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Progesterone and preterm birth prevention: translating clinical trials data into clinical practice

  • Society for Maternal-Fetal Medicine Publications Committee, with the assistance of Vincenzo Berghella, MD
Published:March 19, 2012DOI:https://doi.org/10.1016/j.ajog.2012.03.010

      Objective

      We sought to provide evidence-based guidelines for using progestogens for the prevention of preterm birth (PTB).

      Methods

      Relevant documents, in particular randomized trials, were identified using PubMed (US National Library of Medicine, 1983 through February 2012) publications, written in English, which evaluate the effectiveness of progestogens for prevention of PTB. Progestogens evaluated were, in particular, vaginal progesterone and 17-alpha-hydroxy-progesterone caproate. Additionally, the Cochrane Library, organizational guidelines, and studies identified through review of the above were utilized to identify relevant articles. Data were evaluated according to population studied, with separate analyses for singleton vs multiple gestations, prior PTB, or short transvaginal ultrasound cervical length (CL), and combinations of these factors. Consistent with US Preventive Task Force suggestions, references were evaluated for quality based on the highest level of evidence, and recommendations were graded.

      Results and Recommendations

      Summary of randomized studies indicates that in women with singleton gestations, no prior PTB, and short CL ≤20 mm at ≤24 weeks, vaginal progesterone, either 90-mg gel or 200-mg suppository, is associated with reduction in PTB and perinatal morbidity and mortality, and can be offered in these cases. The issue of universal CL screening of singleton gestations without prior PTB for the prevention of PTB remains an object of debate. CL screening in singleton gestations without prior PTB cannot yet be universally mandated. Nonetheless, implementation of such a screening strategy can be viewed as reasonable, and can be considered by individual practitioners, following strict guidelines. In singleton gestations with prior PTB 20-36 6/7 weeks, 17-alpha-hydroxy-progesterone caproate 250 mg intramuscularly weekly, preferably starting at 16-20 weeks until 36 weeks, is recommended. In these women with prior PTB, if the transvaginal ultrasound CL shortens to <25 mm at <24 weeks, cervical cerclage may be offered. Progestogens have not been associated with prevention of PTB in women who have in the current pregnancy multiple gestations, preterm labor, or preterm premature rupture of membranes. There is insufficient evidence to recommend the use of progestogens in women with any of these risk factors, with or without a short CL.

      Key words

      Introduction

      Progesterone was isolated and characterized in 1934, and its role in myometrial quiescence was first reported in 1954.
      • Csapo A.
      • Goodall M.
      Excitability, length tension relation and kinetics of uterine muscle contraction in relation to hormonal status.
      • Keirse M.J.N.C.
      Progestogen administration in pregnancy may prevent preterm delivery.
      From 2003 through 2011, several randomized trials evaluating the effect of either 17-alpha-hydroxy-progesterone caproate (17P) given intramuscularly (IM) or natural progesterone given vaginally or orally for prevention of preterm birth (PTB) have been published. The term “progestogens” includes both vaginal progesterone and 17P.
      The quality of evidence for each article was evaluated according to the method outlined by the US Preventative Services Task Force:
      • I
        Properly powered and conducted randomized controlled trial (RCT); well-conducted systematic review or metaanalysis of homogeneous RCTs.
      • II-1
        Well-designed controlled trial without randomization.
      • II-2
        Well-designed cohort or case-control analytic study.
      • II-3
        Multiple time series with or without the intervention; dramatic results from uncontrolled experiment.
      • III
        Opinions of respected authorities, based on clinical experience; descriptive studies or case reports; reports of expert committees.
      Recommendations were graded in the following categories:

      Level A

      The recommendation is based on good and consistent scientific evidence.

      Level B

      The recommendation is based on limited or inconsistent scientific evidence.

      Level C

      The recommendation is based on expert opinion or consensus.
      Given this large amount of new important information, the scope of this article is to review the level-1 evidence (randomized controlled trials [RCTs] and metaanalyses of RCTs) evaluating the role of progestogens in the prevention of PTB, and to provide clinicians with current recommendations for their use in possible clinical scenarios. Other publications have not addressed the totality of this new information.
      American College of Obstetricians and Gynecologists
      Use of progesterone to reduce preterm birth: ACOG committee opinion no. 419.
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth.
      • Kilpatrick S.J.
      Society for Maternal-Fetal Medicine
      Progesterone for the prevention of preterm birth.
      As 17P and vaginal progesterone may vary in their effect,
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      they will be addressed separately. The effects of interventions for reduction of PTB often vary by the population studied, and in particular by major risk factor categories for PTB. Major differences exist when analyzing effects of other interventions by number of fetuses (ie, singleton vs multiple gestations), prior PTB (vs not), and short cervical length (CL) on transvaginal ultrasound (TVU) (vs not).
      • Berghella V.
      • Rafael T.J.
      • Szychowski J.M.
      • Rust O.A.
      • Owen J.
      Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis.
      Therefore data will be analyzed according to these major categories of risk.

      What are the mechanism of action and safety data of progestogens? (Levels II and III)

