Matched sample comparison of intramuscular versus vaginal micronized progesterone for prevention of preterm birth

Abstract

Objectives: To compare vaginal with intramuscular progesterone administration to prevent preterm labor in women with singleton pregnancies and at increased risk of preterm birth.

Study design: Prospective comparative clinical trial.

Population: One hundred and sixty pregnant women at 20–24 weeks gestation at the risk of preterm labor were classified into: 80 women who received micronized progesterone tablets 200?mg vaginally daily (Group A) and 80 women who received 100?mg progesterone in the form of intramuscular every third day (Group B).

Methods: Estimation of gestational age, assessment of fetal growth and fetal biophysical profile by trans-abdominal ultrasonographic examination was done every 4 weeks till delivery. Measurement of cervical length was achieved by transvaginal ultrasonography, done every 4 weeks till delivery.

Main outcome measures: Incidence of preterm delivery, mean gestational age and the incidence of adverse events of intramuscular versus vaginal route of progesterone administration.

Results: The incidence of preterm delivery in Group A was 20% and in Group B was 27.5%. The difference between both groups was statistically insignificant. In addition, the rate of adverse events reported in women received injectable progesterone was significantly higher than the rate of adverse events reported in women who received vaginal progesterone therapy.

Conclusion: Vaginally administrated progesterone was nearly as equally effective as intramuscular progesterone in the prevention of preterm labor in women at risk and in the meantime has less undesirable events.     

Oral micronized progesterone for prevention of preterm birth

Objective

To evaluate oral micronized progesterone (OMP) to prevent preterm birth (PTB).

Methods

A randomized, double-blind, placebo-controlled trial of 150 women with at least one PTB who received 100 mg of OMP or placebo twice a day from recruitment (18-24 weeks) until 36 weeks or delivery.

Results

PTB occurred in 29 (39.2%) women in the OMP group (n = 74) compared with 44 (59.5%) in the control group (n = 74, P = 0.002). Mean gestational age at delivery was higher in the OMP group (36.1 vs 34.0 weeks, P < 0.001). Fewer preterm births occurred between 28 and 31 weeks plus 6 days in the OMP group (RR 0.20; 95% CI, 0.05-0.73, P < 0.001). Neonatal age at delivery (34 vs 32 weeks, P < 0.001), birth weight (2400 vs 1890 g, P < 0.001), NICU stay (> 24 h, P < 0.001), and Apgar scores (P < 0.001) were more favorable in the OMP group, and fewer neonatal deaths occurred (3 vs 7, P = 0.190).

Conclusion

OMP reduced the risk of PTB between 28 and 31 weeks plus 6 days, NICU admissions, and neonatal morbidity and mortality in high risk patients.     

Utilization of progesterone and cervical length screening for prevention of recurrent preterm birth

Abstract

Objective: To assess utilization of progesterone and cervical length (CL) screening among women with prior spontaneous preterm birth (sPTB).

Methods: This is a retrospective cohort study of women with prior sPTB. Primary outcomes were the use of progesterone and CL screening. Secondary outcomes were reasons for failure to utilize interventions and factors associated with use of recommended interventions.

Results: 180 women had a prior sPTB. Of 171 women eligible for progesterone, 125 (74%) utilized it. Women who utilized progesterone were more likely to have a prior sPTB <28 weeks (50% vs 26%, OR 2.54 (1.18–5.42) p?=?.006) and a higher number of prior sPTB (1.5?±?0.9 vs 1.2?±?0.5, p?=?.02), and less likely to have a prior full term delivery (54% vs 72%, OR 0.47 (0.22–0.99), p?=?.04). Of 176 women eligible for CL screening, 157 (89%) utilized it. Women who utilized CL screening were less likely to have a prior full term delivery (59% vs 84%, OR 0.27 (0.07–0.95, p?=?.01)). The most frequent reason for lack of progesterone and CL screening was patient declining.

Conclusion: Most women with prior sPTB received progesterone and CL screening. Those at highest risk for PTB based on obstetric history are more likely to utilize recommended interventions.     

Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor

Objective

To evaluate the efficacy of maintenance therapy with oral micronized progesterone (OMP) for prolongation of pregnancy in cases of arrested preterm labor.

Methods

Ninety women at 24–34 weeks of singleton pregnancy with intact membranes and arrested preterm labor were randomly allocated to receive OMP (n = 45) or placebo (n = 45) daily until 37 weeks or delivery, whichever was earlier. Outcome parameters were compared using Student t test, χ² test, Fisher exact test, and log-rank χ² test.

Results

OMP significantly prolonged the latency period (33.29 ± 22.16 vs 23.07 ± 15.42 days; P = 0.013). Log-rank analysis revealed a significant difference in mean time to delivery between the 2 groups (P = 0.014). There were significantly fewer preterm births (33% vs 58%; P = 0.034) and low birth weight neonates (37% vs 64%; P = 0.017), and significantly higher mean birth weight (2.44 ± 0.58 vs 2.14 ± 0.47 kg; P = 0.009) in the OMP group. Perinatal outcomes and adverse effects were similar in the 2 groups.

