The objective of the study was to evaluate the use of 17 alpha-hydroxyprogesterone caproate (17P) to reduce preterm delivery.
This open-label, multicenter, randomized controlled trial included women with singleton pregnancies admitted at 24-31 weeks’ gestation and cervical length less than 25 mm for preterm labor successfully arrested by tocolytic treatment. Randomization assigned them to receive (or not) 500 mg of intramuscular 17P after tocolysis ended, repeated semiweekly until 36 weeks or preterm delivery. The primary outcome was the time from randomization to delivery.
Outcome data were available for 184 of 188 women randomized. The 17P and control groups (similar for most baseline characteristics) did not differ significantly for median [interquartile range] time to delivery (64 [42–79] and 67 [46–83] days, respectively) or rates of delivery before 37, 34, or 32 weeks of gestation or adverse perinatal outcomes.
Semiweekly injections of 17P did not prolong pregnancy significantly in women with tocolysis-arrested preterm labor.
Preterm birth, before 37 completed weeks of gestation, is responsible for most of the neonatal morbidity and mortality in developed countries and is a leading cause of long-term disability. Rates in Europe generally range from 5% to 9%. They have been rising in most industrialized countries, increasing in the United States from 9.5% in 1981 to 12.7% in 2005. Although understanding of the risk factors and mechanisms related to preterm labor continues to advance, lack of knowledge about its precise pathophysiology makes it difficult to improve these results. Tocolytic drugs can attempt to treat only the symptoms of preterm labor. Although all current tocolytic agents are superior to placebo at delaying delivery for both 48 hours and 7 days, maintenance tocolytic therapy after successful treatment of an acute episode of preterm labor does not reduce the incidence of recurrent preterm labor or preterm delivery and does not improve perinatal outcome.
Because of progesterone’s role in maintaining pregnancy, recent randomized trials have compared it with placebo in different groups at high risk for preterm delivery. Encouraging data suggest that prophylactic treatment with progesterone significantly reduces the rate of preterm delivery in women with a documented history of spontaneous preterm delivery and in asymptomatic women with a short cervix measured at midgestation by ultrasound.
Nevertheless, considerable uncertainty still surrounds the actual mechanism of how progesterone works; the indications for its use; and the optimal type, mode of administration, and dose. Both the American College of Obstetricians and Gynecologists and the Society of Obstetricians and Gynecologists of Canada have called for additional studies.
Women who have had an episode of preterm labor arrested by tocolysis and whose cervix was short at that time comprise a group at especially high risk for preterm delivery. Progesterone has not been extensively studied in this population. We therefore conducted a multicenter randomized trial to evaluate the use of 17 alpha-hydroxyprogesterone caproate (17P) to reduce the risk of preterm delivery in this group.
Materials and Methods
Subjects and screening
This open-label, multicenter, randomized controlled trial took place at 13 university hospitals across France. Women older than 18 years were eligible if they carried singletons at 24 +0 through 31 +6 weeks of gestation and were admitted for an episode of preterm labor with intact membranes, successfully arrested by tocolytic treatment. Preterm labor was defined by regular and painful uterine contractions (at least 2 per 10 minutes documented by external tocography during a 1 hour period) and a cervical length less than 25 mm at admission, as measured in the sagittal plane by transvaginal ultrasound. Other inclusion criteria were agreement to regular follow-up and provision of written informed consent.
Women with any of the following criteria were ineligible: cervical dilatation greater than 3 cm, chorioamnionitis, fetal heart rate abnormalities, placenta previa, abruptio placentae, premature rupture of the membranes, polyhydramnios, multiple pregnancy, intrauterine growth restriction, known fetal anomalies, preeclampsia or pregnancy-related hypertension, any other maternal or fetal disease requiring preterm delivery, ongoing anticonvulsant treatment, or participation in any other treatment trial.
Management of women admitted for preterm labor consisted of tocolysis until sedation of painful uterine contractions and a course of betamethasone 12 mg given intramuscularly and repeated after 24 hours. The attending physician determined the type, duration, and regimen of tocolytic (oral nifedipine, intravenous nicardipine, or salbutamol). Abdominal ultrasound was performed at admission to assess fetal well-being, quantity of amniotic fluid, placental site, and fetal weight, and transvaginal ultrasound was performed to measure cervical length according to the standard technique. Three separate measurements were taken, in the absence of contractions, and the shortest was kept for analysis. The inter- and intraobserver variability of ultrasound measurement of cervical length in our group has previously been reported to be around 10%.
Determination of the duration of gestation for all patients included in the study was based on the results of the first trimester ultrasound scan, routinely performed in France.
Upon completion of the corticosteroid course (ie, 48 hours after the first betamethasone injection), eligible women were approached for randomization by the attending physician or a research midwife. The study protocol was approved for all centers by the Ethics Committee of the Poissy Saint-Germain Hospital (Comité de Protection des Personnes), Saint-Germain en Laye, France. The trial is registered at ClinicalTrials.gov ( NCT00331695 ).