      The mechanisms of action and safety of progestogens are not the purpose of this review, and are discussed only briefly. While the exact mechanism of action of progestogens in preventing PTB is unknown, several possibilities have been proposed (Table 1).
      • Renthal N.E.
      • Chen N.N.
      • Williams K.C.
      • et al.
      miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor.
      • Briery C.M.
      • Veillon E.W.
      • Klauser C.K.
      • et al.
      Progesterone does not prevent preterm births in women with twins.
      • Briery C.M.
      • Veillon E.W.
      • Klauser C.K.
      • et al.
      Women with preterm premature rupture of the membranes do not benefit from weekly progesterone.
      • Zakar T.
      • Mesiano S.
      How does progesterone relax the uterus in pregnancy?.
      • Peltier M.R.
      • Tee S.C.
      • Smulian J.C.
      Effect of progesterone on proinflammatory cytokine production by monocytes stimulated with pathogens associated with preterm birth.
      • Xu H.
      • Gonzalez J.M.
      • Ofori E.
      • Elovitz M.A.
      Preventing cervical ripening: the primary mechanism by which pregestational agents prevent preterm birth?.
      • Sfakianaki A.K.
      • Norwitz E.R.
      Mechanisms of progesterone action in inhibiting prematurity.
      • O'Brien J.M.
      • DeFranco E.A.
      • Adair C.D.
      • et al.
      Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.
      • Zakar T.
      • Hertelendy F.
      Progesterone withdrawal: key to parturition.
      In general, the evidence seems to favor 2 mechanisms: an antiinflammatory effect that counteracts the inflammatory process leading to PTB, and a local increase in progesterone in gestational tissues that counteracts the functional decrease in progesterone leading to PTB (Table 1).
      • Renthal N.E.
      • Chen N.N.
      • Williams K.C.
      • et al.
      miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor.
      • Briery C.M.
      • Veillon E.W.
      • Klauser C.K.
      • et al.
      Progesterone does not prevent preterm births in women with twins.
      • Briery C.M.
      • Veillon E.W.
      • Klauser C.K.
      • et al.
      Women with preterm premature rupture of the membranes do not benefit from weekly progesterone.
      • Zakar T.
      • Mesiano S.
      How does progesterone relax the uterus in pregnancy?.
      • Peltier M.R.
      • Tee S.C.
      • Smulian J.C.
      Effect of progesterone on proinflammatory cytokine production by monocytes stimulated with pathogens associated with preterm birth.
      • Xu H.
      • Gonzalez J.M.
      • Ofori E.
      • Elovitz M.A.
      Preventing cervical ripening: the primary mechanism by which pregestational agents prevent preterm birth?.
      • Sfakianaki A.K.
      • Norwitz E.R.
      Mechanisms of progesterone action in inhibiting prematurity.
      • O'Brien J.M.
      • DeFranco E.A.
      • Adair C.D.
      • et al.
      Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.
      • Zakar T.
      • Hertelendy F.
      Progesterone withdrawal: key to parturition.
      TABLE 1Proposed mechanisms of action reported for progestogens to prevent preterm birth
      • Renthal N.E.
      • Chen N.N.
      • Williams K.C.
      • et al.
      miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor.
      • Briery C.M.
      • Veillon E.W.
      • Klauser C.K.
      • et al.
      Progesterone does not prevent preterm births in women with twins.
      • Briery C.M.
      • Veillon E.W.
      • Klauser C.K.
      • et al.
      Women with preterm premature rupture of the membranes do not benefit from weekly progesterone.
      • Zakar T.
      • Mesiano S.
      How does progesterone relax the uterus in pregnancy?.
      • Peltier M.R.
      • Tee S.C.
      • Smulian J.C.
      Effect of progesterone on proinflammatory cytokine production by monocytes stimulated with pathogens associated with preterm birth.
      • Xu H.
      • Gonzalez J.M.
      • Ofori E.
      • Elovitz M.A.
      Preventing cervical ripening: the primary mechanism by which pregestational agents prevent preterm birth?.
      • Sfakianaki A.K.
      • Norwitz E.R.
      Mechanisms of progesterone action in inhibiting prematurity.
      • O'Brien J.M.
      • DeFranco E.A.
      • Adair C.D.
      • et al.
      Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.
      • Zakar T.
      • Hertelendy F.
      Progesterone withdrawal: key to parturition.
      Stimulate transcription of ZEB1 and ZEB2, which inhibit connexin 43 (gap-junction protein that helps synchronize contractile activity) and oxytocin-receptor gene
      Decrease prostaglandin synthesis, infection-mediated cytokine production (antiinflammatory effects) by fetal membranes/placenta
      Changes in PR-A and PR-B expression (decreased PR-A/PR-B ratio keeps uterus quiescent)
      Membrane-bound PR in myometrium
      PRs, when stimulated by progesterone, help selected gene promotion, or prevent binding of other factors
      Interfere with cortisol-mediated regulation of placental gene expression
      Nongenomic pathways
      Reduce cervical stromal degradation in cervix
      Alter barrier to ascending inflammation/infection in cervix
      Reduce contraction frequency in myometrium
      Attenuate response to hemorrhage/inflammation in decidua
      Alter estrogen synthesis in fetal membranes/placenta
      Alter fetal endocrine-mediated effects
      PR, progesterone receptor; ZEB1, zinc finger E-box binding homeobox protein 1; ZEB2, zinc finger E-box binding homeobox protein 2.
      SMFM. Progesterone and preterm birth prevention. Am J Obstet Gynecol 2012.
      Regarding safety, several studies failed to detect any long-term effect from the intrauterine exposure of the fetus to pharmacologic progestogens, even when given in the first trimester.
      • Resseguie L.J.
      • Hick J.F.
      • Bruen J.A.
      • Noller K.L.
      • O'Fallon W.M.
      • Kurland L.T.
      Congenital malformations among offspring exposed in utero to progestins, Olmsted County, Minnesota, 1936-1974.
      Follow-up, at a mean of 4 years, of 278 children randomized in the largest RCT evaluating 17P for prevention of recurrent PTB revealed no differences in physical examination, health status, or performance (motor, problem solving, personal-social) compared to placebo.
      • Northen A.T.
      • Norman G.S.
      • Anderson K.
      • et al.
      National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network
      Follow-up of children exposed in utero to 17 a-hydroxyprogesterone caproate compared with placebo.

      What is the evidence and recommendation for use of progestogens for prevention of PTB in singleton gestations with no prior PTB, with unknown CL? (Levels I and III)

      17P

      In 168 women in active military duty with only a 3% rate of prior PTB and unknown CL, 17P 1000 mg IM weekly starting at 16-20 weeks was not associated with any effect on the incidence of PTB or perinatal outcomes compared to placebo.
      • Hauth J.C.
      • Gilstrap III, L.C.
      • Brekken A.L.
      • Hauth J.M.
      The effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population.

      Vaginal progesterone

      No RCT has evaluated the effect of vaginal progesterone in this population.
      In summary, there is insufficient evidence to determine the impact on PTB of progestogens in singleton gestations with no history of PTB, and with unknown or normal CL.

      What is the evidence and recommendation for use of progestogens for prevention of PTB in singleton gestations with no prior PTB, but short CL? (Levels I, II, and III)

      17P

      It is particularly important to assess the effectiveness of progesterone in women without prior PTB, as most PTBs occur in this population. In 657 nulliparous women with singleton gestations with TVU CL ≤30 mm at 16-22 3/7 weeks, 17P 250 mg IM weekly through 36 weeks was associated with similar incidences of PTB <35 weeks (13.5% vs 16.1%; P = .35) and <37 weeks (25.1% vs 24.2%; P = .80) compared to placebo.
      • Grobman W.A.
      Eunice Kennedy Shriver National Institute of Health and Human Development
      Randomized controlled trial of progesterone treatment for preterm birth prevention in nulliparous women with cervical length less than 30mm.
      This RCT was stopped due to a planned interim analysis that revealed further enrollment was statistically very unlikely to demonstrate a significant difference between the groups.
      In 79 women with singleton pregnancies (66% of whom had no prior PTB) with TVU CL <25 mm between 16-24 weeks, 17P was associated with similar rates of PTB and neonatal morbidity and mortality compared to cerclage.
      • Keeler S.M.
      • Kiefer D.
      • Rochon M.
      • Quinones J.N.
      • Novetsky A.P.
      • Rust O.
      A randomized trial of cerclage vs 17 α-hydroxyprogesterone caproate for treatment of short cervix.
      Cerclage was significantly more effective than 17P at reducing the incidences of PTB <35 weeks and <37 weeks in the subgroup with TVU CL ≤15 mm.
      • Keeler S.M.
      • Kiefer D.
      • Rochon M.
      • Quinones J.N.
      • Novetsky A.P.
      • Rust O.
      A randomized trial of cerclage vs 17 α-hydroxyprogesterone caproate for treatment of short cervix.
      This RCT was stopped before planned recruitment was completed as the authors stated that “it had become impractical, unethical, and unreasonable to withhold progesterone from one study group.”
      • Keeler S.M.
      • Kiefer D.
      • Rochon M.
      • Quinones J.N.
      • Novetsky A.P.
      • Rust O.
      A randomized trial of cerclage vs 17 α-hydroxyprogesterone caproate for treatment of short cervix.

