The use of progestogens to prevent preterm birth, defined as delivery before 37 weeks of gestation, has been widely studied in different clinical conditions. Vaginal progesterone administration seems efficacious in preventing preterm birth in asymptomatic women with a short cervix1 and 17α-hydroxyprogesterone caproate in women with a positive history of spontaneous preterm birth or late abortion.2,3 On the other hand, the use of either progestogen in multiple pregnancies has been shown to be ineffective.4,5
The efficacy of either intervention in women with threatened preterm labor and a short cervix is still controversial. Areja et al in 2013,6 Martinez de Tejada et al,7 and most recently Palacio et al8 did not find vaginal progesterone efficacious in symptomatic women; however, a recent meta-analysis reached the opposite conclusion.9 Another meta-analysis focusing on 17α-hydroxyprogesterone caproate showed no evidence of efficacy of this progestogen in reducing preterm birth among symptomatic women.10
Thus, in the light of the current uncertainty about the efficacy and safety of progestogens, we conducted a trial of maintenance tocolysis with vaginal progesterone and 17α-hydroxyprogesterone caproate.
MATERIALS AND METHODS
This is a multicenter, open-label, randomized controlled trial. The trial was approved by the local ethics committee on February 2010. Patients were randomly assigned to one of the three parallel groups to receive intramuscular 17α-hydroxyprogesterone caproate, vaginal progesterone, or no treatment. An independent data monitoring committee reviewed the data for patient safety. An interim analysis was planned after enrolling 50% of the women.
Women with singleton pregnancies between 22 and 31 6/7 weeks of gestation, who had been admitted to the hospital because of their first threatened preterm labor episode, defined as the simultaneous presence of contractions (greater than six in 30 minutes) and cervical change (shortening, softening, or dilation on manual examination), were considered. Among them, those who had received tocolysis and corticosteroids for fetal lung maturation and who remained at risk of preterm birth at discharge because of cervical length 25 mm or less were eligible for this study. Allocation was stratified by an early (22–27 6/7 weeks of gestation) and late (28–31 6/7 weeks of gestation) preterm labor episode.
At all participating centers, two doses of 12 mg intramuscular betamethasone were administered 24 hours apart for fetal maturation. A second course was administered when the first one was given at less than 26 weeks of gestation. Atosiban was the primary tocolytic after 28 weeks of gestation in four of the participating centers and nifedipine in the fifth. At earlier gestational ages, one center used indomethacin and the remainder atosiban.
Cervical length was measured by trained professionals, who adhered to the same transvaginal ultrasound criteria.11 An endovaginal probe equipped for color Doppler imaging and power Doppler angiography (3–9 MHz) was used. Exclusion criteria were previous spontaneous preterm delivery, multiple pregnancy, rupture of membranes, fetal and maternal conditions indicating delivery, Müllerian malformations, prior cervical surgery such as cervical cerclage, and the presence of regular uterine contractions at discharge.
The study took place at the obstetrics units of five tertiary care–level university hospitals located in Northern Italy, each with more than 3,000 deliveries per year. At discharge, women were randomly assigned to receive 1) a once-a-week intramuscular injection of 341 mg 17α-hydroxyprogesterone caproate, 2) vaginal administration of 200 mg daily of micronized progesterone, or 3) no treatment. Treatments ended at the completion of 36 weeks of gestation.
The primary endpoint was the proportion of women with preterm delivery at less than 37 weeks of gestation. Secondary endpoints included proportion of women delivering before 32 and 35 weeks of gestation, the proportion of women with at least one hospital admission before delivery, mean gestational age at delivery, birth weight centile, percentage of neonatal intensive care unit admissions, average days of neonatal intensive care unit admission, average days of oxygen supply, percentage of births with congenital neonatal anomalies, and percentage of births with composite neonatal complications including respiratory distress syndrome, intraventricular hemorrhage, retinopathy, periventricular leukomalacia, necrotizing enterocolitis, and sepsis.
According to previous data collected in an unpublished pilot observational study carried out at the University of Modena, we hypothesized that the expected proportion of women experiencing preterm birth in the control group would be 0.30 (30%). We estimated that we would need 160 patients per arm, totaling 480 patients, to give 80% power to detect a 50% relative difference between the 17α-hydroxyprogesterone caproate or progesterone groups and the control group (with a two-sided type 1 error of 2.5%), that is, a risk of preterm birth in the intervention groups of 0.15 (15%). An interim analysis was planned at 50% enrollment.
Patients were allocated to the three arms with a one-to-one-to-one ratio by using a computer-generated list of random numbers that was centrally generated in the statistical unit based at the University of Modena and Reggio Emilia. The randomization sequence was generated by a statistician by using Stata 11.0 statistical software and was stratified by center and for early (22–27 6/7 weeks of gestation) and late (28–31 6/7 weeks of gestation) preterm labor episodes. After the gynecologist had obtained the woman's consent, they connected to a website dedicated to the study for registration. Then, randomization sequence allocated the patient to a group. Once the patient was assigned to an intervention or control group, women and gynecologists were aware of the treatment allocation as were the data analysts. At delivery, outcomes were assessed by obstetricians on duty. They were not necessarily aware of the fact that women were enrolled in a study.
