Effectiveness of Oral and Vaginal Progesterone for The Prevention of Preterm Birth: A Systematic Review and Meta-Analysis
Downloads
This systematic review and meta-analysis aimed to compare the effectiveness of oral and vaginal progesterone in preventing spontaneous preterm birth (sPTB). Relevant electronic databases were searched for studies published between January 2000 and May 2025, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines. Randomized controlled trials (RCTs) and observational studies evaluating oral micronized progesterone, vaginal progesterone, or intramuscular 17?-hydroxyprogesterone caproate (17-OHPC) for preterm birth prevention in high-risk pregnancies were considered for inclusion. The risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool for randomized trials and the Newcastle–Ottawa Scale (NOS) for eligible observational studies. Pooled risk ratios (RRs) were calculated using the Mantel–Haenszel fixed-effect model in Review Manager (RevMan) version 5.4.1. Funnel plots were used to explore potential publication bias. Twenty-five studies, comprising 21 double-blind RCTs, three comparative cohort studies, and one cross-sectional study, included 7,045 pregnant women at increased risk of preterm birth due to a history of preterm birth, a short cervix, or twin gestation. Progesterone treatment was initiated between 14 and 24 weeks of gestation. The pooled findings did not demonstrate a statistically significant reduction in preterm birth with oral or vaginal progesterone across the included populations. Differences in baseline risk, pregnancy characteristics, progesterone formulations, and study methodologies may have contributed to the observed findings. Although progesterone plays a physiological role in maintaining uterine quiescence and cervical function, the clinical effectiveness of progesterone supplementation may vary according to patient characteristics, particularly cervical length. Vaginal progesterone may offer benefits for selected patients with a short cervix; however, the available findings do not support a generalized conclusion that all progesterone formulations or routes of administration significantly reduce spontaneous preterm birth.
Azargoon, A., Ghorbani, R., & Aslebahar, F. (2016a). Vaginal progesterone on the prevention of preterm birth and neonatal complications in high risk women: A randomized placebo-controlled double-blind study. International Journal of Reproductive BioMedicine, 14(5), 309–316. https://doi.org/10.29252/ijrm.14.5.309
Azargoon, A., Ghorbani, R., & Aslebahar, F. (2016b). Vaginal progesterone on the prevention of preterm birth and neonatal complications in high risk women: A randomized placebo-controlled double-blind study. International Journal of Reproductive BioMedicine, 14(5), 309–316.
Boelig, R. C., Locci, M., Saccone, G., Gragnano, E., & Berghella, V. (2022). Vaginal progesterone compared to intramuscular 17-alpha-hydroxyprogesterone caproate for prevention of recurrent preterm birth in singleton gestations: A systematic review and meta-analysis. American Journal of Obstetrics & Gynecology MFM, 4(5), 100658.
Brizot, M. L., Hernandez, W., Liao, A. W., Bittar, R. E., Francisco, R. P. V., Krebs, V. L. J., & Zugaib, M. (2015). Vaginal progesterone for the prevention of preterm birth in twin gestations: a randomized placebo-controlled double-blind study. American Journal of Obstetrics and Gynecology, 213(1), 82.e1-82.e9. https://doi.org/10.1016/j.ajog.2015.02.021
Brizot, M. L., Hernandez, W., Liao, A. W., Bittar, R. E., Francisco, R. P. V, & Krebs, V. L. J. (2015). Vaginal progesterone for the prevention of preterm birth in twin gestations: A randomized placebo-controlled double-blind study. American Journal of Obstetrics & Gynecology, 213(1), 82.e1-82.e9.
Care, A., Muller-Myhsok, B., Olearo, E., Todros, T., Caradeux, J., & Goya, M. (2019). Should phenotype of previous preterm birth influence management of women with short cervix in subsequent pregnancy? Comparison of vaginal progesterone and Arabin pessary. Ultrasound in Obstetrics & Gynecology, 53(4), 529–534.
Choi, S. J. (2017). Use of progesterone supplement therapy for prevention of preterm birth: Review of literatures. Obstetrics & Gynecology Science, 60(5), 405–420.
