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Ultrasound Obstet Gynecol 2007; 30 : 697705 698 Published online in Wiley InterScience (www.interscience.wiley.com).

DOI: 10.1002/uog.5159

D e Franco et al.

(= 32 + 0 weeks) among women with a prior hisVaginal progesterone is associatedbirth with a decrease in risk for tory of spontaneous preterm delivery. In that study, we no difference between placebo and progesterone in early preterm birth and improvedfound neonatal outcome in reducing the frequency of preterm birth among women selected only analysis by a documented history of preterm women with a short cervix: a secondary from a birth. The objective of this planned secondary analysis was to evaluate the efficacy of daily vaginal progesterone gel to randomized, double-blind, placebo-controlled trial INTRODUCTION Conclusion Vaginal progesterone may reduce the rate of early preterm birth and improve neonatal outcome in women with a short sonographic cervical length. Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. Despite medical efforts towards its prevention, the rate 2 ,C.D.ADAIR 3 ,D.F.LEWIS 4 ,D.R.HALL 5 ,S.FUSEY 6, of preterm defined 1 as birth occurring prior to E. A. D E birth, FRANCO ,J.M.OBRIEN 37 weeks of gestation, continues to rise among certain 7 ,K.PORTER 8 ,H.HOW 9 ,R.SCHAKIS 10 , D. ELLER 11 ,Y.TRIVEDI 12 , P. SOMA-PILLAY METHODS populations, occurring13 in up to 15% of pregnancies in 14 15 ,D.VIDYADHARI 16 , G. VANBUREN ,M.KHANDELWAL ,K.TROFATTER 1 ,2 . the developed world and 12.7% in the United States This was a planned, but modified, secondary analysis 17 , J. WEEKS 18 , B. DATTEL 19 , E. NEWTON 20 , C. CHAZOTTE 21 , J. VIJAYARAGHAVAN Preterm birth is associated with a high prevalence of of the prospective, randomized, double-blind, placebo22 ,P.CALDA 23 M. BSHARAT 24 and G. W. CREASY 25 G. VALENZUELA severe neurological deficits and developmental ,disabilities controlled trial of progesterone to prevent preterm birth and is a leading cause of infant and neonatal mortality in high-risk women, reported in the accompanying article 1 Department of Obstetrics and Gynecology and Center for Preterm Birth Research, Washington University School of Medicine, St. Louis, 3 5 . Preterm neonates are at increased 2 3 1 7 in the United States in this issue of the Journal . Prior to the trial, we planned Missouri, USA; Perinatal Diagnostic Center, Central Baptist Hospital, Lexington, Kentucky, USA; University of Tennessee College of 4 Medicine, Chattanooga, Tennessee,distress USA; syndrome, Department of Obstetrics and Gynecology, Louisiana State University Health separately Sciences Center, risk of developing respiratory sepsis, to analyze data and report outcomes for the 5 Department of Obstetrics and Gynaecology, Stellenbosch University and Tygerberg Hospital, Tygerberg, Shreveport, Louisiana, USA; intraventricular hemorrhage, necrotizing enterocolitis and women enrolled without a history7of preterm birth but South Africa; 6 Department of Obstetrics and Gynaecology, Government Medical College, Nagpur, India; Department of Obstetrics and 6 . disorders related to gestational age at birth a short cervical length alone (= 25 mm). Due to an 8 University of with 9 University Gynaecology, University of Pretoria, Pretoria, South Africa; South Alabama, Mobile, Alabama, USA; of A short cervix is a known risk factor for preterm birth; insufficient number of subjects recruited into this arm 1 0 Chris Hani Baragwanath Hospital, University Cincinnati, Cincinnati, Ohio, USA; of the Witwatersrand, Soweto, South Africa; 11 inMaternal fact, data support an inverse relationship between 1 2 Department of Obstetrics of the trial ( n =Sheth 9, 1.3% of the study population), the Fetal Specialists, Atlanta, Georgia, USA; and Gynecology, Vadilal Sarabhai General Hosptial, 13 University 1 4 Cooper Hospital, Camden, New Jersey, USA; Gujarat, Case Medical Center, Cleveland, Ohio, USA; cervicalIndia; length and pretermHospitals delivery. In a prospective study separate analysis of these patients was not meaningful. 15 University Medical Group, Greenville, South Carolina, USA; 16 MediCiti Institute of Medical Sciences, Andra Pradesh, India; of 2915 women that investigated the relationship between Therefore, we modified the planned analysis of women 17 Sri. Ramchandra Hospital, Chennai, India; 1 8 Norton Healthcare, Louisville, Kentucky, USA; 1 9 Department of Obstetrics and short cervical length and preterm delivery, researchers based on a short cervix only to include women 2 0 enrolled Gynecology, Eastern Virginia Medical School, Norfolk, Virgina, USA; Brody School of Medicine, East Carolina University, Greenville, found that even a small decrease in cervical length between enrolled with New a prior preterm had a shortRegional 21 Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, 22 North Carolina, USA; York, USA; birth who also Arrowhead th th 23 Department the 24 Center, and Colton, 28 weeks of USA; gestation was associatedof with cervix at First enrollment. accomplish this, we divided Medical California, Obstetrics and Gynaecology, Medical To School, Charles University, Prague, 25 Columbia Laboratories, Inc., Livingston, New Jersey, USA Czech Republic; Quintiles Biostatistics, Overland an increased risk24 of preterm birth (relative risk, Park, 2.03;Kansas, USA; the study population into quartiles based on cervical 7 . At 24 weeks, when compared 95% CI, 1.28 3.22) length. We then subdivided the lowest quartile (= 32 mm) Collaborators are listed in full at the end of the manuscript. th with women whose cervical length was above the 75 sequentially and analyzed the primary and secondary percentile, women who had a cervical length on or below outcomes for women with cervical lengths of = 30 mm t h the 25 percentile (30 mm) had a relative risk of preterm and < 28 mm at the time of enrollment. There were an KEYWORDS : pregnancy; prematurity; preterm birth; progesterone; short cervix delivery of 3.79 (95% CI, 2.32 6.19), and those on or insufficient number of patients with even shorter cervical th below the 10 percentile (26 mm) had a relative risk of lengths to allow further analysis. 