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17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm

Published:September 19, 2012DOI:https://doi.org/10.1016/j.ajog.2012.09.013

      Objective

      We sought to evaluate whether 17 alpha-hydroxyprogesterone caproate (17-OHP) reduces preterm birth (PTB) in nulliparous women with a midtrimester cervical length (CL) <30 mm.

      Study Design

      In this multicenter randomized controlled trial, nulliparous women with a singleton gestation between 16 and 22 3/7 weeks with an endovaginal CL <30 mm (<10th percentile in this population) were randomized to weekly intramuscular 17-OHP (250 mg) or placebo through 36 weeks. The primary outcome was PTB <37 weeks.

      Results

      The frequency of PTB did not differ between the 17-OHP (n = 327) and placebo (n = 330) groups (25.1% vs 24.2%; relative risk, 1.03; 95% confidence interval, 0.79–1.35). There also was no difference in the composite adverse neonatal outcome (7.0% vs 9.1%; relative risk, 0.77; 95% confidence interval, 0.46–1.30).

      Conclusion

      Weekly 17-OHP does not reduce the frequency of PTB in nulliparous women with a midtrimester CL <30 mm.

      Key words

      Preterm birth (PTB) remains a major cause of morbidity and mortality worldwide. Not only is it responsible for approximately 50% of childhood blindness and one-third of cerebral palsy, but it increasingly has been implicated in adult morbidities, such as cardiovascular disease.
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      Prediction and prevention of recurrent spontaneous preterm birth.
      • Rogers L.K.
      • Velten M.
      Maternal inflammation, growth retardation, and preterm birth: insights into adult cardiovascular disease.
      Correspondingly, PTB reduction has been a prominent public health goal and a focus of perinatal research.
      For Editors' Commentary, see Contents
      Progestogens, administered intramuscularly (IM) or vaginally, have been demonstrated to reduce the frequency of recurrent PTB.
      • DaFonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.B.
      • Zugaib M.
      Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
      • Meis P.J.
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      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      Although progestogens in this circumstance have been demonstrated to be efficacious, PTB epidemiology is such that their use for this indication will not markedly reduce the population's frequency of PTB.
      • Petrini J.R.
      • Callaghan W.M.
      • Klebanoff M.
      • et al.
      Estimated effect of 17 alpha-hydroxyprogesterone caproate on preterm birth in the United States.
      Thus, investigators have evaluated whether progestogens also can reduce PTB in other at-risk groups. Although progestogen treatment does not reduce PTB in women with multiple gestations,
      • Rouse D.J.
      • Caritis S.N.
      • Peaceman A.M.
      • et al.
      A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.
      • Norman J.E.
      • Mackenzie F.
      • Owen P.
      • et al.
      Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomized, double-blind, placebo-controlled study and meta-analysis.
      • Combs C.A.
      • Garite T.
      • Maurel K.
      • et al.
      17-Hydroxyprogesterone caproate for twin pregnancy: a double-blind, randomized clinical trial.
      it has been shown in 2 randomized trials to reduce PTB in women with a short cervix.
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      The inclusion criterion for cervical length (CL) was <15 mm in 1 trial, and 10-20 mm in the other trial.
      However, because the frequencies of a CL <15 mm or of 10-20 mm are approximately 1% and 2%, respectively, the restriction of progestogen to such women will not result in a substantial reduction in the overall PTB frequency and will leave many women who might benefit from its use untreated. In this study, we examined whether the use of 17 alpha-hydroxyprogesterone caproate (17-OHP) administered to nulliparous women with a CL <30 mm (ie, the 10th percentile at 16-22 weeks of gestation) would reduce PTB <37 weeks.

