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Progesterone for preterm birth prevention: an evolving intervention

      We sought to review emerging data on the use of progesterone to prevent preterm birth (PTB). Using the terms “preterm or premature” and “progesterone” we queried the PubMed database, restricting our search to January 1, 2000, forward and selected randomized clinical trials (RCTs) and metaanalyses of RCTs that evaluated the use of progesterone for the prevention of PTB. We reviewed 238 abstracts and supplemented our review by a bibliographic search of selected reports. We focused on the pharmacologic aspects of progesterone and risk factor-specific outcomes. We identified a total of 17 relevant reports: 8 individual RCTs, 6 metaanalyses, and 3 national guidelines. Individual trials and metaanalyses support that synthetic intramuscular 17-alpha-hydroxyprogesterone effectively reduces the incidence of recurrent PTB in women with a history of spontaneous PTB. One trial found that vaginally administered natural progesterone reduced the risk of early PTB in women with a foreshortened cervix. The data are suggestive but inconclusive about: (1) the benefits of progesterone in the setting of arrested preterm labor; and (2) whether progesterone lowers perinatal morbidity or mortality. In some women, progesterone reduces the risk of PTB. Further study is required to identify appropriate candidates and optimal formulations.

      Key words

      Preterm birth (PTB) is the number 1 cause of neonatal morbidity and mortality, and a leading cause of long-term disability in the United States and elsewhere.
      • Goldenberg R.L.
      • Culhane J.F.
      • Iams J.D.
      • Romero R.
      Epidemiology and causes of preterm birth.
      • Moster D.
      • Lie R.T.
      • Markestad T.
      Long-term medical and social consequences of preterm birth.
      Overall, PTB accounts for up to 12.7% of births in the developed world; the vast majority of these (∼ 75%) occur spontaneously.
      • Goldenberg R.L.
      • Culhane J.F.
      • Iams J.D.
      • Romero R.
      Epidemiology and causes of preterm birth.
      • Martin J.A.
      • Hamilton B.E.
      • Sutton P.D.
      • et al.
      Centers for Disease Control and Prevention National Center for Health Statistics National Vital Statistics System births: final data for 2005.
      Although secondary or tertiary interventions such as antenatal corticosteroids, postnatal surfactant, and improved neonatal care have led to reduced morbidity and mortality caused by PTB, effective primary preventive interventions have remained elusive. Encouragingly, accumulating data suggest that progesterone may be effective in preventing PTB, and the American College of Obstetricians and Gynecologists (ACOG) recognizes its use for this purpose.
      American College of Obstetricians and Gynecologist
      Use of progesterone to reduce preterm birth: ACOG committee opinion No. 2919.
      Nevertheless, there is still considerable uncertainty surrounding how progesterone actually works, indications for its use, and the optimal progesterone type, mode of administration, and dose. Both ACOG and the Society of Obstetricians and Gynecologists of Canada (SOGC) acknowledge the need for additional studies
      American College of Obstetricians and Gynecologist
      Use of progesterone to reduce preterm birth: ACOG committee opinion No. 2919.
      • Farine D.
      • Mundle W.R.
      • Dodd J.
      The use of progesterone for prevention of preterm birth.
      and, as of August 2008, there were > 20 registered ongoing (or planned) trials of progesterone for the prevention of PTB. The purpose of this report is to present a concise review of more recent data (since 2000) on progesterone use specifically for PTB prevention focusing on pharmacologic options, specific clinical indications, and expected benefits.
      For Editors' Commentary, see Table of Contents

