Objective
The objective of the study was to evaluate the use of 17 alpha-hydroxyprogesterone caproate (17P) to reduce preterm delivery in women with a twin pregnancy and short cervix.
Study Design
This open-label, multicenter, randomized controlled trial included women with a twin pregnancy between 24 +0 and 31 +6 weeks of gestation who were asymptomatic and had a cervical length of 25 mm or less measured by routine transvaginal ultrasound. Women were randomized to receive (or not) 500 mg of intramuscular 17P, repeated twice weekly until 36 weeks or preterm delivery. The primary outcome was time from randomization to delivery. Analysis was performed according to the intent-to-treat principle.
Results
The 17P and control groups did not differ significantly for median [interquartile range] time to delivery: 45 (26–62) and 51 (36–66) days, respectively. However, treatment with 17P was associated with a significant increase in the rate of preterm delivery before 32 weeks.
Conclusion
Twice-weekly injections of 17P did not prolong pregnancy significantly in asymptomatic women with a twin pregnancy and short cervix.
Despite relative stability in the twin birth rate in France between 2003 and 2010, the population of twins remains at high risk of preterm birth (PTB) and low birthweight. The latest French National Perinatal survey (2010), which studied a representative sample of births in France (including 14,761 live births), found twins accounted for 19% of premature babies and 23% of babies with low birthweight. Among live births, 41.7% of twins were preterm vs 5.3% of singletons: the risk of prematurity was almost 8 times higher in twins. Moreover, in 2003, 6.3% of twins were born before 32 weeks of gestation; in 2010, this rate reached 8.4%. In the United States, the rate of PTB <at less than 32 weeks of gestation for twin pregnancies was 11.4%, 7.1 times the rate for singleton pregnancies (1.6%).
See related editorial, page 167
Because of progesterone’s role in maintaining pregnancy, randomized trials have compared it with placebo in different groups of singleton pregnancies at high risk of preterm delivery and found that prenatal progesterone administration significantly reduces the preterm delivery (PTD) rate. In randomized trials of unselected twin pregnancies, however, prophylactic progesterone administration does not appear to reduce this rate.
Cervical ultrasonography seems to improve the selection of twins at especially high risk of PTB. The good predictive value of transvaginal sonographic cervical length measurements in the diagnosis of very PTB in twin pregnancies has been shown in several studies, including 2 separate systematic reviews with metaanalyses. However, no well-designed, large, randomized trial has yet assessed the efficacy of progesterone in prolonging pregnancy in selected women with a twin pregnancy and short cervix, and uncertainty continues to surround the indications for its use, route of administration, and optimal dose in twin pregnancies.
We therefore conducted a multicenter randomized trial to evaluate the use of 17 alpha-hydroxyprogesterone caproate (17P) to reduce the risk of PTD in women with a twin pregnancy and a cervical length of 25 mm or less.
Materials and Methods
Subjects and screening
This open-label, multicenter, randomized controlled trial took place at 10 university hospitals across France. Women older than 18 years, carrying twins, asymptomatic, and with a cervical length of 25 mm or less measured in the sagittal plane by routine transvaginal ultrasound according to the standard technique were eligible for inclusion. They were recruited by the attending physician or a research midwife at 24 +0 through 31 +6 weeks of gestation, immediately (the same day) after an ultrasound measurement of cervical length of 25 mm or less. Other inclusion criteria were agreement to regular follow-up and written informed consent.
Women with any of the following criteria were ineligible: cervical dilatation greater than 3 cm, premature rupture of the membranes, placenta previa, monochorial monoamniotic pregnancy, signs of twin-to-twin transfusion syndrome, severe intrauterine growth restriction of at least 1 fetus, known major structural or chromosomal fetal abnormality, death of 1 fetus, any maternal or fetal disease requiring PTD, progesterone therapy before inclusion, ongoing anticonvulsant treatment, or participation in any other treatment trial. Twin gestations resulting from intentional fetal reduction were also excluded.
A first-trimester ultrasound scan, routinely performed in France, determined gestational age and chorionicity for all patients. Monthly cervical length measurements after this scan until delivery were part of standard management for multiple pregnancies in all participating centers. Three separate measurements were taken each time, in the absence of contractions, and the shortest was kept for analysis.
Abdominal ultrasound was performed before inclusion to assess fetal well-being, quantity of amniotic fluid, placental site(s), and fetal weights.
The Ethics Committee of Poissy Saint-Germain Hospital (Comité de Protection des Personnes), Saint-Germain en Laye, France, approved the study protocol for all centers. 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, to be repeated twice weekly until 36 weeks or PTD, 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 an episode of preterm labor occurred before 34 weeks, the woman was admitted and received tocolysis and a course of betamethasone 12 mg, given intramuscularly, repeated after 24 hours. The attending physician determined the type, duration, and regimen of tocolysis and decided about any maintenance tocolysis. Patients in the progesterone arm continued 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 PTD risk.
