Vaginal progesterone or cerclage to prevent recurrent preterm birth?

Abstract

Until recently, prevention of preterm birth (PTB) seemed to be an elusive goal. In the United States, the rate of PTB rose steadily from 9.4% in 1981 to a peak of 12.8% in 2006.1Martin J.A. Hamilton B.E. Ventura S.J. et al.Births: final data for 2009.Natl Vital Stat Rep. 2011; 60: 1-72PubMed Google Scholar Much of our clinical effort during this time involved tocolytic therapy, which proved to be generally ineffective at prolonging pregnancy or reducing the rate of neonatal complications.2Mercer B.M. Merlino A.A. Society of Maternal-Fetal MedicineMagnesium sulfate for preterm labor and preterm birth.Obstet Gynecol. 2009; 114: 650-668Crossref PubMed Scopus (59) Google Scholar Until recently, antenatal corticosteroid treatment was practically the only evidence-based weapon in our arsenal to attack the problem of PTB.See related article, page 42Now we have at least 2 new weapons, cervical cerclage and progestational agents. Our much happier current dilemma is not determining whether either of them is effective in certain situations (both are) but deciding which of them is better.A growing body of recent evidence shows that targeted use of either cerclage or vaginal micronized progesterone can reduce the risk of PTB in a specific group of women at very high risk, those with all 3 of the following: •A current singleton pregnancy.•A history of spontaneous PTB in a prior pregnancy.•A short cervix (<25 mm) before 24 weeks in the current pregnancy.Untreated, such women have a 15-20% risk of recurrent PTB before 28 weeks of gestation, a 25-30% risk of PTB before 32 weeks, and a 50-60% risk of PTB before 37 weeks.3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar The risks are higher the earlier in the gestation the previous PTB, the shorter the cervical length, and the earlier in pregnancy the short cervix is diagnosed.Benefits of cerclage or vaginal progesteroneThe benefits of cerclage in women with the 3 factors outlined above were shown in a metaanalysis of patient-level data from 5 clinical trials comparing cerclage with no cerclage.4Berghella V. Rafael T.J. Szychowski J.M. Rust O.A. Owen J. Cerclage for short cervix on ultrasonography in women with singleton gestation and previous preterm birth A meta-analysis.Obstet Gynecol. 2011; 117: 663-671Crossref PubMed Scopus (323) Google Scholar Cerclage resulted in significant reductions in the following: •Recurrent PTB before 35 weeks, relative risk (RR) 0.70.•Perinatal mortality, RR 0.65.•Composite neonatal morbidity, RR 0.60.The benefits of vaginal micronized progesterone in women with the same 3 factors were shown in an individual patient data metaanalysis of 5 high-quality placebo-controlled trials.5Romero R. Nicolaides K. Conde-Agudelo A. et al.Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.Am J Obstet Gynecol. 2012; 206: 124.e1-124.e19PubMed Scopus (394) Google Scholar Vaginal progesterone resulted in significant reductions in the following: •Recurrent PTB before 33 weeks, RR 0.54.•Composite neonatal morbidity and mortality, RR 0.41.Choice of cerclage vs vaginal progesteroneWhich treatment is better for these very high-risk women? There have been no clinical trials directly comparing cerclage with vaginal progesterone for such women, and a search of trial registries (clinicaltrials.gov and controlled-trials.com) finds no such trials ongoing. In the absence of direct evidence, it is impossible to give a definitive answer.In the current issue, Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar address this important question with an indirect-comparison metaanalysis. This clever statistical method compares the 2 treatments, cerclage vs vaginal progesterone, which were each tested in clinical trials against a control group but which were never directly tested against each other. The analysis requires the assumption that the control groups were comparable. This assumption appears reasonable, even though the controls were treated differently: those in the cerclage trials received no particular treatment, whereas those in the progesterone trials received the placebo treatment. Despite these differences, the rates of PTB and neonatal morbidity in the control groups (Table 2 of the metaanalysis3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar) were similar.The indirect-comparison metaanalysis3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar shows trends toward better outcomes with vaginal progesterone compared with cerclage (summary RR <1.0), but these did not reach statistical significance because the 95% confidence intervals (CIs) overlap 1. For the primary outcomes, the following was found: •Rate of PTB before 32 weeks: RR, 0.71; 95% CI, 0.34–1.49.