American Journal of Obstetrics & Gynecology
Volume 196
Issue 5
Pages 453.31-453.e4
May 2007
Cervical length changes during preterm cervical ripening: effects of
17-a-hydroxyprogesterone caproate
Fabio Facchinetti, MD1, Simone Paganelli, MD1, Giuseppina Comitini, MD2, Giulia Dante, MD1, Annibale Volpe, MD1
Objective
The purpose of this study was to evaluate whether 17-a-hydroxyprogesterone caproate (17P) treatment affect
changes in cervical length.
Study Design
Women with singleton pregnancy, between 25 and 33 + 6 weeks of gestation, who were hospitalized for preterm
labor were included. Patients with rupture of membranes and/or signs of chorioamnionitis were excluded. Sixty
undelivered patients were allocated randomly to either observation or to receive 341 mg of 17P
intramuscularly, twice each week until gestational week 36. Cervical length was measured by transvaginal
ultrasound scanning at discharge and at day 7 and 21 after discharge. Statistical comparisons were done with
analysis of variance and chi-square test.
Results
Shortening of the cervix in the observation group (30 cases) was higher than in the 17P group (30 cases) both
at day 7 (2.37 ± 2.0 mm vs 0.83 ± 1.74 mm; P = .002) and day 21 (4.60 ± 2.73 mm Vs 2.40 ± 2.46 mm; P =
.002). Treatment with 17P was associated with both a reduction in the risk of cervical shortening of ≥4 mm
(odds ratio, 0.18; 95% CI, 0.04-0.66) and in the risk of preterm delivery (odds ratio, 0.15; 95% CI, 0.04-0.58).
Conclusion
Undelivered patients after preterm labor undergo progressive shortening of the cervix, which is attenuated by
17P treatment.
Table of Contents
Abstracts
Materials and Methods
Protocol
Statistical methods
Results
Comment
Acknowledgment
References
Copyright
Progesterone and 17-a-hydroxyprogesterone caproate (17P) have long been considered important agents in the
maintenance of uterine quiescence and have been used extensively in primary and secondary prevention of
preterm delivery (PTD).1 The effectiveness of 17P in reducing PTD in at-risk pregnancies was first
demonstrated in the 1970s.2, 3 Recently, a multicenter, randomized trial of treatment with 17P injections has
reported efficacy in decreasing the rate of PTD in women with the most powerful and consistent risk factor for
such a condition: a previous preterm birth.4
Despite such promising efficacy, however, very little is known about the mechanisms of action of 17P in
prolonging gestation. According to a recent review, it is possible that 17P increases the tocolytic effectiveness
of endogenous substances that account for uterine quiescence. Such an effect could be mediated by both
genomic (receptor-mediated) and nongenomic mechanisms.5 On the other side, progesterone derivatives have
been demonstrated to inhibit the activation of immune receptors that normally mediate inflammatory response
in the uterus, cervix, and placenta.6 Although contradictory, in vitro data demonstrate that either 17P or
progesterone could affect interleukin production from whole blood.7
Apart from a poor obstetric history, 1 of the main issues in the prediction and prevention of PTD is to identify
correctly women who are at risk of PTD in their first pregnancy or who have a negative obstetric history.
Several studies have compared the reliability, validity, and clinical use of digital examination with transvaginal
ultrasound scanning (TVU) of the cervix for the prediction of PTD in women with the diagnosis of preterm
labor; in each of these studies, TVU was shown to be superior to manual examination.8, 9 In fact, ultrasound
assessment can detect a silent shortening of the cervical canal before it becomes evident with manual
examination.10, 11
Surprisingly, although TVU is considered an accurate method to evaluate cervical length (CL) and dilation
objectively,12, 13 few data are available on the evolution of cervical changes in patients who have been treated
successfully after a preterm labor episode. Indeed, these are patients who are actually at risk because they
deliver preterm in approximately 30%-45% of the cases.14, 15
The aim of the present survey was to assess longitudinally whether 17P treatment affects TVU cervical changes
in women with preterm labor.