Study outcomes
The primary outcome was time from randomization to delivery. Prespecified secondary outcomes were: (1) obstetric criteria: rates of PTD before 37, 34, and 32 weeks and number of readmissions for preterm labor; (2) neonatal criteria: birthweight, transfer to the neonatal intensive care unit (NICU), respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, periventricular leukomalacia, and death; and (3) safety criteria: any severe maternal or neonatal adverse effects (congenital anomalies or other ill effects).
Statistical analysis
The sample size was determined on the basis of French data from a previous study by Vayssiere et al, which estimated a mean time to delivery of 83 days with a standard deviation of 25 days (conservatively estimated here at 27 days to avoid underpowering the study) in this high-risk asymptomatic population with twin pregnancy and a sonographic cervical measurement of less than 25 mm. A sample size of 160 women (80 per group) was thus deemed sufficient to demonstrate a mean prolongation of pregnancy of 14 days with 17P with at least 90% power and a 2-sided 5% type I error rate.
The main analysis was performed according to the intent-to-treat principle, ie, all randomized women were analyzed in the group to which they were allocated, regardless of protocol deviations. 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 occurred first. Patients lost to follow-up were 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 PTD before 37, 34, and 32 weeks, missing data due to loss of follow-up were imputed according to two 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 exact test. Secondary pregnancy, fetal, and neonatal outcomes were assessed with Fisher exact tests. To take within-pair correlation of outcomes into account in analyzing twin neonatal outcomes, the empirical distribution of the test statistic was evaluated by permutation. All tests were 2 sided, at the P = .05 significance level. The R statistical package version 2.13.2 (The R Foundation for Statistical Computing) was used to analyze the data.
Role of the funding source
The study sponsor did not participate in the study design, data analysis, data interpretation, or writing of the report. Raphael Porcher had full access to all the data and Marie-Victoire Senat had final responsibility for the decision to submit for publication.
Results
Women’s characteristics
From June 2006 through January 2010, 165 patients were randomized to 17P or no treatment at 10 study sites ( Figure 1 ). Three centers recruited more than 20 patients, 1 center 10-20, and the remaining centers less than 10. All patients met all inclusion criteria and no exclusion criteria. Four patients, all in the 17P group, were lost to follow up. The following statistical analysis is based on all 165 eligible women who consented to participate and were randomly assigned to the experimental or control arm.
Table 1 summarizes the characteristics of the 82 women in the 17P group and the 83 women in the control group. The groups were similar for maternal age, gestational age at randomization, history of uterine malformation, diethylstilbestrol syndrome, cerclage, previous preterm deliveries or late spontaneous abortions, and cervical length at randomization. The median gestational age at the cervical ultrasound the day of randomization was 27 +6 (25 +2 to 29 +6 ) in the 17P group and 27 +5 (25 +6 to 30 +2 ) in the control group.
| Characteristic | 17P (n = 82) | No 17P (n = 83) |
|---|---|---|
| Maternal age, median (Q 1 -Q 3 ) (y) | 32 (29-34) | 30 (28-33) |
| Gestational age, median (Q 1 -Q 3 ) (wks) | 27 +6 (25 +2 to 29 +6 ) | 27 +5 (25 +6 to 30 +2 ) |
| Smoking during pregnancy, n/total n (%) | 6/77 (8) | 17/76 (22) |
| Previous pregnancies, n | ||
| Patients, n | 81 | 81 |
| Mean ± SD | 0.5 (0.7) | 0.4 (0.7) |
| One or more late spontaneous abortions, n/total n (%) | 4/81 (5) | 5/81 (6) |
| One or more previous preterm deliveries, n/total n (%) | 9/81 (11) | 3/81 (4) |
| One or more previous term deliveries, n/total n (%) | 25/81 (31) | 23/81 (28) |
| Uterine malformation, n/total n (%) | 1/82 (1) | 1/81 (1) |
| Diethylstilbestrol syndrome, n/total n (%) | 1/81 (1) | 1/81 (1) |
| History of cervical surgery, n/total n (%) | 3/80 (4) | 3/81 (4) |
| Cerclage, n/total n (%) | 9/81 (11) | 6/80 (8) |
| Cervical length at randomization, median (Q 1 -Q 3 ), mm | 15 (9-20) | 17 (13-20) |
Primary outcome and preterm delivery
Outcome data were available for 161 of the 165 women (97.6%). Figure 2 and Table 2 present the obstetrical outcomes.
