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CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2019; 79(08): 834-843
DOI: 10.1055/a-0829-3992
GebFra Science
Review/Übersicht
Georg Thieme Verlag KG Stuttgart · New York

Progesterone – Effective for Tocolysis and Maintenance Treatment After Arrested Preterm Labour?

Critical Analysis of the Evidence Article in several languages: English | deutsch
Werner Rath
1   Medizinische Fakultät Gynäkologie und Geburtshilfe, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany
,
Ruben-J. Kuon
2   Universitätsklinikum Heidelberg, Abteilung für Gynäkologische Endokrinologie und Fertilitätsstörungen, Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

received 07 November 2018
revised 05 January 2019

accepted 07 January 2019

Publication Date:
13 May 2019 (online)

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Abstract

Numerous experimental studies indicate that natural progesterone, through various mechanisms, exerts an inhibitory effect on uterine contractility and sensitises the myometrium for tocolytics. It was therefore appropriate to investigate the possible benefits of oral/vaginal progesterone and the synthetic progesterone derivative 17-α-hydroxyprogesterone caproate, applied intramuscularly, in clinical studies on primary tocolysis, additively to established tocolytics (“adjunctive tocolysis”) and as maintenance treatment after successful tocolysis in cases of threatened preterm birth. Three studies with a small number of cases do not yield any sufficient evidence for recommending progesterone/17-α-hydroxyprogesterone caproate as primary tocolysis in women with preterm labour. There is also no evidence that progesterone or 17-α-hydroxyprogesterone caproate combined with commonly used tocolytics leads to a prolongation of pregnancy and a significant decrease in the rate of preterm birth. The data on the use of progesterone as maintenance treatment is controversial. While randomised, controlled studies with low quality showed promising results, studies with high quality did not reveal any significant differences with regard to the rate of preterm birth < 37 weeks of gestation, the latency period until delivery and in the neonatal outcome between progesterone/17-α-hydroxyprogesterone caproate and placebo or no treatment. Significant differences in the methodology, the inclusion and outcome criteria, the mode of application and the dosages of the substances as well as the inadequate statistical power as a result of low numbers of cases make interpretation and comparability of the studies difficult. Therefore, well-designed randomised, placebo-controlled, double-blind studies with uniform primary outcome criteria are needed in order to clarify whether progesterone and via which route of administration and at which dosage is of clinical benefit for patients with manifest preterm contractions and as maintenance treatment after arrested preterm labour.

Key words

preterm labour - progesterone - 17-α-hydroxyprogesterone caproate - tocolysis - maintenance treatment/tocolysis
 