Conclusion

Maintenance tocolysis with OMP significantly prolonged pregnancy and decreased the number of preterm births.Clinical Trial Registry of India: CTRI/2011/10/002043.     

What we have learned about the role of 17-alpha-hydroxyprogesterone caproate in the prevention of preterm birth

Despite major advances in neonatal care, the burden of preterm birth remains high. This is not unexpected since strategies to identify and treat risk factors in early pregnancy have not been very effective in reducing the preterm birth rate. Initial studies suggested a potential benefit for 17-alpha-hydroxyprogesterone caproate (17-OHPC) in decreasing the risk of recurrent preterm birth women with a singleton gestation. However, the use of 17-OHPC has not conferred benefit for other categories of women at high risk for preterm delivery (twins, triplets, and short cervical length). The increasing body of evidence suggests that preterm birth is a complex condition with variable mechanisms of disease and significant individual heterogeneity. This review will examine the plausibility of 17-OHPC in preventing preterm birth and the investigation of its clinical efficacy. We will also highlight factors to explain variations in clinical trial outcomes and outline the trajectory needed for future investigations.     

Efficacy of progesterone for prevention of preterm birth

Preterm birth (PTB) occurs in 5–18% of pregnancies and is the leading cause of neonatal morbidity, mortality and infant death. Up to 30% of PTBs are due to iatrogenic reasons, but the remainder are due to the spontaneous onset of labour or pre-labour premature rupture of membranes (P-PROM). During pregnancy, the uterus remains quiescent and the cervix remains long and closed. Although the exact mechanisms that lead to spontaneous PTB (sPTB) are not fully understood, it is likely that the terminal pathways that are common to term labour are activated prematurely. Despite continued research efforts to develop preventative strategies, there have been no major advances resulting in the reduction of sPTB rates. Progesterone is the most researched prophylactic agent, yet, there is lack of consistency in the reported beneficial effects for the prevention of PTB and improvement in neonatal outcome. This is likely to stem from the multifactorial aetiology of sPTB, the varied patient cohorts recruited and the use of different preparations and routes of administration for progesterone. This review summarises the scientific rationale supporting the efficacy of progesterone and the results of major randomised controlled trials and finally emphasizes how targeted studies with more detailed patient stratification are essential to understand which population would benefit.     

Effectiveness of dydrogesterone, 17-OH progesterone and micronized progesterone in prevention of preterm birth in women with a short cervix

Objective: To compare the efficacy of dydrogesterone, 17-OH progesterone (17OHP) and oral or vaginal micronized progesterone with cerclage for the prevention of preterm birth in women with a short cervix.

Methods: The study included 95 women with singleton gestation and cervical length (CL) ≤?25?mm. Among these, 35 women were asymptomatic at 15–24?weeks and 60 had symptoms of threatened late miscarriage (LM) or preterm delivery (PD) at 15–32 weeks. Patients were randomized to receive dydrogesterone, 17OHP or oral/vaginal micronized progesterone; after one week of therapy 15 women underwent cerclage.

Results: Efficacy of vaginal progesterone (VP) for the prevention of preterm birth reached 94.1%. In asymptomatic women pregnancy outcomes were comparable to cerclage. In women with threatened LM/PD, combination therapy with VP, indomethacin and treatment of bacterial vaginosis (BV) with the subsequent use VP until 36?weeks together with CL monitoring significantly decreased the rate of preterm birth (RR 0.01; 0.0001–0.24) and low birth weight (LBW) (RR 0.04; 0.01–0.96). CL increase during the first week of treatment with a subsequent plateau phase indicated treatment efficacy. Dydrogesterone, 17OHP, and micronized oral progesterone (OP) were associated with PD in 91.7% of women.

Conclusions: Combination management strategy including VP significantly benefits pregnancy outcomes in women with a short cervix compared with cerclage. Dydrogesterone, 17OHP, and OP were not found to be efficacious.     

Progesterone for the prevention of preterm birth: a critical evaluation of evidence

A systematic review of the literature identified nine randomised trials that evaluated the effects of progestational agents in the prevention of preterm delivery. These studies were of variable quality. Meta-analyses showed reductions in delivery rates before 37 weeks (OR 0.42, 95% CI 0.31-0.57) and 34 weeks (OR 0.51, 95% CI 0.34-0.77) as well as in respiratory distress syndrome (OR 0.55, 95% CI 0.31-0.96) with progestational agents. A cumulative meta-analysis showed that the treatment benefit for the outcome of delivery before 37 weeks exceeded the conventional level of statistical significance in 1975 (p<0.01); by 1985, the p-value was <0.001, and by 2003, it was <0.0001. Another cumulative meta-analysis in which the studies were added to the pooled analysis by decreasing quality score showed significant benefit even when the analysis was limited to just the highest quality trials (OR 0.47, 95% CI 0.33, 0.66, p<0.0001). An exploration of the applicability of the effects across various baseline risks using a L'abbe plot found that the benefit was consistent across a range of risks. A comprehensive review of both trial and observational data on harm did not show any demonstrable evidence of harm to mother and baby. Women at high risk of preterm birth should be recommended progestational agent therapy.     

