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Am J Perinatol 2024; 41(01): 001-016
DOI: 10.1055/a-1877-5827
Review Article

Pregnant Populations which Benefit from Vaginal Progesterone for Preventing Preterm Birth at <34 Weeks and Neonatal Morbidities: A Systematic Review and Meta-analysis

Xiaobin Lin
1   School of Pediatrics, Guangzhou Medical University, Guangzhou, China
,
Yu Nie
2   The Mental Health College of Guangzhou Medical University, Guangzhou, China
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Abstract

This study aimed to assess vaginal progesterone's effect on different populations and performed comparation between women with varied risk factors. Embase, PubMed, Cochrane library (CENTRAL) were searched without restriction to language up to February 25, 2021. Randomized controlled trials (RCTs) assessing vaginal progesterone administered to women at risk of preterm birth at <37 weeks. Two reviewers independently extracted data, and pooled relative risk (RR) with 95% confidence intervals (CIs) was calculated as well. Women with short cervix have a significantly lower risk of preterm birth at <34 weeks (pooled RR = 0.65; 95% CI: 0.55–0.77; I 2 = 0; p < 0.001; nine studies) and some neonatal morbidities; interaction tests showed that effect of vaginal progesterone differs significantly between women with short cervix and those with other risk factors (history of preterm birth, exclusive twin gestation, and vaginal bleeding). Evidences of this study showed that singleton gestations, as well as women with short cervix, benefit from vaginal progesterone in preventing preterm birth at <34 weeks and some neonatal morbidities. Women with short cervix are populations who benefit the most among other risk populations.

Key Points

  • Vaginal progesterone reduces preterm birth and neonatal morbidities.

  • Vaginal progesterone effects on some specific populations.

  • Women with short cervix benefit the most.

Keywords

neonatal morbidity - preterm birth - risk factors - short cervix - vaginal progesterone

Authors' Contributions

X.L. conceived the original research. X.L. and Y.N. contributed to the design of the study. X.L. executed the search strategy and study selection. X.L. and Y.N. collected the data and assessed the risk of bias and the quality of the evidence. X.L. and Y.N. conducted the statistical analyses. Y.N. designed the tables and edited the figures. X.L. drafted the manuscript. X.L. and Y.N. contributed to the interpretation of the results and commented on the manuscript. X.L. is the guarantor for the research.


Supplementary Material



Publication History

Received: 18 June 2021

Accepted: 03 June 2022

Accepted Manuscript online:
16 June 2022

Article published online:
05 December 2022

© 2022. Thieme. All rights reserved.