Materials and Methods
Protocol
A randomized, prospective, longitudinal study was performed between September 2004 and February 2006 that
included singleton pregnant women between 25 and 33 weeks + 6 days of gestation who were admitted for
threatened preterm labor. The study was not double blind because it was not sponsored; therefore, the
preparation of true placebo (same vial, same oil without active compound) was not possible.
Preterm labor was defined as the simultaneous presence of contractions (> 6 contractions in 30 minutes) and
cervical changes, either shortening and/or softening or dilation, by manual examination. Inclusion criteria were
singleton pregnancy, intact membranes, cervical dilation of ≤2 cm, and the dating of pregnancy confirmed
through first trimester ultrasound scanning.
Women with suspected intraamniotic infections or large uterine myomas were excluded. Women with vascular
complications of pregnancy, with placenta previa or fetal distress and chronic diseases such as diabetes
mellitus, heart disease, and/or autoimmune disorder were also excluded.
The women underwent standard tocolysis with atosiban (Tractocile, Ferring AG, Denmark), which was infused
according to manufacturer recommendation. Tocolysis was administered to every patient for 48 hours.
Meanwhile, 12 mg betamethasone (intramuscularly) was administered twice, 24 hours apart, for the induction
of fetal lung maturity. Moreover, as for standard protocol, a vaginal swab was collected to check for the
presence of Escherichia coli, group B Streptococcus, and Neisseria gonorrhea. Women who remained
undelivered (with a negative vaginal culture) therefore were eligible for the study.
The study was approved by the institutional review board. After written informed consent was obtained, patients
were assigned randomly in 2 groups. The random list was prepared with a computer-generated number list.
Odds (treatment) and pairs (observation) defined treatment allocation; the list was managed by the senior
midwife.
Patients who were enrolled as cases received 341 mg of 17P (Lentogest, AMSA SrI, Rome, Italy)
intramuscularly every 4 days, until gestational week 36. The remaining patients were included as control
subjects and received no drugs.
Previous studies that enrolled at-risk patients on the basis of obstetric history administered 17P once a week.
From an empiric point of view, we decided that treatment should be increased. This was based on several
considerations: (1) that the cervical ripening processes already had started in more than one half of the
population, (2) the patients were admitted for preterm labor (being very anxious about their future) and thus
required very active actions, and (3) there was a reduced time for an active treatment because patients were
enrolled late in the second trimester.
Patients of both arms of the study underwent the same follow-up procedure. They were invited to the next
check-up 7-9 days later and again 18-21 days after random assignment. Before randomization and at each visit,
a TVU for CL assessment was performed by 2 of us (Drs Paganelli and Comitini) who were blind to the
treatment. After the third check-up was performed, patients returned to their previous caregiver who treated
them until delivery.
TVU was performed by covered ultrasound probe inserted in the introitus after the women had emptied their
bladder. The probe was placed gently in the anterior fornix of the vagina to obtain a sagittal view of cervix and
achieve the long axis image of echogenic endocervical mucosa along the entire length of the canal. Excessive
pressure on cervix and cervical echogenicity was avoided. At this point, the CL was measured from the internal
to external os along cervical canal, and values were expressed in millimeters. A symmetric image of the
external os in absence of transfundal pressure was obtained. Over the course of approximately 5 minutes, we
performed 3 consecutive evaluations, using the mean value for analysis. No treatment changes were made on
the basis of these TVU CL measurements.
Statistical methods
The main outcome variable was the CL change throughout the observation period. The outcome of pregnancy
in terms of gestational age at parturition and birthweight was also collected from birth registry and represented
secondary outcomes, together with tolerance data.
In previous unpublished observations, we observed that, 2-3 weeks after a preterm labor episode, the cervix
shortened by ≥4 mm in 60% of the cases. We hypothesized that treatment would reduce such phenomenon by
50% and that 30 cases per group would be enough to detect a significant difference with 80% power.
