Progesteron zur Prävention der Frühgeburt – Evidenz-basierte Indikationen

 

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Zusammenfassung

Hintergrund: Die Prävention und Behandlung der Frühgeburt gehört auch heute noch zu den ungelösten Problemen der Geburtshilfe. Progesteron entfaltet eine Vielzahl von Wirkungen auf Myometrium und Zervix, u. a. eine Hemmung der Myometriumkontraktion und eine zervixstabilisierende Wirkung durch Inhibition proinflammatorischer Zytokine und konsekutiv der Produktion von Prostaglandinen sowie durch die Reduktion der Expression von Proteinen, die für die Wehentätigkeit von Bedeutung sind. Daher ist Progesteron ein vielversprechender Kandidat zur Prävention der Frühgeburt.

Material und Methode: In PubMed wurde eine Literaturrecherche des Zeitraumes 1956–August 2014 durchgeführt, der folgende Suchbegriffe zugrunde lagen: Frühgeburt und Progesteron oder 17-OHPC oder Progestin.

Ergebnisse: (i) Frauen mit Einlingsschwangerschaften sollten nach vorangegangener Frühgeburt täglich vaginales Progesteron (200 mg Kapsel oder 90 mg Gel) von der 16+0 bis 36+0 SSW erhalten (alternativ: 250 mg 17-OHPC intramuskulär wöchentlich): Level of Evidence Ia, Empfehlungsgrad ++ . Die prophylaktische Applikation von Progesteron führt zu einer signifikanten Senkung der Rate an Frühgeburten <34 und < 37 SSW sowie zu einer Verminderung der perinatalen Mortalität. (ii) Frauen mit Einlingsschwangerschaften und einer sonografisch gemessenen Zervixlänge von ≤25 mm vor der 24+0 SSW sollten täglich Progesteron vaginal (200 mg Kapsel oder 90 mg Gel) bis zur 36+6 SSW erhalten: Level of Evidence Ia, Empfehlungsgrad ++ . Dieses Vorgehen führt zu einer signifikanten Senkung der Rate an Frühgeburten < 28, < 33 und < 35 SSW sowie zu einer Reduktion der neonatalen Morbidität. (iii) Es fehlen bisher Evidenz-basierte Daten, um Progesteron oder 17-OHPC zur primären Tokolyse oder in Kombination mit konventionellen Tokolytika (adjunktive Tokolyse) zu empfehlen. (iv) Es besteht eine zunehmende Evidenz, dass vaginales Progesteron (400 mg/Tag) nach initialer Tokolyse mit Sistieren der Wehen als Erhaltungstherapie zu einer signifikanten Verlängerung der Schwangerschaft führt: Level of Evidence Ib, Empfehlungsgrad +. (v) Die Datenlage zur Anwendung von vaginalem Progesteron nach vorzeitigem Blasensprung und als perioperative Maßnahme im Rahmen einer Zerklage ist unzureichend, um hieraus Evidenz-basierte Empfehlungen ableiten zu können. (vi) Die vaginale Applikation von Progesteron wird von den Schwangeren gut toleriert ohne signifikante Nebenwirkungen, die intramuskuläre Applikation von 17-OHPC intramuskulär ist dagegen mit einer deutlich höheren Rate an mütterlichen Nebenwirkungen (z. B. lokale Schmerzen, Übelkeit, Diarrhoe) assoziiert, die Frauen sind über den off-label use von Progesteron in der Schwangerschaft aufzuklären.

Diskussion: Die prophylaktische Gabe von Progesteron ist eine evidenzbasierte Maßnahme zur Prävention der Frühgeburt bei Frauen mit Einlingsschwangerschaft nach vorangegangener Frühgeburt und bei Schwangeren mit sonografisch verkürzter Zervix (≤ 25 mm) vor der 24. SSW. Die vaginale Applikation von Progesteron ist der intramuskulären Injektion von 17-OHPC insbesondere aufgrund der geringeren Rate maternaler NW vorzuziehen. Ob Progesteron zur primären oder adjunktiven Tokolyse oder zur Erhaltungstherapie nach initialer Tokolyse mit Sistieren der Wehen eine effektive Option zur Behandlung der Frühgeburt darstellt, muss in weiteren gut konzipierten randomisierten klinischen Studien mit ausreichender statistischer Power geklärt werden.

Abstract

Background: The prevention and treatment of preterm birth remains an unsolved problem in modern obstetrics. Progesterone has a variety of actions on the myometrium and the cervix, among others inhibition of myometrial contractility and a cervix strengthening effect by inhibiting the production of proinflammatory cytokines and prostaglandins as well as by reducing the synthesis of proteins, which play a crucial role in initiating labour. Consequently, progesterone may be a promising candidate for the prevention of preterm birth.

Material and Methods: We searched PubMed from 1956 to August 2014 using a combination of key words and text words related to preterm birth and progesterone. (‘progesterone’, progestins, 17-OHPC). The aim of the literature search was to determine evidence-based indications for the use of progesterone in the prevention of preterm birth.

Results: (i) Patients with a singleton pregnancy and history of preterm birth should receive vaginal progesterone daily (200 mg capsule or 90 mg containing gel) from 16+0 to 36+0 weeks of gestation (alternatively 250 mg intramuscular 17-OHPC weekly): level of evidence 1a, grade of recommendation ++ . Prophylactic progesterone reduces the incidence of preterm birth <34 and <37 weeks of gestation and perinatal mortality significantly. (ii) Patients with singleton pregnancies and a sonographically short cervix (≤25 mm) before 24 weeks of gestation should receive vaginal progesterone daily (200 mg capsule or 90 mg containing gel) until 36+6 weeks of gestation: level of evidence 1a, grade of recommendation ++ . Prophylactic progesterone leads to a significant reduction in the incidence of preterm birth <28, <33, and <35 weeks of gestation and is associated with a significant reduction of neonatal morbidity. (III) There is a lack of evidence to recommend vaginal progesterone or intramuscular 17-OHPC for primary tocolysis or for “adjunctive” tocolysis (in combination with conventional tocolytic agents). (IV) There is a growing body of evidence that vaginal progesterone (400 mg/day) after successful tocolysis (“maintenance therapy”) is a promising option for prolongation of pregnancy: level of evidence 1b, grade of recommendation +. (V) Data from the literature are insufficient to recommend progesterone in patients with preterm rupture of membranes or in the perioperative management of patients requiring transvaginal cervical cerclage. (VI) The vaginal administration of progesterone is well-tolerated by the patients and has only minor maternal side effects, whereas intramuscular injections of 17-OHPC are associated with a significant higher rate of side effects (e. g. local pain, nausea, diarrhoea). It is mandatory to inform patients on the off-label use of progesterone in pregnancy.

Discussion: Prophylactic progesterone administration is an evidence-based method for the prevention of preterm birth in women with a previous preterm birth and in pregnant women with a sonographically short cervix (≤25 mm) before 24 weeks of gestation. Vaginal progesterone is favoured over intramuscularly applied 17-OHPC, especially because of the lower rate of maternal side effects. Whether progesterone is an effective approach for the treatment of preterm birth as a tocolytic agent (primary, adjunctive) or for maintenance therapy after arrest of preterm labour has to be shown in further well-designed randomised and controlled trials with adequate statistical power.

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