      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.
      • Carey J.C.
      • Klebanoff M.A.
      • Hauth J.C.
      • et al.
      Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis.
      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
      • Iams J.
      • Goldenberg R.
      • Meis P.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      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.
      • Wei L.J.
      • Lachin J.M.
      Properties of the urn randomization in clinical trials [Erratum in Control Clin Trials 1989;10:following 126].
      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.
      • Iams J.
      • Goldenberg R.
      • Meis P.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      • Goldenberg R.L.
      • Iams J.D.
      • Mercer B.M.
      • et al.
      The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births.
      • Hibbard J.U.
      • Tart M.
      • Moawad A.H.
      Cervical length at 16-22 weeks' gestation and risk for preterm delivery.
      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 χ2 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.
      • Lan K.K.G.
      • DeMets D.L.
      Discrete sequential boundaries for clinical trials.
      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).
      Figure thumbnail gr1
      FIGURE 1Flow diagram detailing patient enrollment
      Grobman. 17 alpha-hydroxyprogesterone caproate for nulliparas with cervical length <30 mm. Am J Obstet Gynecol 2012.
      TABLE 1Baseline characteristics of study population stratified by treatment group
      Characteristic17-OHP (n = 327)Placebo (n = 330)
      Maternal age at screening, y22.8 ± 5.321.6 ± 4.4
      Prepregnancy body mass index, kg/m2
      Values were unavailable for 4 mothers in 17-OHP group and 9 mothers in placebo group;
      26.1 ± 6.925.4 ± 6.5
      Race/ethnicity
      Self-reported;
       Non-Hispanic white76 (23.2)74 (22.4)
       Non-Hispanic black179 (54.7)161 (48.8)
       Hispanic white19 (5.8)38 (11.5)
       Hispanic black2 (0.6)0
       Asian4 (1.2)3 (0.9)
       Other47 (14.4)54 (16.4)
      Prior pregnancy
       <13 wk of gestation92 (28.1)82 (24.8)
       13-19 wk of gestation13 (4.0)10 (3.0)
      Payment for obstetric care
       Uninsured/self-pay17 (5.2)30 (9.1)
       Private insurance74 (22.6)62 (18.8)
       Government-assisted insurance236 (72.2)238 (72.1)
      Married or living with partner125 (38.2)110 (33.3)
      Alcohol use during pregnancy33 (10.1)20 (6.1)
      Smoking during pregnancy48 (14.7)62 (18.8)
      Illicit substance use during pregnancy15 (4.6)24 (7.3)
      Gestational age at randomization, wk21.4 ± 1.221.3 ± 1.3
      Cervical length at screening, mm23.9 ± 5.623.8 ± 5.7
      Cervical length at screening <15 mm25 (7.6)31 (9.4)
      Cervical funnel present88 (26.9)69 (20.9)
      Cervical funnel length, mm
      Values were available for all mothers with funnel present: 88 in 17-OHP group and 69 in placebo group.
      14.8 ± 8.016.7 ± 8.7
      Debris present39 (11.9)39 (11.8)
      Data are presented as mean ± SD or n (%). The only between-group difference that was significant was maternal age at screening (P = .003). Percentages may not total 100% due to rounding.
      17-OHP, 17 alpha-hydroxyprogesterone caproate.
      Grobman. 17 alpha-hydroxyprogesterone caproate for nulliparas with cervical length <30 mm. Am J Obstet Gynecol 2012.