•Composite perinatal morbidity/mortality: RR, 0.67; 95% CI, 0.29–1.57.Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar concluded that vaginal progesterone and cerclage are equally efficacious in this setting and suggested that factors other than efficacy should guide the choice of treatment for individual patients. How does this conclusion fit into the context of current existing recommendations for management of women with a prior spontaneous PTB?Expert recommendations: management of singleton pregnancy with prior PTBIn a comprehensive review, Iams and Berghella6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar recommended serial sonographic cervical length measurement from 16 to 23 weeks of gestation for women with a history of a prior spontaneous PTB. In addition, prophylactic intramuscular 17-hydroxyprogesterone caproate (17P) is recommended weekly from 16 to 36 weeks of gestation, regardless of cervical length because the large trial of Meis et al7Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17-alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1256) Google Scholar showed benefit of this agent without any selection based on cervical length screening.If the cervical length falls below 25 mm in a woman who is already receiving 17P, Iams and Berghella6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar offer cerclage. A clinical guideline from the Society of Maternal-Fetal Medicine (SMFM) also recommends cerclage, adding that 17P should be continued after the cerclage is placed.8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar A similar recommendation was made in a practice bulletin from the American College of Obstetricians and Gynecologists.9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar In contrast, Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar conclude that vaginal progesterone should be offered in this setting, providing equal efficacy and fewer safety concerns than the combination of cerclage and 17P.If the cervical length falls below 25 mm in a woman with a singleton pregnancy and prior PTB who has not started 17P, the results of Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar impy that either vaginal progesterone or cerclage can be considered as the first-line treatment. The choice between them should be based on patient preference after a discussion with her provider of the pros and cons of the 2 options.Management of other combinations of risk factorsThe analysis of Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar and the preceding discussion focus on women with a singleton pregnancy, a short cervix, and a history of prior PTB. Current evidence favors different management for women who have different combinations of risk factors including the following: •Singleton pregnancy, short cervix, no prior PTB: vaginal progesterone is recommended because it reduces the rates of both PTB and neonatal morbidity.5Romero R. Nicolaides K. Conde-Agudelo A. et al.Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.Am J Obstet Gynecol. 2012; 206: 124.e1-124.e19PubMed Scopus (394) Google Scholar, 8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar A significant benefit from cerclage10Berghella V. Odibo A.O. To M.S. Rust O.A. Althuisius S.M. Cerclage for short cervix on ultrasonography Meta-analysis of trials using individual patient-level data.Obstet Gynecol. 2005; 106: 181-189Crossref PubMed Scopus (473) Google Scholar or 17P11Grobman W.A. Thom E.A. Spong C.Y. et al.17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm.Am J Obstet Gynecol. 2012; 207: 390.e1-390.e8Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar has not been shown.•Singleton pregnancy, prior PTB, normal cervical length: prophylactic 17P is recommended6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar along with serial cervical length screening.6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar•Twins, no prior PTB, normal cervical length: both 17P and vaginal progesterone have been shown not to reduce risk of PTB and are not recommended.8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar•Twins, no prior PTB, short cervix: cerclage is not recommended because it may actually increase the rate of PTB.10Berghella V. Odibo A.O. To M.S. Rust O.A. Althuisius S.M. Cerclage for short cervix on ultrasonography Meta-analysis of trials using individual patient-level data.Obstet Gynecol. 2005; 106: 181-189Crossref PubMed Scopus (473) Google Scholar Although the SMFM8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar and ACOG9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar do not recommend treatment with progestins, there is evidence that vaginal progesterone may reduce neonatal morbidity.5Romero R. Nicolaides K. Conde-Agudelo A. et al.Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.Am J Obstet Gynecol. 2012; 206: 124.e1-124.e19PubMed Scopus (394) Google Scholar•Twins, prior PTB, normal cervical length: there is no evidence of benefit from vaginal progesterone12Klein K. Rode L. Nicolaides K.H. Krampl-Bettelheim E. Tabor A. PREDICT GroupVaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies: secondary analysis of a placebo-controlled randomized trial and meta-analysis.Ultrasound Obstet Gynecol. 2011; 38: 281-287Crossref PubMed Scopus (52) Google Scholar or 17P,13Combs C.A. Garite T.J. Maurel K. Cebrik D. Obstetrix Collaborative Research Network17-hydroxyprogesterone caproate for women with history of preterm birth in a prior pregnancy and twins in the current pregnancy.Am J Obstet Gynecol. 2012; 206: S213Abstract Full Text Full Text PDF PubMed Google Scholar but this conclusion is based on very small numbers.Several relevant ongoing and upcoming clinical trials may yield new evidence that will modify these recommendations. An intriguing new option for treatment of short cervix is a cervical pessary, which was recently shown to substantially reduce early PTB in one trial14Goya M. Pratcorona L. Merced C. et al.Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial.Lancet. 2012; 379: 1800-1806Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar but not in another.15Hui S.Y. Chor C.M. Lau T.K. Lao T.T. Leung T.Y. Cerclage pessary for preventing preterm birth in women with a singleton pregnancy and a short cervix at 20 to 24 weeks: a randomized controlled trial.Am J Perinatol. 2012 Aug 8; ([epub ahead of print])PubMed Google Scholar This device is not currently approved for prevention of PTB by the Food and Drug Administration in the United States but is undergoing further evaluation in several randomized clinical trials throughout the world. Until recently, prevention of preterm birth (PTB) seemed to be an elusive goal. In the United States, the rate of PTB rose steadily from 9.4% in 1981 to a peak of 12.8% in 2006.1Martin J.A. Hamilton B.E. Ventura S.J. et al.Births: final data for 2009.Natl Vital Stat Rep. 2011; 60: 1-72PubMed Google Scholar Much of our clinical effort during this time involved tocolytic therapy, which proved to be generally ineffective at prolonging pregnancy or reducing the rate of neonatal complications.2Mercer B.M. Merlino A.A. Society of Maternal-Fetal MedicineMagnesium sulfate for preterm labor and preterm birth.Obstet Gynecol. 2009; 114: 650-668Crossref PubMed Scopus (59) Google Scholar Until recently, antenatal corticosteroid treatment was practically the only evidence-based weapon in our arsenal to attack the problem of PTB. See related article, page 42 See related article, page 42 Now we have at least 2 new weapons, cervical cerclage and progestational agents. Our much happier current dilemma is not determining whether either of them is effective in certain situations (both are) but deciding which of them is better. A growing body of recent evidence shows that targeted use of either cerclage or vaginal micronized progesterone can reduce the risk of PTB in a specific group of women at very high risk, those with all 3 of the following: •A current singleton pregnancy.•A history of spontaneous PTB in a prior pregnancy.•A short cervix (<25 mm) before 24 weeks in the current pregnancy. Untreated, such women have a 15-20% risk of recurrent PTB before 28 weeks of gestation, a 25-30% risk of PTB before 32 weeks, and a 50-60% risk of PTB before 37 weeks.3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar The risks are higher the earlier in the gestation the previous PTB, the shorter the cervical length, and the earlier in pregnancy the short cervix is diagnosed. Benefits of cerclage or vaginal progesteroneThe benefits of cerclage in women with the 3 factors outlined above were shown in a metaanalysis of patient-level data from 5 clinical trials comparing cerclage with no cerclage.4Berghella V. Rafael T.J. Szychowski J.M. Rust O.A. Owen J. Cerclage for short cervix on ultrasonography in women with singleton gestation and previous preterm birth A meta-analysis.Obstet Gynecol. 2011; 117: 663-671Crossref PubMed Scopus (323) Google Scholar Cerclage resulted in significant reductions in the following: •Recurrent PTB before 35 weeks, relative risk (RR) 0.70.•Perinatal mortality, RR 0.65.•Composite neonatal morbidity, RR 0.60.The benefits of vaginal micronized progesterone in women with the same 3 factors were shown in an individual patient data metaanalysis of 5 high-quality placebo-controlled trials.5Romero R. Nicolaides K. Conde-Agudelo A. et al.Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.Am J Obstet Gynecol. 