      Materials and methods

      We conducted a search of the entire PubMed database (January 2000-October 2008) using the key words “progesterone” and “preterm.” A total of 240 abstracts were reviewed to identify all relevant clinical trials or metaanalyses of clinical trials evaluating the effect of antenatal maternal use of progesterone on the risk of PTB. We then conducted a bibliographic review of the selected reports. We also reviewed national guidelines for the use of progesterone to prevent PTB. Of a total of 17 reports identified, there were 8 clinical trials,
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.
      • Rouse D.J.
      • Caritis S.N.
      • Peaceman A.
      • et al.
      A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.
      • 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.
      • 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.
      • 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.
      • Facchinetti F.
      • Paganelli S.
      • Comitini G.
      • Dante G.
      • Volpe A.
      Cervical length changes during preterm cervical ripening: effects of a 17-a-hydrosyprogesterone caproate.
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.B.
      • Zugaib 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.
      6 metaanalyses,
      • Sanchez-Ramos L.
      • Kaunitz A.M.
      • Delke I.
      Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials.
      • Dodd J.M.
      • Crowther C.A.
      • Cincotta R.
      • Flenady V.
      • Robinson J.S.
      Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth [review].
      • 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.
      • Coomarasamy A.
      • Thangaratinam S.
      • Gee H.
      • Khan K.S.
      Progesterone for the prevention of preterm birth: a critical evaluation of evidence.
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      and 3 reports of national recommendations or guidelines.
      American College of Obstetricians and Gynecologist
      Use of progesterone to reduce preterm birth: ACOG committee opinion No. 2919.
      • Farine D.
      • Mundle W.R.
      • Dodd J.
      The use of progesterone for prevention of preterm birth.
      American College of Obstetricians and Gynecologist
      Use of progesterone to reduce preterm birth: ACOG committee opinion No. 419.
      We abstracted relevant pharmacologic data on progesterone formulation (type, dose, route, and side effects) and pregnancy outcome by risk group under study. We applied an analytic (as opposed to a synthetic) approach to the synthesis of the data from these reports (ie, we analyzed observed similarities and/or differences without conducting additional metaanalyses). Relative risk (RR) and 95% confidence interval (CI) for pertinent outcomes were obtained either from the reports themselves or, when not available, calculated from the reported data.

      Results

      Among the 8 clinical trials identified,
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.
      • Rouse D.J.
      • Caritis S.N.
      • Peaceman A.
      • et al.
      A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.
      • 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.
      • 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.
      • 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.
      • Facchinetti F.
      • Paganelli S.
      • Comitini G.
      • Dante G.
      • Volpe A.
      Cervical length changes during preterm cervical ripening: effects of a 17-a-hydrosyprogesterone caproate.
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.B.
      • Zugaib 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.
      1 was a subgroup analysis of another included trial.
      • 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.
      The characteristics of the 7 primary clinical trials and 6 metaanalyses are summarized in TABLE 1, TABLE 2, respectively. In addition, we identified 3 relevant national recommendations or technical reports, 2 from ACOG and 1 from SOGC.
      American College of Obstetricians and Gynecologist
      Use of progesterone to reduce preterm birth: ACOG committee opinion No. 2919.
      • Farine D.
      • Mundle W.R.
      • Dodd J.
      The use of progesterone for prevention of preterm birth.
      American College of Obstetricians and Gynecologist
      Use of progesterone to reduce preterm birth: ACOG committee opinion No. 419.
      The clinical trials were all reported between 2003 and 2008; 2 trials were not placebo controlled and, therefore, not blinded. The metaanalyses were all reported between 2005 and 2008 but included clinical trials conducted as early as the 1950s. The type and dose of progesterone, the characteristics of the studied subjects, the nature of the study outcomes, and the corresponding results varied considerably.
      TABLE 1Individual clinical trials of progesterone for preventing preterm birth since 2000
      StudyDesignSample SizeProgesterone interventionPopulation (indication)Primary outcome(s)
      Borna and Sahabi
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.
      RCT (no placebo)70400 mg vaginal suppository dailyArrested (threatened) PTL
      • (1) Latency (days)
      • (2) Recurrence of PTL
      O'Brien et al
      • 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.
      RCT (placebo controlled)65990 mg vaginal gelPrior SPTB, 18-22 wkPTB ≤ 32 wk
      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.
      RCT (placebo controlled)250200 mg vaginal capsule daily until 34 wkShort cervix ≤ 15 mm at 20-25 wkSpontaneous PTB < 34 wk
      Rouse et al
      • Rouse D.J.
      • Caritis S.N.
      • Peaceman A.
      • et al.
      A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.
      RCT (placebo controlled661250 mg 17P IM until 35 wkTwins at 16-20 wk(1) PTB < 35 wk or IUFD < 35 wk
      Facchinetti et al
      • Facchinetti F.
      • Paganelli S.
      • Comitini G.
      • Dante G.
      • Volpe A.
      Cervical length changes during preterm cervical ripening: effects of a 17-a-hydrosyprogesterone caproate.
      RCT (no placebo)60341 mg 17P IM twice weeklyArrested PTLChange in cervical length
      Meis et al
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      RCT (placebo controlled)463250 mg 17P IM weeklyPrior SPTB, 16 wkPTB < 37 wk
      da Fonseca et al
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.B.
      • Zugaib 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.
      RCT (placebo controlled)142100 mg daily vaginal suppository until 34 wkPrior SPTB, 24 wk onwardPTB < 37 wk
      IM, intramuscular; IUFD, intrauterine fetal demise; PTB, preterm birth; PTL, preterm labor; RCT, randomized clinical trial; SPTB, spontaneous preterm birth; 17P, 17-alpha-hydroxyprogesterone.
      Tita. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol 2009.
      TABLE 2Metaanalyses of clinical trials of progesterone for preterm birth prevention since 2000
      StudyNo. of trialsNo. of women (infants)Progesterone interventionPopulation (indication)Primary outcome(s)
      Dodd et al
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      112425 (3187)Any antenatal use to prevent PTB
      • (1) Prior SPTB
      • (2) Multiples (twins)
      • (3) Short cervix
      • (4) Threatened PTL
      • (1) Perinatal death
      • (2) PTB < 34 wk
      • (3) Neurodevelopmental handicap
      Coomarasamy et al
      • Coomarasamy A.
      • Thangaratinam S.
      • Gee H.
      • Khan K.S.
      Progesterone for the prevention of preterm birth: a critical evaluation of evidence.
      9 (cumulative metaanalysis)> 1062Any antenatal use(1) Risk factors for PTB excluding multiples
      • (1) PTB < 37 wk
      • (2) PTB < 34 wk
      • (3) RDS
      Mackenzie et al
      • 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.
      3648Second-trimester use(1) Increased risk for SPTBPTB < 37 wk
      Dodd et al
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth [review].
      6988Any antenatal useAny pregnancy
      • (1) Perinatal death
      • (2) PTB < 34 wk
      • (3) Neurodevelopmental handicap
      Dodd et al
      • Dodd J.M.
      • Crowther C.A.
      • Cincotta R.
      • Flenady V.
      • Robinson J.S.
      Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.
      71020Any antenatal useSingletonsMultiple adverse infant and maternal outcomes
      Sanchez-Ramos et al
      • Sanchez-Ramos L.
      • Kaunitz A.M.
      • Delke I.
      Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials.
      101339Any antenatal use (placebo controlled)Women at risk for PTB
      • (1) PTB < 37 wk
      • (2) Perinatal mortality
      PTB, preterm birth; PTL, preterm labor; RDS, respiratory distress syndrome; SPTB, spontaneous preterm birth.
      Tita. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol 2009.