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  • References

  • 1 Gibson JL, Macara LM, Owen P, Young D, Macauley J, Mackenzie F. Prediction of preterm delivery in twin pregnancy: a prospective, observational study of cervical length and fetal fibronectin testing. Ultrasound Obstet Gynecol 2004; 23 (06) 561-566
    CrossrefPubMedGoogle Scholar
  • 2 Goldenberg RL, Iams JD, Miodovnik M. et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. The preterm prediction study: risk factors in twin gestations. Am J Obstet Gynecol 1996; 175 (4, pt. 1): 1047-1053
    CrossrefPubMedGoogle Scholar
  • 3 Hamilton BE, Martin JA, Osterman MJ, Curtin SC, Matthews TJ. Births: Final data for 2014. Natl Vital Stat Rep 2015; 64 (12) 1-64
    PubMedGoogle Scholar
  • 4 Medley N, Vogel JP, Care A, Alfirevic Z. Interventions during pregnancy to prevent preterm birth: an overview of Cochrane systematic reviews. Cochrane Database Syst Rev 2018; 11 (11) CD012505
    PubMedGoogle Scholar
  • 5 Matei A, Saccone G, Vogel JP, Armson AB. Primary and secondary prevention of preterm birth: a review of systematic reviews and ongoing randomized controlled trials. Eur J Obstet Gynecol Reprod Biol 2019; 236: 224-239
    CrossrefPubMedGoogle Scholar
  • 6 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6 (07) e1000097
    CrossrefPubMedGoogle Scholar
  • 7 Cobo T, Kacerovsky M, Jacobsson B. Risk factors for spontaneous preterm delivery. Int J Gynaecol Obstet 2020; 150 (01) 17-23
    CrossrefPubMedGoogle Scholar
  • 8 Torchin H, Ancel PY. Epidemiology and risk factors of preterm birth [in French]. J Gynecol Obstet Biol Reprod (Paris) 2016; 45 (10) 1213-1230
    PubMedGoogle Scholar
  • 9 Higgins JPT, Altman DG, Sterne JAC. Assessing risk of bias in included studies. In: Higgins JPT, Green S. eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Accessed June 24, 2022 at: https://handbook-5-1.cochrane.org/
    CrossrefGoogle Scholar
  • 10 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414): 557-560
    CrossrefPubMedGoogle Scholar
  • 11 Deeks JJ, Higgins JPT, Altman DG. Analyzing data and undertaking meta-analyses. In: Higgins JPT, Green S. eds. Cochrane handbook for systematic reviews of interventions. Version 5.1.0. Accessed June 24, 2022 at: https://handbook-5-1.cochrane.org/
    Google Scholar
  • 12 Sun X, Ioannidis JP, Agoritsas T, Alba AC, Guyatt G. How to use a subgroup analysis: users' guide to the medical literature. JAMA 2014; 311 (04) 405-411
    CrossrefPubMedGoogle Scholar
  • 13 Rothwell PM. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet 2005; 365 (9454): 176-186
    CrossrefPubMedGoogle Scholar
  • 14 Klebanoff MA. Subgroup analysis in obstetrics clinical trials. Am J Obstet Gynecol 2007; 197 (02) 119-122
    CrossrefPubMedGoogle Scholar
  • 15 Brizot ML, Hernandez W, Liao AW. et al. Vaginal progesterone for the prevention of preterm birth in twin gestations: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2015; 213 (01) 82.e1-82.e9
    CrossrefPubMedGoogle Scholar
  • 16 Cetingoz E, Cam C, Sakallı M, Karateke A, Celik C, Sancak A. Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial. Arch Gynecol Obstet 2011; 283 (03) 423-429
    CrossrefPubMedGoogle Scholar
  • 17 Coomarasamy A, Devall AJ, Cheed V. et al. A randomized trial of progesterone in women with bleeding in early pregnancy. N Engl J Med 2019; 380 (19) 1815-1824
    CrossrefPubMedGoogle Scholar
  • 18 Coomarasamy A, Harb HM, Devall AJ. et al. Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT. Health Technol Assess 2020; 24 (33) 1-70
    CrossrefPubMedGoogle Scholar
  • 19 Crowther CA, Ashwood P, McPhee AJ. et al; PROGRESS Study Group. 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 Med 2017; 14 (09) e1002390
    CrossrefPubMedGoogle Scholar
  • 20 El-Refaie W, Abdelhafez MS, Badawy A. Vaginal progesterone for prevention of preterm labor in asymptomatic twin pregnancies with sonographic short cervix: a randomized clinical trial of efficacy and safety. Arch Gynecol Obstet 2016; 293 (01) 61-67
    CrossrefPubMedGoogle Scholar
  • 21 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 (02) 419-424
    CrossrefPubMedGoogle Scholar
  • 22 Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007; 357 (05) 462-469