| Variable | 17P (n = 82) | No 17P (n = 83) | Mean difference or risk difference (95% CI) | Relative risk (95% CI) | P value |
|---|---|---|---|---|---|
| Intent-to-treat analysis | |||||
| Analysis with censoring at last follow-up | |||||
| Time to delivery, mean (SE) a | 45 (3) | 52 (3) | −7 (−15 to +1) | .090 | |
| Median (Q 1 -Q 3 ) b | 45 (26–62) | 51 (36–66) | |||
| Analysis of imputed data: missing data considered as failure | |||||
| Delivery <37 wks, n (%) | 66 (80) | 64 (77) | +2.4% (−10.0 to 14.8) | 1.04 (0.74−1.47) | .70 |
| Delivery <34 wks, n (%) | 33 (40) | 23 (28) | +12.2% (−2.3 to 26.0) | 1.45 (0.85−2.50) | .10 |
| Delivery <32 wks, n (%) | 24 (29) | 10 (12) | +17.1% (4.7−29.0) | 2.41 (1.18−5.31) | .007 |
| Analysis of imputed data: missing data considered as failure if experimental/success if control | |||||
| Delivery <37 wks, n (%) | 66 (80) | 60 (72) | +7.3% (−5.6 to 20.0) | 1.11 (0.78−1.58) | .27 |
| Delivery <34 wks, n (%) | 33 (40) | 19 (23) | +17.1% (2.8−30.4) | 1.75 (1.00−3.15) | .019 |
| Delivery <32 wks, n (%) | 24 (29) | 6 (7) | +22.0% (10.3−33.3) | 3.97 (1.72−10.9) | .0002 |
| Analysis of evaluated cases | |||||
| Time to delivery | |||||
| Patients, n | 82 | 79 | |||
| Median (Q 1 -Q 3 ) b | 45 (26−62) | 51 (36−66) | −7 (−15 to +1) | .094 | |
| Delivery <37 wks, n/total n (%) | 66/82 (80) | 60/79 (76) | +7.3% (−5.6 to 20.0) | 1.06 (0.75−1.51) | .57 |
| Delivery <34 wks, n/total n (%) | 33/82 (40) | 19/79 (24) | +17.1% (2.8−30.4) | 1.67 (0.96−2.99) | .03 |
| Delivery <32 wks, n/total n (%) | 24/82 (29) | 6/79 (8) | +22.0% (10.3−33.3) | 3.78 (1.64−10.3) | .0005 |
| Cerclage during trial, n/total n (%) | 2/81 (2) | 1/78 (1) | +1.2% (−4.5 to 7.4) | 1.93 (0.10−113.6) | > .99 |
The intent-to-treat analysis with censoring at the last follow-up showed no significant difference between the 17P and control groups for median (interquartile range: first quartile [Q 1 ] to the third quartile [Q 3 ]) time to delivery: 45 (26–62) and 51 (36–66) days, respectively; mean difference, −7; 95% confidence interval [CI], −15 to +1) ( Table 2 and Figure 2 ). After adjustment for gestational age at randomization, mean time to delivery was not significantly shorter in the 17P group (mean difference of −7.3 days; 95% CI, −8.9 to +0.3). Treatment with 17P was associated with a significantly higher rate of preterm deliveries before 32 weeks’ gestation (29% vs 12%; P = .007). The 17P and control groups did not differ significantly in their rates of PTD before 37 weeks (80% vs 77%; P = .70) or 34 (44% vs 28%; P = .10).
Before 32 weeks of gestation, all but one preterm births were spontaneous. The only elective cesarean delivery was in the control group for severe IUGR of 1 twin.
The rates of corticosteroid administration for fetal lung maturity, acute tocolysis, and maintenance of nifedipine tocolysis did not differ significantly in the 17P and control groups (40% vs 42%, P = .75; 26% vs 19%, P = .34; 40% vs 49%, P = .27) ( Table 3 ). Mode of delivery was also similar.
| Variable | 17P (n = 82) | No 17P (n = 79) | P value |
|---|---|---|---|
| Weeks of gestation at delivery | |||
| Patients, n | 82 | 79 | |
| Median (Q 1 -Q 3 ) | 34 +6 (31 +4 to 36 +3 ) | 35 +3 (34 +0 to 36 +6 ) | .029 |
| Delivery before 37 wks of gestation | .73 | ||
| Patients, n | 66 | 60 | |
| Preterm labor, n (%) | 26 (40) | 21 (35) | |
| Preterm PROM, n (%) | 19 (29) | 16 (27) | |
| Elective delivery | 20 (31) | 23 (38) | |
| Corticosteroids for fetal lung maturity, n/total n (%) | 32/81 (40) | 33/78 (42) | .75 |
| Acute tocolysis, n/total n (%) | 21/80 (26) | 15/78 (19) | .34 |
| Maintenance tocolysis, n/total n (%) | 32/81 (40) | 38/78 (49) | .27 |
| Mode of delivery, n (%) | .28 | ||
| Patients, n | 82 | 79 | |
| Vaginal delivery | 31 (38) | 36 (46) | |
| Laboring cesarean section | 33 (40) | 26 (33) | |
| Elective cesarean section | 15 (18) | 17 (22) | |
| Emergency cesarean section for second twin | 3 (4) | 0 (0) |
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