      a Values were unavailable for 4 mothers in 17-OHP group and 9 mothers in placebo group;
      b Self-reported;
      c Values were available for all mothers with funnel present: 88 in 17-OHP group and 69 in placebo group.
      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.
      TABLE 2Maternal outcomes and interventions stratified by treatment group
      Variable17-OHP (n = 327)Placebo (n = 330)RR (95% CI)
      Delivery <37 wk82/327 (25.1)80/330 (24.2)1.03 (0.79–1.35)
       Spontaneous54/327 (16.5)55/330 (16.7)0.99 (0.70–1.40)
       Medically indicated27/327 (8.3)25/330 (7.6)1.09 (0.65–1.84)
       Fetal loss/abortion <20 wk1/327 (0.3)0/330
      Gestational age at delivery, wk37.6 ± 3.937.4 ± 4.3P = .93
      Preterm premature rupture of membranes25/327 (7.6)24/330 (7.3)1.05 (0.61–1.80)
      Delivery <35 wk44/327 (13.5)53/330 (16.1)0.84 (0.58–1.21)
      Delivery <32 wk28/327 (8.6)32/330 (9.7)0.88 (0.54–1.43)
      Delivery <28 wk15/327 (4.6)22/330 (6.7)0.69 (0.36–1.30)
      Hospital visit for preterm labor145/327 (44.3)151/330 (45.8)0.97 (0.82–1.15)
      Tocolytic therapy35/321 (10.9)42/325 (12.9)0.84 (0.55–1.29)
      Corticosteroid therapy55/321 (17.1)51/325 (15.7)1.09 (0.77–1.55)
      Cerclage placement6/321 (1.9)4/325 (1.2)1.52 (0.43–5.33)
      Gestational hypertension or preeclampsia46/327 (14.1)40/329 (12.2)1.16 (0.78–1.72)
      Gestational diabetes mellitus15/327 (4.6)13/330 (3.9)1.16 (0.56–2.41)
      Cholestasis1/327 (0.3)0/329
      Placental abruption11/327 (3.4)15/328 (4.6)0.74 (0.34–1.58)
      Chorioamnionitis29/327 (8.9)20/328 (6.1)1.45 (0.84–2.52)
      Cesarean delivery67/327 (20.5)63/329 (19.1)1.07 (0.79–1.46)
      Side effects
       Any223/326 (68.4)220/328 (67.1)1.02 (0.92–1.13)
       Injection site217/326 (66.6)209/328 (63.7)1.04 (0.93–1.17)
       Urticaria10/326 (3.1)2/328 (0.6)5.03 (1.11–22.78)
       Nausea7/326 (2.1)10/328 (3.0)0.70 (0.27–1.83)
      Data are presented as mean ± SD or n/N (%).
      CI, confidence interval; RR, relative risk; 17-OHP, 17 alpha-hydroxyprogesterone caproate.
      Grobman. 17 alpha-hydroxyprogesterone caproate for nulliparas with cervical length <30 mm. Am J Obstet Gynecol 2012.
      Figure thumbnail gr2
      FIGURE 2Survival 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 3Perinatal outcomes stratified by treatment group
      Outcome17-OHP (n = 327)Placebo (n = 330)RR (95% CI)
      Composite adverse outcome23/327 (7.0)30/330 (9.1)0.77 (0.46–1.30)
       Fetal death4/327 (1.2)1/330 (0.3)4.04 (0.45–35.92)
       Neonatal death6/327 (1.8)8/330 (2.4)0.76 (0.27–2.16)
       Respiratory distress syndrome13/320 (4.1)16/323 (5.0)0.82 (0.40–1.68)
       Bronchopulmonary dysplasia3/320 (0.9)5/322 (1.6)0.60 (0.15–2.51)
       Necrotizing enterocolitis, grade II or III2/320 (0.6)5/322 (1.6)0.40 (0.08–2.06)
       Intraventricular hemorrhage, grade III or IV2/320 (0.6)1/322 (0.3)2.01 (0.18–22.08)
       Periventricular leukomalacia4/320 (1.3)1/322 (0.3)4.03 (0.45–35.81)
       Early-onset sepsis3/320 (0.9)11/322 (3.4)0.27 (0.08–0.97)
       Retinopathy of prematurity, grade III or IV1/320 (0.3)3/322 (0.9)0.34 (0.04–3.21)
      Birthweight, g2855 ± 7472824 ± 807P = .82
       <2500 g72/323 (22.3)75/328 (22.9)0.97 (0.73–1.30)
       <1500 g23/323 (7.1)29/328 (8.8)0.81 (0.48–1.36)
      Small for gestational age
       <10th percentile54/323 (16.7)47/328 (14.3)1.17 (0.81–1.67)
