Materials and Methods

From April 2007 through May 2011, the 14 centers of the Maternal-Fetal Medicine Units Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development participated in this randomized double-blind placebo-controlled trial. The study was approved by the institutional review board at each clinical site and at the data coordinating center.

Women were eligible for participation if they were nulliparous with a viable singleton gestation and had a CL <30 mm between 16 weeks 0 days and 22 weeks 3 days. This gestational age range was chosen because it is during this period that women typically receive a sonographic examination for fetal evaluation. A woman was defined as nulliparous if she had no prior pregnancy that progressed >19 weeks 6 days. Women were excluded from participation if they had undergone a selective fetal reduction to a singleton gestation; had sonographic evidence of an additional fetal pole/embryo at ≥12 weeks of gestation; had received progestogen treatment >14 weeks 6 days; had experienced vaginal bleeding heavier than spotting >15 weeks 6 days; had amniotic membranes prolapsing beyond the external os; had premature rupture of membranes; had a known major fetal anomaly or aneuploidy; had a current or planned cervical cerclage; had a known müllerian abnormality; had a contraindication to IM injections; had maternal medical conditions that increase the probability of preterm delivery (eg, hypertension); had prior cervical surgery (ie, cold knife conization, laser vaporization, or loop electrosurgical excision procedure); or were planned to have an indicated preterm delivery.

For women who conceived spontaneously, the duration of gestation at the time of randomization was determined according to a previously described algorithm on the basis of the last menstrual period and the results of ultrasonography. For women who conceived by in vitro fertilization, the duration of gestation was calculated on the basis of the date of embryo transfer and the age of the embryo when transferred.

CL was measured endovaginally by trained and certified sonographers. Sonographer training consisted of a didactic program based on the method described by Iams et al for endovaginal CL measurement. To become certified, a sonographer submitted 3 cervical images from each of 5 separate women, designating which of the 3 images per patient was the best image with the shortest measurement, and whether a funnel and/or debris (defined as echogenic material adjacent to the cervix within the amniotic cavity) were present. The images were reviewed centrally by an expert (J.D.I.). Study personnel were certified only when the images of at least 4 of the 5 studies submitted were considered acceptable. Once certified, sonographers performed CL screening of women potentially eligible for the randomized trial in a standard fashion, by obtaining 3 CL images and measuring each cervix along the line of the cervical canal made by the interface of the mucosal surfaces, with calipers placed at the external and internal os. The shortest measurement was recorded and was the basis for eligibility for the trial.

Eligible women were offered participation into the randomized, double-blind, placebo-controlled trial. Women who signed informed consent received an IM “compliance” injection of the placebo (1 mL inert oil) and were asked to return at least 3 days later, at which time randomization occurred. If a woman did not return for a randomization visit <23 weeks 0 days of gestation, she was excluded from participation in the trial. Additionally, before randomization, all women were required to have a sonographic examination to exclude fetal anomalies and to estimate gestational age if no previous dating ultrasound had been performed. Women who met inclusion criteria and returned at the appropriate time after the compliance injection were assigned in a 1:1 ratio to receive identically appearing active (250 mg 17-OHP) or placebo (castor oil) IM injections prepared according to current good manufacturing process guidelines by a research pharmacy (Eminent Services, Frederick, MD). The simple urn method of randomization, with stratification according to clinical center, was used by the data coordinating center to create the computer-generated randomization sequence. The active and placebo study medications were distributed according to this randomization sequence. The study was double masked; neither the patient nor medical staff (including research and clinical personnel) was aware of the treatment assignment. After randomization, participants received weekly IM injections of 250 mg 17-OHP or placebo given by a study nurse, until 36 weeks 6 days of gestation or delivery, whichever occurred first. Compliance with the intervention was determined by the proportion of protocol-specified injections (1 injection every 5-9 days from randomization to 36 weeks 6 days or delivery, whichever occurred first) that was received prior to delivery.

