Prevention of preterm delivery with vaginal progesterone in women with preterm labour (4P) A randomised double-blind placebo-controlled trial The 4P trial group

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Clinical Scenario A woman, 32 weeks pregnant, attends antenatal assessment unit with regular and painful uterine contractions. She describes 2 contractions every 10 min. She had one previous preterm delivery at 33 weeks of gestation and this is her second pregnancy. Transvaginal ultrasound on admission shows her cervical length to be 20mm. Antenatal corticosteroids and tocolysis with atosiban have just been initiated. She asked, “is there anything else you can do to stop the baby coming early again?”

Background Preterm delivery (PTD) is the leading cause of neonatal morbidity & mortality. Progesterone (P) is efficient in preventing PTD in some asymptomatic women at high risk for PTD.

Background What are the clinical indications for vaginal progesterone? Are they based on robust evidence?

The Clinical Question Can daily vaginal natural progesterone (200mg) prevent preterm births in women presenting with threatened preterm labour?

Description of Research ParticipantsWomen presenting with preterm labour (24+0 to 33+6 weeks) to 29 centers in Switzerland and Argentina, who have been started on tocolysis for less than 48 hours Intervention200mg of vaginal progesterone daily (self-administered) ComparisonPlacebo OutcomesPrimary outcome: delivery before 37 weeks of gestation Secondary outcomes: delivery before 32 and 34 weeks, side- effects, duration of tocolysis, re-admissions for signs and symptoms of preterm labour, length of hospital stay, and neonatal morbidity and mortality DesignA multicentre, randomized, double-blind, placebo-controlled trial

Methods Trial registration: NCT ( 9 hospitals in Switzerland ( ) and 20 hospitals in Argentina ( ) Pregnant women with signs of threatened preterm birth between 24+0 and 33+6 weeks of gestation and treated with tocolysis Randomisation was done in a 1:1 ratio using a list created with an independent, centralised computer-generated sequence Boxes were clearly labelled with the corresponding study number, gestational age group and the number of capsules Self-administration of vaginal progesterone

Methods What are the advantages and disadvantages of prospective registration of clinical trials ( During an interim analysis, what are the potential reasons for a steering committee to recommend stopping study enrolment early?

Results [379 women; 39.1% preterm rate] Comparing progesterone to placebo Preterm delivery : – <37 w: 42.5% vs. 35.5%; p:0.20 (RR 1.2; 95% CI ) – <34 w: 19.7% vs. 12.9%; p:0.10 (RR 1.5; 95% CI ) – <32 w: 12.9% vs. 9.7%; p:0.48 (RR 1.3; 95% CI ) Neonatal morbidity – 44 (22.8%) vs 35 (18.8%);p:0.30 (RR: 1.2; 95% CI ) Local side effects: – 11 (5.7%) vs Placebo:12(6.5%); p:1

Distribution of time to delivery The time-to-event (preterm delivery) analysis with censoring at 37 weeks when delivering at term showed a hazard ratio of 1.3 (95% CI ; log-rank Mantel-Cox: 0.11)

Other results After excluding women with elective PTD, there were 74/185 (40.0%) spontaneous PTD in the P group and 48/168 (28.6%) in the placebo group (RR 1.4; 95% CI ; P=0.03). Duration of tocolysis, hospitalisation, and frequency of a new episode of PTL were comparable between the study groups

Results How did the early closure of this clinical trial influence its results? Critically appraise this trial using the Critical Appraisal Skill Programme (CASP) checklist for randomised controlled trials (available from

Conclusion Can you summarise the available evidence in a single sentence? How would the results of this study influence your practice?

Authors’ conclusion In women with PTL treated with acute tocolysis, treatment with 200 mg daily of vaginal natural progesterone did not reduce preterm delivery or improve perinatal outcomes. Progesterone treatment had no effect on the duration of tocolysis, the duration of the first or any subsequent hospital stays, or the rate of recurrence of PTL.

Suggested reading Khan KS, Hills R. Can we trust the results of trials that are stopped early? BJOG Jul;113(7): The accompanying mini-commentary

The 4P trial group B Martinez de Tejada, A Karolinski, MC Ocampo,C Laterra, I Hösli, D Fernández, D Surbek, M Huespe, G Drack, A Bunader, S Rouillier, G López de Degani, E Seidenstein, E Prentl, J Antón, F Krähenmann, D Nowacki, M Poncelas, JC Nassif, R Papera, C Tuma, R Espoile, O Tiberio, G Breccia, A Messina, B Peker, E Schinner, B W Mol, L Kanterewicz, V Wainer, M Boulvain, V Othenin-Girard, MV Bertolino, O Irion Corresponding author: Dr. Martinez de Tejada

Funding The project was supported by grants from the University Hospitals of Geneva (PRD-05103), the Swiss National Foundation (main sponsor), Department of Reproductive Health and Research, World Health Organization, Ministry of Health of Ciudad Autónoma de Buenos Aires (grant for A Karolinski, resolution N° /2011- Investigator’s career) and a personal scholarship for Mrs MC Ocampo (degree N° /10). Besins Laboratory produced and supplied the study drugs (utrogestan and placebo) free of charge. The funding sources did not participate in the study design, data analysis, data interpretation, or writing the report