2012; 206: 124.e1-124.e19PubMed Scopus (394) Google Scholar Vaginal progesterone resulted in significant reductions in the following: •Recurrent PTB before 33 weeks, RR 0.54.•Composite neonatal morbidity and mortality, RR 0.41. The benefits of cerclage in women with the 3 factors outlined above were shown in a metaanalysis of patient-level data from 5 clinical trials comparing cerclage with no cerclage.4Berghella V. Rafael T.J. Szychowski J.M. Rust O.A. Owen J. Cerclage for short cervix on ultrasonography in women with singleton gestation and previous preterm birth A meta-analysis.Obstet Gynecol. 2011; 117: 663-671Crossref PubMed Scopus (323) Google Scholar Cerclage resulted in significant reductions in the following: •Recurrent PTB before 35 weeks, relative risk (RR) 0.70.•Perinatal mortality, RR 0.65.•Composite neonatal morbidity, RR 0.60. The benefits of vaginal micronized progesterone in women with the same 3 factors were shown in an individual patient data metaanalysis of 5 high-quality placebo-controlled trials.5Romero R. Nicolaides K. Conde-Agudelo A. et al.Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.Am J Obstet Gynecol. 2012; 206: 124.e1-124.e19PubMed Scopus (394) Google Scholar Vaginal progesterone resulted in significant reductions in the following: •Recurrent PTB before 33 weeks, RR 0.54.•Composite neonatal morbidity and mortality, RR 0.41. Choice of cerclage vs vaginal progesteroneWhich treatment is better for these very high-risk women? There have been no clinical trials directly comparing cerclage with vaginal progesterone for such women, and a search of trial registries (clinicaltrials.gov and controlled-trials.com) finds no such trials ongoing. In the absence of direct evidence, it is impossible to give a definitive answer.In the current issue, Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar address this important question with an indirect-comparison metaanalysis. This clever statistical method compares the 2 treatments, cerclage vs vaginal progesterone, which were each tested in clinical trials against a control group but which were never directly tested against each other. The analysis requires the assumption that the control groups were comparable. This assumption appears reasonable, even though the controls were treated differently: those in the cerclage trials received no particular treatment, whereas those in the progesterone trials received the placebo treatment. Despite these differences, the rates of PTB and neonatal morbidity in the control groups (Table 2 of the metaanalysis3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar) were similar.The indirect-comparison metaanalysis3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar shows trends toward better outcomes with vaginal progesterone compared with cerclage (summary RR <1.0), but these did not reach statistical significance because the 95% confidence intervals (CIs) overlap 1. For the primary outcomes, the following was found: •Rate of PTB before 32 weeks: RR, 0.71; 95% CI, 0.34–1.49.•Composite perinatal morbidity/mortality: RR, 0.67; 95% CI, 0.29–1.57.Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar concluded that vaginal progesterone and cerclage are equally efficacious in this setting and suggested that factors other than efficacy should guide the choice of treatment for individual patients. How does this conclusion fit into the context of current existing recommendations for management of women with a prior spontaneous PTB? Which treatment is better for these very high-risk women? There have been no clinical trials directly comparing cerclage with vaginal progesterone for such women, and a search of trial registries (clinicaltrials.gov and controlled-trials.com) finds no such trials ongoing. In the absence of direct evidence, it is impossible to give a definitive answer. In the current issue, Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar address this important question with an indirect-comparison metaanalysis. This clever statistical method compares the 2 treatments, cerclage vs vaginal progesterone, which were each tested in clinical trials against a control group but which were never directly tested against each other. The analysis requires the assumption that the control groups were comparable. This assumption appears reasonable, even though the controls were treated differently: those in the cerclage trials received no particular treatment, whereas those in the progesterone trials received the placebo treatment. Despite these differences, the rates of PTB and neonatal morbidity in the control groups (Table 2 of the metaanalysis3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar) were similar. The indirect-comparison metaanalysis3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar shows trends toward better outcomes with vaginal progesterone compared with cerclage (summary RR <1.0), but these did not reach statistical significance because the 95% confidence intervals (CIs) overlap 1. For the primary outcomes, the following was found: •Rate of PTB before 32 weeks: RR, 0.71; 95% CI, 0.34–1.49.