7 . 6.19 (95% CI, 3.84 9.97) Women with a documented history of spontaneous Progesterone administration has been advocated for preterm birth ( < 35 weeks) in a singleton pregnancy in the prevention of preterm birth in women considered to the immediate preceding pregnancy, regardless of cervical ABSTRACT with cervical length < 28 mm at enrollment. The primary be at high risk 8 , 9 , although the primary focus has been length, and women without a history of preterm birth but outcome was preterm birth at = 32 weeks. Objective To investigate the efficacy of vaginal on patients with a prior history of preterm birth proges- 1 0 13 . with a short cervix (= 25 mm) in the midtrimester of the terone to prevent early preterm birth in women with There has been increasing interest in the efficacy of current were screened investigator or in 46 Results pregnancy A cervical length < by 28the mm was identified sonographic evidence of a short cervical length in the vaginally administered progesterone to prevent preterm study coordinator between 16 + 0 and 22 + 6 progesterone weeks of randomized women: 19 of 313 who received midtrimester. birth in women at especially high risk of preterm delivery, gestation. Subjects meeting the study criteria were and 27 of 307 who received the placebo. Baseline offered those with a short sonographic cervical length. The enrollment into of the study 18 + 0to22+ 6 weeks Methods This was a planned, but modified, secondary characteristics the two at groups were similar. In women use of progesterone to treat all women at risk for of gestation to receive daily treatment with 90 mg of analysis of our multinational, multicenter, randomized, with a cervical length < 28 mm, the rate of preterm birth preterm birth does not have uniform support at present, vaginal progesterone gel (Prochieve 8%/Crinone 8%) placebo-controlled trial, in which women were randomat = 32 weeks was significantly lower for those receiving but it has rapidly become accepted as a prophylactic or placebo (Replens ), both provided by Columbia ized between 18 + 0 and 22 + 6 weeks of gestation to progesterone than it was for those receiving the placebo measure to prevent preterm birth in women with a Laboratories, Inc. (Livingston, NJ, USA). Cervical length receive daily treatment with 90 mg of vaginal proges(0% vs. 29.6%,with transvaginal P = 0.014). With progesterone, there documented history of spontaneous preterm birth. Several was measured ultrasound at enrollment terone gel or placebo. Cervical length was measured with were fewer admissions into the neonatal was intensive care authors have ultrasound expressed the need for adequately and at 28 weeks of gestation. Treatment continued transvaginal at enrollment and at 28designed, weeks unit (NICU; 15.8% vs. P =or 0.016) and shorter randomized in larger populations identify the until either delivery, 3751.9%, weeks of gestation development of gestation.trials Treatment continued until to either delivery, ideal progesterone formulation and dosage, and to NICU of preterm stays rupture (1.1 vs. of 16.5 membranes. days, P = 0 .013). There was also 37 weeks of gestation or development of preterm rupdemonstrate whether progesterone administration results Details of the study period, exclusion criteria, randoma trend toward a decreased rate of neonatal respiratory ture of membranes. Maternal and neonatal outcomes in a decline in preterm births before 37 weeks and a ization drug/placebo treatment well were evaluated for the subset of all randomized women distressand syndrome (5.3% vs. 29.6%,procedures, P = as0.060). 8 , 1 4 1 6 reduction in perinatal morbidity and mortality . as the definition of preterm labor are provided in the 17 . The primary objective of our prospective, randomaccompanying report of the randomized clinical trial ized, double-blind, placebo-controlled, multicenter study, The outcomes for this study were defined apriori. The 1 7 , was Correspondence to: Dr E. A. DeFranco, University School Department of Obstetrics and Gynecology, 4566 Scott Secdescribed in an accompanying article Washington to assess theof Medicine, primary outcome was preterm birth at =32 weeks. Avenue, Campus Box 8064, St. Louis, Missouri 63110, USA (e-mail: efficacy and safety of 90-mg progesterone vaginal gel com- defrancoe@wudosis.wustl.edu) ondary outcomes included: preterm birth at < 37 weeks, pared with to decrease the rate of early preterm = 35 weeks, and = 28 weeks; treatment-related adverse Accepted: 20 placebo August 2007 prevent preterm birth in women with a short cervix in the midtrimester.

