Progesterone in women with arrested premature labor, a report of a randomised clinical trial and updated meta-analysis

Women presenting in premature labor to our center, the Foothills Medical Center in Calgary, Alberta, Canada, were approached by the primary investigator or study nurse for enrollment in the study. Inclusion criteria were women with gestational age 23⁰–32⁶ weeks with symptomatic contractions successfully arrested for at least 12 h with tocolytics or those with contractions that spontaneously resolved but had a positive vaginal fetal fibronectin (>50 ng/ml). Exclusion criteria were multiple pregnancy, placenta previa, preterm premature rupture of membranes (PPROM) at presentation and any contraindication to progesterone use. Consenting subjects were allocated by a randomization schedule developed by the trial statistician (R.B) using a random number generator and in random blocks of 2 or 4. Randomization was stratified into two strata to ensure balance in these important risk factors for preterm birth between the two groups: (i) tocolytic use; (ii) no tocolytic use. The primary investigators and study personnel involved in recruitment were not aware of the allocation sequence. Treatment packs containing 200 mg tablets of either micronized progesterone (Utrogestan, Besins-Healthcare) or an identical placebo were dispensed by a central research pharmacy. The treatment duration was from the time of randomization until 35⁶ weeks gestation or until delivery of the fetus, if sooner. The primary outcomes of the trial were gestational age at delivery and latency to delivery. Outcome assessors were blind to treatment status. The expected date of delivery recorded in the chart, at the time of randomization, was used subsequently to determine gestational age at delivery. Secondary outcomes included delivery <37 and <35 weeks gestation, recurrent premature labor and neonatal outcomes including death, broncho-pulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, respiratory distress syndrome, hyperbilirubinemia, sepsis and need for ventilation. Our planned sample size was 60 per group, based on a 90% power to detect a 2 week difference in gestational age at delivery [7] at a significance level of (0.05). The outcomes were analyzed by intention to treat with the subjects remaining in the group they were randomized to, regardless of compliance with treatment. The gestational age at delivery were compared between the two groups using the Mann-Whitney U test, as the data was skewed. Mean latency to delivery was assessed using the student’s t-test. For preterm delivery <37 weeks and <35 weeks, a relative risk was calculated and statistical significance assessed by Fisher’s exact test. The other secondary outcomes were analyzed similarly. The trial was registered at ClinicalTrials.gov (NCT01286246). The trial was reported following CONSORT guidelines.

The primary research question of the meta-analysis was: Does maintenance tocolysis with progesterone prevent prematurity, (<37 and <34 weeks gestation) or extend latency to delivery? The secondary question was: Does treatment reduce perinatal mortality. A literature search up to April 2015 was performed using the following databases and MeSH terms: Medline (Tocolytic Agents, or Tocolysis, or Obstetric labor, premature and Progesterone and Clinical trial), Embase (Premature labor or Tocolysis and Progesterone and Clinical trial), PubMed (premature labor and Progesterone and Clinical trial) and the Cochrane Central Register of Controlled Trials (Obstetric labor, premature or Tocolysis and Progesterone). These searches were subsequently updated in October 2015 and again in April 2016 and February 2017. The identified abstracts and appropriate manuscripts were reviewed by two of the authors (SW, SR). Studies were included if they were clinical trials of progesterone in women with premature labor following tocolysis. Risk of bias and quality of the manuscripts was judged independently by the reviewers using standard criteria [8]. All studies were graded as high or low quality based on four key quality indicators: adequate randomization and allocation concealment, blinding, limited losses to follow up (<20%) and intention to treat analysis. Studies that were deficient in any of these areas were graded as low quality. Studies were not included in the quantitative summary analysis unless intent to treat analysis was presented or could be calculated from the available data. Authors were contacted to obtain missing data. The primary outcomes of the meta-analysis were premature delivery <37 and <34 weeks gestation and latency to delivery. Quantitative analysis with a fixed and random effects models were performed with RevMan 5.1. Statistical assessment for heterogeneity was performed and considered statistically significant if p < .05. Random effects models were used for analyses with significant heterogeneity. A subgroup analysis by type of progesterone (oral, vaginal or intra-muscular) and by trial quality was planned a priori. This analysis was done with a fixed effects model even if there was significant heterogeneity between high and low quality studies then pooled analysis of all studies would not be meaningful. The meta-analysis results were reported as per PRISMA guidelines.

