Vaginal progesterone for asymptomatic cervical shortening and the case for universal screening of cervical length
Vaginal progesterone for asymptomatic cervical shortening
and the case for universal screening of cervical length
C. Andrew Combs, MD, PhD
short cervix detected in midpregnancy by transvaginal short cervix, whether or not there is a history of PTB. Using a
sonography carries a high risk of early preterm birth (PTB).
sophisticated individual patient data metaanalysis based on 5 pla-
The shorter the transvaginal cervical length (TVCL) and the ear-
cebo-controlled trials, they report that vaginal progesterone re-
lier in pregnancy a short cervix is detected, the higher the
duced the rate of early PTB (Ͻ33 weeks) among those with TVCL
strong association between cervical shortening and early PTB
Յ25 mm (12.4% with progesterone vs 22.0% with placebo) and
raises 2 critical but independent clinical questions:
reduced neonatal complications. The 2 largest trials in the meta-
● If we detect a short cervix, are there any treatments that will
analysis, comprising 91% of the subjects, had remarkably consis-
tent results despite differences in the TVCL (10-20 mm at enroll-
● Is it worthwhile to screen asymptomatic women to try to
(90 mg vs 200 mg progesterone reduced early PTBby and compared to placebo.
Treatments for short cervix: cerclage, progesterone
The analysis of Romero and clearly establishes
It does no good for individuals to know that they are at risk if
that treatment with vaginal progesterone is beneficial for
there is no effective treatment. Instead, it may actually do
asymptomatic women with singleton pregnancies in whom a
harm, triggering anxiety and a desperate search for unproven,
short cervix is detected. The metaanalysis of the combined pa-
costly, or hazardous treatments. For those at risk for PTB, well-
tient-level data yields key insights that could not have been
meaning clinicians are tempted to deploy a host of unproven or
even discredited interventions, including activity restrictions,
● The beneficial effects of progesterone on early PTB and neo-
bedrest, long-term tocolysis, or antibiotic treatment. Cervical
natal morbidity was similar in various subgroups of TVCL
cerclage and progesterone are treatments proposed specifically
(21-25 mm vs 10-20 mm vs Ͻ10 mm), but only the subgroup
for women with a short cervix. But as recently as 2001, Owen
with TVCL 10-20 mm had sufficient statistical power to
and cautioned, “Until properly designed trials of
cerclage or other interventions prove a benefit from the finding
● The benefits of progesterone were similar whether or not the
of a ‘short’ cervix in the midtrimester, we recommend that
cervical length measurement . . . remain investigational.”
● The benefits were similar whether the dose of progesterone
Since then, evidence has accumulated that cerclage can in-
was 90-100 mg daily or 200 mg daily.
deed reduce PTB and neonatal morbidity in a specific subset of
● The benefits did not appear to depend on maternal age, body
women with short cervix: those with a singleton pregnancy and
a history of a spontaneous Because there is an effective
● Although the subgroup of twin pregnancies with short cervix
treatment, experts now recommend serial midtrimester
in the 5 trials was small, progesterone treatment was associ-
screening of TVCL in women with a history of spontaneous
ated with a significant reduction of neonatal morbidity but
On the other hand, cerclage has not been shown to re-
not a significant reduction in early PTB.
duce PTB in women without a history of PTB and may actuallybe harmful to those with
Should we screen for short cervix?
In this issue of the journal, Romero and present
evidence that vaginal micronized progesterone treatment reduces
Even though the metaanalysis clearly establishes that treatment
PTB and neonatal morbidity in asymptomatic women with a
with vaginal progesterone is effective for women in whom ashort cervix has been detected, it would be a large leap to con-clude that it would necessarily be worthwhile to embark on alarge-scale, costly program to screen all pregnant women with
From the Obstetrix Medical Group, San Jose, CA, and Mednax
transvaginal sonography to detect those with a short cervix.
Center for Research, Education, and Quality, Sunrise, FL.
