Progesteron – effektiv zur Wehenhemmung und zur Erhaltungstherapie nach Wehenstopp?

Zusammenfassung

Zahlreiche experimentelle Studien weisen darauf hin, dass natürliches Progesteron über verschiedene Mechanismen einen inhibitorischen Effekt auf die uterine Kontraktilität ausübt und das Myometrium für Tokolytika sensibilisiert. Daher war es sinnvoll, die möglichen Vorteile von oralem/vaginalem Progesteron und des intramuskulär applizierten synthetischen Progesteronderivats 17-α-Hydroxyprogesteroncaproat in klinischen Studien zur primären Tokolyse, additiv zu etablierten Tokolytika („adjunktive Tokolyse“) und zur Erhaltungstherapie nach erfolgreicher Wehenhemmung bei drohender Frühgeburt zu untersuchen. Aus drei Studien mit kleiner Fallzahl ergibt sich keine ausreichende Evidenz, Progesteron/17-α-Hydroxyprogesteroncaproat zur primären Tokolyse bei Frauen mit vorzeitiger Wehentätigkeit zu empfehlen. Es gibt ebenfalls keine Evidenz dafür, dass Progesteron oder 17-α-Hydroxyprogesteroncaproat in Kombination mit gebräuchlichen Tokolytika zu einer Verlängerung der Schwangerschaft und zu einer signifikanten Senkung der Rate an Frühgeburten führt. Die Datenlage zur Anwendung von Progesteron zur Erhaltungstherapie ist kontrovers. Während randomisierte, kontrollierte Studien mit niedriger Qualität vielversprechende Ergebnisse zeigten, ergaben sich aus Studien mit hoher Qualität keine signifikanten Unterschiede hinsichtlich der Frühgeburtenrate < 37 SSW, der Latenzzeit bis zur Geburt und im neonatalen Outcome zwischen Progesteron/17-α-Hydroxyprogesteroncaproat und Placebo oder keiner Behandlung. Erhebliche Unterschiede in der Methodologie, den Einschluss- und Zielkriterien, dem Applikationsmodus und den Dosierungen der Substanzen sowie die inadäquate statistische Power infolge niedriger Fallzahlen macht eine Interpretation und Vergleichbarkeit der Studien schwierig. Daher sind gut konzipierte, randomisierte, placebokontrollierte Doppelblindstudien mit einheitlichen primären Zielkriterien notwendig, um zu klären, ob Progesteron und auf welchem Applikationsweg und mit welcher Dosierung bei Patientinnen mit manifesten vorzeitigen Wehen und zur Erhaltungstherapie nach initialer Wehenhemmung von klinischem Nutzen ist.

Schlüsselwörter

vorzeitige Wehen - Progesteron - 17-α-Hydroxyprogesteroncaproat - Tokolyse - Erhaltungstherapie/-tokolyse

• 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
• 2 Fuchs F, Stakemann G. Treatment of threatened premature labor with large doses of progesterone. Obstet Gynecol 1960; 79: 172-176
• 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
• 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
• 5 Sykes L, Bennett PR. Efficacy of progesterone for prevention of preterm birth. Best Pract Res Clin Obstet Gynaecol 2018;
• 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
• 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
• 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
• 9 Keirse MJNC. Progesterone administration in pregnancy may prevent preterm delivery. BJOG 1990; 97: 149-154
• 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
• 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
• 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
• 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
• 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
• 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;
• 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
• 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
• 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
• 19 ACOG Practice Bulletin No. 171. Management of Preterm Labor. Obstet Gynecol 2016; 128: e155-e164
• 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
• 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
• 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
• 23 Su LL, Samuel M, Chong YS. Progestational agents for treating threatened or established preterm labour. Cochrane Database Syst Rev 2014; (01) CD006770
• 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
• 25 Navathe R, Berghella V. Progesterone as a tocolytic agent for preterm labor: a systematic review. Curr Opin Obstet Gynecol 2016; 28: 464-469
• 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
• 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
• 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
• 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
• 30 Areia A, Fonseca E, Moura P. Progesterone use after successful treatment of threatened preterm delivery. J Obstet Gynaecol 2013; 33: 678-681
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 39 Gargari SS, Habibolohi M, Zonobi Z. et al. Outcome of vaginal progesterone as a tocolytic agent: randomized clinical trials. ISRN Obstet Gynecol 2012;
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 48 Rath W, Kehl S. Acute Tocolysis – a Critical Analysis of Evidence-Based Data. Geburtsh Frauenheilk 2018; 78: 1245-1255
• 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
• 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
• 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
• 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
• 53 Ziegler D, Buletti C, Monstier D. et al. The first uterine pass effect. Ann N Y Acad Sci 1997; 828: 291-299
• 54 Kyvernitakis I, Maul H, Bahlmann F. Controversies about the Secondary Prevention of Spontaneous Preterm Birth. Geburtsh Frauenheilk 2018; 78: 585-595