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2007 ISUOG. Published by John Wiley & Sons, Ltd. O R I GI N AL P A PE R

Ultrasound Obstet Gynecol

2007; 30 : 697705.

Progesterone in women with short cervix events; hospital admission for preterm labor; prolongation of latency period after treatment for preterm labor; change in cervical length between randomization and 28 weeks; and neonatal morbidity and mortality. Statistical analysis Statistical power was calculated apriori for the entire study population based on the primary outcome: a 50% reduction in the rate of preterm birth at = 32 weeks. The methods used to calculate power for the primary 17 . study are detailed in the accompanying article Because performing retrospective power analyses can be considered statistically inappropriate, a supplemental power calculation for this secondary analysis was not undertaken 1 8 , 1 9 . Data were analyzed based on the intentto-treat (ITT) principle using the SAS 9.1 statistical software package (SAS Institute Inc., Cary, NC, USA). Chi-square or Fishers exact tests were used for categorical data and ANOVA was used for continuous data. Pregnancy prolongation was evaluated using life-table analysis and the Kaplan Meier method to estimate the time-to-delivery event curve for treatment groups. The log-rank and Wilcoxon tests were used to evaluate Kaplan Meier curves. A P -value of < 0 . 05 was considered statistically significant.

699 and for whom information was available regarding the date of delivery were included in the ITT population. Patients without a record of delivery date were considered lost to follow-up. Using a cervical length of < 28 mm (the 9 t h percentile of the ITT population) to expand the criteria for short cervix resulted in a cohort of 46 women: 19 who received progesterone and 27 who received placebo (Figure 1). The randomization provided treatment groups in which the baseline demographic and obstetric characteristics were similar (Table 1). Effect of progesterone on preterm birth in women with a short cervix The original planned secondary analysis involved evaluating the efficacy of progesterone to prevent preterm birth in women enrolled with only a short cervix (= 25 mm) at baseline. The frequency of preterm birth at = 32 weeks gestation in these women was 0% in the progesterone group (0/4) compared with 40% in the placebo group (2/5). Because cervical length is a stronger predictor of 20 , an evaluation of preterm birth than is obstetric history outcomes based on the baseline cervical length of all randomized patients in the main trial was added to the analysis. Kaplan Meier curves comparing the progesterone and placebo groups for time to delivery were prepared for all women enrolled in the trial with a baseline cervical length measurement ( n = 609) 1 7 ,forwomenwiththelowest quartile of cervical length (= 32 mm; n = 172; Figure 2a) and for women with the highest three quartiles combined (> 32 mm; n = 437; Figure 2b). Women in the lowest quartile of cervical length (= 32 mm) who were treated with progesterone did not demonstrate a significant delay
Table 1 Baseline demographic and obstetric characteristics of womenwithashortcervix( < 28 mm) Group Progesterone ( n = 19 ) Placebo ( n = 27 )