Only of asymptomatic women have a TVCL Յ15 mm
Received Nov. 27, 2011; revised Dec. 7, 2011; accepted Dec. 12, 2011.
and have TVCL of 10-20 mm in the late second trimes-
The author reports no conflict of interest.
ter. Even among those few with a short cervix, progesterone
Reprints not available from the author.
reduces but does not entirely eliminate PTB and neonatal mor-
bidity. Do these reductions in such a small subset of women
justify the costs of a screening program?
The World Health Organization has outlined 10 general
principles for a good screening Let us examine how well
FEBRUARY 2012 American Journal of Obstetrics & Gynecology
1. The condition being sought should be an important
as a whole.
Two independent cost-effectiveness analyses
The importance of PTB as a health prob-
concluded that there would be a net cost savings due to a
reduction in neonatal complications with a program in-
2. There should be an accepted treatment for patients with
volving universal TVCL screening followed by vaginal pro-
The metaanalysis provides compelling
gesterone treatment if a short cervix is Despite
evidence that vaginal progesterone is beneficial for those
differences in assumptions regarding costs for screening
with singleton pregnancy and TVCL 10-20 mm, whether or
and treatment, the 2 reports agreed that universal TVCL
not there is a history of PTB. For women with a singleton
screening would result in a net savings of at least $19 million
pregnancy and history of PTB, the efficacy of vaginal pro-
dollars for every 100,000 women screened, averting hun-
dreds of cases of early PTB and dozens of cases of perinatal
3. Facilities for diagnosis and treatment should be available.
death and severe neonatal morbidity.
Endovaginal sonography is standard for any center that per-
10. Case-finding should be a continuing process and not a
forms first-trimester or gynecologic ultrasound examina-
“once and for all” project.
This principle requires that a
tions. Valid TVCL measurement requires a standardized
screening program enroll new patients over time. It does not
protocol (empty bladder, standardized placement of trans-
imply that we need to do serial TVCL measurements in each
ducer and calipers, and observations over several minutes at
woman. Indeed, the studies in the metaanalysis of Romero et
rest and after application of fundal pressure or Valsalva).
were mainly based on a single measurement at 19-25
Training for physicians and sonographers requires a small
weeks of gestation. The 2 cost-effectiveness also
investment of time and should be available through a World
assumed a single TVCL measurement. Cost-effectiveness cer-
Wide Web– based training program similar to the program
tainly decreases if screening becomes more expensive, as
used by the Nuchal Translucency Quality Review Program.
would happen with serial measurements.
Many centers have already been routinely measuring TVCL
Universal TVCL screening in midpregnancy thus appears
in women with history of and other risk factors.
to satisfy all the World Health Organization principles for
4. There should be a recognizable latent stage.
cervical shortening is often present on serial TVCL mea-
Public and private health care payers frequently balk at pay-
surements in women who later deliver preterm, with a rate
ing for new or expensive screening tests or treatments. Payers
of shortening almost identical among those who later pres-
should take notice: universal TVCL screening followed with
ent with preterm labor and those with preterm prelabor
progesterone treatment for those with a short cervix should
rupture of These observations suggest that
result in substantial net cost savings and reductions in perinatal
cervical shortening is part of a long latent phase of the spon-
5. There should be a suitable test or examination.
measurement is such a test. Transabdominal cervical length
Questions for future research
measurement is not a reliable screen because the cervix of-ten cannot be imaged well transabdominally with an empty
Romero and colleaguesclose their report with some impor-
bladder, but bladder filling tends to make the cervix appear
● Is progesterone effective for women with a short cervix and twin
6. The test should be acceptable to the population.
pregnancy? The number of twins in the metaanalysis was too
women readily accept a vaginal sonogram once they under-
small to answer this question. With twins, the prevalence of
short cervix (roughly 15%) and the risk for early PTB (roughly
7. The natural history of the disease, including development
50% with a short cervix) are much higher than in singletons.
from latent to declared disease, should be adequately under-
● Is progesterone beneficial for women with very short cervical
Although we do not understand all the mechanisms
lengths (Յ10 mm)? There is a high rate of intraamniotic
involved, there is substantial observational experience about
the natural history of the short Many women remain
● Will additional childhood follow-up studies confirm the
asymptomatic for weeks or months before presenting with
limited existing observations demonstrating the long-term
preterm labor or rupture of the membranes. Others deliver
shortly after diagnosis. Still others deliver at or near term.