      Vaginal progesterone

      In 250 women from the United Kingdom, Chile, Brazil, and Greece, with mostly (90%) singleton gestations and TVU CL ≤15 mm at 20-25 weeks, of whom about 85% had no prior PTB, vaginal progesterone 200 mg nightly started at 24 weeks until 34 weeks was associated with a 44% significant decrease in spontaneous PTB (SPTB) <34 weeks (19% vs 34%; relative risk [RR], 0.56; 95% confidence interval [CI], 0.36–0.86), but no significant effect on neonatal morbidities (composite neonatal adverse outcome: RR, 0.57; 95% CI, 0.23–1.31).
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      A subgroup analysis of only women without prior PTB confirmed significant benefit of progesterone in preventing PTB <34 weeks (RR, 0.54; 95% CI, 0.34–0.88).
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      The prevalence of TVU CL ≤15 mm in the population screened for the study was 1.7%. Based on the frequency of short TVU CL and effectiveness for prevention of SPTB <34 weeks from the work of Fonseca et al,
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      the number of women needed to be screened with CL to prevent 1 SPTB <34 weeks is approximately 387, if all women with a CL ≤15 mm receive vaginal progesterone. Once a TVU CL ≤15 mm is identified, the number needed to treat to prevent 1 PTB <34 weeks is about 7.
      In 458 women with singleton gestations and TVU CL 10-20 mm at 19-23 6/7 weeks, of whom about 84% had no prior PTB, vaginal progesterone 90-mg gel daily started at 20-23 6/7 weeks until 36 6/7 weeks was associated with a 45% significant reduction in PTB <33 weeks (9% vs 16%; RR, 0.55; 95% CI, 0.33–0.92), and a 43% significant reduction in composite neonatal morbidity and mortality (8% vs 14%; RR, 0.57; 95% CI, 0.33–0.99).
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      PREGNANT Trial
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      The incidences of PTB <28 and <35 weeks, and respiratory distress syndrome (RDS), were also significantly decreased. Analysis of only women without prior PTB confirmed significant benefit of progesterone in preventing PTB <33 weeks (8% vs 15%; RR, 0.50; 95% CI, 0.27–0.90).
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      PREGNANT Trial
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      The prevalence of CL 10-20 mm was 2.3% in the population screened. The study enrolled patients in 44 centers in 10 countries (largest enrollment from United States, 46% of total), and the ethnic distribution of those included was about a third Caucasian, a third African American, and a third Asian. Protocol violations may have influenced the outcomes, and the study was both industry- and National Institutes of Health–sponsored. After evaluating data from this trial only, the Food and Drug Administration (FDA) concluded that the study did not meet the statistical significance generally expected to support the approval of the product in the US market from a single trial. The FDA raised the issue of robustness in efficacy in the US subgroup as compared to overall efficacy in the trial, and stated that additional clinical work would be required to support the approval.
      US Food and Drug Administration
      Advisory committees.
      Based on the frequency of short CL and effectiveness for prevention of PTB <33 weeks from this study,
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      PREGNANT Trial
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      the number of women needed to be screened with CL to prevent 1 PTB <33 weeks is approximately 604, if all women with a CL 10-20 mm receive vaginal progesterone. Once a TVU CL 10-20 mm is identified, the number needed to treat to prevent 1 PTB <33 weeks is about 14. The study did not address the management of women with a CL <10 mm.
      In a metaanalysis, including 554 singleton gestations, with no prior PTB, and TVU CL ≤25 mm mostly <25 weeks, vaginal progesterone was associated with a significant reduction in PTB <33 weeks (RR, 0.60; 95% CI, 0.39–0.92) and a nonsignificant reduction in composite neonatal morbidity and mortality (RR, 0.70; 95% CI, 0.42–1.16).
      • Romero 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 meta-analysis of individual patient data.
      Two cost-effectiveness analyses evaluating universal CL screening in singleton gestations, to identify those with short CL eligible for vaginal progesterone, have been published so far.
      • Cahill A.G.
      • Odibo A.O.
      • Caughey A.B.
      • et al.
      Universal cervical length screening and treatment with vaginal progesterone to prevent preterm birth: a decision and economic analysis.
      • Werner E.F.
      • Han C.S.
      • Pettker C.M.
      • et al.
      Universal cervical-length screening to prevent preterm birth: a cost-effectiveness analysis.
      Both reported that such a strategy would be cost-effective. In one study, compared to other managements, including no screening, universal sonographic screening of CL in singletons was predicted to result in a reduction of 95,920 PTBs <37 weeks annually in the United States, and was actually cost-saving (almost $13 billion saved).
      • Cahill A.G.
      • Odibo A.O.
      • Caughey A.B.
      • et al.
      Universal cervical length screening and treatment with vaginal progesterone to prevent preterm birth: a decision and economic analysis.
      Even varying the assumptions (eg, the cost of vaginal progesterone or of TVU screening), universal screening was the preferred strategy 99% of the time.
      • Cahill A.G.
      • Odibo A.O.
      • Caughey A.B.
      • et al.
      Universal cervical length screening and treatment with vaginal progesterone to prevent preterm birth: a decision and economic analysis.
      The other cost-effectiveness analysis targeted women with singleton gestation without prior PTB. A strategy of universal screening with a single TVU CL at 18-24 weeks and treatment with vaginal progesterone if the CL was ≤1.5 cm resulted in >$12 million saved, 424 quality-adjusted life-years gained, and 22 neonatal deaths or long-term neurologic deficits prevented for every 100,000 women screened compared with no screening. Even varying the assumptions over a wide range of possible values (eg, the cost of vaginal progesterone or of TVU screening), universal screening was cost-effective >99% of the time.
      • Werner E.F.
      • Han C.S.
      • Pettker C.M.
      • et al.
      Universal cervical-length screening to prevent preterm birth: a cost-effectiveness analysis.
      This cost-effectiveness analysis initially addressed only women with a TVU CL ≤1.5 mm. In an addendum, the authors mention that a reanalysis adding progesterone treatment for women with TVU CL between 1.6-2.5 mm did not change their conclusions, with the details of the reanalysis not provided.
      In summary, in women with singleton gestations, no prior SPTB, and short TVU CL, vaginal progesterone is associated with reduction in PTB and composite perinatal morbidity and mortality. Based on these results,
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      PREGNANT Trial
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      if a TVU CL ≤20 mm is identified at ≤24 weeks, vaginal progesterone can be offered for prevention of PTB. The 2 studies used different progesterone preparations and dosages. Vaginal progesterone 200-mg suppository was used in the trial for CL ≤15 mm,
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      and 90-mg gel for the trial for CL 10-20 mm.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      PREGNANT Trial
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      There is insufficient evidence that any of the vaginal preparations or doses are superior, as they have not been compared. CL, cost, availability, and other factors may influence preferred dosing.
      • Cahill A.G.
      • Odibo A.O.
      • Caughey A.B.
      • et al.
      Universal cervical length screening and treatment with vaginal progesterone to prevent preterm birth: a decision and economic analysis.
      • Werner E.F.
      • Han C.S.
      • Pettker C.M.
      • et al.
      Universal cervical-length screening to prevent preterm birth: a cost-effectiveness analysis.
      A decision of whether to institute a policy of universal screening for short cervix with TVU in women with singleton gestations without prior PTB requires several careful considerations:
      • The available trials have addressed efficacy of progesterone for women identified with a TVU short cervix. There are no data regarding effectiveness of universal TVU screening for short cervix followed by vaginal progesterone for those with a short cervix, compared to no screening. The only evidence in favor of such an approach is based on cost-effectiveness analyses.
      • It is possible that a proportion of women with a short cervix may be identified without a specific universal TVU screening. This may result in a lower than estimated added benefit of universal screening over current practice of visualization of the lower uterine segment on all transabdominal ultrasound performed in the second trimester. Data are currently insufficient to suggest benefit, or harm, of transabdominal screening of CL for prevention of PTB using progesterone or any other intervention as therapy if a short CL is identified. Transabdominal ultrasound may not detect 57% of women with a short TVU CL.