RESULTS Population demographics There were 53 study sites participating in the full trial. The 17 US study sites initially recruited enrolled women with either a history of spontaneous preterm birth (< 35 weeks) or a short cervix only (= 25 mm), while the 36 sites subsequently recruited worldwide enrolled only women with a history of spontaneous preterm birth (< 35 weeks), because the primary objective of the trial was to evaluate the effect of progesterone in patients with a previous preterm birth. A total of 711 women gave written informed consent, of whom 42 were not randomized. The most common reasons for exclusion after consent were planned cerclage, comorbid conditions and failure to document a previous spontaneous preterm birth, as determined by review of medical charts of previous pregnancies. A record of screened patients was constructed when consent was obtained. The exact number of those prescreened is not available; an estimate of 1500 prescreened subjects was obtained by querying the study sites after trial completion. One patient was lost to follow-up prior to randomization, so a total of 668 women at high risk for preterm birth participated in the trial. Outcome data were available for 620 of these women (92.8%): 313 who received progesterone (309 enrolled with a prior preterm birth at < 35 weeks and four enrolled with only a short cervix = 25 mm) and 307 who received the placebo (302 enrolled with a prior preterm birth and five enrolled with only a short cervix). Patients who took at least one dose of study medication

Characteristic

Maternal age (years, mean 27.4 (4.9) 25.4 (4.8) 0.18 (SD)) Race/ethnicity ( n (%)) Caucasian 9 (47.4) 10 (37) 0.55 African-American 3 (15.8) 11 (40.7) 0.10 Hispanic 1 (5.3) 0 0.40 Asian/Pacific Islander 0 4 (14.8) 0.13 Other 6 (31.6) 2 (7.4) 0.05 Body mass index (mean (SD)) 28.5 (8.3) 26.9 (6.7) 0.52 Prior preterm births ( 1.2 (0.5) 1.4 (0.8) 0.26 n ,mean (SD)) > 1 prior preterm birth ( n (%)) 7 (37) 5 (19) 0.80 Prior cervical surgery ( n (%)) 3 (16) 6 (22) 0.70 Prior spontaneous miscarriages 0.8 (1.4) 0.4 (0.7) 0.22 ( n ,mean(SD)) GA at randomization (weeks, 20.4 (1.3) 20.4 (1.6) 0.98 mean (SD)) GA, gestational age.

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2007 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol

2007; 30 : 697705.

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711 patients provided written informed consent 42 patients provided written informed consent but were not randomized 669 patients enrolled 1 patient lost to follow-up prior to randomization 668 patients randomized

336 patients randomized to the progesterone arm of the study 332 with a prior spontaneous preterm birth ( = 35 weeks) 4 with a short cervix ( = 25 mm)

332 patients randomized to the placebo arm of the study 327 with a prior spontaneous preterm birth ( = 35 weeks) 5 with a short cervix ( = 25 mm)

23 patients lost to follow-up

25 patients lost to follow-up

Outcomes of 313 patients analyzed (intent-to-treat population)

Outcomes of 307 patients analyzed (intent-to-treat population)

294 women with cervical length = 28 mm at randomization

280 women with cervical length = 28 mm at randomization

Secondary analysis of 19 women with cervical length < 28 mm at randomization Figure 1 Trial profile.