      Pharmacologic aspects of progesterone

      The key pharmacologic aspects of progesterone in the reviewed studies are summarized in Table 3. Two types of progesterone predominate: natural and synthetic.
      TABLE 3Progesterone: pharmacologic types and protocols
      TypeRouteDose (mg)TimingReferences
      Synthetic 17PIM250Weekly from 16-20 wk
      • Rouse D.J.
      • Caritis S.N.
      • Peaceman A.
      • et al.
      A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      • Dodd J.M.
      • Crowther C.A.
      • Cincotta R.
      • Flenady V.
      • Robinson J.S.
      Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      IM341Twice weekly
      • Facchinetti F.
      • Paganelli S.
      • Comitini G.
      • Dante G.
      • Volpe A.
      Cervical length changes during preterm cervical ripening: effects of a 17-a-hydrosyprogesterone caproate.
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      IM250Thrice weekly
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      IM500Weekly
      • Dodd J.M.
      • Crowther C.A.
      • Cincotta R.
      • Flenady V.
      • Robinson J.S.
      Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.
      IM250Every 3 days from 28 wk
      • Dodd J.M.
      • Crowther C.A.
      • Cincotta R.
      • Flenady V.
      • Robinson J.S.
      Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.
      IM1000Weekly from 16 wk
      • Dodd J.M.
      • Crowther C.A.
      • Cincotta R.
      • Flenady V.
      • Robinson J.S.
      Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.
      IM25Every 5 days
      • Sanchez-Ramos L.
      • Kaunitz A.M.
      • Delke I.
      Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials.
      Natural progesteroneVaginal200Nightly, 24-33 wk
      • 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.
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      Vaginal400Daily, 18 wk to delivery
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      Vaginal100Daily capsules to 34 wk
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.B.
      • Zugaib 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.
      Vaginal90Daily, 18 wk to delivery
      • 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.
      Oral900-1600Daily, from onset of PTL
      • Coomarasamy A.
      • Thangaratinam S.
      • Gee H.
      • Khan K.S.
      Progesterone for the prevention of preterm birth: a critical evaluation of evidence.
      IM, intramuscular; PTL, preterm labor; 17P, 17-alpha-hydroxyprogesterone.
      Tita. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol 2009.