        Hernandez-Andrade E, Romero R, Ahn H, et al. Transabdominal evaluation of uterine cervical length during pregnancy fails to identify a substantial number of women with a short cervix. J Mat Fetal Neo Med 2012 Mar 16 [Epub ahead of print]. Level II-1.

        The randomized data on benefit from vaginal progesterone for women with short CL screened women utilizing TVU.
        • Fonseca E.B.
        • Celik E.
        • Parra M.
        • Singh M.
        • Nicolaides K.H.
        Progesterone and the risk of preterm birth among women with a short cervix.
        • Hassan S.S.
        • Romero R.
        • Vidyadhari D.
        • et al.
        PREGNANT Trial
        Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      • Universal screening approach may not produce the same results in practice as those in a controlled trial. This may be due to differences in population, logistical differences in screening methods, stretching of the eligibility and management criteria (scope creep), and unintended consequences of universal screening. Performing multiple follow-up scans, doing them outside of the studied gestational age (18-24 weeks), applying the treatment to women outside the studied CL range, or using other interventions for a short CL, such as bed rest or cerclage, may potentially result in adverse unintended consequences. The eligibility criteria were different between the 2 RCTs, and neither included all the women who had a CL below what is traditionally considered as short in the United States (<25 mm). The Fonseca et al
        • Fonseca E.B.
        • Celik E.
        • Parra M.
        • Singh M.
        • Nicolaides K.H.
        Progesterone and the risk of preterm birth among women with a short cervix.
        trial did not include women with a CL between 15-25 mm, and the Hassan et al
        • Hassan S.S.
        • Romero R.
        • Vidyadhari D.
        • et al.
        PREGNANT Trial
        Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
        trial did not include women with a CL <10 mm or between 20-25 mm. Neither trial included women with CL >20 mm, and therefore there is very limited evidence that vaginal progesterone is beneficial in these women.
        • Fonseca E.B.
        • Celik E.
        • Parra M.
        • Singh M.
        • Nicolaides K.H.
        Progesterone and the risk of preterm birth among women with a short cervix.
        • Hassan S.S.
        • Romero R.
        • Vidyadhari D.
        • et al.
        PREGNANT Trial
        Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
        • Romero 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 meta-analysis of individual patient data.
        It should be noted that only 1.7-2.3% of women were identified to have short CL in the 2 large trials published,
        • Fonseca E.B.
        • Celik E.
        • Parra M.
        • Singh M.
        • Nicolaides K.H.
        Progesterone and the risk of preterm birth among women with a short cervix.
        • Hassan S.S.
        • Romero R.
        • Vidyadhari D.
        • et al.
        PREGNANT Trial
        Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
        but that the incidence of CL ≤20 mm at 22-24 weeks in the largest blinded US study was 5%.
        • Iams J.D.
        • Goldenberg R.L.
        • Meis P.J.
        • et al.
        The length of the cervix and the risk of spontaneous premature delivery.
        The use of different progesterone formulations (90-mg gel and 200-mg suppository) between the 2 trials should also be taken into account. There is no evidence that the 2 preparations are interchangeable in that the one that was efficacious in the 10–20 mm range would also be efficacious in those with a CL <10 mm. In a metaanalysis, both of these 2 preparations had similar significant efficacy.
        • Romero 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 meta-analysis of individual patient data.
      • If an approach of universal screening is to be adopted, then TVU CL screening needs to be done with proper technique and with quality assurance to be effective.
      • There may be lack of availability of this screening test in some geographic areas.
      All of the above need to be taken into consideration when deciding on whether to change prenatal care for million of women by instituting universal screening with a single TVU assessment of CL at around 18-24 weeks in women with a singleton gestation without prior SPTB. On the other hand, TVU CL screening of singleton gestations does fulfill many criteria for an effective screening test (Table 2).
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      • Rafael T.J.
      Short cervical length.
      • Carlan S.J.
      • Richmond L.B.
      • O'Brien W.F.
      Randomized trial of endovaginal ultrasound in preterm premature rupture of membranes.
      • Dutta R.L.
      • Economides D.L.
      Patient acceptance of transvaginal sonography in the early pregnancy unit setting.
      A number of experts have recommended TVU CL universal screening.
      • Lockwood C.J.
      The real progesterone story.
      • Campbell S.
      Universal cervical-length screening and vaginal progesterone prevents early preterm births, reduces neonatal morbidity and is cost saving: doing nothing is no longer an option.
      • Combs C.A.
      Vaginal progesterone for asymptomatic cervical shortening and the case for universal screening of cervical length.
      This is based mostly, in addition to what is listed on Table 2, on the following facts:
      • There is level-1 evidence of prevention of PTB and neonatal benefits based on treating with vaginal progesterone low-risk singleton gestations identified with TVU screening to have a short CL.
      • This strategy is not only beneficial in terms of improvement in health in a condition (PTB) of utmost importance to society, but also cost-effective, and in fact cost-saving.
      • TVU CL is a safe, acceptable, reproducible, and accurate screening test, with potentially widespread availability.
      TABLE 2Cervical length as screening test in singleton gestations
      TVU CL screening test criteria
      Characteristic of screening testCommentsTVU fulfills criteria
      Disease
       Disease is clinically importantPTB: no. 1 cause of perinatal mortality and morbidity in developed countries; associated with 1 million deaths annually worldwideYes
       Disease is clearly definedBirth <37 wkYes
       Disease prevalence is well known12% in United States, about 10% worldwideYes
       Disease natural history is known/recognizable early asymptomatic phaseFirst cervical changes associated with later PTB occur at internal os, and can only be detected early by ultrasoundYes
      Screening
      Screening technique well describedDescribed in several articles
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      • Rafael T.J.
      Short cervical length.
      • Carlan S.J.
      • Richmond L.B.
      • O'Brien W.F.
      Randomized trial of endovaginal ultrasound in preterm premature rupture of membranes.
      Yes
      Screening is safe and acceptableTVU is safe even in women with PPROM
      • Carlan S.J.
      • Richmond L.B.
      • O'Brien W.F.
      Randomized trial of endovaginal ultrasound in preterm premature rupture of membranes.
      ; 99% of women would have TVU again; <2% have severe pain
      • Dutta R.L.
      • Economides D.L.
      Patient acceptance of transvaginal sonography in the early pregnancy unit setting.
      Yes
      Screening has reasonable cutoff identified20 mm is 5th percentile, 25 mm is 10th percentile in general US population
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      Yes
      Results are reproducible (reliable)<10% intraobserver and interobserver variabilityYes; extremely important to control quality of TVU CL
      Results are accurate (valid)Better than manual examination; predictive in all populations studiedYes
      Intervention, cost-effectiveness, and feasibility
       “Early” intervention is effectiveTwo positive randomized trials both reported that using vaginal progesterone for short TVU CL is effective in preventing PTB
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      PREGNANT Trial
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      • Romero 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 meta-analysis of individual patient data.
      Yes
       Screening and treating abnormals is cost-effectiveTwo cost-effectiveness articles published
      • Cahill A.G.
      • Odibo A.O.
      • Caughey A.B.
      • et al.
      Universal cervical length screening and treatment with vaginal progesterone to prevent preterm birth: a decision and economic analysis.
      • Werner E.F.
      • Han C.S.
      • Pettker C.M.
      • et al.
      Universal cervical-length screening to prevent preterm birth: a cost-effectiveness analysis.
      Yes, in fact cost-saving
       Facilities for screening are readily availableAll pregnancies are offered ultrasound for fetal anatomy screening at around 18-24 wkYes, but must be properly organized
       Facilities for treatment are readily availableVaginal progesterone is easily administered as outpatientYes
      CL, cervical length; PPROM, preterm premature rupture of membranes; PTB, preterm birth; TVU, transvaginal ultrasound.
      SMFM. Progesterone and preterm birth prevention. Am J Obstet Gynecol 2012.
      Therefore, both proponents and opponents of universal screening raise valid issues. CL screening in singleton gestations without prior PTB cannot yet be mandated universally. Nonetheless, implementation of such a screening strategy should be viewed as reasonable, and can be considered by individual practitioners. Third-party payers should not deny reimbursements for this screening. Practitioners who decide to implement universal CL screening should follow strict guidelines:
      • TVU CL needs to be performed with proper technique to yield accurate results, with quality control and monitoring. To ensure quality, the Perinatal Quality Foundation is setting up a program on the proper training for clinical use of TVU CL measurement.
      • Randomized trials and cost-effectiveness studies were mostly based on performing a single TVU CL at 18-24 weeks on singleton gestations, and on using vaginal progesterone, either 90-mg gel or 200-mg suppository, as intervention when the TVU CL was ≤20 mm at <24 weeks. Clinicians should refrain from screening different populations, screening at different gestational ages, and stretching the definition of short CL to include measurements >20 mm. There is also no evidence that other preparations (eg, IM 17P) or doses would be efficacious, even within the specified CL range.