Values pertinent with characteristics of each group were expressed as mean ± SD. Because the distribution of
variables was normal, chi-square and the Student t test were used for between-subject analysis when
appropriate. Analysis of variance was used for repeated measure analyses. Data elaboration was performed by
professional statistic software (SPSS 7.5 for Windows; SPSS Inc, Chicago, IL). A probability value of < .05 was
chosen to be the significant statistical level.
Results
In agreement with inclusion criteria, 106 patients were hospitalized for preterm labor. Twenty-one women
delivered within 48 hours, and 19 women had suspected chorioamnionitis. Six of the remaining women refused
to participate to the study. Sixty women were assigned randomly; 30 women received 17P, and 30 women did
not receive 17P. None of the patients were lost to follow-up. Patients were compliant, and none of the women
reported adverse events that were linked apparently to the treatment. Baseline characteristics of the patients
are given in the Table. No differences were found among the 2 groups.
Table. Clinical characteristics of the 2 groups of randomly assigned patients
Characteristic
Observation group
17P treatment group
Significance
Age (y)
29.8±2.7(22-33)
29.9±3.5(20-35)
NS
Nulliparous women (n)
17(73.9%)
16(66.7%)
NS
Previous PTD (n)
2(8.7%)
1(4.2%)
NS
Gestational age (d)
212.3±18.1(171-238)
208.4±22.1(157-238)
NS
CL (mm)
22.8±9.6(10-38)
24.5±8.9(5-44)
NS
CL ≤25 mm (n)
17(56%)
16(53%)
NS
1 cm
10(33%)
11(37%)
NS
≤2 cm
2(7%)
1(3%)
NS
Cervical dilation (n)
Data are given as mean ± SD (range).
According to analysis of variance, CL significantly changed throughout the observation period in both groups (P < .001). However, at
both 7 and 21 days after randomization, patients in the no 17P group reported shorter CL compared with patient who were treated
with 17P (Figure). The shortening of the cervix in the observation group was higher than in the 17P group, both at day 7 (2.37 ± 2.0
mm vs 0.83 ± 1.74 mm; P = .002) and at day 21 (4.60 ± 2.73 mm vs 2.40 ± 2.46 mm; P = .002) of follow-up. Treatment with 17P was
associated with a reduction in the risk of cervical shortening of ≥4 mm of 0.175 (95% CI, 0.04-0.66).
Figure. Changes of cervical length
Transvaginal ultrasound evaluation (mean ± SE) of CL in patients who were assigned randomly to observation
(dotted line) or 17P treatment (solid line). Bars indicate the net changes compared with baseline in the
observation group (open bar) and 17P treatment group (black bar). Statistical significant differences were
assessed with the use of the Student t test for independent samples.
The difference between the 2 groups was even higher when the analysis was restricted only to patients with a
short cervix (≤25 mm) at enrolment. Indeed, women who were treated with 17P had lower shortening of the
cervix both at day 7 (0.69 ± 1.71 mm) and 21 (1.38 ± 1.31 mm), with respect to women who had not received
17P (day 7, 2.35 ± 2.23 mm; P = .024; day 21, 4.88 ± 3.14 mm; P < .0001). During the follow-up period, 3
patients who received 17P and 1 patient who did not receive treatment underwent an increase of CL of >2 mm,
with respect to the values that were measured at inclusion.
Patients who did not receive 17P reported a rate of PTD at <37 weeks of gestation of 57% (17/30 cases),
whereas patients who were treated with 17P had a significantly lower rate (5/30 cases; 16%; P = .004). The
relative risk was 0.15 (95% CI, 0.04-0.58). Accordingly, birthweight in the latter group (3103 ± 468 g) was
higher than in the former group (2809 ± 317 g). No significant differences were found in the rate of PTD at <35
weeks of gestation between the 17P (3/30 cases; 10%) and the observation (7/30 cases; 23.3%) groups. The
time from randomization to parturition was significantly longer in 17P group (35.3 ± 19.1 days) than in the
observation group (25.5 ± 15.1 days; P = .003).