      Natural progesterone

      Almost exclusively administered vaginally, doses of natural progesterone ranged from 90-400 mg daily, initiated variably at 18-25 weeks (TABLE 2, TABLE 3). Only 1 metaanalysis included a study with oral (micronized) progesterone, and this was among women in preterm labor.
      • Coomarasamy A.
      • Thangaratinam S.
      • Gee H.
      • Khan K.S.
      Progesterone for the prevention of preterm birth: a critical evaluation of evidence.
      Compared with oral administration, vaginal progesterone bypasses hepatic first-pass effects and, therefore, has better bioavailability. Vaginal administration is virtually without side effects such as sleepiness, fatigue, and headache that can occur with oral use.
      • 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.
      • 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.
      Endometrial bioavailability after vaginal progesterone use is also reported to be higher than with the intramuscular (IM) route despite lower serum levels with the former.
      • 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.
      • Miles R.A.
      • Paulson R.J.
      • Lobo R.A.
      • Press M.F.
      • Dahmoush L.
      • Sauer M.V.
      Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study.
      This is attributed to direct transport of progesterone from vagina to the uterus: the so-called uterine first-pass effect.
      • Cicinelli E.
      • de Ziegler D.
      • Bulletti C.
      • Matteo M.G.
      • Schonauer L.M.
      • Galantino P.
      Direct transport of progesterone from vagina to uterus.

      Synthetic progesterone (17-alpha-hydroxyprogesterone)

      This synthetic progesterone was given exclusively by the IM route in variable doses (25-1000 mg) and schedules (weekly-thrice weekly). Side effects occur in the majority of patients (> 50%) but are mild and generally restricted to the injection site (injection site reaction, swelling, itching, bruising).
      • Rouse D.J.
      • Caritis S.N.
      • Peaceman A.
      • et al.
      A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      Follow-up (to an average age of 4 years) of children exposed to 17-alpha-hydroxyprogesterone (17P) as fetuses in the Meis trial did not suggest any long-term harmful effects including genital anomalies or alteration of gender-specific roles.
      • 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 alpha-hydroxyprogesterone caproate compared with placebo.