      What is the evidence and recommendation for use of progestogens for prevention of PTB in singleton gestations with prior PTB, and unknown or normal CL? (Levels I, II, and III)

      17P

      In 43 women with mostly singleton gestation (>90%) and either prior PTB or >1 prior spontaneous abortion, 17P 250 mg IM weekly started as soon as prenatal care began was associated with significant reduction in PTB <37 weeks and perinatal mortality compared to placebo.
      • Johnson J.W.
      • Austin K.L.
      • Jones G.S.
      • Davis G.H.
      • King T.M.
      Efficacy of 17alpha-hydroxyprogesterone caproate in the prevention of premature labor.
      In 463 women with singleton gestation and prior SPTB at 20-36 6/7 weeks of a singleton gestation, compounded 17P 250 mg IM weekly started at 16-20 6/7 weeks was associated with reduction in the incidences of PTB <35 (RR, 0.66; 95% CI, 0.54–0.81), PTB <37 and <32 weeks, and supplemental oxygen and intraventricular hemorrhage (IVH) compared to placebo.
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      Based mostly on this clinical trial, 17P has been recommended for all women with prior SPTB 20-36 6/7 weeks.
      American College of Obstetricians and Gynecologists
      Use of progesterone to reduce preterm birth: ACOG committee opinion no. 419.
      • Kilpatrick S.J.
      Society for Maternal-Fetal Medicine
      Progesterone for the prevention of preterm birth.
      The estimated number of prevented PTBs <37 weeks in the United States by this policy is about 9870 annually.
      • Petrini J.R.
      • Callaghan W.M.
      • Klebanoff M.
      • et al.
      Estimated effect of 17 alpha-hydroxyprogesterone caproate on preterm birth in the United States.
      While the best evidence for efficacy is for 17P to be started <21 weeks, beneficial effects have been reported when 17P is started by ≤27 weeks.
      • González-Quintero V.H.
      • Istwan N.B.
      • Rhea D.J.
      • Smarkusky L.
      • Hoffman M.C.
      • Stanziano G.J.
      Gestational age at initiation of 17-hydroxyprogesterone caproate (17P) and recurrent preterm delivery.
      • How H.Y.
      • Barton J.R.
      • Istwan N.B.
      • Rhea D.J.
      • Stanziano G.J.
      Prophylaxis with 17 alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery: does gestational age at initiation of treatment matter?.
      17P should not be stopped early (eg <32 weeks), as this is associated with increased incidence of PTB.
      • Rebarber A.
      • Ferrara L.A.
      • Harley M.L.
      • et al.
      Increased recurrence of preterm delivery with early cessation of 17-alpha-hydroxyprogester-one caproate.

      Vaginal progesterone

      In 142 women with singleton gestations and mostly prior PTB (>90%), vaginal progesterone 100 mg nightly from 24-34 weeks was associated with significant reduction in the incidences of PTB <37 weeks (RR, 0.48; 95% CI, 0.25–0.96) and <34 weeks, as well as reduction in contraction frequency compared to placebo.
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.
      • Sugaib M.
      Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
      In 659 women with singleton gestation and prior SPTB 20-35 0/7 weeks, vaginal progesterone 90-mg gel every morning starting at 18-22 6/7 weeks and continued until 37 0/7 weeks was not associated with significantly different rates of PTB <37, 36, 33, or 29 weeks, or neonatal morbidity and mortality.
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      Several women screened for this trial were excluded because of short CL.
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.

      Effect of progesterone on CL

      In singleton gestations with prior PTB, 17P has not been associated with an effect on the development of short CL.
      • Durnwald C.P.
      • Lynch C.D.
      • Walker H.
      • Iams J.D.
      The effect of treatment with 17 alpha-hydroxyprogesterone caproate on changes in cervical length over time.
      On the other hand, vaginal progesterone was associated with significant reduction in the incidence of short CL in women with singleton gestations and prior PTB.
      • O'Brien J.M.
      • DeFranco E.A.
      • Adair C.D.
      • et al.
      Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.

      Oral progesterone

      In 148 women with singleton gestation and prior SPTB 20-36 6/7 weeks, oral progesterone 100 mg twice a day was associated with significantly reduced rates of PTB <37 weeks and neonatal intensive care unit admission compared to placebo.
      • Rai P.
      • Rajaram S.
      • Goel N.
      • Ayalur Gopalakrishnan R.
      • Agarwal R.
      • Mehta S.
      Oral micronized progesterone for prevention of preterm birth.
      In 33 women with singleton gestation and prior PTB 20-36 6/7 weeks, oral progesterone 400 mg daily was associated with trend (but no significant differences) for reduced rates of PTB <37 weeks (26% vs 57%; P = .15) and ventilator use (0% vs 21%; P = .07) compared to placebo.
      • Glover M.M.
      • McKenna D.S.
      • Downing C.M.
      • et al.
      A randomized trial of micronized progesterone for the prevention of recurrent preterm birth.
      In summary, in singleton gestation with prior SPTB, in which CL is unknown, progestogen administration is beneficial in preventing PTB. Although we have limited data comparing the different preparations of progestogens, there is at present stronger evidence of effectiveness for 17P than for vaginal progesterone, based on the 2 largest trials.
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      Therefore, 17P 250 mg IM weekly starting at 16-20 weeks until 36 weeks should be recommended to women with singleton gestations and prior SPTB 20-36 6/7 weeks. In cases in which 17P is unavailable, other progesterone preparations may be considered.
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.
      • Sugaib M.
      Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.