The study data set was filled in by each participant center, with time limitation to compilation according to the different planned follow-ups. The quality of the data was independently reviewed by statistical unit personnel (R.V. and R.D.).
We used relative risks and their 97.5% confidence intervals (CIs) for the primary endpoint and for secondary dichotomous endpoints. Mean differences were estimated for continuous and normally distributed secondary endpoints; otherwise, comparisons between medians were carried out. We aimed to assess whether 17α-hydroxyprogesterone caproate, progesterone, and no treatment were different in terms of efficacy and safety.
Statistical analyses were performed at the Statistics Unit, University of Modena and Reggio Emilia according to the intention-to-treat principle. An unplanned subgroup analysis was also carried out. This analysis compared the intervention group with the control group according to the main outcome preterm birth stratified by cervical length: 1) less than 15 mm; and 2) between 15 and 25 mm.
Between July 2010 and June 2015, 257 women were found eligible to participate in the study. Three of them declined to participate and 254 were subsequently randomly assigned to vaginal progesterone, 17α-hydroxyprogesterone caproate, or to the control group. Ultimately, 235 women were considered in the analysis (Fig. 1). Baseline characteristics in the three randomization groups were similar (Table 1).
After enrolling 50% of the sample planned, the data were discussed by the independent data monitoring committee, which, on the basis of the results of a futility analysis, established that “even completing the expected enrolment, findings will unlikely demonstrate a statistical significant benefit in the primary outcome.” The trial was therefore stopped. The preterm birth rate did not differ significantly between groups: 23% in the 17α-hydroxyprogesterone caproate group, 39% in the progesterone group, and 22% in the women in the control group (Table 2).
No statistical differences were found between interventions and control arms in relation to the other secondary outcomes, except for vaginal progesterone when the outcome is preterm delivery at less than 35 weeks of gestation. The unplanned analyses performed by stratifying women according to cervical length suggested an increased risk associated with the administration of vaginal progesterone in patients with cervical length 15 mm or greater, both for preterm birth at 37 weeks of gestation (relative risk 2.42, 97.5% CI 1.05–5.60) and 35 weeks of gestation (relative risk 3.73, 97.5% CI 0.93–15.06), with respect to controls (Table 3).
Most preterm births were associated with preterm prelabor rupture of membranes (65% in women in the control group, 67% in the progesterone group, and 67% in the 17α-hydroxyprogesterone caproate group). The rate of spontaneous preterm labor was similar in the three groups, ranging from 28% to 33%. Medically indicated preterm birth occurred in one woman in the control group (as a result of preeclampsia) and in one woman in the 17α-hydroxyprogesterone caproate group (as a result of cholestasis). Considering the entire population, vaginal delivery rate was similar in the three groups (62% in women in the control group, 77% in women receiving progesterone, and 71% in those receiving 17α-hydroxyprogesterone caproate).
This study demonstrates that maintenance tocolysis with progestogens does not lower the rate of preterm birth in women who experience an episode of preterm labor and remain undelivered with a short cervix. The lack of efficacy of 17α-hydroxyprogesterone caproate for preterm birth prevention seen in this trial does not support the results obtained in our previous study.12 The possible reasons for that can be found in the different treatment regimens (drug administered weekly and not twice a week) as well as the more stringent inclusion criteria. However, our study does not exclude the possibility that administration of 17α-hydroxyprogesterone caproate could be effective in the subpopulation of women at very high risk (cervix less than 15 mm).
The main limitation of this study is represented by its premature interruption. However, the decision against continuing the study was made after an interim analysis originally planned at an enrollment of 50% of the sample, in which the results showed an unexpected lack of efficacy associated with a safety concern (specifically that the rate of preterm birth was higher, although not statistically significantly so, in the vaginal progesterone group than in the women in the control group). The independent data monitoring committee deemed that the study hypothesis—that progestogens would reduce the risk of preterm birth by 50%—was highly unlikely to be demonstrated if the trial proceeded to complete enrollment.
Although several randomized controlled trials and meta-analyses had been carried out, the efficacy of progestogens for maintenance tocolysis is still uncertain.13,14 The difference among randomized controlled trials in terms of the methodologic quality15 and participants' characteristics could explain the heterogeneity of results and conclusions. In some studies the inclusion of women with additional risk factors for preterm birth such as previous preterm birth and late abortion could have resulted in an overestimation of the efficacy of progestogens, because progestogens have been shown to reduce the risk of recurrent preterm birth.10 Thus, the effect of progestogens could be explained by the obstetric history of the women enrolled rather than their actual risk factors of preterm labor.12
In other studies, the inclusion of women was based on subjective cervical length changes, and this could have “diluted” the magnitude of progestogen effect. Indeed, it is well known that the clinical diagnosis of preterm labor is imprecise.
Maintenance tocolysis remains a clinical and scientific challenge. Pregnant women who experience an episode of preterm labor but do not deliver continue to be at risk of preterm birth even after hospital discharge. It has always been assumed that the progestogens would be a useful intervention.9,10 However, our results do not support this assumption.
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