      Outcomes

      Individual clinical trials have focused on specific populations at increased risk for PTB such as those with a history of a spontaneous PTB (SPTB) or a short cervix (Table 1). Although other risk groups such as those with presumed cervical incompetence or uterine malformations were included in 1 trial,
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.B.
      • Zugaib 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.
      the overwhelming majority of women had a prior SPTB and we, therefore, considered the trial to be reflective of this latter risk group. Although some metaanalyses also stratified results by these risk factors (TABLE 4, TABLE 5), others presented summary results without regard to risk factors (Table 6).
      TABLE 4Selected perinatal outcomes among women with a history of spontaneous preterm birth: progesterone vs placebo
      StudyPTB
      GA cut-off given;
      wk: RR (95% CI)
      Perinatal death RR (95% CI)Neonatal death wk: RR (95% CI)Mean GA (wk)
      Actual mean GA or difference in mean GA (95% confidence interval [CI]) for progesterone use compared with placebo or no treatment;
      RDS wk: RR (95% CI)
      Dodd et al
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      • < 34: 0.15 (0.04-0.64)
        Results indicate statistical significance.
      • < 37: 0.68 (0.45-1.02)
      0.65 (0.38-1.11)0.44 (0.16-1.18)n/a0.79 (0.57-1.10)
      O'Brien et al
      • 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.
      • ≤ 32: 0.9 (0.52-1.56)
      • < 37: 1.08 (0.76-1.52)
      n/a0.87 (0.29-2.60)36.6 vs 36.60.91 (0.56-1.50)
      Mackenzie et al
      • 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.
      < 37: 0.57 (0.36-0.90)
      Results indicate statistical significance.
      0.39 (0.07-2.24)n/a+1.92 (0.37-4.21)
      Results indicate statistical significance.
      0.64 (0.39-1.07)
      Meis et al
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      • < 37: 0.66 (0.54-0.81)
        Results indicate statistical significance.
      • < 32: 0.58 (0.37-0.94)
        Results indicate statistical significance.
      0.64 (0.30-1.37)0.44 (0.17-1.13)n/a0.63 (0.38-1.05)
      da Fonseca et al
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.B.
      • Zugaib 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.
      < 37: 0.49 (0.25-0.96)
      Results indicate statistical significance.
      n/an/an/an/a
      CI, confidence interval; GA, gestational age; n/a, not available; PTB, preterm birth; RDS, respiratory distress syndrome.
      Except where indicated, all data represent relative risks (95% CI) that, when < 1, favor progesterone.
      Tita. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol 2009.
      a GA cut-off given;
      b Actual mean GA or difference in mean GA (95% confidence interval [CI]) for progesterone use compared with placebo or no treatment;
      c Results indicate statistical significance.
      TABLE 5Outcomes for progesterone vs placebo among other groups at risk for preterm birth
      Study/indicationPTB
      GA cut-off given;
      wk: RR (95% CI)
      Mean GA (wk)
      Difference in mean GA(respective mean GA) for progesterone use compared with placebo or no treatment;
      Perinatal death wk: RR (95% CI)Neonatal death wk: RR (95% CI)RDS wk: RR (95% CI)
      SHORT CERVIX
      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.
      < 34: 0.56 (0.36-0.86)
      Results indicate statistical significance.
      0.38 (0.10-1.38)0.29 (0.06-1.42)0.59 (0.26-1.29)
      DeFranco et al
      • 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.
       (< 28 mm)
      ≤ 32: 0 vs 29.6%
      Results indicate statistical significance.
      +1.7 (36.3 vs 34.6)n/a0 vs 3.7%0.18 (0.02-1.31)
      Dodd et al
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      < 34: 0.58 (0.38-0.87)
      Results indicate statistical significance.
      n/a0.38 (0.10-1.40)0.29 (0.06-1.37)0.59 (0.29-1.19)
      MULTIPLE
      Rouse et al
      • Rouse D.J.
      • Caritis S.N.
      • Peaceman A.
      • et al.
      A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.
      < 35: 1.1 (0.9-1.4)-0.3 (34.6 vs 34.9)n/an/a1.2 (0.8-1.6)
      Dodd et al
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth [review].
      < 37: 1.62 (0.81-3.25)n/a1.95 (0.37-10.33)n/an/a
      Dodd et al
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      < 37: 1.01 (0.92-1.12)1.95 (0.37-10.33)n/a1.13 (0.86-1.47)
      THREATENED PTB
      Borna and Sahabi
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.
      n/a+2 (36.7 vs 34.5)
      Results indicate statistical significance.
      n/an/a0.30 (0.11-0.83)
      Results indicate statistical significance.
      Facchinetti et al
      • Facchinetti F.
      • Paganelli S.
      • Comitini G.
      • Dante G.
      • Volpe A.
      Cervical length changes during preterm cervical ripening: effects of a 17-a-hydrosyprogesterone caproate.
      < 37: 0.29 (0.12-0.69)
      Results indicate statistical significance.
      n/an/an/an/a
      Dodd et al
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      < 37: 0.29 (0.12-0.69
      Results indicate statistical significance.
      n/an/an/a0.30 (0.11-0.83)
      Results indicate statistical significance.
      CI, confidence interval; GA, gestational age; n/a, not available; PTB, preterm birth; RDS, respiratory distress syndrome; RR, relative risk.
      Except where indicated, all data represent relative risks (95% confidence interval) that, when < 1, favor progesterone.
      Tita. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol 2009.
      a GA cut-off given;
      b Difference in mean GA (respective mean GA) for progesterone use compared with placebo or no treatment;
      c Results indicate statistical significance.
      TABLE 6Outcomes for progesterone vs placebo for metaanalyses without stratification by risk factors for preterm birth
      Study/indicationPTB
      GA cut-off given for progesterone use compared with placebo or no treatment;
      wk: RR (95% CI)
      Perinatal death RR (95% CI)Neonatal death wk: RR (95% CI)Mean GA (wk)RDS wk: RR (95% CI)
      Coomarasamy et al
      • Coomarasamy A.
      • Thangaratinam S.
      • Gee H.
      • Khan K.S.
      Progesterone for the prevention of preterm birth: a critical evaluation of evidence.
      • < 37: 0.42 (0.31-0.57)
        Results indicate statistical significance.
      • < 34: 0.51 (0.34-0.77)
        Results indicate statistical significance.
      n/an/an/a0.55 (0.31-0.96)
      Results indicate statistical significance.
      Dodd et al
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth [review].
      • < 37: 0.65 (0.54-0.79)
        Results indicate statistical significance.
      • < 34: 0.15 (0.04-0.64)
        Results indicate statistical significance.
      0.66 (0.37-1.19)0.59 (0.27-1.30)n/a0.63 (0.38-1.05)
      Dodd et al
      • Dodd J.M.
      • Crowther C.A.
      • Cincotta R.
      • Flenady V.
      • Robinson J.S.
      Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.
      < 37: 0.59 (0.49-0.72)
      Results indicate statistical significance.
      0.60 (0.32-1.12)0.44 (0.14-1.13)n/a0.63 (0.38-1.05)
      Sanchez-Ramos et al
      • Sanchez-Ramos L.
      • Kaunitz A.M.
      • Delke I.
      Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials.
      < 37: 0.45 (0.25-0.80)
      Results indicate statistical significance.
      0.69 (0.38-1.26)n/an/a0.83 (0.25-2.76)
      CI, confidence interval; GA, gestational age; n/a, not available; PTB, preterm birth; RDS, respiratory distress syndrome; RR, relative risk.
      Except where indicated, all data represent relative risks (95% confidence interval) that, when < 1, favor progesterone.
      Tita. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol 2009.
      a GA cut-off given for progesterone use compared with placebo or no treatment;
      b Results indicate statistical significance.