      What is the evidence and recommendation for use of progestogens for prevention of PTB in singleton gestations with prior PTB, and short CL? (Levels I, II, and III)

      17P

      There are no RCTs evaluating the effectiveness of 17P compared to placebo in women with singleton gestations, prior PTB, and short CL. In this population, 17P has only been evaluated as an adjunct or an alternative to cervical cerclage.
      In singleton gestations with prior SPTB and a short TVU CL <25 mm at <23 weeks, 17P was associated with statistically significant decrease in PTB <24 weeks and perinatal death in women not receiving cerclage in a secondary analysis of a cerclage trial.
      • Berghella V.
      • Figueroa D.
      • Szychowski J.M.
      • et al.
      Vaginal Ultrasound Trial Consortium
      17-alpha-hydroxyprogesterone caproate for the prevention of preterm birth in women with prior preterm birth and a short cervical length.
      Beneficial effects of 17P were noted primarily for women with CL 15-24.9 mm, while they were nonsignificant for women with CL <15 mm. Overall, women with a CL <25 mm had a 34% risk of PTB <32 weeks if they received neither 17P nor cerclage, 25% if they received cerclage, 21% if they received 17P, and 17% if they received both.
      • Berghella V.
      • Figueroa D.
      • Szychowski J.M.
      • et al.
      Vaginal Ultrasound Trial Consortium
      17-alpha-hydroxyprogesterone caproate for the prevention of preterm birth in women with prior preterm birth and a short cervical length.
      While these results were not statistically significant, they suggest that further research is needed to evaluate the relationship and possible cumulative beneficial effect of progesterone and cerclage.
      In a randomized trial that did not recruit the planned sample size, 17P had similar effects compared to cerclage in preventing PTB in women with a TVU CL <25 mm, but cerclage was more beneficial in women with CL <15 mm.
      • Keeler S.M.
      • Kiefer D.
      • Rochon M.
      • Quinones J.N.
      • Novetsky A.P.
      • Rust O.
      A randomized trial of cerclage vs 17 α-hydroxyprogesterone caproate for treatment of short cervix.
      While cerclage seems to be more efficacious (lower RRs) for CL on the lower end of the range,
      • Owen J.
      • Szychowski J.
      Can the optimal cervical length for placing ultrasound-indicated cerclage be identified?.
      • Owen J.
      • Hankins G.
      • Iams J.D.
      • et al.
      Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length.
      progesterone seems to be most efficacious for moderately short CL.
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      PREGNANT Trial
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      • Romero 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 meta-analysis of individual patient data.

      Vaginal progesterone

      In a secondary analysis of an RCT
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      evaluating just the 46 singleton gestations with prior SPTB <35 weeks and short TVU CL <28 mm at 18-22 6/7 weeks, vaginal progesterone 90-mg gel daily started at 18-23 6/7 weeks until 37 weeks was associated with significant decreases in the rates of both PTB <32 weeks and neonatal intensive care unit admission compared to placebo.
      • DeFranco E.A.
      • O'Brien J.M.
      • Adair C.D.
      • et al.
      Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial.
      In 71 singleton gestations with prior PTB, vaginal progesterone 100-mg suppositories daily between 24-34 weeks was associated with significant reduction in incidences of PTB <37 weeks (24% vs 50%; odds ratio [OR], 3.11; 95% CI, 1.13–8.53) and <34 weeks (5.4% vs 26.5%; OR, 6.30; 95% CI, 1.25–31.70) compared to placebo.
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • et al.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      In a metaanalysis, including 169 singleton gestations with prior PTB and TVU CL ≤25 mm mostly <25 weeks, vaginal progesterone was associated with a significant reduction in PTB <33 weeks (RR, 0.54; 95% CI, 0.30–0.98) and in composite neonatal morbidity and mortality (RR, 0.41; 95% CI, 0.17–0.98).
      • Romero 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 meta-analysis of individual patient data.
      Based on the pooled results of 5 clinical trials, in 504 singleton pregnancies with prior SPTB at <34 weeks and TVU CL <25 mm at <24 weeks' gestation, cerclage was associated with a significant 30% reduction in the risk of PTB <35 weeks (28% vs 41%; RR, 0.70; 95% CI, 0.55–0.89) and a 36% reduction in composite perinatal mortality and morbidity (16% vs 25%; RR, 0.64; 95% CI, 0.45–0.91).
      • Berghella V.
      • Rafael T.J.
      • Szychowski J.M.
      • Rust O.A.
      • Owen J.
      Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis.
      Therefore screening women with singleton gestations with prior SPTB with TVU CL starting usually at 16 weeks and every 2 weeks until 23 weeks is suggested, so that cerclage can be offered for those who develop a TVU CL <25 mm. As the vast majority of women in this metaanalysis and its included randomized trials did not receive 17P, there is insufficient evidence to determine if the concurrent use of progesterone and cerclage offers an additive effect in reducing the risk of PTB in this group of women with prior PTB.
      • Berghella V.
      • Figueroa D.
      • Szychowski J.M.
      • et al.
      Vaginal Ultrasound Trial Consortium
      17-alpha-hydroxyprogesterone caproate for the prevention of preterm birth in women with prior preterm birth and a short cervical length.
      Therefore, the optimal management of the patient with progressive cervical shortening despite progesterone therapy remains uncertain.
      In summary, 17P should be recommended to women with prior SPTB starting at 16 weeks, as described above. If the cervix shortens <25 mm by TVU <24 weeks in such a woman with singleton gestation and prior SPTB, there is insufficient evidence to assess efficacy of a different progesterone therapy, and therefore it is reasonable to continue 17P until 36 weeks, and to offer cervical cerclage (Figure).
      Figure thumbnail gr1
      FIGUREAlgorithm for use of progestogens in prevention of PTB in clinical care
      aIf TVU CL screening is performed; b17P 250 mg intramuscularly every week from 16-20 weeks to 36 weeks; ceg, daily 200-mg suppository or 90-mg gel from time of diagnosis of short CL to 36 weeks.
      CL, cervical length; PTB, preterm birth; 17P, 17-alpha-hydroxy-progesterone caproate; TVU, transvaginal ultrasound.
      SMFM. Progesterone and preterm birth prevention. Am J Obstet Gynecol 2012.