Secondary analysis of 27 women with cervical length < 28 mm at randomization

in preterm delivery when compared to placebo patients (Wilcoxons P = 0 .37, log-rank P = 0 . 34; Figure 2a), nor did women in the upper three quartiles ( > 32 mm; Figure 2b). Women with cervical lengths in the upper three quartiles had a Kaplan Meier curve for time to delivery no different from all randomized women in the main trial 1 7 . The maternal/fetal outcomes of the 172 women enrolled with a cervical length = 32 mm did not differ significantly between treatment groups. Of these women, 83 received progesterone and 89 received the placebo. The rate of preterm birth at = 32 weeks of gestation for this group of women was 7.2% for those treated with progesterone compared with 13.5% for those treated with placebo (P = 0 . 21). The rates of preterm birth at < 37, < 35 and < 28 weeks were 44.6% vs. 51.7%, 22.9% vs. 30.3% and 1.2% vs. 6.7%, respectively, for the progesterone and placebo groups ( P-values were 0.36, 0.30 and 0.12, respectively). The number of neonates admitted to the neonatal intensive care unit (NICU) did not differ significantly for progesterone compared with placebo groups (13 vs. 21, P = 0 .25), nor did the length of NICU stay (13.0 vs. 32.7 days, P = 0 . 14). Neonatal morbidities of intraventricular hemorrhage (1.2% vs. 2.4%, P = 1 . 0),

respiratory distress syndrome (7.2% vs. 13.5%, P = 0 .21) and necrotizing enterocolitis (1.2% vs. 1.1%, P = 1 .0) did not differ between the groups. Kaplan Meier curves were also generated for subsets of all randomized women within the lowest quartile of cervical lengths (= 30 mm and < 28 mm). Figure 3 shows that there was a statistical trend towards delay in preterm delivery for progesterone-treated patients relative to placebo-treated patients in the 116 women with a baseline cervical length = 30 mm (Wilcoxons P = 0 . 043, log-rank P = 0 . 057). Among women with a baseline cervical length of = 30 mm, progesterone treatment was associated with a significant reduction in NICU days when compared with the placebo results (2 vs. 12 days, P = 0 . 026). The progesterone vs. placebo groups were not significantly different with respect to the number of neonates admitted to the NICU (16% vs. 32%, P = 0 . 077), total number of neonatal hospital days (7 vs. 14 days, P = 0 . 095) and occurrence of neonatal respiratory distress syndrome (7% vs. 19%, P = 0 . 09). Figure 4 demonstrates Kaplan Meier curves for the 46 randomized women with a baseline cervical length of < 28 mm. This subgroup of women with a short cervix experienced a significant reduction in the frequency of

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2007 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol

2007; 30 : 697705.

Progesterone in women with short cervix preterm birth for the primary end point of this study, = 32 weeks of gestation (0% vs. 29.6%, P = 0 . 014) (Table 2). There were decreasing rates of preterm birth for secondary outcomes, < 37 weeks, = 35 weeks and = 28 weeks; however, these differences did not reach statistical significance (Table 2). In women with a cervical length < 28 mm the number of admissions to the NICU was lower in those receiving progesterone than it was in those receiving placebo (15.8% vs. 51.9%, P = 0 .016) and the length of NICU stay was shorter in the progesterone group than it was in the placebo group (1.1 vs . 16.5 days, P = 0 .013).
1.0

701

0.8

0.6

0.4

0.2 (a) 1.0 0 0.8 21 25 27 23 29 Time (weeks) Figure 3 Probability of patients with a baseline cervical length =30 mm remaining undelivered according to treatment group (placebo ( , n = 58 ) or progesterone ( , n = 58 )). The KaplanMeier method was used for calculation (Wilcoxons P = 0 . 043 ,log-rank P = 0 . 057 ). 31 33 35 37

0.6

0.4 1.0 0.2 0.8 0

21

23 25 27 29 Time (weeks)