The global epidemiology of preterm birth

This article is a part of a series that focuses on the current state of evidence and practice related to preterm birth prevention. We provide an overview of current knowledge (and limitations) on the global epidemiology of preterm birth, particularly around how preterm birth is defined, measured, and classified, and what is known regarding its risk factors, causes, and outcomes. Despite the reported associations between preterm birth and a wide range of socio-demographic, medical, obstetric, fetal, and environmental factors, approximately two-thirds of preterm births occur without an evident risk factor. Efforts to standardize definitions and compare preterm birth rates internationally have yielded important insights into the epidemiology of preterm birth and how it could be prevented.     

Cervical cerclage for prevention of preterm birth in women with twin pregnancy.

OBJECTIVE: To compare the effect of elective cervical cerclage in women with twin pregnancy on gestational age at time of delivery. METHOD: In a pragmatic fashion women in Abha Maternity Hospital, Saudi Arabia with twin gestations were allocated to receive either an elective cerclage (group I) or no cerclage (group II). Elective cerclage was performed at 12 to 14 weeks of gestation after sonographic examination of the fetus to confirm gestational age and exclude major congenital anomalies. In all cases, follow up of the pregnancy was continued until delivery. RESULTS: Of the 176 twin pregnancies included, cerclage was performed in 76 women, and no cerclage in 100 women. In Group I: 12 pregnancies ended in spontaneous miscarriage, 37 in preterm labor, and 27 women reached full term. There were a total of 106 live births in 62 women. In Group II: 8 women aborted, 44 women ended in preterm labor and 48 women reached full term. There were a total of 160 live births in 89 women. The gestational age at delivery ranged from 20 to 41 weeks. Multiple regression analysis did not show association between cerclage and time of delivery, although a trend was observed (P=0.056). CONCLUSION: Elective cerclage contributes little in prolongation of gestational age at the time of delivery in women with twin pregnancy, especially in women of high parity. Those with a previous history of preterm labor may be a subgroup that could benefit from elective cerclage.     

Salivary progesterone and cervical length measurement as predictors of spontaneous preterm birth

Objective: To evaluate the efficacy of salivary progesterone, cervical length measurement in predicting preterm birth (PTB).

Methods: Prospective observational study included 240 pregnant women with gestational age (GA) 26–34 weeks classified into two equal groups; group one are high risk for PTB (those with symptoms of uterine contractions or history of one or more spontaneous preterm delivery or second trimester abortion) and group 2 are controls.

Results: There was a highly significant difference between the two study groups regarding GA at delivery (31.3?±?3.75 in high risk versus 38.5?±?1.3 in control), cervical length measured by transvaginal ultrasound (24.7?±?8.6 in high risk versus 40.1?±?4.67 in control) and salivary progesterone level (728.9?±?222.3 in high risk versus 1099.9?±?189.4 in control; p?p value 0.035) but not in low risk group (p value 0.492). CL measurement showed a sensitivity of 71.5% with 100% specificity, 100% PPV, 69.97% NPV and accuracy of 83%, while salivary progesterone showed a sensitivity of 84% with 90% specificity, 89.8% PPV, 85.9% NPV and accuracy of 92.2%.

Conclusion: The measurement of both salivary progesterone and cervical length are good predictors for development of PTB.     

孕激素在预防早产中的作用

早产的发生率仍持续不降,甚至逐年攀升,早产及由此出生的早产儿是导致围产儿死亡及致残的重要原因,究其原因是早产的预防及治疗效果不佳。早产的预防和治疗中强调以综合方案为主,近年来孕激素在早产的预防和治疗中的应用取得了一定的效果,但也存在较大的争议,文章就国内外相关的临床研究、专家共识等文献资料进行回顾,希望对临床有所裨益。     

Novel developments on cervical length screening and progesterone for preventing preterm birth

Cervical length (CL) measured by transvaginal ultrasound is an effective screening test for the prevention of preterm birth (PTB). The criteria for an effective screening test are all met by CL. It studies an important condition (PTB); it is safe and acceptable by >99% of women; it recognises an early asymptomatic phase that precedes PTB by many weeks; it has a well-described technique, is reproducible, is predictive of PTB in all populations studies so far; and, perhaps most importantly, it has been shown that 'early' treatment is effective in prevention. These two interventions, effective only in specific populations, are ultrasound-indicated cerclage and vaginal progesterone.