      What is the evidence and recommendation for use of progestogens for prevention of PTB in multiple gestations, and unknown or normal CL? (Levels I and III)

      17P

      In 77 women with twin gestation, 17P 250 mg IM weekly from 28-33 weeks was not associated with any effect on PTB rates or perinatal morbidity and mortality compared to placebo.
      • Hartikainen-Sorri A.L.
      • Kauppila A.
      • Tuimala R.
      Inefficacy of 17 a-hydroxyprogesterone caproate in the prevention of prematurity in twin pregnancy.
      In 655 women with dichorionic (DC) twin gestation, of whom <10% had prior PTB, 17P 250 mg IM weekly starting at 16-20 weeks and ending at 35 weeks was not associated with any effect on PTB rates or perinatal morbidity and mortality in a National Institute of Child Health and Human Development–sponsored RCT compared to placebo.
      • Rouse D.J.
      • Caritis S.N.
      • Peaceman A.M.
      • et al.
      National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network
      A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.
      In 30 women with twin gestation, of whom 27% had a prior PTB, 17P 250 mg IM weekly starting at 20-30 weeks and ending at 34 weeks was associated with similar incidences of PTB <35 weeks and <30 weeks, as well as similar rates of neonatal morbidity and mortality compared to placebo. CL was not reported.
      • Briery C.M.
      • Veillon E.W.
      • Klauser C.K.
      • et al.
      Progesterone does not prevent preterm births in women with twins.
      In 240 women with DC twin gestation, 17P 250 mg IM weekly starting at 16-24 weeks until 34 weeks was associated with similar incidences of PTB and neonatal morbidity compared to placebo.
      • Combs C.A.
      • Garite T.
      • Maurel K.
      • Das A.
      • Porto M.
      Obstetrix Collaborative Research Network
      17-hydroxyprogesterone caproate for twin pregnancy: a double-blind, randomized clinical trial.
      Two RCTs have evaluated the effect of 17P in triplet gestations. In a total of about 190 triplet gestations, 17P 250 mg IM weekly started at around 16-20/22 weeks' gestation until 34/35 weeks was not associated with effects on incidence of PTB or perinatal morbidity and mortality compared to placebo.
      • Caritis S.N.
      • Rouse D.J.
      • Peaceman A.M.
      • et al.
      Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Maternal-Fetal Medicine Units Network (MFMU)
      Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial.
      • Combs C.A.
      • Garite T.
      • Maurel K.
      • et al.
      Obstetrix Collaborative Research Network
      Failure of 17-hydroxyprogesterone to reduce neonatal morbidity or prolong triplet pregnancy: a double-blind, randomized clinical trial.

      Vaginal progesterone

      In 500 women with twin gestation, vaginal progesterone 90 mg daily starting at 24 weeks and continued for at least 10 weeks was not associated with significant effects in incidences of PTB or perinatal morbidity and mortality compared to placebo.
      • Norman J.E.
      • Mackenzie F.
      • Owen P.
      • et al.
      Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomized, double-blind, placebo-controlled study and meta-analysis.
      In 677 women with diamniotic twin gestation, vaginal progesterone 200-mg pessaries starting at 20-24 weeks until 34 weeks were not associated with significant effects on incidences of PTB or perinatal complications compared to placebo.
      • Rode L.
      • Klein K.
      • Nicolaides K.H.
      • Krampl-Bettelheim E.
      • Tabor A.
      PREDICT Group
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo-controlled trial on the effect of vaginal micronized progesterone.
      In 67 twin gestations, vaginal progesterone 100-mg suppositories daily between 24-34 weeks were associated with significant reduction in incidences of PTB <37 weeks (51% vs 79%; OR, 3.48; 95% CI, 1.16–10.46) but not <34 weeks (10% vs 25%; OR, 2.90; 95% CI, 0.76–11.20) compared to placebo.
      • DeFranco E.A.
      • O'Brien J.M.
      • Adair C.D.
      • et al.
      Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial.
      No RCT has yet been reported on the effect of vaginal progesterone on triplet gestations.
      In summary, the evidence does not support the use of any type of progestogen for prevention of PTB in multiple gestations with unknown CL. In women with prior SPTB, and a current multiple gestation, some experts have suggested the use of 17P starting at 16 weeks based on the historic risk factor,
      • Iams J.D.
      • Berghella V.
      Care for women with prior preterm birth.
      but there is insufficient evidence to make this a recommendation.

      What is the evidence and recommendation for use of progestogens for prevention of PTB in multiple gestations, and short CL? (Levels I and III)

      17P

      In a secondary analysis of a trial involving women with DC twin gestation, 52 women, of whom 18.5% had prior PTB, were identified to have a TVU CL of ≤35 mm (25th percentile) between 16-20 weeks. 17P 250 mg IM weekly starting at 16-20 weeks and ending at 35 weeks was associated with similar incidences of PTB <35 weeks (64% vs 46%; P = .18) compared to placebo.
      • Durnwald C.P.
      • Momirova V.
      • Rouse D.J.
      • et al.
      Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network
      Second-trimester cervical length and risk of preterm birth in women with twin gestations treated with 17-α hydroxyprogesterone caproate.

      Vaginal progesterone

      In a secondary analysis of a trial involving women with diamniotic twin gestation, 47 women, of whom 9% had prior PTB, were identified to have TVU CL ≤30 mm between 20-24 weeks. Vaginal progesterone 200-mg pessaries starting at 20-24 weeks until 34 weeks were not associated with an effect on PTB <34 weeks (29% vs 40%; RR, 0.63; 95% CI, 0.18–2.23) compared to placebo.
      • Klein K.
      • Rode L.
      • Nicolaides K.H.
      • Krampl-Bettelheim E.
      • Tabor A.
      PREDICT Group
      Vaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies: secondary analysis of a placebo-controlled randomized trial and meta-analysis.
      In a metaanalysis, including 52 twin gestations found to have a TVU CL <25 mm at ≤24 weeks, vaginal progesterone was associated with similar incidence of PTB <33 weeks (30% vs 45%; RR, 0.70; 95% CI, 0.34–1.44) and <35 weeks (52% vs 62%; RR, 0.91; 95% CI, 0.57–1.46), but a significant reduction in composite neonatal morbidity and mortality (24% vs 40%; RR, 0.56; 95% CI, 0.30–0.97) compared to placebo.
      • Romero 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 meta-analysis of individual patient data.
      In summary, there is insufficient evidence to assess the effect of progestogens in women with both multiple gestation and short CL.

      What is the evidence and recommendation for use of progestogens for prevention of PTB in preterm labor? (Levels I, II, and III)

      Primary tocolysis

      In 57 women admitted between 13-36 weeks with contractions, progesterone 400 mg orally once was associated with a significant decrease in the frequency of contractions, but no PTB or neonatal outcomes were reported compared to placebo.
      • Erny R.
      • Pigne A.
      • Prouvost C.
      • et al.
      The effects of oral administration of progesterone for premature labor.

      Adjunctive tocolysis

      In 44 women with mostly singleton gestations (>90%) and threatened preterm labor (PTL) at <35 weeks treated with ritodrine, natural progesterone 400 mg orally every 6 hours × 24 hours (then 400 mg every 8 hours for next 24 hours, and then 300 mg every 8 hours onward) was associated with similar rates of PTB, but with lower total dose of ritodrine administered and shorter maternal hospital stay compared to placebo.
      • Noblot G.
      • Audra P.
      • Dargent D.
      • Faguer B.
      • Mellier G.
      The use of micronized progesterone in the treatment of menace of preterm delivery.

      Maintenance tocolysis

      17P

      In 60 women with singleton gestation still pregnant after successful tocolysis for PTL, 17P 341 mg twice weekly started at 25-33 6/7 weeks until 36 weeks was associated with significant reduction in the incidence of PTB <37 weeks (but not 35 weeks) and of risk of cervical shortening compared to no such treatment.
      • Facchinetti F.
      • Paganelli S.
      • Comitini G.
      • Dante G.
      • Volpe A.
      Cervical length changes during preterm cervical ripening: effects of 17-α-hydroxyprogesterone caproate.
      In 188 women with singleton gestations still pregnant after successful tocolysis for PTL, 17P 500 mg IM twice weekly started at 24-31 6/7 weeks until 36 weeks was associated with similar incidences of PTB <37, <34, and <32 weeks, and of perinatal morbidity and mortality compared to no such treatment.
      • Rozenberg P.
      • Chauveaud A.
      • Deruelle P.
      • et al.
      Prevention of preterm delivery after successful tocolysis in preterm labor by 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial.

