K.
        • et al.
        Vaginal compared with intramuscular progestogen for preventing preterm birth in high-risk pregnant women (VICTORIA study): a multicentre, open-label randomised trial and meta-analysis.
        BJOG. 2020; 127: 1646-1654
        • Society for Maternal-Fetal Medicine
        SMFM preterm birth tookit.
        (Available at:) (Accessed February 4, 2022)