At each study visit, participants were asked whether they had experienced adverse symptoms since the last injection. In addition, they were asked whether they had consulted a physician for preterm labor symptoms, had undergone any medical procedures, or had been given any corticosteroids or tocolytic medications since their last visit. Participants also were queried about any activity restrictions that had been prescribed by their health provider. Prenatal, delivery, newborn, and postpartum records were abstracted by study personnel after delivery. Participating women and their infants were followed until hospital discharge.

PTB was defined as delivery <37 weeks 0 days of gestation. Prespecified secondary outcomes included PTB <35 weeks 0 days and <32 weeks 0 days gestation, a composite of serious adverse fetal or neonatal outcomes (ie, respiratory distress syndrome, bronchopulmonary dysplasia, early-onset sepsis, grade II or III necrotizing enterocolitis, grade III or IV intraventricular hemorrhage, periventricular leukomalacia, grade III or IV retinopathy of prematurity, or fetal or neonatal death), and selected individual maternal and neonatal morbidities.

We estimated that 20% of the women in the placebo group would deliver <37 weeks of gestation. Based on this estimate, a total sample size of 1000 women (500 in each group) was estimated to be sufficient to detect a reduction of 33% in the frequency of preterm delivery <37 weeks, under the assumptions of a type I error (2-sided) of 5% and a power of at least 80%. This sample size also would yield >90% power to detect the same effect size if the frequency of PTB in the placebo group was as high as 25%. The analysis was performed according to the intention-to-treat principle. Continuous variables were compared with the use of the Wilcoxon rank sum test, and categorical variables were compared with the use of the χ ² or Fisher exact test, as appropriate. The proportion of women in each study group remaining pregnant was compared using survival analysis with the log rank test used to assess for the difference between the survival curves. A priori subgroup analyses were planned for the primary outcome with respect to the selected variables of gestational age at randomization (<21 weeks 0 days vs at least 21 weeks 0 days), CL at screening (<15 mm vs at least 15 mm), and the presence or absence of a cervical funnel at screening. These analyses utilized Mantel-Haenszel stratification with the Breslow-Day test to assess for homogeneity. All tests were 2-tailed and P < .05 was used to define statistical significance. Analyses were performed using software (SAS, version 9.2; SAS Institute Inc, Cary, NC).

An independent data and safety monitoring committee monitored the trial. A group sequential method was used to characterize the rate at which the type I error was spent; the chosen function was the Lan-DeMets characterization of the O’Brien-Fleming boundary. At the third interim analysis, conducted when outcome data were available for 591 patients (59.1% of the planned sample), a conditional power analysis revealed that even if recruitment continued to the final sample size of 1000 women, and the primary outcome frequencies in the remaining women were as assumed for the alternative hypothesis (13.3% in the 17-OHP arm and 20% in the placebo arm) the probability of showing a benefit was extremely low (<2.5%). Based on these data and the recommendation of the data and safety monitoring committee, enrollment in the trial was halted on May 9, 2011.

Results

A total of 15,435 women were screened, of whom 1588 (10.3%) had a CL <30 mm. At the time the study was halted, 657 women had been randomized. Outcome data were available for all randomized participants and their neonates ( Figure 1 ). Baseline characteristics of the 2 study groups were largely similar, although women randomized to 17-OHP treatment were slightly older ( Table 1 ). The mean compliance rate was 88.8% in the 17-OHP group and 89.1% in the placebo group ( P = .89). Seven women (1.1%) also were prescribed vaginal progesterone by their health care provider (2 in the 17-OHP group and 5 in the placebo group, P = .45).

Flow diagram detailing patient enrollment

Grobman. 17 alpha-hydroxyprogesterone caproate for nulliparas with cervical length <30 mm. Am J Obstet Gynecol 2012.