      Vaginal progesterone

      In 70 women with singleton gestation still pregnant after successful tocolysis for PTL, vaginal progesterone 400 mg daily until delivery was associated with longer latency until delivery, later gestational age at delivery (PTB was not reported), and RDS compared to no such treatment.
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.
      In summary, there is currently insufficient evidence to recommend progestogens for primary, adjunctive, or maintenance tocolysis.

      What is the evidence and recommendation for use of progestogens for prevention of PTB in preterm premature rupture of membranes? (Levels I and III)

      17P

      In 69 women with singleton gestations and preterm premature rupture of membranes (PPROM) at 24-30 weeks, 17P 250 mg IM is associated with no effect on interval to delivery, gestational age at delivery, or neonatal mortality and morbidity compared to placebo.
      • Briery C.M.
      • Veillon E.W.
      • Klauser C.K.
      • et al.
      Women with preterm premature rupture of the membranes do not benefit from weekly progesterone.

      Vaginal progesterone

      No RCT has evaluated the effect of vaginal progesterone in this population.
      In summary, there is insufficient evidence to assess effect of progesterone in women with PPROM. In a woman who has been receiving 17P for prior SPTB, in the absence of evidence to the contrary, it is reasonable to continue 17P once membranes have ruptured.

      Conclusions

      Assessment of efficacy of progestogens for prevention of PTB should be done separately for each type of progestogens, with vaginal and IM routes of administration the most studied types (Table 3). Efficacy probably varies also depending on each different risk factor. In addition, dose, gestational age at initiation and termination, compliance, and other issues are factors that influence efficacy of progestogens for prevention of PTB. Therefore, singleton vs multiple gestation, history (eg, prior PTB), short TVU CL (and degree of) or not, asymptomatic vs PTL and PPROM, etc, are all factors that should be considered, as progestogens have different effects in populations with any one (or combination of) risk factor. Several metaanalyses have been published,
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth.
      • Su L.L.
      • Samuel M.
      • Chong Y.S.
      Progestational agents for treating threatened or established preterm labor.
      • MacKenzie R.
      • Walker M.
      • Armson A.
      • Hannah M.E.
      Progesterone for the prevention of preterm birth among women at increased risk: a systematic review and meta-analysis of randomized controlled trials.
      • Sanchez-Ramos L.
      • Kaunitz A.M.
      • Delke I.
      Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials.
      but they either do not evaluate these studies according to the different populations just mentioned, or soon become out of date because of publications of new RCTs.
      TABLE 3Current Society for Maternal-Fetal Medicine recommendations regarding use of progestogens for prevention of preterm birth
      PopulationRecommendation regarding use of progestogens
      Asymptomatic
       Singletons without prior SPTB and unknown or normal TVU CLNo evidence of effectiveness
       Singletons with prior SPTB17P 250 mg IM weekly from 16-20 wk until 36 wk
       Singletons without prior SPTB but CL ≤20 mm at ≤24 wkVaginal progesterone 90-mg gel or 200-mg suppository daily from diagnosis of short CL until 36 wk
       Multiple gestationsNo evidence of effectiveness
      Symptomatic
       PTLNo evidence of effectiveness
       PPROMNo evidence of effectiveness
      17P, 17-alpha-hydroxy-progesterone caproate; CL, cervical length; IM, intramuscularly; PPROM, preterm premature rupture of membranes; PTL, preterm labor; SPTB, spontaneous preterm birth; TVU, transvaginal ultrasound.
      SMFM. Progesterone and preterm birth prevention. Am J Obstet Gynecol 2012.

      Recommendations

      Level I and level III evidence, level A recommendation

      • 1
        There is insufficient evidence to recommend the use of progestogens in singleton gestations with no prior PTB, and unknown CL.

      Level I evidence, level A recommendation

      • 2
        In women with singleton gestations, no prior SPTB, and short TVU CL ≤20 mm at ≤24 weeks, vaginal progesterone, either 90-mg gel or 200-mg suppository, is associated with reduction in PTB and perinatal morbidity and mortality, and can be offered in these cases.

      Level I and level III evidence, level B recommendation

      • 3
        The issue of universal TVU CL screening of singleton gestations without prior PTB for the prevention of PTB remains an object of debate. CL screening in singleton gestations without prior PTB cannot yet be universally mandated. Nonetheless, implementation of such a screening strategy can be viewed as reasonable, and can be considered by individual practitioners. Given the impact on prenatal care and potential misuse of universal screening, stretching the criteria and management beyond those tested in RCTs should be prevented. Practitioners who decide to implement universal TVU CL screening should follow strict guidelines. Practitioners who choose to screen low-risk singleton gestations may consider offering vaginal progesterone, either 90-mg gel or 200-mg suppositories, for short TVU CL ≤20 mm at ≤24 weeks.

      Level I and level III evidence, level A and B recommendations

      • 4
        In singleton gestations with prior SPTB 20-36 6/7 weeks, 17P 250 mg IM weekly preferably starting at 16-20 weeks until 36 weeks is recommended. In these women, if the TVU CL shortens to <25 mm at <24 weeks, cervical cerclage may be offered.

      Level I, level II, and level III evidence, level B recommendation

      • 5
        Progestogens have not been associated with prevention of PTB in multiple gestations, PTL, or PPROM. There is insufficient evidence to recommend the use of progestogens in women with any of these risk factors, with or without a short CL. Some experts offer 17P to women with a prior SPTB and a current multiple gestation, but there are insufficient data to evaluate the risks and benefits of this intervention in this population.
      This opinion was developed by the Publications Committee of the Society for Maternal–Fetal Medicine with the assistance of Vincenzo Berghella, MD, and was approved by the executive committee of the society on March 11, 2012. Dr Berghella and each member of the publications committee (Vincenzo Berghella, MD [chair], Sean Blackwell, MD [vice-chair], Brenna Anderson, MD, Suneet P. Chauhan, MD, Joshua Copel, MD, Cynthia Gyamfi, MD, Donna Johnson, MD, George Saade, MD, Hyagriv Simhan, MD, Lynn Simpson, MD, Joanne Stone, MD, Alan Tita, MD, Michael Varner, MD, Ms Deborah Gardner) have submitted a conflict of interest disclosure delineating personal, professional, and/or business interests that might be perceived as a real or potential conflict of interest in relation to this publication.
      The practice of medicine continues to evolve, and individual circumstances will vary. This opinion reflects information available at the time of its submission for publication and is neither designed nor intended to establish an exclusive standard of perinatal care. This publication is not expected to reflect the opinions of all members of the Society for Maternal–Fetal Medicine.

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      Linked Article

      • Correction: May 2012 (vol. 206, no. 5, page 376)
        American Journal of Obstetrics & GynecologyVol. 208Issue 1
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          An incorrect word appeared in an SMFM Clinical Guideline (Society for Maternal-Fetal Medicine Publications Committee, Berghella V. Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol 2012;206:376-86) published in the May 2012 issue of the Journal.
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      • The source of 17P used in NICHD trial
        American Journal of Obstetrics & GynecologyVol. 207Issue 5
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          I read with great interest the recent Society for Maternal-Fetal Medicine Clinical Guideline concerning progesterone treatment to prevent preterm birth.1
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