       <3rd percentile15/323 (4.6)14/328 (4.3)1.09 (0.53–2.22)
      5-min Apgar <715/323 (4.6)19/328 (5.8)0.80 (0.41–1.55)
      Major congenital anomaly6/326 (1.8)2/328 (0.6)3.02 (0.61–14.85)
      Patent ductus arteriosus2/320 (0.6)8/322 (2.5)0.25 (0.05–1.18)
      Seizures1/320 (0.3)2/322 (0.6)0.50 (0.05–5.52)
      NICU admission63/322 (19.6)69/329 (21.0)0.93 (0.69–1.27)
      Length of NICU stay, d17 (6.0-43.0)15.5 (6.0-57.5)P = .61
      Data are presented as mean ± SD, n/N (%), or median (interquartile range).
      CI, confidence interval; NICU, neonatal intensive care unit; RR, relative risk; 17-OHP, 17 alpha-hydroxyprogesterone caproate.
      Grobman. 17 alpha-hydroxyprogesterone caproate for nulliparas with cervical length <30 mm. Am J Obstet Gynecol 2012.
      Planned subgroup analyses were performed to determine whether any interaction existed between selected variables and treatment group (Table 4). Stratification based on gestational age at randomization <21 weeks of gestation, CL <15 mm at screening, or the presence of a funnel at screening did not reveal any interaction with treatment group. Additional subgroup analyses, not defined a priori, were performed to examine the effect of 17-OHP on PTB <37 weeks and <34 weeks among women with a CL of 10-20 mm, and on PTB <34 weeks among women with a CL of <15 mm (Table 5). Stratification by these CLs also failed to demonstrate any interaction with treatment group.
      TABLE 4A priori subgroup analyses for preterm birth <37 weeks
      Variable17-OHP (n = 327)Placebo (n = 330)RR (95% CI)P value
      P value for Breslow-Day interaction term.
      Gestational age at randomization, wk.20
       <2121/104 (20.2)26/101 (25.7)0.78 (0.47–1.30)
       ≥2161/223 (27.4)54/229 (23.6)1.16 (0.85–1.59)
      Cervical length, mm.70
       <1513/25 (52.0)17/31(54.8)0.95 (0.58–1.55)
       ≥1569/302 (22.8)63/299 (21.1)1.08 (0.80–1.47)
      Cervical funnel.08
       Absent54/239 (22.6)50/261 (19.2)1.18 (0.84–1.66)
       Present28/88 (31.8)30/69 (43.5)0.73 (0.49–1.10)
      Data are presented as n/N (%).
      CI, confidence interval; RR, relative risk; 17-OHP, 17 alpha-hydroxyprogesterone caproate.
      Grobman. 17 alpha-hydroxyprogesterone caproate for nulliparas with cervical length <30 mm. Am J Obstet Gynecol 2012.
      a P value for Breslow-Day interaction term.
      TABLE 5Additional subgroup analyses for preterm birth <37 and 34 weeks
      Variable17-OHP (n = 327)Placebo (n = 330)RR (95% CI)P value
      P value for Breslow-Day interaction term.
      Preterm birth <37 wk
       Cervical length, mm.59
        <105/9 (55.6)10/16 (62.5)0.89 (0.44–1.78)
        10-2019/50 (38.0)18/40 (45.0)0.84 (0.52–1.38)
        >2058/268 (21.6)52/274 (19.0)1.14 (0.82–1.59)
      Preterm birth <34 wk
       Cervical length, mm.82
        <159/25 (36.0)13/31(41.9)0.86 (0.44–1.67)
        ≥1532/302 (10.6)35/299 (11.7)0.91 (0.58–1.42)
       Cervical length, mm.49
        <105/9 (55.6)6/16 (37.5)1.48 (0.63–3.51)
        10-2011/50 (22.0)12/40 (30.0)0.73 (0.36–1.48)
        >2025/268 (9.3)30/274 (10.9)0.85 (0.52–1.41)
      Data are presented as n/N (%).
      CI, confidence interval; RR, relative risk; 17-OHP, 17 alpha-hydroxyprogesterone caproate.
      Grobman. 17 alpha-hydroxyprogesterone caproate for nulliparas with cervical length <30 mm. Am J Obstet Gynecol 2012.
      a P value for Breslow-Day interaction term.

