Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: A secondary analysis from a randomized, double-blind, placebo-controlled trial

ArticleinUltrasound in Obstetrics and Gynecology 30(5):697-705 · October 2007with174 Reads
Impact Factor: 3.85 · DOI: 10.1002/uog.5159 · Source: PubMed
Abstract

To investigate the efficacy of vaginal progesterone to prevent early preterm birth in women with sonographic evidence of a short cervical length in the midtrimester. This was a planned, but modified, secondary analysis of our multinational, multicenter, randomized, placebo-controlled trial, in which women were randomized between 18 + 0 and 22 + 6 weeks of gestation to receive daily treatment with 90 mg of vaginal progesterone gel or placebo. Cervical length was measured with transvaginal ultrasound at enrollment and at 28 weeks of gestation. Treatment continued until either delivery, 37 weeks of gestation or development of preterm rupture of membranes. Maternal and neonatal outcomes were evaluated for the subset of all randomized women with cervical length < 28 mm at enrollment. The primary outcome was preterm birth at </= 32 weeks. A cervical length < 28 mm was identified in 46 randomized women: 19 of 313 who received progesterone and 27 of 307 who received the placebo. Baseline characteristics of the two groups were similar. In women with a cervical length < 28 mm, the rate of preterm birth at </= 32 weeks was significantly lower for those receiving progesterone than it was for those receiving the placebo (0% vs. 29.6%, P = 0.014). With progesterone, there were fewer admissions into the neonatal intensive care unit (NICU; 15.8% vs. 51.9%, P = 0.016) and shorter NICU stays (1.1 vs. 16.5 days, P = 0.013). There was also a trend toward a decreased rate of neonatal respiratory distress syndrome (5.3% vs. 29.6%, P = 0.060). Vaginal progesterone may reduce the rate of early preterm birth and improve neonatal outcome in women with a short sonographic cervical length.

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Ultrasound Obstet Gynecol 2007; 30: 697705
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.5159
Vaginal progesterone is associated with a decrease in risk for
early preterm birth and improved neonatal outcome in
women with a short cervix: a secondary analysis from a
randomized, double-blind, placebo-controlled trial
E. A. DEFRANCO
1
,J.M.OBRIEN
2
,C.D.ADAIR
3
,D.F.LEWIS
4
,D.R.HALL
5
,S.FUSEY
6
,
P. SOMA-PILLAY
7
,K.PORTER
8
,H.HOW
9
,R.SCHAKIS
10
, D. ELLER
11
,Y.TRIVEDI
12
,
G. VANBUREN
13
,M.KHANDELWAL
14
,K.TROFATTER
15
,D.VIDYADHARI
16
,
J. VIJAYARAGHAVAN
17
, J. WEEKS
18
, B. DATTEL
19
, E. NEWTON
20
, C. CHAZOTTE
21
,
G. VALENZUELA
22
,P.CALDA
23
, M. BSHARAT
24
and G. W. CREASY
25
1
Department of Obstetrics and Gynecology and Center for Preterm Birth Research, Washington University School of Medicine, St. Louis,
Missouri, USA;
2
Perinatal Diagnostic Center, Central Baptist Hospital, Lexington, Kentucky, USA;
3
University of Tennessee College of
Medicine, Chattanooga, Tennessee, USA;
4
Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center,
Shreveport, Louisiana, USA;
5
Department of Obstetrics and Gynaecology, Stellenbosch University and Tygerberg Hospital, Tygerberg,
South Africa;
6
Department of Obstetrics and Gynaecology, Government Medical College, Nagpur, India;
7
Department of Obstetrics and
Gynaecology, University of Pretoria, Pretoria, South Africa;
8
University of South Alabama, Mobile, Alabama, USA;
9
University of
Cincinnati, Cincinnati, Ohio, USA;
10
Chris Hani Baragwanath Hospital, University of the Witwatersrand, Soweto, South Africa;
11
Maternal Fetal Specialists, Atlanta, Georgia, USA;
12
Department of Obstetrics and Gynecology, Sheth Vadilal Sarabhai General Hosptial,
Gujarat, India;
13
University Hospitals Case Medical Center, Cleveland, Ohio, USA;
14
Cooper Hospital, Camden, New Jersey, USA;
15
University Medical Group, Greenville, South Carolina, USA;
16
MediCiti Institute of Medical Sciences, Andra Pradesh, India;
17
Sri. Ramchandra Hospital, Chennai, India;
18
Norton Healthcare, Louisville, Kentucky, USA;
19
Department of Obstetrics and
Gynecology, Eastern Virginia Medical School, Norfolk, Virgina, USA;
20
Brody School of Medicine, East Carolina University, Greenville,
North Carolina, USA;
21
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA;
22
Arrowhead Regional
Medical Center, Colton, California, USA;
23
Department of Obstetrics and Gynaecology, First Medical School, Charles University, Prague,
Czech Republic;
24
Quintiles Biostatistics, Overland Park, Kansas, USA;
25
Columbia Laboratories, Inc., Livingston, New Jersey, USA
Collaborators are listed in full at the end of the manuscript.