      History of SPTB

      Three clinical trials
      • 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.
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.B.
      • Zugaib 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.
      and 2 metaanalyses
      • 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.
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      evaluated the impact of prophylactic progesterone on women with a history of SPTB (Table 4). Two of 3 trials reported significant reductions in PTB on the order of 30-50%.
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.B.
      • Zugaib 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.
      Vaginal progesterone (100 mg) was used in 1 of these studies,
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.B.
      • Zugaib 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.
      whereas 250 mg of IM 17P was used in the other.
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      The third trial did not demonstrate a reduction in PTB with use of 90 mg of vaginal progesterone gel.
      • 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.
      Both relevant metaanalyses demonstrated significant reductions in PTB < 37 weeks and/or early PTB < 34 weeks and approximately a 30-40% reduction in low birthweight (LBW) < 2500 g.
      • 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.
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      On average, birthweight was 475 g higher in the progesterone group.
      • 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.
      RR for perinatal or neonatal death and respiratory distress syndrome (RDS), although not significant, were < 1 in all reports, suggesting progesterone may be associated with reduced risks of these outcomes. In addition, the US multicenter trial of 17P found significant reductions in necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH) (by 75%), and need for oxygen (by 38%)
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      ; 1 metaanalysis also reported trends suggesting reductions in NEC and need for ventilator support.
      • 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.

      Short cervix

      Two trials and 1 metaanalysis specifically evaluated the impact of progesterone on women with short cervices (Table 5). Both clinical trials reported significant reductions in measures of early 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.
      • 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.
      One trial primarily demonstrated a 45-50% reduction in early PTBs < 34 weeks among women with a foreshortened cervix who received 200 mg of vaginal progesterone.
      • 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 cervical length entry criterion was ≤ 15 mm, and using this criterion, 1.7% of screened women were eligible. Furthermore, progesterone was associated with a nonsignificant reduction in a composite neonatal morbidity outcome (comprising IVH, RDS, retinopathy of prematurity, and NEC: 0.59 RR (95% CI, 0.26-1.25).
      • 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 metaanalysis included only this 1 study evaluating women with a short cervix and, therefore, presents identical results.
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      The other trial,
      • 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.
      was not really an independent trial, but rather a subgroup analysis involving only 49 women with cervical length < 28 mm from another reviewed trail.
      • 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.
      It suggested a reduction in PTB at ≤ 32 weeks but not in overall PTB < 37 weeks among those receiving 90 mg of vaginal progesterone compared with those on placebo. Because this cervical length criterion was generated post hoc, the results of this subgroup analysis should be viewed cautiously.