Crowther, C. A., Ashwood, P., McPhee, A. J., Flenady, V., Tran, T., & Dodd, J. M. (2017). Vaginal progesterone pessaries for pregnant women with a previous preterm birth to prevent neonatal respiratory distress syndrome (the PROGRESS Study): A multicentre, randomised, placebo-controlled trial. PLOS Medicine, 14(9), 1–18.
Crowther, C. A., Ashwood, P., McPhee, A. J., Flenady, V., Tran, T., Dodd, J. M., & Robinson, J. S. (2017). Vaginal progesterone pessaries for pregnant women with a previous preterm birth to prevent neonatal respiratory distress syndrome (the PROGRESS Study): A multicentre, randomised, placebo-controlled trial. PLoS Medicine, 14(9), 1–18. https://doi.org/10.1371/journal.pmed.1002390
Cuijpers, C. J. J., Van’t Hooft, J., Schneeberger, C., Van Der Lee, J. H., Simons, N. E., & Van Os, M. A. (2021). Progesterone for prevention of preterm birth in women with short cervical length: 2-year infant outcomes. Ultrasound in Obstetrics & Gynecology, 57(3), 431–439.
Cuijpers, C. J. J., Van’t Hooft, J., Schneeberger, C., Van Der Lee, J. H., Simons, N. E., Van Os, M. A., Van Der Ven, J., De Groot, C. J. M., Mol, B. W. J., & Van Wassenaer-leemhuis, A. G. (2021). Progesterone for prevention of preterm birth in women with short cervical length: 2-year infant outcomes. Ultrasound in Obstetrics and Gynecology, 57(3), 431–439. https://doi.org/10.1002/uog.23126
Dang, V. Q., Dang, V. Q., He, Y. T. N., He, Y. T. N., Pham, H. N. H., Trieu, T. T. T., Bui, T. Q., Vuong, N. T., Nguyen, L. M. T., Nguyen, D. T. N., Le, T. V., Li, W., Le, C. H., Mol, B. W., & Vuong, L. N. (2020). Effectiveness of cervical pessary compared to cervical cerclage with or without vaginal progesterone for the prevention of preterm birth in women with twin pregnancies and a short cervix: Study protocol for a two-by-two factorial randomised clinical trial. BMJ Open, 10(6), 1–17. https://doi.org/10.1136/bmjopen-2019-036587
Dang, V. Q., He, Y. T. N., Pham, H. N. H., & Trieu, T. T. T. (2020). Effectiveness of cervical pessary compared to cervical cerclage with or without vaginal progesterone for the prevention of preterm birth in women with twin pregnancies and a short cervix: Study protocol for a two-by-two factorial randomised clinical trial. BMJ Open, 10(6), 1–17.
Dodd, J. M., & Crowther, C. A. (2009). The role of progesterone in prevention of preterm birth. International Journal of Women’s Health, 1(1), 73–84.
Elimian, A., Smith, K., Williams, M., Knudtson, E., Goodman, J. R., & Escobedo, M. B. (2016a). A randomized controlled trial of intramuscular versus vaginal progesterone for the prevention of recurrent preterm birth. International Journal of Gynecology and Obstetrics, 134(2), 169–172. https://doi.org/10.1016/j.ijgo.2016.01.010
Elimian, A., Smith, K., Williams, M., Knudtson, E., Goodman, J. R., & Escobedo, M. B. (2016b). A randomized controlled trial of intramuscular versus vaginal progesterone for the prevention of recurrent preterm birth. International Journal of Gynecology & Obstetrics, 134(2), 169–172.
Frey, H. A., Finneran, M. M., Hade, E. M., Waickman, C., Lynch, C. D., & Iams, J. D. (2019). 549: A comparison of vaginal and intramuscular progesterone for the prevention of recurrent preterm birth. American Journal of Obstetrics & Gynecology, 220(1), S367.
Frey, H. A., Finneran, M. M., Hade, E. M., Waickman, C., Lynch, C. D., Iams, J. D., & Landon, M. B. (2019). 549: A comparison of vaginal and intramuscular progesterone for the prevention of recurrent preterm birth. American Journal of Obstetrics and Gynecology, 220(1), S367. https://doi.org/10.1016/j.ajog.2018.11.571
Hezelgrave, N. L., Suff, N., Seed, P., Robinson, V., Carter, J., & Watson, H. (2024). Comparing cervical cerclage, pessary and vaginal progesterone for prevention of preterm birth in women with a short cervix (SuPPoRT): A multicentre randomised controlled trial. PLOS Medicine, 21(7), 1–15.