KEYWORDS: pregnancy; prematurity; preterm birth; progesterone; short cervix
ABSTRACT
Objective To investigate the efficacy of vaginal proges-
terone to prevent early preterm birth in women with
sonographic evidence of a short cervical length in the
midtrimester.
Methods This was a planned, but modified, secondary
analysis of our multinational, multicenter, randomized,
placebo-controlled trial, in which women were random-
ized between 18 + 0 and 22 + 6 weeks of gestation to
receive daily treatment with 90 mg of vaginal proges-
terone gel or placebo. Cervical length was measured with
transvaginal ultrasound at enrollment and at 28 weeks
of gestation. Treatment continued until either delivery,
37 weeks of gestation or development of preterm rup-
ture of membranes. Maternal and neonatal outcomes
were evaluated f or the subset of all randomized women
with cervical length < 28 mm at enrollment. The primary
outcome was preterm birth at 32 weeks.
Results A cervical length < 28 mm was identified in 46
randomized women: 19 of 313 who received progesterone
and 27 of 307 who received the placebo. Baseline
characteristics of the two groups were similar. In women
with a cervical length < 28 mm, the rate of preterm birth
at 32 weeks was significantly lower for those receiving
progesterone than it was for those receiving the placebo
(0% vs. 29.6%, P = 0.014). With progesterone, there
were fewer admissions into the neonatal intensive care
unit (NICU; 15.8% vs. 51.9%, P = 0.016) and shorter
NICU stays (1.1 vs. 16.5 days, P = 0.013). There was also
a trend toward a decreased rate of neonatal respiratory
distress syndrome (5.3% vs. 29.6%, P = 0.060).
Correspondence to: Dr E. A. DeFranco, Washington University School of Medicine, Department of Obstetrics and Gynecology, 4566 Scott
Avenue, Campus Box 8064, St. Louis, Missouri 63110, USA (e-mail: defrancoe@wudosis.wustl.edu)
Accepted: 20 August 2007
Copyright
2007 ISUOG. Published by John Wiley & Sons, Ltd. O R IG IN AL P A P E R
Page 1
698 DeFranco et al.
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.
INTRODUCTION
Despite medical efforts towards its prevention, the rate
of preterm birth, defined as birth occurring prior to
37 weeks of gestation, continues to rise among certain
populations, occurring in up to 15% of pregnancies in
the developed world and 12.7% in the United States
1,2
.
Preterm birth is associated with a high prevalence of
severe neurological deficits and developmental disabilities
and is a leading cause of infant and neonatal mortality
in the United States
3–5
. Preterm neonates are at increased
risk of developing respiratory distress syndrome, sepsis,
intraventricular hemorrhage, necrotizing enterocolitis and
disorders related to gestational age at birth
6
.
A short cervix is a known risk factor for preterm birth;
in fact, data support an inverse relationship between
cervical length and preterm delivery. In a prospective study
of 2915 women that investigated the relationship between
short cervical length and preterm delivery, researchers
found that even a small decrease in cervical length between
the 24
th
and 28
th
weeks of gestation was associated with
an increased risk of preterm birth (relative risk, 2.03;
95% CI, 1.283.22)
7
. At 24 weeks, when compared
with women whose cervical length was above the 75
th
percentile, women who had a cervical length on or below
the 25
th
percentile (30 mm) had a relative risk of preterm
delivery of 3.79 (95% CI, 2.326.19), and those on or
below the 10
th
percentile (26 mm) had a relative risk of
6.19 (95% CI, 3.849.97)
7
.
Progesterone administration has been advocated for
the prevention of preterm birth in women considered to
be at high risk
8,9
, although the primary focus has been
on patients with a prior history of preterm birth
10 13
.
There has been increasing interest in the efficacy of
vaginally administered progesterone to prevent preterm
birth in women at especially high risk of preterm delivery,
those with a short sonographic cervical length. The
use of progesterone to treat all women at risk for
preterm birth does not have uniform support at present,
but it has rapidly become accepted as a prophylactic
measure to prevent preterm birth in women with a
documented history of spontaneous preterm birth. Several
authors have expressed the need for adequately designed,
randomized trials in larger populations to identify the
ideal progesterone formulation and dosage, and to
demonstrate whether progesterone administration results
in a decline in preterm births before 37 weeks and a
reduction in perinatal morbidity and mortality
8,14 16
.