      Multiple pregnancies

      One clinical trial
      • Rouse D.J.
      • Caritis S.N.
      • Peaceman A.
      • et al.
      A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.
      and 2 metaanalyses
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth [review].
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      reported the impact on twin pregnancy (Table 5). The relatively large clinical trial using 250 mg of IM 17P found no impact on the composite primary outcome of early PTB < 35 weeks or stillbirth, early PTB alone, or any of several morbidities including RDS.
      • Rouse D.J.
      • Caritis S.N.
      • Peaceman A.
      • et al.
      A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.
      The 2 metaanalyses together included only 2 trials (including the above) of progesterone for the prevention of PTB in multiple gestation, and found no impact on either PTB or perinatal morbidity or mortality.
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth [review].
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      Both these studies involved IM progesterone in unselected multiple pregnancies. A subgroup analysis of the positive trial of vaginal progesterone (200 mg) among women with a foreshortened cervix by the plurality of their pregnancy yielded a significant reduction in PTB < 34 weeks among singletons but a nonsignificant reduction among twins. This lack of a significant reduction in twins could be either a result of a true lack of effectiveness in this group, or alternatively, inadequate statistical power.

      Arrested preterm labor

      As shown in Table 5, only 2 clinical trials
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.
      • Facchinetti F.
      • Paganelli S.
      • Comitini G.
      • Dante G.
      • Volpe A.
      Cervical length changes during preterm cervical ripening: effects of a 17-a-hydrosyprogesterone caproate.
      and 1 metaanalysis
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.
      reported on the use of progesterone for arrested preterm labor. One clinical trial involved 70 women with arrested preterm labor who received vaginal progesterone (400 mg daily).
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.
      The primary outcome of mean latency to delivery was significantly longer in the progesterone group by approximately 12 days (36 vs 24 days), corresponding to higher mean gestational age and birthweight at delivery of more than 2 weeks and 500 g, respectively. Progesterone also significantly reduced the risk of LBW (RR, 0.52; 95% CI, 0.28-0.98) and RDS (RR, 0.30; 95% CI, 0.11-0.83).
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.
      In addition, recurrent preterm labor occurred less often in the progesterone group (35% vs 58%), as did neonatal intensive care department admission (24% vs 39%) and neonatal sepsis (5% vs 18%). The second trial involved twice-weekly administration of 341 mg of 17P (vs no treatment) to 60 women with singleton pregnancy and arrested preterm labor.
      • Facchinetti F.
      • Paganelli S.
      • Comitini G.
      • Dante G.
      • Volpe A.
      Cervical length changes during preterm cervical ripening: effects of a 17-a-hydrosyprogesterone caproate.
      PTB was significantly lower (Table 5), time to delivery nearly 10 days longer (35 vs 25 days), and mean birthweight approximately 300 g higher (3103 vs 2809 g) in the progesterone group. The difference in PTB < 35 weeks (10% vs 23%) was not statistically significant (RR, 0.43; 95% CI, 0.12-1.5) but cervical shortening was significantly attenuated among women receiving progesterone. Together with their small sample sizes the major limitation of these trials was the lack of blinding. The reviewed metaanalysis included only these 2 trials and, therefore, reflected their findings.
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth.

      Combined outcomes (without stratification by risk factors)