•Composite perinatal morbidity/mortality: RR, 0.67; 95% CI, 0.29–1.57. Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar concluded that vaginal progesterone and cerclage are equally efficacious in this setting and suggested that factors other than efficacy should guide the choice of treatment for individual patients. How does this conclusion fit into the context of current existing recommendations for management of women with a prior spontaneous PTB? Expert recommendations: management of singleton pregnancy with prior PTBIn a comprehensive review, Iams and Berghella6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar recommended serial sonographic cervical length measurement from 16 to 23 weeks of gestation for women with a history of a prior spontaneous PTB. In addition, prophylactic intramuscular 17-hydroxyprogesterone caproate (17P) is recommended weekly from 16 to 36 weeks of gestation, regardless of cervical length because the large trial of Meis et al7Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17-alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1256) Google Scholar showed benefit of this agent without any selection based on cervical length screening.If the cervical length falls below 25 mm in a woman who is already receiving 17P, Iams and Berghella6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar offer cerclage. A clinical guideline from the Society of Maternal-Fetal Medicine (SMFM) also recommends cerclage, adding that 17P should be continued after the cerclage is placed.8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar A similar recommendation was made in a practice bulletin from the American College of Obstetricians and Gynecologists.9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar In contrast, Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar conclude that vaginal progesterone should be offered in this setting, providing equal efficacy and fewer safety concerns than the combination of cerclage and 17P.If the cervical length falls below 25 mm in a woman with a singleton pregnancy and prior PTB who has not started 17P, the results of Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar impy that either vaginal progesterone or cerclage can be considered as the first-line treatment. The choice between them should be based on patient preference after a discussion with her provider of the pros and cons of the 2 options. In a comprehensive review, Iams and Berghella6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar recommended serial sonographic cervical length measurement from 16 to 23 weeks of gestation for women with a history of a prior spontaneous PTB. In addition, prophylactic intramuscular 17-hydroxyprogesterone caproate (17P) is recommended weekly from 16 to 36 weeks of gestation, regardless of cervical length because the large trial of Meis et al7Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17-alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1256) Google Scholar showed benefit of this agent without any selection based on cervical length screening. If the cervical length falls below 25 mm in a woman who is already receiving 17P, Iams and Berghella6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar offer cerclage. A clinical guideline from the Society of Maternal-Fetal Medicine (SMFM) also recommends cerclage, adding that 17P should be continued after the cerclage is placed.8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar A similar recommendation was made in a practice bulletin from the American College of Obstetricians and Gynecologists.9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar In contrast, Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar conclude that vaginal progesterone should be offered in this setting, providing equal efficacy and fewer safety concerns than the combination of cerclage and 17P. If the cervical length falls below 25 mm in a woman with a singleton pregnancy and prior PTB who has not started 17P, the results of Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar impy that either vaginal progesterone or cerclage can be considered as the first-line treatment. The choice between them should be based on patient preference after a discussion with her provider of the pros and cons of the 2 options. Management of other combinations of risk factorsThe analysis of Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar and the preceding discussion focus on women with a singleton pregnancy, a short cervix, and a history of prior PTB. Current evidence favors different management for women who have different combinations of risk factors including the following: •Singleton pregnancy, short cervix, no prior PTB: vaginal progesterone is recommended because it reduces the rates of both PTB and neonatal morbidity.5Romero R. Nicolaides K. Conde-Agudelo A. et al.Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.Am J Obstet Gynecol. 2012; 206: 124.e1-124.e19PubMed Scopus (394) Google Scholar, 8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar A significant benefit from cerclage10Berghella V. Odibo A.O. To M.S. Rust O.A. Althuisius S.M. Cerclage for short cervix on ultrasonography Meta-analysis of trials using individual patient-level data.Obstet Gynecol. 2005; 106: 181-189Crossref PubMed Scopus (473) Google Scholar or 17P11Grobman W.A. Thom E.A. Spong C.Y. et al.17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm.Am J Obstet Gynecol. 2012; 207: 390.e1-390.e8Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar has not been shown.•Singleton pregnancy, prior PTB, normal cervical length: prophylactic 17P is recommended6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar along with serial cervical length screening.6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar•Twins, no prior PTB, normal cervical length: both 17P and vaginal progesterone have been shown not to reduce risk of PTB and are not recommended.8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar•Twins, no prior PTB, short cervix: cerclage is not recommended because it may actually increase the rate of PTB.10Berghella V. Odibo A.O. To M.S. Rust O.A. Althuisius S.M. Cerclage for short cervix on ultrasonography Meta-analysis of trials using individual patient-level data.Obstet Gynecol. 2005; 106: 181-189Crossref PubMed Scopus (473) Google Scholar Although the SMFM8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar and ACOG9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar do not recommend treatment with progestins, there is evidence that vaginal progesterone may reduce neonatal morbidity.5Romero R. Nicolaides K. Conde-Agudelo A. et al.Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.Am J Obstet Gynecol. 2012; 206: 124.e1-124.e19PubMed Scopus (394) Google Scholar•Twins, prior PTB, normal cervical length: there is no evidence of benefit from vaginal progesterone12Klein K. Rode L. Nicolaides K.H. Krampl-Bettelheim E. Tabor A. PREDICT GroupVaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies: secondary analysis of a placebo-controlled randomized trial and meta-analysis.Ultrasound Obstet Gynecol. 2011; 38: 281-287Crossref PubMed Scopus (52) Google Scholar or 17P,13Combs C.A. Garite T.J. Maurel K. Cebrik D. Obstetrix Collaborative Research Network17-hydroxyprogesterone caproate for women with history of preterm birth in a prior pregnancy and twins in the current pregnancy.Am J Obstet Gynecol. 2012; 206: S213Abstract Full Text Full Text PDF PubMed Google Scholar but this conclusion is based on very small numbers.Several relevant ongoing and upcoming clinical trials may yield new evidence that will modify these recommendations. An intriguing new option for treatment of short cervix is a cervical pessary, which was recently shown to substantially reduce early PTB in one trial14Goya M. Pratcorona L. Merced C. et al.Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial.Lancet. 2012; 379: 1800-1806Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar but not in another.15Hui S.Y. Chor C.M. Lau T.K. Lao T.T. Leung T.Y. Cerclage pessary for preventing preterm birth in women with a singleton pregnancy and a short cervix at 20 to 24 weeks: a randomized controlled trial.Am J Perinatol. 2012 Aug 8; ([epub ahead of print])PubMed Google Scholar This device is not currently approved for prevention of PTB by the Food and Drug Administration in the United States but is undergoing further evaluation in several randomized clinical trials throughout the world. The analysis of Conde-Agudelo et al3Conde-Agudelo A. Romero R. Nicolaides K. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis.Am J Obstet Gynecol. 2013; 208: 42.e1-42.e8Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar and the preceding discussion focus on women with a singleton pregnancy, a short cervix, and a history of prior PTB. Current evidence favors different management for women who have different combinations of risk factors including the following: •Singleton pregnancy, short cervix, no prior PTB: vaginal progesterone is recommended because it reduces the rates of both PTB and neonatal morbidity.5Romero R. Nicolaides K. Conde-Agudelo A. et al.Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.Am J Obstet Gynecol. 2012; 206: 124.e1-124.e19PubMed Scopus (394) Google Scholar, 8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar A significant benefit from cerclage10Berghella V. Odibo A.O. To M.S. Rust O.A. Althuisius S.M. Cerclage for short cervix on ultrasonography Meta-analysis of trials using individual patient-level data.Obstet Gynecol. 2005; 106: 181-189Crossref PubMed Scopus (473) Google Scholar or 17P11Grobman W.A. Thom E.A. Spong C.Y. et al.17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm.Am J Obstet Gynecol. 2012; 207: 390.e1-390.e8Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar has not been shown.•Singleton pregnancy, prior PTB, normal cervical length: prophylactic 17P is recommended6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar along with serial cervical length screening.6Iams J.D. Berghella V. Care for women with prior preterm birth.Am J Obstet Gynecol. 2010; 203: 89-100Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar•Twins, no prior PTB, normal cervical length: both 17P and vaginal progesterone have been shown not to reduce risk of PTB and are not recommended.8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar•Twins, no prior PTB, short cervix: cerclage is not recommended because it may actually increase the rate of PTB.10Berghella V. Odibo A.O. To M.S. Rust O.A. Althuisius S.M. Cerclage for short cervix on ultrasonography Meta-analysis of trials using individual patient-level data.Obstet Gynecol. 2005; 106: 181-189Crossref PubMed Scopus (473) Google Scholar Although the SMFM8Society for Maternal-Fetal Medicine Publications Committee, with assistance of Berghella VProgesterone and preterm birth prevention: translating clinical trials into clinical practice.Am J Obstet Gynecol. 2012; 206: 376-386Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar and ACOG9American College of Obstetricians and GynecologistsACOG committee on practice bulletins: obstetrics. Prediction and prevention of preterm birth.Practice bulletin no. 130. ACOG, Washington, DC2012Google Scholar do not recommend treatment with progestins, there is evidence that vaginal progesterone may reduce neonatal morbidity.5Romero R. Nicolaides K. Conde-Agudelo A. et al.Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.Am J Obstet Gynecol. 2012; 206: 124.e1-124.e19PubMed Scopus (394) Google Scholar•Twins, prior PTB, normal cervical length: there is no evidence of benefit from vaginal progesterone12Klein K. Rode L. Nicolaides K.H. Krampl-Bettelheim E. Tabor A. PREDICT GroupVaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies: secondary analysis of a placebo-controlled randomized trial and meta-analysis.Ultrasound Obstet Gynecol. 2011; 38: 281-287Crossref PubMed Scopus (52) Google Scholar or 17P,13Combs C.A. Garite T.J. Maurel K. Cebrik D. Obstetrix Collaborative Research Network17-hydroxyprogesterone caproate for women with history of preterm birth in a prior pregnancy and twins in the current pregnancy.Am J Obstet Gynecol. 2012; 206: S213Abstract Full Text Full Text PDF PubMed Google Scholar but this conclusion is based on very small numbers. Several relevant ongoing and upcoming clinical trials may yield new evidence that will modify these recommendations. An intriguing new option for treatment of short cervix is a cervical pessary, which was recently shown to substantially reduce early PTB in one trial14Goya M. Pratcorona L. Merced C. et al.Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial.Lancet. 2012; 379: 1800-1806Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar but not in another.15Hui S.Y. Chor C.M. Lau T.K. Lao T.T. Leung T.Y. Cerclage pessary for preventing preterm birth in women with a singleton pregnancy and a short cervix at 20 to 24 weeks: a randomized controlled trial.Am J Perinatol. 2012 Aug 8; ([epub ahead of print])PubMed Google Scholar This device is not currently approved for prevention of PTB by the Food and Drug Administration in the United States but is undergoing further evaluation in several randomized clinical trials throughout the world. Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysisAmerican Journal of Obstetrics & GynecologyVol. 208Issue 1PreviewNo randomized controlled trial has compared vaginal progesterone and cervical cerclage directly for the prevention of preterm birth in women with a sonographic short cervix in the mid trimester, singleton gestation, and previous spontaneous preterm birth. We performed an indirect comparison of vaginal progesterone vs cerclage using placebo/no cerclage as the common comparator. Full-Text PDF