      Comment

      In this randomized trial conducted among nulliparous women with singleton gestations and midtrimester CLs <30 mm, weekly IM injections of 250 mg 17-OHP neither altered the frequency of PTB <37 weeks nor had a discernable effect on PTB at lower gestational age thresholds, maternal outcomes, or most neonatal complications. While there was a lower frequency of early-onset sepsis among the neonates of mothers exposed to 17-OHP, the lack of difference between the 2 groups in either gestational age at delivery or other neonatal outcomes suggests that this may be a chance finding.
      Unlike women with a prior PTB, nulliparous women with a singleton gestation have no risk factor that can be derived from their obstetric history that allows for targeted PTB prevention. A short CL is useful in risk stratification for nulliparous women, as it has been shown in this population to have the greatest population-attributable risk associated with PTB.
      • Goldenberg R.L.
      • Iams J.D.
      • Mercer B.M.
      • et al.
      The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births.
      A threshold of 30 mm during the gestational age range that we studied not only would allow approximately 10% of nulliparous women to be eligible for treatment aimed at PTB prevention but would also identify women at clinically significant risk of PTB.
      • Goldenberg R.L.
      • Iams J.D.
      • Mercer B.M.
      • et al.
      The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births.
      • Hibbard J.U.
      • Tart M.
      • Moawad A.H.
      Cervical length at 16-22 weeks' gestation and risk for preterm delivery.
      • Taipale P.
      • Hiilesmaa V.
      Sonographic measurement of uterine cervix at 18-22 weeks gestation and the risk of preterm delivery.
      Indeed, the probability of PTB in the present cohort was 25%, a frequency similar to that cited for a general population of women who have had a prior PTB.
      • Goldenberg R.L.
      • Iams J.D.
      • Mercer B.M.
      • et al.
      The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births.
      The primary outcome of our study, PTB <37 weeks' gestation, was chosen given the recognition that prevention of all PTBs, even those in the late preterm period between 34 weeks 0 days and 36 weeks 6 days, is desirable given the health and economic burden associated with these births.
      • Kramer M.S.
      • Demissie K.
      • Yang H.
      • Platt R.W.
      • Sauve R.
      • Liston R.
      The contribution of mild and moderate preterm birth to infant mortality.
      • Moster D.
      • Lie R.T.
      • Markestad T.
      Long-term medical and social consequences of preterm birth.
      • Lindström K.
      • Winbladh B.
      • Haglund B.
      • Hjern A.
      Preterm infants as young adults: a Swedish national cohort study.
      The results of this study contrast with the results of 2 prior randomized trials that have shown that vaginal progesterone treatment reduces the frequency of PTB in women with a short cervix. One potential explanation is that those trials enrolled women with notably shorter CLs (<15 mm and 10-20 mm) that are present in only 1% and 2% of women, respectively.
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      The presence of a “short” cervix, defined according to a population standard and not underlying pathophysiology, may not reflect a single parturitional process that is uniformly amenable to progestogen therapy. Indeed, PTB is best understood as a complex condition with multiple potential etiologies.
      • Pennell C.E.
      • Jacobsson B.
      • Williams S.M.
      • et al.
      Genetic epidemiologic studies of preterm birth: guidelines for research.
      • Kramer M.S.
      • Papageorghiou A.
      • Culhane J.
      • et al.
      Challenges in defining and classifying the preterm birth syndrome.
      Investigators of prior trials have recognized this possibility; one reason that Hassan et al
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      chose 10-20 mm for progesterone treatment was their concern that women with a cervix <10 mm “have a higher rate of intra-amniotic infection/inflammation” and would be “less likely to benefit from progesterone administration than are patients with a longer cervix.” Although the present study was unable to demonstrate benefit from 17-OHP at shorter CLs, it was underpowered to do so, and thus cannot be used to make conclusions about progestogen treatment for women with such CLs. Conversely, the current study is the largest trial to date of women treated with a progestogen for a short cervix, the substantial majority of whom had a CL >20 mm. While one metaanalysis did suggest that progesterone was effective for women with a CL up to 25 mm, >90% of women in that analysis were from studies that restricted enrollment to women with a CL ≤20 mm, and all women with a CL >20 mm had high-risk conditions, such as prior PTB.
      • Romero R.
      • Nicolaides K.
      • Conde-Agudelo A.
      • et al.
      Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.
      Accordingly, in light of our negative findings, there is at present no evidence from any randomized trial that progestogens benefit nulliparous women with a CL >20 mm.
      There are other possible reasons for the discrepant findings as well. Both Fonseca et al
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      and Hassan et al
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      used vaginal progesterone, albeit different formulations. Although both 17-OHP and vaginal progesterone have been shown to be efficacious at reducing recurrent PTB, it is possible that a vaginally administered progesterone may be of particular benefit for women with a short cervix. However, this possibility remains purely speculative, as 17-OHP has not been evaluated in an adequately powered trial of women with a CL ≤20 mm, and vaginal progesterone has not been evaluated in an adequately powered trial of women with singleton gestations and no prior PTB with a CL >20 mm. Additional comparative effectiveness or placebo-controlled trials may provide further insight. The previously published 2 trials also differed from the present study with regard to their populations. These trials included women with other risk factors for PTB, including multiple gestations, prior PTBs, and prior cervical surgeries. The present study, in contrast, excluded women with such conditions, and focused instead on an otherwise low-risk population of women who were nulliparous and had no other indication for either progestogen treatment or PTB surveillance. Such differences in the study population also may explain the different results.
      The population that was selected should be generalizable to the general population of nulliparous women with a singleton gestation. Women were enrolled from across the United States in 14 different centers, and were socioeconomically diverse. Approximately 10% had a CL <10th percentile, as predicted from prior observational studies.
      • Goldenberg R.L.
      • Iams J.D.
      • Mercer B.M.
      • et al.
      The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births.
      • Hibbard J.U.
      • Tart M.
      • Moawad A.H.
      Cervical length at 16-22 weeks' gestation and risk for preterm delivery.
      • Taipale P.
      • Hiilesmaa V.
      Sonographic measurement of uterine cervix at 18-22 weeks gestation and the risk of preterm delivery.
      The frequency of PTB, moreover, was 24.7%, which similarly is consistent with the frequency of PTB for nulliparous women with a cervix <10th percentile that has been cited in other studies.
      • Goldenberg R.L.
      • Iams J.D.
      • Mercer B.M.
      • et al.
      The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births.
      • Hibbard J.U.
      • Tart M.
      • Moawad A.H.
      Cervical length at 16-22 weeks' gestation and risk for preterm delivery.
      In summary, the results of our trial show no demonstrable benefit from the use of weekly IM 17-OHP to reduce the frequency of PTB in nulliparous women with a midtrimester CL <30 mm. Further investigation is needed to determine whether 17-OHP may benefit women with a CL below a lower percentile threshold, or whether other forms of progestogens provide benefit for women other than the 1-2% of the population identified by the CL criteria used in prior trials.