      A total of 4 metaanalyses presented overall results without stratifying by specific risk population (Table 6).
      • Sanchez-Ramos L.
      • Kaunitz A.M.
      • Delke I.
      Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials.
      • Dodd J.M.
      • Crowther C.A.
      • Cincotta R.
      • Flenady V.
      • Robinson J.S.
      Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth [review].
      • Coomarasamy A.
      • Thangaratinam S.
      • Gee H.
      • Khan K.S.
      Progesterone for the prevention of preterm birth: a critical evaluation of evidence.
      The findings revealed a consistent significant reduction in PTB and early PTB corresponding to a 40-50% reduction in LBW. Perinatal or neonatal mortality and RDS were also consistently reduced, albeit nonsignificantly. Based on the Meis trial alone, 2 metaanalyses also reported a significant 75% reduction in IVH
      • Dodd J.M.
      • Crowther C.A.
      • Cincotta R.
      • Flenady V.
      • Robinson J.S.
      Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth [review].
      and 1 reported a reduction in NEC.
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth [review].
      Evaluation by commencement of treatment before or after 20 weeks and by cumulative weekly dose of progesterone > 500 mg or < 500 mg (without regard to route) did not reveal any differential impact.
      • Dodd J.M.
      • Flenady V.
      • Cincotta R.
      • Crowther C.A.
      Prenatal administration of progesterone for preventing preterm birth [review].
      Cumulative metaanalysis by progressively adding trials from the earliest to the more recent showed significant reductions in birth < 37 weeks as early as 1975.
      • Coomarasamy A.
      • Thangaratinam S.
      • Gee H.
      • Khan K.S.
      Progesterone for the prevention of preterm birth: a critical evaluation of evidence.
      This latter metaanalysis was limited by the inclusion of data on women who received progesterone for habitual abortion.
      • Coomarasamy A.
      • Thangaratinam S.
      • Gee H.
      • Khan K.S.
      Progesterone for the prevention of preterm birth: a critical evaluation of evidence.

      National recommendation/guidelines

      We reviewed 3 reports providing recommendations or guidelines from both ACOG and SOGC.
      American College of Obstetricians and Gynecologist
      Use of progesterone to reduce preterm birth: ACOG committee opinion No. 2919.
      • Farine D.
      • Mundle W.R.
      • Dodd J.
      The use of progesterone for prevention of preterm birth.
      American College of Obstetricians and Gynecologist
      Use of progesterone to reduce preterm birth: ACOG committee opinion No. 419.
      ACOG recommends that progesterone supplementation be offered to women with a prior SPTB to prevent recurrent PTB.
      American College of Obstetricians and Gynecologist
      Use of progesterone to reduce preterm birth: ACOG committee opinion No. 2919.
      ACOG has just reaffirmed this position specifically for women with a current singleton pregnancy, and further recommends that progesterone may be considered for women with an incidentally discovered shortened cervix (< 15 mm) but recommends against routine ultrasonographic screening to identify a shortened cervix.
      American College of Obstetricians and Gynecologist
      Use of progesterone to reduce preterm birth: ACOG committee opinion No. 419.
      The SOGC recommends further clinical trials of progesterone for all women at risk for PTB.
      • Farine D.
      • Mundle W.R.
      • Dodd J.
      The use of progesterone for prevention of preterm birth.
      However, they also recommend that women with a prior SPTB or with a short cervix (< 15 mm) be counseled and offered progesterone supplementation if desired. Both organizations recognize the need for further studies to determine the optimal dose and route of progesterone, and the impact of progesterone on perinatal morbidity and mortality.

      Conclusions

      Taken together, the reviewed data strongly suggest that prophylactic use of progesterone leads to significant reductions in measures of PTB and LBW. The data also suggest, but less conclusively, that progesterone may confer neonatal morbidity and mortality benefit. However, the benefit of progesterone may vary by risk group, route of administration, and dose. Therefore, additional research is needed to clarify these issues. For now, when progesterone is used for PTB prevention, the following approach would appear rational based on the available data: (1) for women with a prior SPTB, weekly IM 17P (250 mg) initiated at 16-20 weeks, or daily vaginal progesterone (at least 100 mg) beginning before week 24 should be given; (2) for women with a short cervix (≤ 15 mm), 200 mg of vaginal progesterone suppositories may be reasonable, although only 1 properly conducted and analyzed trial supports such an approach; (3) for women with a twin pregnancy, progesterone is not routinely indicated, although its use may be prudent in the specific scenarios of a prior SPTB (250 mg 17P IM) or significantly (≤ 15 mm) foreshortened cervix (200 mg suppository vaginally); and (4) for women with arrested preterm labor, progesterone (400 mg daily vaginal suppository or 341 mg 17P IM twice weekly) may be considered but the available data are seriously limited by lack of blinding. It is encouraging that there are multiple ongoing trials that should further clarify the role of progesterone in PTB prevention.

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