31 33 35 37

0.6

(b) 1.0 0.4 0.8 0.2 0.6 0 0.4 21 25 27 23 29 Time (weeks) Figure 4 Probability of patients with a baseline cervical length < 28 mm remaining undelivered according to treatment group group (placebo ( , n = 27 ) or progesterone ( , n = 19 )). The KaplanMeier method was used for calculation (Wilcoxons P = 0 . 242 ,log-rank P = 0 . 334 ). 21 25 27 23 29 Time (weeks) Figure 2 Probability of patients remaining undelivered according to treatment group (placebo ( ) or progesterone ( )). The KaplanMeier method was used for calculation. (a) Baseline cervical length = 32 mm (first quartile): placebo group, n = 89 ; progesterone group, n = 83 ; Wilcoxons P = 0 . 37 ,log-rank P = 0 . 34 . (b) Baseline cervical length > 32 mm (second, third and fourth quartiles): placebo group, n = 211 ; progesterone group, ; Wilcoxons ,log-rank n = 226 P = 0 . 91 P = 0 . 83 . 31 33 35 37 31 33 35 37

0.2

There was a trend, although it was not statistically significant, towards a reduction in total neonatal hospital days (5.8 vs. 18.2 days, P = 0 . 055) and decreased occurrence of neonatal respiratory distress syndrome (5.3% vs . 29.6%, P = 0 . 060) with progesterone therapy (Table 3). In the main trial, there was no difference between the vaginal progesterone gel group and the placebo group with respect to the frequency of adverse events

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2007 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol

2007; 30 : 697705.

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Table 2 Preterm birth outcomes in women with a cervical length
< 28 mm at enrollment

D e Franco et al.

Group Progesterone ( n = 19 ) Placebo ( n = 27 )

Outcome

GA at birth (weeks, mean (SD)) 36.3 (2.4) 34.6 (4.6) 0.160 Preterm birth ( n (%)) 8 (42.1) 16 (59.3) 0.370 < 37 weeks 7 (36.8) 13 (48.1) 0.551 =35 weeks 0 8 (29.6) =32 weeks * 0 3 (11.1) 0.257 =28 weeks Cervical length at enrollment (mm) Mean (SD) 24 (0.2) 22 (0.5) 0.07 Median (range) 25 (1927) 25 (1127) Cervical length at 28 weeks (mm, mean (SD)) 25 (0.8) 22 (0.8) 0.27 Change in cervical length (mm, mean (SD)) 2 (0.9) 0 (0.9) 0.70 Admission for preterm labor ( n (%)) 6 (31.6) 7 (25.9) 1.0 Latency period to delivery after tocolysis for preterm labor (days, mean (SD)) 42.7 (52.3) 10.0 (18.0) 0.287 Compliance (% (SD)) 93.9 (9.77) 94.7 (13.03)
* Primary outcome.

0.014

Percent compliance was assessed as total treatment duration compliance: (total applicators used/total dosing days) 100. A compliance of 96% represents missing one application every 25 dosing days. Four of these patients had a baseline cervical length < 25 mm and one had a baseline cervical length < 15 mm. Adjusted for cervical length at baseline using logistic regression, P = 0 . 016 . GA, gestational age.

Table 3 Neonatal outcomes in women with a cervical length < 28 mm at enrollment Group Progesterone (n = 19) Placebo (n = 27)

Outcome

Birth weight (g, mean (SD)) 2726 (645) 2290 (937) 0.1 Hospital days ( n , mean (SD)) 5.8 (9) 18.2 (25.5) 0.055 NICU admission ( n (%)) 3 (15.8) 14 (51.9) 0.016 Days in NICU per admission 1.1 (2.7) 16.5 (24.9) 0.013 ( n ,mean(SD)) Respiratory distress 1 (5.3) 8 (29.6) 0.060 syndrome ( n (%)) Intraventricular hemorrhage ( n (%)) Grade 1 0 2 (7.4) 0.5 Grade 2 0 0 Grade 3 0 0 Grade 4 0 0 Necrotizing enterocolitis ( n (%)) Surgical 0 0 Clinical 0 1 (3.7) 1.0 Proven sepsis ( n (%)) 1 (5.3) 3 (11.1) 1.0 Neonatal death ( n (%)) 0 1 (3.7) 1.0 NICU, neonatal intensive care unit.

