Materials and Methods

This is a planned secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development-sponsored randomized trial evaluating cerclage for women with singleton gestations, prior SPTB (17-33 6/7 weeks), and short CL <25 mm measured between 16-22 6/7 weeks. This randomized controlled trial was performed by 15 US clinical centers from January 2003 through November 2007. Each center obtained institutional review board approval. Exclusion criteria were fetal anomaly, planned history-indicated cerclage, and clinically significant maternal-fetal complications. Gestational age was always confirmed by standard sonographic biometric measurements at <20 weeks’ gestation. Sonologists underwent a uniform certification process by a single investigator (J.O.) to ensure uniformity in sonographic measurements of TVU CL screening.

Women with prior SPTB were screened with TVU CL starting at 16 0/7-21 6/7 weeks, then every 2 weeks until 22 6/7 weeks unless the CL was observed to be 25-29 mm, after which the scan frequency was increased to every week. Women who were detected by TVU screening to have a short CL <25 mm at 16-22 6/7 weeks were randomized after informed consent to cerclage or no cerclage.

Very early in the trial (May 2003), after the first 10 women were randomized, the results of a randomized trial of 17P became available. In response to this report the steering committee and an independent data and safety monitoring board recommended that women eligible for the cerclage trial be counseled regarding the use of progesterone for PTB prevention, and an additional randomization stratum, reflecting the patient’s stated intent to use progesterone, was added. The suggested 17P dose was 250 mg intramuscularly starting at 16 weeks and continued weekly until 36 weeks. Subsequent use of 17P was recorded and actual use was utilized for these analyses.

Study nurses contacted patients weekly to record medication use. To determine if the reported use on the study data forms reflected actual use of 17P, medical records were reviewed for study patients at the center with the largest number of recruited study patients. Of the 23 patients at this center with a reported dose, 20 (91%) received at least 1 recorded dose of 17P. There was 85% agreement between the reported 17P and the administered 17P (kappa = 0.85). Therefore we concluded that the reported 17P on the study data forms was an accurate reflection of actual 17P use. We then defined actual use of 17P for our analyses as at least 1 reported dose on the study data forms.

The effect of 17P use was analyzed separately for the cerclage and no-cerclage groups. Randomization to cerclage/no-cerclage (intent to treat) was used in the primary analysis. We also planned to analyze data by actual cerclage/no-cerclage placement groups. In this latter analysis, women were allocated to the cerclage group if they actually received a cerclage, and to the no-cerclage group if they did not receive cerclage.

The primary outcome of this secondary analysis as well as that of the primary analysis was PTB <35 weeks. Secondary outcomes included birth <7 days from randomization; PTB <24, <28, <32, and <37 weeks; and perinatal death. Perinatal death was defined as either a stillbirth or a postnatal death prior to hospital discharge. Maternal age, race, smoking, drug use, shortest CL, gestational age of the qualifying PTB, prior induced abortion, number of sonograms, and gestational age at randomization were considered as possible confounders.

The primary study outcome and other categorical variables were compared with χ ² tests and, where appropriate, Fisher exact test. Continuous variables were analyzed using the t test and Wilcoxon rank sum test where appropriate. Differences in time to birth were assessed with Kaplan-Meier curves and the log rank test. Multivariable logistic regression and Cox proportional hazard models considered possible confounders for the outcomes of PTB <35 weeks and time to birth, respectively. We selected an alpha level of <0.05 to represent statistical significance.

Results

Of 1014 women with prior SPTB who were screened with TVU CL at 16-22 6/7 weeks, 318 had a CL <25 mm, of which 302 agreed to randomization. Of these, 300 were available for this analysis, because 1 woman was lost to follow-up and 1 woman was excluded because she received vaginal progesterone, not 17P. Of these 300, 148 were randomized to cerclage and 152 were randomized to no cerclage.

Of the 148 women with a prior SPTB, with a short CL <25 mm, and who were randomized to receive cerclage, characteristics were similar except for race/ethnicity ( P < .01), smoking ( P = .036), and total number of vaginal sonograms ( P = .03) between the 47 women who used progesterone, and the 101 who did not use 17P ( Table 1 ). 17P had no effect on PTB <35 weeks ( P = .64), or on other outcomes ( Table 2 ).

TABLE 2

Perinatal outcomes for women randomized to cerclage

Outcome	17P (n = 47)	No 17P (n = 101)	P value	OR (95% CI)
Preterm birth <35 wk	14 (30)	34 (34)	.64	0.84 (0.40–1.77)
Birth <7 d from randomization	0 (0)	4 (4)	.31 a	0.23 (0.01–4.32)
Previable birth <24 wk	2 (4)	7 (7)	.72 a	0.60 (0.12–2.99)
Preterm birth <28 wk	4 (9)	17 (17)	.18	0.46 (0.16–1.45)
Preterm birth <32 wk	8 (17)	25 (25)	.29	0.62 (0.26–1.51)
Preterm birth <37 wk	23 (49)	43 (43)	.47	1.29 (0.65–2.59)
Perinatal death	3 (6)	10 (10)	.76 a	0.62 (0.16–2.37)

 

CI , confidence interval; OR , odds ratio; 17P , 17-alpha-hydroxyprogesterone caproate.

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