The frequency of the primary outcome did not differ significantly between groups ( Table 2 ). Delivery <37 weeks of gestation occurred in 25.1% of women in the 17-OHP group and 24.2% of women in the placebo group (relative risk, 1.03; 95% confidence interval, 0.79–1.35). The proportion of spontaneous and medically indicated deliveries was similar between the groups ( Table 2 ). The proportion of births <35 weeks and <32 weeks also was similar between the groups, as were the survival curves from randomization to delivery ( P = .55) ( Figure 2 ). The median gestational ages at delivery were similar as well (38.9 weeks; interquartile range, 36.9–40.0 in the 17-OHP group vs 38.9 weeks; interquartile range, 37.1–40.0 in the placebo group; P = .93). There were no differences in other selected maternal outcomes. A majority of women in both groups noted side effects from the injections, the majority of which were related to irritation at the injection site.

Survival curve illustrating proportion of participants remaining pregnant after randomization

Grobman. 17 alpha-hydroxyprogesterone caproate for nulliparas with cervical length <30 mm. Am J Obstet Gynecol 2012.

Table 3 presents selected perinatal outcomes. There were no differences between groups in the composite adverse perinatal outcome or in most individual outcomes. The exception was that early-onset sepsis was less frequent in the 17-OHP group (0.9% vs 3.4%; relative risk, 0.27; 95% confidence interval, 0.08–0.97). There were no differences between groups with regard to the frequency of low birthweight, small-for-gestational-age birthweight, or admission to the neonatal intensive care unit.

TABLE 3

Perinatal outcomes stratified by treatment group

Outcome	17-OHP (n = 327)	Placebo (n = 330)	RR (95% CI)
Composite adverse outcome	23/327 (7.0)	30/330 (9.1)	0.77 (0.46–1.30)
Fetal death	4/327 (1.2)	1/330 (0.3)	4.04 (0.45–35.92)
Neonatal death	6/327 (1.8)	8/330 (2.4)	0.76 (0.27–2.16)
Respiratory distress syndrome	13/320 (4.1)	16/323 (5.0)	0.82 (0.40–1.68)
Bronchopulmonary dysplasia	3/320 (0.9)	5/322 (1.6)	0.60 (0.15–2.51)
Necrotizing enterocolitis, grade II or III	2/320 (0.6)	5/322 (1.6)	0.40 (0.08–2.06)
Intraventricular hemorrhage, grade III or IV	2/320 (0.6)	1/322 (0.3)	2.01 (0.18–22.08)
Periventricular leukomalacia	4/320 (1.3)	1/322 (0.3)	4.03 (0.45–35.81)
Early-onset sepsis	3/320 (0.9)	11/322 (3.4)	0.27 (0.08–0.97)
Retinopathy of prematurity, grade III or IV	1/320 (0.3)	3/322 (0.9)	0.34 (0.04–3.21)
Birthweight, g	2855 ± 747	2824 ± 807	P = .82
<2500 g	72/323 (22.3)	75/328 (22.9)	0.97 (0.73–1.30)
<1500 g	23/323 (7.1)	29/328 (8.8)	0.81 (0.48–1.36)
Small for gestational age
<10th percentile	54/323 (16.7)	47/328 (14.3)	1.17 (0.81–1.67)
<3rd percentile	15/323 (4.6)	14/328 (4.3)	1.09 (0.53–2.22)
5-min Apgar <7	15/323 (4.6)	19/328 (5.8)	0.80 (0.41–1.55)
Major congenital anomaly	6/326 (1.8)	2/328 (0.6)	3.02 (0.61–14.85)
Patent ductus arteriosus	2/320 (0.6)	8/322 (2.5)	0.25 (0.05–1.18)
Seizures	1/320 (0.3)	2/322 (0.6)	0.50 (0.05–5.52)
NICU admission	63/322 (19.6)	69/329 (21.0)	0.93 (0.69–1.27)
Length of NICU stay, d	17 (6.0-43.0)	15.5 (6.0-57.5)	P = .61

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