or in any of the subgroups analyzed. Among women with a cervical length = 30 mm at enrollment, there were four fetal/infant deaths in the placebo group ((1) 23 weeks of gestation, 590 g, prematurity; (2) 26 weeks of gestation, 620 g, intrauterine fetal demise; (3) 35 weeks of gestation, aspiration pneumonia; (4) term, expired at 11 months of age, sudden infant death syndrome (SIDS)) and two fetal/infant deaths in the vaginal progesterone group ((1) 21 weeks of gestation, 250 g, intrauterine fetal demise; (2) term, expired at 6 months of age, gastroenteritis). In the subgroup of women enrolled with a cervical length of < 28 mm, two fetal/infant deaths occurred in the placebo group ((1) term, expired at 11 months of age, SIDS; (2) 35 weeks of gestation, aspiration pneumonia) and there were none in the vaginal progesterone group. DISCUSSION This study is a secondary analysis of the largest randomized trial conducted to date to evaluate the efficacy of progesterone for the prevention of preterm birth 1 7 . While progesterone did not reduce the frequency of preterm birth in women at high risk based on history alone, an objective screening tool, transvaginal sonographic determination of cervical length, was useful to identify patients responding to therapy. Our analysis suggests that progesterone may prevent early preterm birth (= 32 weeks of gestation) and improve neonatal outcome in women with short cervical lengths < 28 mm identified between 18 + 0 and 22 + 6 weeks of gestation. The cohort of women evaluated in this study included a population of high-risk pregnancies with at least one of two well-known risk factors for preterm birth: a history of preterm birth and a short cervix in the midtrimester. AccordingtodatafromTo et al .2 0 , short cervical length

overall (81.3% vs . 83.2%) or the frequency of serious adverse events 1 7 . Complaints about vaginal discharge occurred in 9.2% of placebo patients and 8.4% of progesterone patients, but for only 4.4% and 4.0%, respectively, was the vaginal discharge attributed to the vaginal gel. No miscarriages occurred among the trial participants, although 53% of all subjects began therapy prior to 20 weeks of gestation. There was also no difference in the occurrence of congenital anomalies between the progesterone and placebo groups. Finally, there was no increase in fetal/infant mortality overall

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2007 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol

2007; 30 : 697705.

Progesterone in women with short cervix is the best single predictor for preterm birth, predicting 61.2% of cases, while the combination of cervical length and a history of preterm birth predicts only an additional 4.4% (65.6% total). Data from the Preterm Prediction th percentile of cervical length Study has shown that the 10 7 . The measurement of in a low-risk population is 26 mm baseline cervical length in all patients and exclusion of women with a plan for cervical cerclage placement may have resulted in the exclusion of most of the subjects we expected to enroll with a short cervix in the midtrimester. Although the number of patients recruited into the shortcervix-only population (= 25 mm) was small, the rate of preterm birth in those receiving the placebo was 40%. In comparison, the preterm birth rate for the placebo group of women with a cervical length < 28 mm at enrollment (including a large proportion of patients with both a short cervix and a previous preterm birth) was 30%, with no apparent increase. These results lead us to speculate that the responders in the previously published trials of progestin administration in women with a history 1 2 , 1 3 may well have been those women of preterm birth with early-onset cervical shortening. Neither of the two largest previous trials in the population of women with a history of preterm birth included a measurement of baseline cervical length 1 2 , 13 . Cervical length is the best predictor of preterm birth according to data previously published from the research centers of Iams 7 , Nicolaides 2 0 and Berghella 2 1 , 2 2 .This fact was noted by the American College of Obstetricians and Gynecologists in ACOG Practice Bulletin Number 24 , 31 2 3 and was cited in the Institute of Medicine Report Preterm Birth: Causes, Consequences, and Prevention. In addition to providing improved prognostication, this objective screening tool for preterm birth risk offers other advantages compared with screening by historical factors. Any population better defined by useful objective characteristics is more likely to share a similar pathophysiology to the end point of preterm birth, which has multiple etiologies. In well-defined populations, an intervention may be better directed toward interrupting a specific mechanism or mechanisms of disease. Several studies have addressed the mechanism with which progesterone might reduce the rate of cervical 2 4 . Cervical ripening can be shortening or ripening characterized as a reduction in total collagen content by an increase in collagen solubility and collagenolytic activity. Collectively, these activities cause a remodeling 2 5 . A number of the extracellular matrix of the cervix of hormones, including progesterone, in uence this activity. Estrogen stimulates collagen degradation in vitro and progesterone blocks estrogen-induced collagenolysis in vitro 2 6 . Progesterone also down-regulates interleukin 2 7 . Likewise, administration 8 production by the cervix of a progesterone-receptor antagonist induces cervical 2 8 . Taken together, these ripening in the first trimester observations suggest that progesterone inhibits the cervical ripening that is known to precede labor. The efficacy of progesterone in our study population is noteworthy and encouraging. Although we do not believe