The primary objective of our prospective, random-
ized, double-blind, placebo-controlled, multicenter study,
described in an accompanying article
17
, was to assess the
efficacy and safety of 90-mg progesterone vaginal gel com-
pared with placebo to decrease the rate of early preterm
birth ( 32 + 0 weeks) among women with a prior his-
tory of spontaneous preterm delivery. In that study, we
found no difference between placebo and progesterone in
reducing the frequency of preterm birth among women
selected only by a documented history of preterm birth.
The objective of this planned secondary analysis was to
evaluate the efficacy of daily vaginal progesterone gel to
prevent preterm birth in women with a short cervix in the
midtrimester.
METHODS
This was a planned, but modified, secondary analysis
of the prospective, randomized, double-blind, placebo-
controlled trial of progesterone to prevent preterm birth
in high-risk women, reported in the accompanying article
in this issue of the Journal
17
. Prior to the trial, we planned
to analyze data and report outcomes separately for the
women enrolled without a history of preterm birth but
with a short cervical length alone ( 25 mm). Due to an
insufficient number of subjects recruited into this arm
of the trial (n = 9, 1.3% of the study population), the
separate analysis of these patients was not meaningful.
Therefore, we modified the planned analysis of women
enrolled based on a short cervix only to include women
enrolled with a prior preterm birth who also had a short
cervix at enrollment. To accomplish this, we divided
the study population into quartiles based on cervical
length. We then subdivided the lowest quartile ( 32 mm)
sequentially and analyzed the primary and secondary
outcomes for women with cervical lengths of 30 mm
and < 28 mm at the time of enrollment. There were an
insufficient number of patients with even shorter cervical
lengths to allow further analysis.
Women with a documented history of spontaneous
preterm birth (< 35 weeks) in a singleton pregnancy in
the immediate preceding pregnancy, regardless of cervical
length, and women without a history of preterm birth but
with a short cervix ( 25 mm) in the midtrimester of the
current pregnancy were screened by the investigator or
study coordinator between 16 + 0 and 22 + 6 weeks of
gestation. Subjects meeting the study criteria were offered
enrollment into the study at 18 + 0to22+ 6 weeks
of gestation to receive daily treatment with 90 mg of
vaginal progesterone gel (Prochieve
8%/Crinone
8%)
or placebo (Replens
), both provided by Columbia
Laboratories, Inc. (Livingston, NJ, USA). Cervical length
was measured with transvaginal ultrasound at enrollment
and at 28 weeks of gestation. Treatment was continued
until either delivery, 37 weeks of gestation or development
of preterm rupture of membranes.
Details of the study period, exclusion criteria, random-
ization and drug/placebo treatment procedures, as well
as the definition of preterm labor are provided in the
accompanying report of the randomized clinical trial
17
.
The outcomes for this study were defined apriori.The
primary outcome was preterm birth at 32 weeks. Sec-
ondary outcomes included: preterm birth at < 37 weeks,
35 weeks, and 28 weeks; treatment-related adverse
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2007; 30: 697705.
Page 2
Progesterone in women with short cervix 699
events; hospital admission for preterm labor; prolonga-
tion 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 apriorifor 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
study are detailed in the accompanying article
17
.
Because performing retrospective power analyses can
be considered statistically inappropriate, a supplemental
power calculation for this secondary analysis was not
undertaken
18,19
. Data were analyzed based on the intent-
to-treat (ITT) principle using the SAS 9.1 statistical
software package (SAS Institute Inc., Cary, NC, USA).
Chi-square or Fisher’s exact tests were used for categorical
data and ANOVA was used for continuous data.
Pregnancy prolongation was evaluated using life-table
analysis and the KaplanMeier method to estimate the
time-to-delivery event curve for treatment groups. The
log-rank and Wilcoxon tests were used to evaluate
KaplanMeier curves. A P-value of < 0.05 was considered
statistically significant.
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
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
th
percentile of
the ITT population) to expand the criteria for short cervix
resulted in a cohort of 46 women: 19 who received pro-
gesterone 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 evalu-
ating 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
preterm birth than is obstetric history
20
, an evaluation of
outcomes based on the baseline cervical length of all ran-
domized patients in the main trial was added to the analy-
sis. KaplanMeier 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)
17
,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
Characteristic
Progesterone
(n = 19)
Placebo
(n = 27) P
Maternal age (years, mean
(SD))
27.4 (4.9) 25.4 (4.8) 0.18
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 (
n,mean
(SD))
1.2 (0.5) 1.4 (0.8) 0.26
> 1 prior preterm birth (n (%)) 7 (37) 5 (19) 0.80
Prior cervical surgery (
n (%)) 3 (16) 6 (22) 0.70
Prior spontaneous miscarriages
(
n,mean(SD))
0.8 (1.4) 0.4 (0.7) 0.22
GA at randomization (weeks,
mean (SD))
20.4 (1.3) 20.4 (1.6) 0.98
GA, gestational age.
Copyright
2007 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2007; 30: 697705.
