Plasma progesterone, estradiol, and unconjugated estriol concentrations in twin pregnancies: Relation with cervical length and preterm delivery

Progesterone is a key hormonal regulator of the female reproductive system. It plays a major role to prepare the uterus for implantation and in the establishment and maintenance of pregnancy. Actions of progesterone on the uterine tissues (endometrium, myometrium and cervix) are mediated by the combined effects of two progesterone receptor (PR) isoforms, designated PR-A and PR-B. Both receptors function primarily as ligand-activated transcription factors. Progesterone action on the uterine tissues is qualitatively and quantitatively determined by the relative levels and transcriptional activities of PR-A and PR-B. The transcriptional activity of the PR isoforms is affected by specific transcriptional coregulators and by PR post-translational modifications that affect gene promoter targeting. In this context, appropriate temporal and cell-specific expression and function of PR-A and PR-B are critical for normal uterine function.

ABSTRACT Objective To assess the efficacy of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a twin gestation and a sonographic short cervix (cervical length ≤ 25 mm) in the mid‐trimester. Methods This was an updated systematic review and meta‐analysis of individual patient data (IPD) from randomized controlled trials comparing vaginal progesterone with placebo/no treatment in women with a twin gestation and a mid‐trimester sonographic cervical length ≤ 25 mm. MEDLINE, EMBASE, POPLINE, CINAHL and LILACS (all from inception to 31 December 2016), the Cochrane Central Register of Controlled Trials, Research Registers of ongoing trials, Google Scholar, conference proceedings and reference lists of identified studies were searched. The primary outcome measure was preterm birth < 33 weeks' gestation. Two reviewers independently selected studies, assessed the risk of bias and extracted the data. Pooled relative risks (RRs) with 95% confidence intervals (CI) were calculated. Results IPD were available for 303 women (159 assigned to vaginal progesterone and 144 assigned to placebo/no treatment) and their 606 fetuses/infants from six randomized controlled trials. One study, which included women with a cervical length between 20 and 25 mm, provided 74% of the total sample size of the IPD meta‐analysis. Vaginal progesterone, compared with placebo/no treatment, was associated with a statistically significant reduction in the risk of preterm birth < 33 weeks' gestation (31.4% vs 43.1%; RR, 0.69 (95% CI, 0.51–0.93); moderate‐quality evidence). Moreover, vaginal progesterone administration was associated with a significant decrease in the risk of preterm birth < 35, < 34, < 32 and < 30 weeks' gestation (RRs ranging from 0.47 to 0.83), neonatal death (RR, 0.53 (95% CI, 0.35–0.81)), respiratory distress syndrome (RR, 0.70 (95% CI, 0.56–0.89)), composite neonatal morbidity and mortality (RR, 0.61 (95% CI, 0.34–0.98)), use of mechanical ventilation (RR, 0.54 (95% CI, 0.36–0.81)) and birth weight < 1500 g (RR, 0.53 (95% CI, 0.35–0.80)) (all moderate‐quality evidence). There were no significant differences in neurodevelopmental outcomes at 4–5 years of age between the vaginal progesterone and placebo groups. Conclusion Administration of vaginal progesterone to asymptomatic women with a twin gestation and a sonographic short cervix in the mid‐trimester reduces the risk of preterm birth occurring at < 30 to < 35 gestational weeks, neonatal mortality and some measures of neonatal morbidity, without any demonstrable deleterious effects on childhood neurodevelopment. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Studies on high-risk singleton gestations have shown a preventive effect of progesterone treatment on preterm delivery. This study was conducted to investigate the preventive effect of vaginal micronized progesterone in a large population of twin gestations. This was a double-blind, placebo-controlled randomized trial performed in 17 centers in Denmark and Austria. Women with twin gestations were randomized to daily treatment with progesterone pessaries or apparently identical placebo pessaries, starting from 20-24 weeks until 34 weeks' gestation. Primary outcome was incidence of delivery before 34 weeks' gestation. Secondary outcomes were maternal and neonatal complications and long-term infant follow-up, by Ages and Stages Questionnaire (ASQ), 6 months and 18 months after the expected date of delivery. We also updated a published meta-analysis to include our data and those of another recently published twin trial. A total of 677 women were randomized to the two treatments. Two women in the placebo group were lost to follow-up. Baseline characteristics for the groups were similar. Incidence of delivery before 34 weeks was 15.3% in the progesterone group vs 18.5% in the placebo group (odds ratio, 0.8 (95% CI, 0.5-1.2)). Risks of maternal and neonatal complications were comparable for the two groups. Mean ASQ scores at 6 months and 18 months were not significantly different between the two groups (215 for infants in the progesterone group and 218 for infants in the placebo group at 6 months (P = 0.45) and 193 and 194, respectively, at 18 months (P = 0.89)). The meta-analysis gave a pooled odds ratio of 1.06 (95% CI, 0.86-1.31). Progesterone treatment did not prevent preterm delivery in twin gestations. There were no harmful effects to fetuses and infants of maternal progesterone treatment. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.