  • References/Literatur

  • 1 Csapo A, Goodall M. Excitability, length tension relation and kinetics of uterine muscle contraction in relative to the hormonal status. J Physiol 1954; 126: 384-395
    CrossrefPubMedGoogle Scholar
  • 2 Fuchs F, Stakemann G. Treatment of threatened premature labor with large doses of progesterone. Obstet Gynecol 1960; 79: 172-176
    CrossrefPubMedGoogle Scholar
  • 3 Erny R, Pigne A, Prouvost C. et al. The effects of oral administration of progesterone for premature labor. Obstet Gynecol 1986; 154: 525-529
    CrossrefPubMedGoogle Scholar
  • 4 Kuon RJ, Abele H, Berger R. et al. Progesterone for prevention of preterm birth – evidence-based indications. Z Geburtsh Neonatol 2015; 219: 125-135
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Sykes L, Bennett PR. Efficacy of progesterone for prevention of preterm birth. Best Pract Res Clin Obstet Gynaecol 2018; DOI: 10.1016/j.bpobgyn.2018.08.006.
    CrossrefPubMedGoogle Scholar
  • 6 Baumbach J, Shi S, Shi L. et al. Inhibition of uterine contractility with various tocolytics with and without progesterone: in vitro studies. Am J Obstet Gynecol 2012; 206: 254.e1-254.e5
    CrossrefPubMedGoogle Scholar
  • 7 Gaspar R, Ducza E, Mihalyi A. et al. Pregnancy-induced decrease in the relaxant effect of terbutaline in the late-pregnant rat myometrium: role of G-protein activation and progesterone. Reproduction 2005; 130: 113-122
    CrossrefPubMedGoogle Scholar
  • 8 Lucovnik M, Bregar AT, Bombac L. et al. Effects of vaginal progesterone for maintenance tocolysis on uterine electrical activity. J Obstet Gynaecol Res 2018; 44: 408-416
    CrossrefPubMedGoogle Scholar
  • 9 Keirse MJNC. Progesterone administration in pregnancy may prevent preterm delivery. BJOG 1990; 97: 149-154
    CrossrefPubMedGoogle Scholar
  • 10 da Fonseca EB, Bittar RE, Carvalho MH. et al. 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
    CrossrefPubMedGoogle Scholar
  • 11 Chawanpaiboon S, Pimos K, Sirisamboon R. Comparison of success rate of nifedipine, progesterone, and bed rest for inhibiting uterine contraction in threatened preterm labour. J Obstet Gynaecol Res 2011; 37: 387-391
    PubMedGoogle Scholar
  • 12 Noblot G, Audra P, Dargent D. et al. The use of micronized progesterone in the treatment of menace of preterm delivery. Eur J Obstet Reprod Biol 1991; 40: 203-209
    CrossrefPubMedGoogle Scholar
  • 13 Arikan I, Barut A, Harma M. et al. Effect of progesterone as a tocolytic and in maintenance therapy during preterm labor. Gynecol Obstet Invest 2011; 72: 269-273
    CrossrefPubMedGoogle Scholar
  • 14 Tan PC, King ASJ, Vallikkannu N. et al. Single dose 17 alpha-hydroxyprogesterone caproate in preterm labor: a randomized trial. Arch Gynecol Obstet 2012; 285: 585-590
    CrossrefPubMedGoogle Scholar
  • 15 Areeruk W, Phupon V. A randomized, double blind placebo-controlled trial of oral dydrogesterone supplementation in the management of preterm labour. Scientific Reports 2016; DOI: 10.1038/srep20638.
    CrossrefPubMedGoogle Scholar
  • 16 Martinez de Tejada B, Karolinski A, Ocampo MC. et al. Prevention of preterm delivery with vaginal progesterone in women with preterm labour (4P): randomised double-blind placebo-controlled trial. BJOG 2015; 122: 80-91
    CrossrefPubMedGoogle Scholar
  • 17 Bomba-Opon DA, Kosinska-Kaczynska K, Kosinski P. et al. Vaginal progesterone after tocolytic therapy in threatened preterm labor. J Matern Fetal Neonatal Med 2017; 25: 1156-1159
    PubMedGoogle Scholar
  • 18 Di Renzo GC, Roura LC, Facchinetti F. et al. Preterm Labor and birth management: Recommendations from the European Association of Perintal Medicine. J Matern Fetal Neonatal Med 2017; 30: 2011-2030
