Vaginal Progesterone Reduces the Rate of Preterm Birth in Women With a Sonographic Short Cervix: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Boston University, Boston, Massachusetts, United States
Ultrasound in Obstetrics and Gynecology (Impact Factor: 3.14). 07/2011; 38(1):18-31. DOI: 10.1002/uog.9017
Source: PubMed

ABSTRACT Women with a sonographic short cervix in the mid-trimester are at increased risk for preterm delivery. This study was undertaken to determine the efficacy and safety of using micronized vaginal progesterone gel to reduce the risk of preterm birth and associated neonatal complications in women with a sonographic short cervix.
This was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled asymptomatic women with a singleton pregnancy and a sonographic short cervix (10-20 mm) at 19 + 0 to 23 + 6 weeks of gestation. Women were allocated randomly to receive vaginal progesterone gel or placebo daily starting from 20 to 23 + 6 weeks until 36 + 6 weeks, rupture of membranes or delivery, whichever occurred first. Randomization sequence was stratified by center and history of a previous preterm birth. The primary endpoint was preterm birth before 33 weeks of gestation. Analysis was by intention to treat.
Of 465 women randomized, seven were lost to follow-up and 458 (vaginal progesterone gel, n=235; placebo, n=223) were included in the analysis. Women allocated to receive vaginal progesterone had a lower rate of preterm birth before 33 weeks than did those allocated to placebo (8.9% (n=21) vs 16.1% (n=36); relative risk (RR), 0.55; 95% CI, 0.33-0.92; P=0.02). The effect remained significant after adjustment for covariables (adjusted RR, 0.52; 95% CI, 0.31-0.91; P=0.02). Vaginal progesterone was also associated with a significant reduction in the rate of preterm birth before 28 weeks (5.1% vs 10.3%; RR, 0.50; 95% CI, 0.25-0.97; P=0.04) and 35 weeks (14.5% vs 23.3%; RR, 0.62; 95% CI, 0.42-0.92; P=0.02), respiratory distress syndrome (3.0% vs 7.6%; RR, 0.39; 95% CI, 0.17-0.92; P=0.03), any neonatal morbidity or mortality event (7.7% vs 13.5%; RR, 0.57; 95% CI, 0.33-0.99; P=0.04) and birth weight < 1500 g (6.4% (15/234) vs 13.6% (30/220); RR, 0.47; 95% CI, 0.26-0.85; P=0.01). There were no differences in the incidence of treatment-related adverse events between the groups.
The administration of vaginal progesterone gel to women with a sonographic short cervix in the mid-trimester is associated with a 45% reduction in the rate of preterm birth before 33 weeks of gestation and with improved neonatal outcome.

Download full-text


Available from: Harish M Sehdev, Jul 05, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Preterm birth is the leading cause of perinatal morbidity and mortality worldwide, and is the most important challenge to modern obstetrics. A major obstacle has been that preterm birth is treated (implicitly or explicitly) as a single condition. Two thirds of preterm births occur after the spontaneous onset of labor, and the remaining one third after "indicated" preterm birth; however, the causes of spontaneous preterm labor and "indicated" preterm birth are different. Spontaneous preterm birth is a syndrome caused by multiple etiologies, one of which is a decline in progesterone action, which induces cervical ripening. A sonographic short cervix (identified in the midtrimester) is a powerful predictor of spontaneous preterm delivery. Randomized clinical trials and individual patient meta-analyses have shown that vaginal progesterone reduces the rate of preterm delivery at <33 weeks of gestation by 44%, along with the rate of admission to the neonatal intensive care unit, respiratory distress syndrome, requirement for mechanical ventilation, and composite neonatal morbidity/mortality score. There is no evidence that 17-α-hydroxyprogesterone caproate can reduce the rate of preterm delivery in women with a short cervix, and therefore, the compound of choice is natural progesterone (not the synthetic progestin). Routine assessment of the risk of preterm birth with cervical ultrasound coupled with vaginal progesterone for women with a short cervix is cost-effective, and the implementation of such a policy is urgently needed. Vaginal progesterone is as effective as cervical cerclage in reducing the rate of preterm delivery in women with a singleton gestation, history of preterm birth, and a short cervix (<25 mm).
    Journal of Perinatal Medicine 01/2013; 41(1):27-44. DOI:10.1515/jpm-2012-0272 · 1.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The importance of progesterone (P4) for maintenance of pregnancy, its role in cervical ripening and uterine contractions is at least partly established and therefore, not surprisingly, the basis for the concept to use P4 as a treatment for preterm birth. Due to the complexity of the condition of preterm birth there are still questions concerning the optimal population that might benefit, timing of treatment, dosage, vehicle and route of administration. Recently vaginal P4 and intramuscular 17-alpha-hydroxyprogesterone caproate (17P) have been used to prevent preterm birth in patients with a high risk for early delivery. The aim of this study was to assess cervical changes throughout pregnancy in rats and the timing of term and preterm delivery after various progestin treatments given by different routes and vehicles in hope of identifying better treatment regimens. This paper presents results that suggest that there are better routes of treatment than the vaginal route (e.g. topical), that the vehicle used in many of the clinical studies (Replens®) is not appropriate due to a low release of the steroid and consequently low uptake of P4, and that inhibition of birth is primarily due to inhibition of uterine contractility that can be achieved by supplementation of P4 but not with 17P.
    03/2012; 4(2):110-119.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The uterine cervix plays a vital role in maintaining pregnancy and an equally important role in allowing parturition to occur. Progesterone, either endogenously produced or supplied exogenously, supports the function of the cervix in sustaining intrauterine pregnancy, and the withdrawal of progesterone, either through natural processes or pharmacologic intervention, leads to delivery which underscores the importance of the progesterone's biological activities manifest in normal gestation and pregnancy that ends prematurely. Research crossing many scientific disciplines has demonstrated that progesterone is a pleotropic compound that affects the cervix through cytoplasmic and membrane receptors with profound effects on cellular and molecular functions that influence inflammatory cascades and extracellular matrix, both of which have consequences for parturition. Beyond the local cell and molecular biology of progesterone, it has systemic effects of relevance to pregnancy as well. This paper examines the biology of the cervix from its gross to cellular structure and biological activities of its cell and molecular processes that may be affected by progesterone. The implications of these processes for preterm birth are explored, and direction of current research is in relation to translational medicine implications for diagnostic, prognostic, and therapeutic approaches to threatened preterm birth.
    Infectious Diseases in Obstetrics and Gynecology 10/2011; 2011(1064-7449):353297. DOI:10.1155/2011/353297