Randomization and follow-up
After verification of the inclusion and exclusion criteria, eligible consenting women were randomly assigned in a 1:1 ratio to receive 500 mg of intramuscular 17P and repeated twice a week until 36 weeks or preterm delivery, whichever occurred first, or to no treatment with 17P (control group). Additional management in both arms was determined by the attending physician, except that progesterone was not allowed in the control group. An independent, centralized, computer-generated randomization sequence (CleanWeb; Télémedecine Technologies, Boulogne, France) was used for this allocation, based on a randomization list established by the study statistician, according to a permuted block method, balanced, and stratified by center.
If a new episode of preterm labor occurred before 34 weeks, the patient was readmitted and received tocolysis. If the physician’s usual practices or the department’s standard protocol called for a second course of betamethasone (identical to the first), it was repeated. The use of maintenance tocolysis with nifedipine was left to the physician’s discretion. Patients in the progesterone arm continued to receive treatment with 17P while hospitalized, if delivery did not occur. In addition to the monthly visits for the study, the women received prenatal care at their institutions, as judged appropriate by their caregivers for their known level of risk of preterm delivery.
The primary outcome was time from randomization to delivery. Prespecified secondary outcomes were the following: (1) obstetric criteria included the rates of preterm delivery before 37, 34, and 32 weeks and the number of readmissions for preterm labor; (2) neonatal criteria included birthweight, transfer to neonatal intensive care unit (NICU), transient respiratory distress, bronchopulmonary dysplasia, necrotizing enterocolitis, periventricular leukomalacia, and death; and (3) safety criteria included any severe maternal or neonatal adverse effect (congenital anomalies or other ill effects).
The main analysis was performed according to the intent-to-treat principle (ie, for all randomized women). Prolongation of pregnancy was assessed by life-table methods that defined duration as the period between randomization and delivery or loss to follow-up, whichever came first. One patient underwent a medical abortion and was censored at that time. The distribution of prolongation of pregnancy was compared across groups with the Gehan-Wilcoxon test.
An additional comparison, adjusted for gestational age at randomization, used the Cox proportional hazards model. An adjusted estimate of the mean difference in prolongation of pregnancy was derived from a Weibull model. For the rates of preterm delivery before 37, 34, and 32 weeks, missing data because of loss of follow-up or medical abortion were imputed according to 2 different strategies: all missing data were first treated as failures for all subjects and then as failures for patients in the experimental arm and as successes for those in the control arm.
A secondary analysis of evaluated cases compared continuous variables with the Wilcoxon rank-sum test and categorical variables with Fisher’s exact test. All tests were 2 sided at the 0.05 significance level. Analysis was performed with SAS software (SAS Institute, Cary, NC) and R 2.6.2 (The R Foundation for Statistical Computing).
On the basis of data from a previous study by Rozenberg et al, we estimated a mean time to delivery of 53 days with a standard deviation of 27 days in this high-risk symptomatic population (with an episode of preterm labor and an ultrasound cervical measurement less than 25 mm). A total sample size of 160 women (80 patients per group) was deemed to be sufficient to demonstrate a mean prolongation of pregnancy of 14 days with 17P with at least 90% power and a 2-sided type I error rate fixed at 5%.
Role of the funding source
The study sponsor did not participate in the study design, data analysis, data interpretation, or writing of the report. Patrick Rozenberg and Raphael Porcher had full access to all the data and Patrick Rozenberg had final responsibility for the decision to submit for publication.
The study took place from February 2006 through July 2008. Although the initially planned sample size was 160 patients, 28 additional subjects were included after inclusion should have stopped. The following statistical analysis is based on all 188 eligible women who consented to participate and were randomly assigned to the experimental or control arm ( Figure 1 ) . The characteristics of the 94 women in the 17P group and the 94 women in the control group are shown in Table 1 and were similar in terms of median maternal age, median gestational age at randomization, history of uterine malformation, diethylstilbestrol syndrome, cerclage, mean number of previous preterm deliveries or late spontaneous abortions, and smoking status.
|Characteristic||17P (n = 94)||No 17P (n = 94)|
|Maternal age, median (Q 1 -Q 3 ), y||29 (25-34)||29 (26-33)|
|Gestational age, median (Q 1 -Q 3 ), wks||28 +4 (26 +2 to 30 +2 )||27 +6 (26 +0 to 29 +3 )|
|Smoking during pregnancy, n/total n (%)||14/94 (15)||12/92 (13)|
|Previous pregnancies, n|
|Mean ± SD||0.6 ± 1.0||0.8 ± 1.0|
|One or more late spontaneous abortion, n/total n (%)||4/94 (4)||7/91 (8)|
|One or more previous preterm delivery, n/total n (%)||11/94 (12)||22/92 (24)|
|One or more previous term deliveries, n/total n (%)||27/94 (29)||27/92 (29)|
|Uterine malformation, n/total n (%)||1/94 (1)||1/92 (1)|
|Diethylstilbestrol syndrome, n/total n (%)||2/94 (2)||3/92 (3)|
|History of cervical surgery, n/total n (%)||2/94 (2)||2/92 (2)|
|Cerclage, n/total n (%)||10/94 (11)||13/92 (13)|
|Cervical length at admission, median (Q 1 -Q 3 ), mm||17 (10-20)||15 (10-20)|