    CrossrefPubMedGoogle Scholar
  • 19 ACOG Practice Bulletin No. 171. Management of Preterm Labor. Obstet Gynecol 2016; 128: e155-e164
    CrossrefPubMedGoogle Scholar
  • 20 Sentilhes L, Senat MV, Aucel PY. et al. Prevention of spontaneous preterm birth. Guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF). Eur J Obstet Gynecol Reprod Biol 2017; 210: 217-224
    CrossrefPubMedGoogle Scholar
  • 21 Rath W. Geburtseinleitung und Wehenhemmung. In: Dimpfl T, Fischer T, Jackisch C, Mallmann P. Hrsg. Gyn-Update 2012. Handbuch Gynäkologie/Geburtshilfe. Wiesbaden: med publico GmbH; 2012
    Google Scholar
  • 22 van Vliet E, Dijkema GH, Schmitt E. et al. Nifedipine maintenance tocolysis and perinatal outcome: an individual participant data meta-analysis. BJOG 2016; 123: 1753-1760
    CrossrefPubMedGoogle Scholar
  • 23 Su LL, Samuel M, Chong YS. Progestational agents for treating threatened or established preterm labour. Cochrane Database Syst Rev 2014; (01) CD006770
    PubMedGoogle Scholar
  • 24 Facchinetti F, Paganelli S, Comitini G. et al. Cervical length changes during preterm cervical ripening: effects of 17-α-hydroxyprogesterone caproate. Am J Obstet Gynecol 2007; 196: 453e1-453e4
    CrossrefPubMedGoogle Scholar
  • 25 Navathe R, Berghella V. Progesterone as a tocolytic agent for preterm labor: a systematic review. Curr Opin Obstet Gynecol 2016; 28: 464-469
    CrossrefPubMedGoogle Scholar
  • 26 Suhag A, Saccone G, Berghella V. Vaginal progesterone for maintenance tocolysis: a systematic review and metaanalysis of randomized trials. Obstet Gynecol 2015; 213: 479-487
    CrossrefPubMedGoogle Scholar
  • 27 Saccone G, Suhag A, Berghella V. 17-α-hydroxyprogesterone caproate for maintenance tocolysis: a systematic review and metaanalysis of randomized trials. Obstet Gynecol 2015; 213: 16-22
    CrossrefPubMedGoogle Scholar
  • 28 Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial. Aust N Z J Obstet Gynaecol 2008; 48: 58-63
    CrossrefPubMedGoogle Scholar
  • 29 Sharami SH, Zahri Z, Shakiba M. et al. Maintenance therapy by vaginal progesterone after threatened idiopathic preterm labor: a randomized placebo-controlled double-blind trial. Int J Fertil Steril 2010; 4: 45-50
    PubMedGoogle Scholar
  • 30 Areia A, Fonseca E, Moura P. Progesterone use after successful treatment of threatened preterm delivery. J Obstet Gynaecol 2013; 33: 678-681
    CrossrefPubMedGoogle Scholar
  • 31 Lotfalizadeh M, Ghomian N, Reyhani A. The effects of progesterone therapy on the gestation length and reduction of neonatal complications in patients who has received tocolytic therapy for acute phase of preterm labor. Irania Red Crescent Med J 2013; 15: e7947
    PubMedGoogle Scholar
  • 32 Rozenberg P, Chauveaud A, Deruelle P. et al. Prevention of preterm delivery after successful tocolysis in preterm labor by 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Am J Obstet Gynecol 2012; 206: 206.e1-206.e9
    CrossrefPubMedGoogle Scholar
  • 33 Regni MC, Rijal P, Agrawai A. et al. Progesterone for prevention of recurrent preterm labor after arrested preterm labor: a randomized controlled trial. Gynecol Obstet 2012; 2: 125-127
    PubMedGoogle Scholar
  • 34 Briery CM, Klauser CK, Martin RW. et al. The use of 17-hydroxy progesterone in women with arrested preterm labor: a randomized clinical trial. J Matern Fetal Neonatal Med 2014; 27: 1892-1896
    CrossrefPubMedGoogle Scholar
  • 35 Eke AC, Chalaan T, Shukr G. et al. A systematic review and meta-analysis of progestogen use for maintenance tocolysis after preterm labor in women with intact membranes. Int J Gynaecol Obstet 2016; 132: 11-16
    CrossrefPubMedGoogle Scholar
