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Vaginal progesterone for asymptomatic cervical shortening and the case for universal screening of cervical length

www.AJOG.org
Vaginal progesterone for asymptomatic cervical shortening
and the case for universal screening of cervical length
C. Andrew Combs, MD, PhD

Ashort 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
www.AJOG.org
1. The condition being sought should be an important
as a whole. Two independent cost-effectiveness analyses
health problem. 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- recognized disease. 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. Progressive
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. TVCL
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. Most
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 stood. 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 tients. 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 FEBRUARY 2012
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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 denceestablishesbenefitwithscreeningat19-25weeksofgestation, 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 veybeforethistime.Shouldwehavethemsuffertheinconvenience 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? P values of .033 using a Cochran-Mantel-Haenszel test and a ● Should we repeat the TVCL for women with “borderline” val- P 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-
REFERENCES
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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 2. 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- 3. 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.
4. 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- 6. 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- 7. 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- 9. 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 10. 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- 11. 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- 12. Werner EF, Han CS, Pettker CM, et al. Universal cervical-length
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To approve a new indication, the FDA usually requires 2 13. 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

Source: http://obgyn.med.wayne.edu/pdfs/vag_prog_short_cx_ajog_feb_2012_editorial.pdf

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