8. There should be an agreed policy on whom to treat as pa-
● Is progesterone better than cerclage for women with a prior
Professional organizations have yet to issue consen-
spontaneous PTB who are found to have a short cervix? Or is
sus statements regarding treatment of women with a short
cerclage better? Or should both treatments be combined?
cervix. The most compelling evidence favors treatment for
● Is 17-hydroxyprogesterone caproate (17Pc) as effective as vag-
women with singleton pregnancy and TVCL Յ20 mm.
inal micronized progesterone for women with short cervix?
9. The cost of case-finding (including diagnosis and treat-
● Currently, 17Pc is favored for prophylactic treatment in women
ment of patients diagnosed) should be economically bal-
with a prior spontaneous But what should we do if a
anced in relation to possible expenditure on medical care
woman who is already receiving 17Pc is later found to have a
102 American Journal of Obstetrics & Gynecology
short cervix? Should we add vaginal progesterone or substitute
the FDA defines as having a P
value of Ͻ But for the trial
it? Should we continue 17Pc if we perform cerclage?
in the primary outcome (a 45% reduction of pre-
● What is the optimal gestational age for TVCL screening? The evi-
term birth before 33 weeks of gestation) failed to meet this
strict standard because it had a P
value of .02. The FDA statis-
but many women are seen for routine sonographic anatomy sur-
tical reviewer further parsed the results by various risk strata
including maternal race, cervical length, gestational age at first
and expense of an additional visit? Should we screen their cervix a
dose, and region. These post-hoc calculations yielded adjusted
little earlier? Should we delay the anatomy screen?
values of .033 using a Cochran-Mantel-Haenszel test and a
● Should we repeat the TVCL for women with “borderline” val-
value of .056 using logistic regression. Again, however, such
ues, say 21-25 mm? If so, at what interval? How many times?
post-hoc analyses should be viewed with some skepticism.
● Do interventions such as activity restriction or hospitaliza-
Lack of FDA approval for a specific indication does not pre-
tion further improve outcomes for women with a short cer-
vent US physicians from prescribing vaginal micronized pro-
vix? At present, there is no evidence to support any interven-
gesterone for women with a short cervix. “Off-label” prescrib-
tions other than progesterone or cerclage.
ing is permitted if a physician judges that the benefits of a drugoutweigh the risks.
Routine cervical length screening
Substantial evidence supports a program of universal midtri-
mester TVCL screening for all women with singleton pregnan-
Berghella V, Roman A, Daskalakis, Ness A, Baxter JK. Gestational age
cies, followed by treatment with vaginal progesterone for those
at cervical length measurement and incidence of preterm birth. Obstet
who are found to have TVCL Յ20 mm. Purists may argue that
a randomized trial of screening vs no screening is required to
Owen J, Yost N, Berghella V, et al. Mid-trimester endovaginal sonog-
definitively prove that screening is beneficial. But no such trial
raphy in women at high risk for spontaneous preterm birth. JAMA2001;286:1340-8.
is ongoing. For now, there is compelling evidence that screen-
Berghella V, Rafael TJ, Szychowski JM, Rust OA, Owen J. Cerclage for
ing will reduce the “trifecta” of PTB, neonatal morbidity, and
short cervix on ultrasonography in women with singleton gestations and
costs. Cervical length screening should no longer “remain in-
previous preterm birth: a meta-analysis. Obstet Gynecol 2011;117:663-71.