  • 36 Ding MX, Luo X, Zhang XM. et al. Progesterone and nifedipine for maintenance tocolysis after arrested preterm labor. A systematic review and meta-analysis of randomized controlled trial. Taiwan J Obstet Gynecol 2016; 55: 399-404
    CrossrefPubMedGoogle Scholar
  • 37 Kamat S, Veena P, Rani R. Comparison of nifedipine and progesterone for maintenance tocolysis after arrested labour. J Obstet Gynaecol 2014; 34: 322-325
    CrossrefPubMedGoogle Scholar
  • 38 Choudkary M, Suneja A, Vaid NB. et al. Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested labor. Int J Gynaecol Obstet 2014; 126: 60-63
    CrossrefPubMedGoogle Scholar
  • 39 Gargari SS, Habibolohi M, Zonobi Z. et al. Outcome of vaginal progesterone as a tocolytic agent: randomized clinical trials. ISRN Obstet Gynecol 2012; DOI: 10.5402/2012/607906.
    CrossrefPubMedGoogle Scholar
  • 40 Palacio M, Cobo T, Antolin E. et al. Vaginal progesterone and maintenance treatment after an episode of preterm labour (PROMISE) study: a multicentre, double-blind, randomised placebo-controlled trial. BJOG 2016; 123: 1990-1999
    CrossrefPubMedGoogle Scholar
  • 41 Palacio M, Rontoni S, Sanchez-Ramos L. et al. Progestogens as maintenance treatment in arrested preterm labor: a systematic review and meta-analysis. Obstet Gynecol 2016; 128: 989-1000
    CrossrefPubMedGoogle Scholar
  • 42 El-Abidin E, Mahmood M, Rashwan H. et al. Efficacy of vaginal progesterone for maintenance tocolysis: a recent trend in the management of arrested preterm labour. Med J Cairo Univ 2009; 77: 99-104
    PubMedGoogle Scholar
  • 43 Mishra G, Inamdar S. Role of micronized progesterone in maintenance therapy following arrested preterm labor: a randomized controlled trial. Int J Reprod Contracept Obstet Gynecol 2014; 3: 1050-1055
    CrossrefPubMedGoogle Scholar
  • 44 Higgins JP, Altman DG, Gotzsche PC. et al. The Cochrane Collaborationʼs tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d.5928
    CrossrefPubMedGoogle Scholar
  • 45 Jadad AR, Moore RA, Carroll D. et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials 1996; 17: 1-12
    CrossrefPubMedGoogle Scholar
  • 46 Facchinetti F, Verjani P, Tommaso M. et al. Progesterone for maintenance tocolysis in women with a short cervix. Obstet Gynecol 2017; 130: 64-70
    CrossrefPubMedGoogle Scholar
  • 47 Wood S, Rabi Y, Tang S. et al. Progesterone in women with arrested premature labor, a report of a randomised clinical trial and updated meta-analysis. BMC Pregnancy Childbirth 2017; 17: 258 doi:10.1186/s12884-017-1400-y
    CrossrefPubMedGoogle Scholar
  • 48 Rath W, Kehl S. Acute Tocolysis – a Critical Analysis of Evidence-Based Data. Geburtsh Frauenheilk 2018; 78: 1245-1255
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Ruddock NK, Shi S-Q, Jain S. et al. Progesterone, but not 17-α-hydroxyprogesterone caproate, inhibits human myometrial contractions. Am J Obstet Gynecol 2008; 199: 391.e1-391.e7
    CrossrefPubMedGoogle Scholar
  • 50 Anderson I, Martin W, Higgins C. et al. The effect of progesterone on myometrial contractility, potassium channels, and tocolytic efficacy. Reprod Sci 2009; 16: 1052-1061
    CrossrefPubMedGoogle Scholar
  • 51 Miles RA, Paulson RJ, Lobo RA. et al. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertil Steril 1994; 62: 485-490
    CrossrefPubMedGoogle Scholar
  • 52 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.e1-455.e9
    CrossrefPubMedGoogle Scholar
  • 53 Ziegler D, Buletti C, Monstier D. et al. The first uterine pass effect. Ann N Y Acad Sci 1997; 828: 291-299
    CrossrefPubMedGoogle Scholar
  • 54 Kyvernitakis I, Maul H, Bahlmann F. Controversies about the Secondary Prevention of Spontaneous Preterm Birth. Geburtsh Frauenheilk 2018; 78: 585-595
    Article in Thieme ConnectPubMedGoogle Scholar