Hezelgrave, N. L., Suff, N., Seed, P., Robinson, V., Carter, J., Watson, H., Ridout, A., David, A. L., Pereira, S., Hoveyda, F., Girling, J., Vinayakarao, L., Tribe, R. M., & Shennan, A. H. (2024). Comparing cervical cerclage, pessary and vaginal progesterone for prevention of preterm birth in women with a short cervix (SuPPoRT): A multicentre randomised controlled trial. PLoS Medicine, 21(7 July), 1–15. https://doi.org/10.1371/journal.pmed.1004427
Hina, H., Nisa, Z. U., Nisa, S. U., & Khan, R. (2024). Comparison of efficacy of vaginal and intramuscular progesterone in preventing preterm birth in high-risk pregnant women. Indus Journal of Bioscience Research, 2(2), 1595–1600.
Hina, H., Nisa, Z. U., Nisa, Z. U., Nisa, S. U., & Khan, R. (2024). Comparison of Efficacy of Vaginal and Intramuscular Progesterone in Preventing Preterm Birth in High-Risk Pregnant Women. Indus Journal of Bioscience Research., 2(2), 1595–1600. https://doi.org/10.70749/ijbr.v2i02.389
Iqbal, S., Hanif, S., Nisa, Z. U., Shabbir, A., Anwar, K., & Afridi, N. (2023a). Comparison of the effectiveness of oral progesterone and micronized progesterone pessary in reducing the spontaneous preterm birth incidences. Pakistan Journal of Medical and Health Sciences, 17(2), 395–398.
Iqbal, S., Hanif, S., Nisa, Z. U., Shabbir, A., Anwar, K., & Afridi, N. (2023b). Comparison of the Effectiveness of Oral Progesterone and Micronized Progesterone Pessary in Reducing the Spontaneous Preterm Birth Incidences. Pakistan Journal of Medical and Health Sciences, 17(2), 395–398. https://doi.org/10.53350/pjmhs2023172395
Kabiri, D., Raif Nesher, D., Luxenbourg, D., Rottenstreich, A., Rosenbloom, J. I., & Ezra, Y. (2023). The role of vaginal progesterone for preterm birth prevention in women with threatened labor and shortened cervix diagnosed after 24 weeks of pregnancy. International Journal of Gynecology & Obstetrics, 161(2), 423–431.
Kabiri, D., Raif Nesher, D., Luxenbourg, D., Rottenstreich, A., Rosenbloom, J. I., Ezra, Y., Yagel, S., Porat, S., & Romero, R. (2023). The role of vaginal progesterone for preterm birth prevention in women with threatened labor and shortened cervix diagnosed after 24 weeks of pregnancy. International Journal of Gynecology and Obstetrics, 161(2), 423–431. https://doi.org/10.1002/ijgo.14465
Khashukoyeva, A. Z., Agayeva, M., Savchenko, T. N., Agayeva, Z. A., Burdenko, M. V, & Lobacheva, Y. I. (2024). The role of progesterone preparations in the prevention of premature birth: A modern view of the problem.
Le, K. D., Nguyen, L. K., Nguyen, L. T. M., Mol, B. W. J., & Dang, V. Q. (2020). Cervical pessary vs vaginal progesterone for prevention of preterm birth in women with twin pregnancy and short cervix: Economic analysis following randomized controlled trial. Ultrasound in Obstetrics & Gynecology, 55(3), 339–347.
McLindon, L. A., James, G., Beckmann, M. M., Bertolone, J., Mahomed, K., & Vane, M. (2023). Progesterone for women with threatened miscarriage (STOP trial): A placebo-controlled randomized clinical trial. Human Reproduction, 38(4), 560–568.
Mclindon, L. A., James, G., Beckmann, M. M., Bertolone, J., Mahomed, K., Vane, M., Baker, T., Gleed, M., Grey, S., Tettamanzi, L., Mol, B. W. J., & Li, W. (2023). Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial. Human Reproduction, 38(4), 560–568. https://doi.org/10.1093/humrep/dead029
Nelson, D. B., Lafferty, A., Venkatraman, C., McDonald, J. G., Eckert, K. M., & McIntire, D. D. (2022). Association of vaginal progesterone treatment with prevention of recurrent preterm birth. JAMA Network Open, 5(10), e2237600.