Page 3
700 DeFranco et al.
711 patients provided
written informed consent
669 patients enrolled
668 patients randomized
23 patients lost to
follow-up
294 women with
cervical length
28 mm at
randomization
280 women with
cervical length
28 mm at
randomization
Outcomes of 313 patients analyzed
(intent-to-treat population)
Outcomes of 307 patients analyzed
(intent-to-treat population)
Secondary analysis of 19 women
with cervical length < 28 mm at
randomization
Secondary analysis of 27 women
with cervical length < 28 mm at
randomization
25 patients lost to
follow-up
42 patients provided written
informed consent but were not
randomized
1 patient lost to follow-up
prior to randomization
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)
Figure 1 Trial profile.
in preterm delivery when compared to placebo patients
(Wilcoxon’s 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 KaplanMeier curve for time to
delivery no different from all randomized women in the
main trial
17
.
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.
KaplanMeier 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 (Wilcoxon’s 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 KaplanMeier 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
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2007; 30: 697705.
Page 4
Progesterone in women with short cervix 701
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).
21
0
0.2
0.4
0.6
Probability of not delivering
0.8
1.0(a)
23 25 27 29
Time (weeks)
31 33 35 37
0
0.2
0.4
0.6
Probability of not delivering
0.8
1.0
(b)
2321 25 27 29
Time (weeks)
31 33 35 37
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; Wilcoxon’s 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,
n = 226; Wilcoxon’s P = 0.91,log-rankP = 0.83.
0
0.2
0.4
0.6
Probability of not delivering
0.8
1.0
2321 25 27 29
Time (weeks)
31 33 35 37
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 (Wilcoxon’s
P = 0.043,log-rankP = 0.057).
0
0.2
0.4
0.6
Probability of not delivering
0.8
1.0
2321 25 27 29
Time (weeks)
31 33 35 37
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 (Wilcoxon’s
P = 0.242,log-rankP = 0.334).
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
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2007; 30: 697705.
Page 5
702 DeFranco et al.
Table 2 Preterm birth outcomes in women with a cervical length < 28 mm at enrollment
Group
Outcome
Progesterone
(n = 19)
Placebo
(n = 27) P
GA at birth (weeks, mean (SD)) 36.3 (2.4) 34.6 (4.6) 0.160
Preterm birth (
n (%))
< 37 weeks 8 (42.1) 16 (59.3) 0.370
35 weeks 7 (36.8) 13 (48.1) 0.551
32 weeks* 0 8 (29.6) 0.014§
28
weeks 0 3 (11.1) 0.257
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. 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
Outcome
Progesterone
(n = 19)
Placebo
(n = 27) P
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
(
n,mean(SD))
1.1 (2.7) 16.5 (24.9) 0.013
Respiratory distress
syndrome (
n (%))
1 (5.3) 8 (29.6) 0.060
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.
overall (81.3% vs. 83.2%) or the frequency of serious
adverse events
17
. 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
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
17
. 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.
AccordingtodatafromToet al.
20
, short cervical length
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2007; 30: 697705.
Page 6
Progesterone in women with short cervix 703
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
Study has shown that the 10
th
percentile of cervical length
in a low-risk population is 26 mm
7
. The measurement of
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 short-
cervix-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
of preterm birth
12,13
may well have been those women
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
12,13
.
Cervical length is the best predictor of preterm birth
according to data previously published from the research
centers of Iams
7
, Nicolaides
20
and Berghella
21,22
.This
fact was noted by the American College of Obstetricians
and Gynecologists in ACOG Practice Bulletin Number
31
23
and was cited in the Institute of Medicine Report
24
,
‘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
shortening or ‘ripening’
24
. Cervical ripening can be
characterized as a reduction in total collagen content
by an increase in collagen solubility and collagenolytic
activity. Collectively, these activities cause a remodeling
of the extracellular matrix of the cervix
25
. A number
of hormones, including progesterone, influence this
activity. Estrogen stimulates collagen degradation in vitro
and progesterone blocks estrogen-induced collagenolysis
in vitro
26
. Progesterone also down-regulates interleukin
8 production by the cervix
27
. Likewise, administration
of a progesterone-receptor antagonist induces cervical
ripening in the first trimester
28
. Taken together, these
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
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, 0.360.86).
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.
Rates of admission to the NICU
30,31
and NICU days
32
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
fertilization cycles
33
.
The results from our study and that of Fonseca et al.
29
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.
29
, 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 early-
onset cervical shortening.
ACKNOWLEDGMENT
This trial was funded by Columbia Laboratories, Inc.
Conflict of interest
J. M. O’Brien is a consultant and has received honoraria
from Cook Biotech, Inc. G. W. Creasy is an employee of
Columbia Laboratories, Inc.
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2007; 30: 697705.
Page 7
704 DeFranco et al.
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).
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