    CrossrefPubMedGoogle Scholar
  • 23 Hassan SS, Romero R, Vidyadhari D. et al; PREGNANT Trial. 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 (01) 18-31
    CrossrefPubMedGoogle Scholar
  • 24 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 (9680): 2034-2040
    CrossrefPubMedGoogle Scholar
  • 25 Norman JE, Marlow N, Messow CM. et al. Does progesterone prophylaxis to prevent preterm labour improve outcome? A randomised double-blind placebo-controlled trial (OPPTIMUM). Health Technol Assess 2018; 22 (35) 1-304
    CrossrefPubMedGoogle Scholar
  • 26 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 (05) 687-696
    CrossrefPubMedGoogle Scholar
  • 27 DeFranco EA, O'Brien JM, Adair CD. et al. Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2007; 30 (05) 697-705
    CrossrefPubMedGoogle Scholar
  • 28 Rehal A, Benkő Z, De Paco Matallana C. et al. Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial. Am J Obstet Gynecol 2021; 224 (01) 86.e1-86.e19
    CrossrefPubMedGoogle Scholar
  • 29 Rode L, Klein K, Nicolaides KH, Krampl-Bettelheim E, Tabor A. PREDICT Group. Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo-controlled trial on the effect of vaginal micronized progesterone. Ultrasound Obstet Gynecol 2011; 38 (03) 272-280
    CrossrefPubMedGoogle Scholar
  • 30 Klein K, Rode L, Nicolaides KH, Krampl-Bettelheim E, Tabor A. PREDICT Group. Vaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies: secondary analysis of a placebo-controlled randomized trial and meta-analysis. Ultrasound Obstet Gynecol 2011; 38 (03) 281-287
    CrossrefPubMedGoogle Scholar
  • 31 Salim R, Hakim M, Zafran N, Nachum Z, Romano S, Garmi G. Double-blind randomized trial of progesterone to prevent preterm birth in second-trimester bleeding. Acta Obstet Gynecol Scand 2019; 98 (10) 1318-1325
    CrossrefPubMedGoogle Scholar
  • 32 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 (01) 50-57
    CrossrefPubMedGoogle Scholar
  • 33 van Os MA, van der Ven AJ, Kleinrouweler CE. et al. Preventing preterm birth with progesterone in women with a short cervical length from a low-risk population: a multicenter double-blind placebo-controlled randomized trial. Am J Perinatol 2015; 32 (10) 993-1000
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Wood S, Ross S, Tang S, Miller L, Sauve R, Brant R. Vaginal progesterone to prevent preterm birth in multiple pregnancy: a randomized controlled trial. J Perinat Med 2012; 40 (06) 593-599
    CrossrefPubMedGoogle Scholar
  • 35 Romero R, Nicolaides KH, Conde-Agudelo A. et al. Vaginal progesterone decreases preterm birth ≤ 34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study. Ultrasound Obstet Gynecol 2016; 48 (03) 308-317
    CrossrefPubMedGoogle Scholar
  • 36 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 (02) 161-180
    CrossrefPubMedGoogle Scholar
  • 37 Jarde A, Lutsiv O, Beyene J, McDonald SD. 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 (05) 556-567
    CrossrefPubMedGoogle Scholar
  • 38 Romero R, Conde-Agudelo A, El-Refaie W. et al. Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta-analysis of individual patient data. Ultrasound Obstet Gynecol 2017; 49 (03) 303-314
    CrossrefPubMedGoogle Scholar
  • 39 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 (02) 124.e1-124.e19
    CrossrefPubMedGoogle Scholar
  • 40 Jarde A, Lutsiv O, Park CK. et al. Preterm birth prevention in twin pregnancies with progesterone, pessary, or cerclage: a systematic review and meta-analysis. BJOG 2017; 124 (08) 1163-1173
    CrossrefPubMedGoogle Scholar
  • 41 Schuit E, Stock S, Rode L. et al; Global Obstetrics Network (GONet) collaboration. Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis. BJOG 2015; 122 (01) 27-37
    CrossrefPubMedGoogle Scholar
  • 42 Dodd JM, Grivell RM, OBrien CM, Dowswell T, Deussen AR. Prenatal administration of progestogens for preventing spontaneous preterm birth in women with a multiple pregnancy. Cochrane Database Syst Rev 2019; 2019 (11) CD012024
    PubMedGoogle Scholar
  • 43 Wahabi HA, Fayed AA, Esmaeil SA, Bahkali KH. Progestogen for treating threatened miscarriage. Cochrane Database Syst Rev 2018; 8: CD005943
    PubMedGoogle Scholar