      Acknowledgments

      We thank the following subcommittee members who participated in protocol/data management and statistical analysis (Sharon Gilbert, MS, MBA) and protocol development and coordination between clinical research centers (Gail Mallett, RN, BSN, CCRC, and Cynthia Milluzzi, RN).
      In addition to the authors, other members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network are as follows:
      • Northwestern University, Chicago, IL–A. Peaceman, M. Dinsmoor (NorthShore University HealthSystem), G. Mallett, J. Senka (NorthShore University HealthSystem)
      • Ohio State University, Columbus, OH–F. Johnson, D. Cline, C. Latimer, S. Frantz, S. Fyffe, P. Shubert (St Ann's), L. Gerwig (St Ann's)
      • University of Texas Medical Branch, Galveston, TX–J. Moss, A. Salazar, G. D. V. Hankins, G. Olson, A. Jackson, C. Sutherland
      • Case Western Reserve University-MetroHealth Medical Center, Cleveland, OH–C. Milluzzi, W. Dalton, J. Russo, S. Myers, T. Waters, T. Dotson
      • University of Alabama at Birmingham, Birmingham, AL–W. Andrews, A. Northen, J. Sheppard, J. Grant, D. J. Rouse
      • Brown University, Providence, RI–D. Allard, J. Hunt, J. Tillinghast, M. Barthelemy, D. Gardner, C. Duquette
      • Wayne State University, Detroit, MI–N. Hauff, G. Norman, M. King (RDMS), D. Allen (RDMS), T. Smith
      • Columbia University, New York, NY–R. Miller, S. Bousleiman, L. Plante (Drexel), C. Tocci (Drexel), A. Ranzini (St Peter's), M. Lake (St Peter's), M. Hoffman (Christiana), S. Lynch (Christiana)
      • University of Texas Southwestern Medical Center, Dallas, TX–J. Dashe, L. Moseley, J. Kingsbery, V. Bludau, R. Benezue
      • University of Texas Health Science Center at Houston, Houston, TX–F. Ortiz, P. Givens, B. Rech, C. Moran
      • University of Utah Health Sciences Center, Salt Lake City, UT–P. Reed, K. Hill, M. W. Varner, A. Weaver (McKay-Dee), S. Alexander (Latter Day Saints Hospital), D. Thompson-Garbrecht (Intermountain Medical Center), J. Miller (Utah Valley Regional Medical Center)
      • Oregon Health and Science University, Portland, OR–R. Acosta (Providence Sacred Heart Medical Center), C. Flores (Providence Sacred Heart Medical Center), M. Ricon, W. Smith (Kaiser Permanente), S. Butcher (Kaiser Permanente), S. Segel, L. Pereira
      • University of North Carolina at Chapel Hill, Chapel Hill, NC–K. Dorman, K. Pena-Centeno, K. Clark, S. Timlin
      • University of Pittsburgh, Pittsburgh, PA–M. H. Birkland, H. Simhan, P. Cotroneo, R. Zubic, D. Nowinski
      • George Washington University Biostatistics Center, Washington, DC–S. Gilbert, A. Lozitska
      • Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD–S. Tolivaisa

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