703 that every patient will respond identically, in women with a short cervix, no treated patients delivered at less than 32 weeks of gestation. This treatment effect was not seen in the overall study population or in the remaining 75% of trial participants who were at high risk for preterm birth based only on a previous preterm birth earlier than 35 weeks gestation. Unfortunately, for women with longer cervical lengths, other strategies to prevent preterm birth using other objective criteria for risk assessment are needed. A recent trial by Fonseca et al .29 also demonstrated that women with a short cervical length identified in the midtrimester by transvaginal sonography are less likely to deliver preterm if they are treated with vaginal progesterone. In that trial women were screened between 20 and 25 weeks of gestation and offered randomization to 200-mg vaginal progesterone suppositories or placebo from 24 to 34 weeks if the midtrimester cervical length was = 15 mm. Progesterone treatment was associated with a significant reduction in preterm birth at < 34 weeks (relative risk, 0.56; 95% CI, 0.36 0.86). To our knowledge, ours is the only trial of a progestin in the prevention of preterm birth to be associated with a significant improvement in neonatal outcome. 3 0 , 3 1 and NICU days 32 Rates of admission to the NICU are recognized measures of infant morbidity, as they relate to other neonatal complications. The intravaginal formulation of natural progesterone utilized in our trial had an adverse event profile similar to the placebo, and its route of administration was not associated with miscarriage. There were no safety issues identified with natural progesterone in this trial, or in a previous study when it was used as luteal support during in-vitro 3 3 fertilization cycles . The results from our study and that of Fonseca et al .2 9 suggest that objective criteria to determine indications for prophylactic treatment with progesterone, specifically sonographic evidence of a short cervix, should be utilized to prevent preterm birth. We found that women with second-trimester sonographic evidence of a short cervical length ( < 28 mm) have a reduction in the risk of early preterm birth (= 32 weeks) and neonatal morbidity when treated with vaginal progesterone gel. Given the findings of this trial and those of Fonseca et al .2 9 , we suggest that midtrimester cervical length assessment by transvaginal ultrasound be incorporated into routine clinical practice, as prophylactic vaginal progesterone supplementation benefits asymptomatic high-risk pregnancies with earlyonset cervical shortening. ACKNOWLEDGMENT This trial was funded by Columbia Laboratories, Inc. Con ict of interest J. M. OBrien is a consultant and has received honoraria from Cook Biotech, Inc. G. W. Creasy is an employee of Columbia Laboratories, Inc.

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2007 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol

2007; 30 : 697705.

704 Additional collaborators W. Hansen (Lexington, KY), M. Newman (Baton Rouge, LA), B. Rosenn (New York, NY), S. Dabak (Pune, India), L. Parker, (Winston-Salem, NC), J. Stern (Memphis, TN), L. Bayer-Zwirello (Boston, MA), L. Cousins (San Diego, CA), A. Kekre (Vellore, India), R. McDuffie, (Denver, CO), J. Schucker (Danville, PA), C. Barrera (Santiago, Chile), C. Goldberg (Tucson, AZ), A. Jiratko (Zlinska, Czech Republic), K. Swenson (Austin, TX), A. Evans (Lubbock, TX), G. Gross (St. Louis, MO), M. Short (Baltimore, MD), S. Sunderji (Toledo, OH), R. Artal (St. Louis, MO), M. Binstock (Bedford, OH), J. Hibbard (Chicago, IL), R Kelly (Odessa, TX), X. Sandovol-Lopez (San Salvador, El Salvador), L. Smith (Livingston, NJ), M. Stitley (Morgantown, WV), E. Wang (Chicago, IL), M. Beall (Torrence, CA), J. Carvajal (Santiago, Chile), V. Rappaport (Albuquerque, NM), L. Wilkins-Haug (Boston, MA), B. Sibai (Cincinnati, OH). REFERENCES
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2007 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol

2007; 30 : 697705.