Comment
These data demonstrate that patients who remained undelivered after an episode of preterm labor underwent
progressive cervical shortening during the 3 weeks of the observation period. As a consequence, in the absence
of treatment, they delivered preterm in more than one-half of the cases. Conversely, the treatment with a highdose of 17P was associated with both a lower shortening of the cervix and a reduced rate of PTD.
Cervical ripening has been hypothesized to be the effect of a local activation of diverse biochemical pathways
that share the pathways of an aseptic, proinflammatory reaction.16 The increased secretion of interleukins17 and
nitric oxide18 has been reported in cervical fluids to be associated with PTD. Such mediators ultimately
stimulate apoptosis, activation of proteases, and disaggregation of collagen fibrils that allows cervical
shortening.19
One-half of our population simultaneously had 2 risk factors. In addition to the preterm labor episode, they also
had a short cervix (≤25 mm). Of paramount interest, the effect of 17P in the inhibition of further cervical
shortening in this group is much more evident. This seems to suggest that, once the preterm cervical ripening
processes are activated, the inhibitory effect of 17P could have a major impact.
Some experiences with progestin derivatives in women with preterm labor have been reported already.20, 21, 22,
23 24
, However, the comparison with our data is difficult because of the different study design (eg,
inclusion/exclusion criteria, drug used for treatment, way of administration, time of interventions). The main
difference is related to the fact that previous studies were all performed to stop preterm labor (mainly
contractions) with the use of progestin derivatives as acute tocolytics. We included patients after tocolysis was
obtained. Moreover, the only study that used 17P (associated to cortisol) reported a slightly better, although
not significant, prolongation of pregnancy with respect to the use of ritodrine.24
Several studies indicate that progesterone exerts immunomodulation. Progesterone receptors were found on
lymphocytes, and the activation of such receptors interferes with interleukin secretion through the
progesterone-induced blocking factor.25 Whether 17P interacts with such mechanisms is unknown at present,
considering that this steroid seems unlikely to be reconverted to progesterone. Conversely, it was demonstrated
that the administration of 17P acutely reduced progesterone levels.24 Moreover, a recent study that was
performed on whole blood that had been taken from nonpregnant women seems to demonstrate that 17P
increases proinflammatory cytokine tumor necrosis factor alpha.7 These data, however, evaluate only an in
vitro release and cannot be transferred to pregnant women in whom the immune response is inhibited
physiologically and differs from nonpregnant status.
The strength of the actual study is that the clinical effects of 17P have been described so far only in patients
who were at risk for PTD because of their poor obstetric history, whereas our findings were obtained in
patients who were at risk because of a preterm labor episode. The limit of our observation is the lack of double
blinding in the design. Moreover, a multicenter trial on this kind of obstetric patients is required before
conclusions can be drawn about any clinical advantage of 17P treatment.
In conclusion, patients who were treated successfully for a preterm labor episode underwent a progressive
shortening of the cervix that was attenuated by 17P treatment. Such an effect is associated with a reduction in
the rate of PTD.
Acknowledgment
We thank Dr Vincenzo Berghella (Jefferson University) for advice in writing the article.
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1 Unit of Obstetrics, Mother-Infant Department, University of Modena and Reggio Emilia, Reggio Emilia, Italy
2 Division of Obstetrics and Gynecology, Ospedale S Maria Nuova, Reggio Emilia, Italy.
Reprint requests: Fabio Facchinetti, MD, U.O. Ostetricia e Ginecologia, Dip. Materno Infantile, Via del Pozzo
71, 41100 Modena, Italy.
Cite this article as: Facchinetti F, Paganelli S, Comitini G, Dante G, Volpe A. Cervical length changes during
preterm cervical ripening: effects of 17-a-hydroxyprogesterone caproate. Am J Obstet Gynecol
2007;196:453.e1-453.e4.
PII: S0002-9378(06)01204-X
doi:10.1016/j.ajog.2006.09.009