Between February 2011 and February 2014 41 women were enrolled in the trial. Unfortunately, this did not meet our recruitment goals. Furthermore, the study drug we had been provided reached an expiry in August 2014 and the provider had changed its progesterone product. To continue the trial a new application would have been necessary to Health Canada. Given all these factors a decision was made to terminate the trial.

The patient characteristics are provided in the Appendix Table 3 and were adequately balanced between the two groups. The flow diagram for the trial is provided in Appendix Figure 8. There were no losses to follow up nor post randomization exclusions. Treatment with progesterone, compared to placebo, did not result in an increase in median gestational age at delivery: 36⁺² weeks versus 36⁺⁴ weeks, mean difference − .0² (−3⁺¹ to 2⁺³) nor in mean latency to delivery: 44.5 days versus 46.6 days, mean difference − 2.1 (−22.8, 16.8). No significant differences were detected in any of the secondary outcomes, Appendix Table 4. There were no perinatal deaths. Only 50% of subjects returned their treatment diaries and unused capsules so reliable estimates of compliance could not be made.

The initial literature search initially identified 96 (Medline), 167 (Embase), 163 (PubMed) and 18 (Cochrane) abstracts. The updated literature search identified a further 60 abstracts. The details of the review process are presented in Fig. 1. Ultimately, 18 trials (including ours) were identified and 15 were included in the meta-analysis. The reasons for exclusion were: two trials were single dose progesterone treatment for acute tocolysis only not maintenance tocolysis [9, 10] and one was a trial of prophylactic 17-hydroxyprogesterone caporate in women with previous premature delivery [11]. The details of the included trials are presented in Table 1. Two trials employed oral progesterone [12, 13], three used intra-muscular 17-hydroxyprogesterone caporate [14‐16], our trial and seven others used vaginal progesterone [17‐23] and one trial compared intramuscular 17-hydroxyprogesterone caporate or vaginal progesterone to no treatment [24]. Eight authors were contacted by email requesting additional information regarding outcomes not reported in their manuscripts and responses were received from three. All the trials were reviewed for quality by two reviewers (SW, JR). Five were judged to be high quality and nine low quality (Table 2). Overall, treatment with progesterone reduced preterm birth less than 37 weeks gestation (OR 0.77, 95% CI 0.62, 0.96). However, this was not statistically significant for the vaginal progesterone nor intra-muscular 17-hydroxyprogesterone caporate subgroups (Fig. 2). The proportion of births before 34 weeks gestation was also reduced with treatment (OR 0.80, 95% CI 0.60, 1.08) but this difference was not statistically significant (Fig. 3). Additionally, a statistically significant increase in latency to delivery was apparent for all three progesterone treatments (Fig. 4). Planned subgroup analysis by quality revealed that the results varied significantly between high and low quality trials (Figs. 5, 6 and 7). The pooled results of the low quality trials suggested a reduction in the risk of delivery less than 37 weeks (OR 0.47, 95% CI 0.34, 0.64), less than 34 weeks (OR 0.55, 95% CI 0.35, 0.86) and increased latency to delivery (15.97 days, 95% CI 14.09, 17.84). However, the summary of high quality trials did not reveal any benefit for any of the outcomes: delivery less than 37 weeks (OR 1.23, 95% CI 0.91, 1.67), delivery less than 34 weeks (OR 1.12, 95% CI 0.74, 1.69) nor latency to delivery (−0.95 days, 95% CI −5.54, 3.64). Only five trials reported any perinatal deaths, 31 in the low quality trials and 9 in the high quality trials. Progesterone treatment was associated with a reduction in risk of perinatal death in the low quality trials: (OR 0.39, 95% CI 0.17, 0.87) but not the high quality trials: (OR 0.52, 95% CI 0.14, 1.95).