Iams JD, Berghella V. Care for women with prior preterm birth. Am J
Obstet Gynecol 2010;203:89-100.5.
Berghella V, Odibo AO, To MS, Rust OA, Althuisius SM. Cerclage for
Recent FDA action on vaginal progesterone
short cervix on ultrasonography: a meta-analysis of trials using individual
As this Editorial was going to print, on January 20, 2012, an
patient-level data. Obstet Gynecol 2005;106:181-9.
Advisory Committee of the United States Food & Drug Ad-
Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progester-
ministration (US FDA) recommended against approval of a
one in women with an asymptomatic sonographic short cervix in the
new indication (prevention of preterm birth in women with
midtrimester decreases preterm delivery and neonatal morbidity: a sys-tematic review and metaanalysis of individual patient data. Am J Obstet
singleton pregnancy and short cervical length) for a specific
formulation of vaginal progesterone (8% in synthetic gel, con-
Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone re-
taining 90 mg of micronized progesterone).
duces the rate of preterm birth in women with a sonographic short cervix:
The FDA Committee recommendation does not negate the
a multicenter, randomized, double-blind, placebo-controlled trial. Ultra-
substantial evidence that vaginal micronized progesterone is
sound Obstet Gynecol 2011;38:18-31.8.
Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH; Fetal Medicine
effective for reduction of early preterm birth and neonatal
Foundation Second Trimester Screening Group. Progesterone and the
morbidity in women with a short cervix, as presented in the
risk of preterm birth among women with a short cervix. N Engl J Med
The Committee apparently focused its on the spe-
Wilson JMG, Jungner G. Principles and practice of screening for dis-
cific progesterone gel preparation for which the new indication
ease. Geneva: World Health Organization; 1968. Available at: Accessed Dec. 28, 2011.
was requested, with little weight given to the trials that used
Iams JD, Cebrik D, Lynch C, Behrendt N, Das A. The rate of cervical
change and the phenotype of spontaneous preterm birth. Am J Obstet
The recommendation was influenced by a post-hoc sub-
group analysis of 1 that found that the benefit of proges-
Cahill AG, Odibo AO, Caughey AB, et al. Universal cervical length screen-
terone was statistically significant in non-US sites but not in US
ing and treatment with vaginal progesterone to prevent preterm birth: adecision and economic analysis. Am J Obstet Gynecol 2010;202:548.e1-8.
But the trial was not designed to have adequate statis-
Werner EF, Han CS, Pettker CM, et al. Universal cervical-length
tical power to test effects in subgroups, so the post-hoc analysis
screening to prevent preterm birth: a cost-effectiveness analysis. Ultra-
should be viewed with some skepticism.
To approve a new indication, the FDA usually requires 2
Division of Reproductive and Urologic Products, United States Food
trials with a specific formulation. Only a single Phase 3 trial had
and Drug Administration. Background document for meeting of AdvisoryCommittee for Reproductive Health Drugs, January 20, 2012. Available
studied this precise formulation for this precise
The FDA sometimes grants exceptions to the 2-trial standard if
the demonstrated benefit is “compelling and robust,” which
FEBRUARY 2012 American Journal of Obstetrics & Gynecology
Rheumatrex Package Insert 10/30/03 12:36 PM Page 1Methotrexate Sodium Tablets for oral administration are available in bottles of 100 andIn dogs, synovial fluid concentrations after oral dosing were higher in inflamed thanafter therapy for male patients, and during and for at least one ovulatory cycle after RHEUMATREX® in a packaging system designated as the RHEUMATREX® Methotrexate Sodium
TABLE OF CONTENTS Pray these prayers out loud, you can do this on your own, but do it whilst you are fasting, not in the beginning of your fast but when you have been fasting for 24 hours or so then you are combining fasting and prayer according to Mark 9:29 It is recommended to pray twice at different times or days, because the second time you have more understanding it is a long list but i