Nelson, D. B., Lafferty, A., Venkatraman, C., McDonald, J. G., Eckert, K. M., McIntire, D. D., & Spong, C. Y. (2022). Association of Vaginal Progesterone Treatment With Prevention of Recurrent Preterm Birth. JAMA Network Open, 5(10), e2237600. https://doi.org/10.1001/jamanetworkopen.2022.37600
Norman, J. E., Marlow, N., Messow, C. M., Shennan, A., Bennett, P. R., & Thornton, S. (2016). Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): A multicentre, randomised, double-blind trial. The Lancet, 387(10033), 2106–2116.
Norman, J. E., Marlow, N., Messow, C. M., Shennan, A., Bennett, P. R., Thornton, S., Robson, S. C., McConnachie, A., Petrou, S., Sebire, N. J., Lavender, T., Whyte, S., & Norrie, J. (2016). Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): A multicentre, randomised, double-blind trial. The Lancet, 387(10033), 2106–2116. https://doi.org/10.1016/S0140-6736(16)00350-0
Palareti, G., Legnani, C., Cosmi, B., Antonucci, E., Erba, N., & Poli, D. (2016). Comparison between different D-Dimer cutoff values to assess the individual risk of recurrent venous thromboembolism: Analysis of results obtained in the DULCIS study. International Journal of Laboratory Hematology, 38(1), 42–49.
Rehal, A., Benk?, Z., De Paco Matallana, C., Syngelaki, A., Janga, D., & Cicero, S. (2021). Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: A randomized, double-blind trial. American Journal of Obstetrics & Gynecology, 224(1), 86.e1-86.e19.
Rehal, A., Benk?, Z., De Paco Matallana, C., Syngelaki, A., Janga, D., Cicero, S., Akolekar, R., Singh, M., Chaveeva, P., Burgos, J., Molina, F. S., Savvidou, M., De La Calle, M., Persico, N., Quezada Rojas, M. S., Sau, A., Greco, E., O’Gorman, N., Plasencia, W., … Nicolaides, K. H. (2021). Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial. American Journal of Obstetrics and Gynecology, 224(1), 86.e1-86.e19. https://doi.org/10.1016/j.ajog.2020.06.050
Romero, R., Meyyazhagan, A., Hassan, S. S., Creasy, G., & Conde-Agudelo, A. (2024). Vaginal progesterone to prevent spontaneous preterm birth in women with a sonographic short cervix: The story of the PREGNANT trial. Clinical Obstetrics and Gynecology.
Sykes, L., & Bennett, P. R. (2018). Efficacy of progesterone for prevention of preterm birth. Best Practice & Research Clinical Obstetrics & Gynaecology, 52, 126–136.
van Dijk, C. E., van Gils, A. L., van Zijl, M. D., Koullali, B., van der Weide, M. C., & van den Akker, E. S. (2024). Cervical pessary versus vaginal progesterone in women with a singleton pregnancy, a short cervix, and no history of spontaneous preterm birth at less than 34 weeks’ gestation: Open label, multicentre, randomised, controlled trial. BMJ.
van Dijk, C. E., van Gils, A. L., van Zijl, M. D., Koullali, B., van der Weide, M. C., van den Akker, E. S., Hermsen, B. J., van Baal, W. M., Visser, H., van Drongelen, J., Vollebregt, K. C., Muller, M., van der Made, F. W., Gordijn, S. J., de Mooij, Y. M., Oudijk, M. A., de Boer, M. A., Mol, B. W. J., Kazemier, B. M., & Pajkrt, E. (2024). Cervical pessary versus vaginal progesterone in women with a singleton pregnancy, a short cervix, and no history of spontaneous preterm birth at less than 34 weeks’ gestation: open label, multicentre, randomised, controlled trial. Bmj. https://doi.org/10.1136/bmj-2023-077033
Copyright (c) 2026 I Made Wira Saputra, Salmon Charles Pardomuan Tua Siahaan, Ni Putu Abdi Mahadewi
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-ShareAlike 4.0 International (CC-BY-SA). that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.
