Progesterone for preterm birth prevention: an evolving intervention
2009; Elsevier BV; Volume: 200; Issue: 3 Linguagem: Inglês
10.1016/j.ajog.2008.12.035
ISSN1097-6868
AutoresAlan T. Tita, Dwight J. Rouse,
Tópico(s)Maternal and Perinatal Health Interventions
ResumoWe 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. 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. 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.1Goldenberg R.L. Culhane J.F. Iams J.D. Romero R. Epidemiology and causes of preterm birth.Lancet. 2008; 371: 75-84Abstract Full Text Full Text PDF PubMed Scopus (5297) Google Scholar, 2Moster D. Lie R.T. Markestad T. Long-term medical and social consequences of preterm birth.N Engl J Med. 2008; 359: 262-273Crossref PubMed Scopus (1043) Google Scholar Overall, PTB accounts for up to 12.7% of births in the developed world; the vast majority of these (∼ 75%) occur spontaneously.1Goldenberg R.L. Culhane J.F. Iams J.D. Romero R. Epidemiology and causes of preterm birth.Lancet. 2008; 371: 75-84Abstract Full Text Full Text PDF PubMed Scopus (5297) Google Scholar, 3Martin 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.Natl Vital Stat Rep. 2007; 56: 1-103PubMed Google Scholar 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.4American College of Obstetricians and GynecologistUse of progesterone to reduce preterm birth: ACOG committee opinion No. 2919.Obstet Gynecol. 2003; 102: 1115-1116Crossref PubMed Scopus (87) Google Scholar 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 studies4American College of Obstetricians and GynecologistUse of progesterone to reduce preterm birth: ACOG committee opinion No. 2919.Obstet Gynecol. 2003; 102: 1115-1116Crossref PubMed Scopus (87) Google Scholar, 5Farine D. Mundle W.R. Dodd J. The use of progesterone for prevention of preterm birth.J Obstet Gynaecol Can. 2008; 30: 67-71Abstract Full Text PDF PubMed Scopus (46) Google Scholar 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 For Editors' Commentary, see Table of Contents 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,6Borna S. Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.Aust N Z J Obstet Gynaecol. 2008; 48: 58-63Crossref PubMed Scopus (97) Google Scholar, 7Rouse D.J. Caritis S.N. Peaceman A. et al.A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.N Engl J Med. 2007; 357: 454-461Crossref PubMed Scopus (317) Google Scholar, 8Fonseca E.B. Celik E. Parra M. Singh M. Nicolaides K.H. Progesterone and the risk of preterm birth among women with a short cervix.N Engl J Med. 2007; 357: 462-469Crossref PubMed Scopus (848) Google Scholar, 9O'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.Ultrasound Obstet Gynecol. 2007; 30: 687-696Crossref PubMed Scopus (239) Google Scholar, 10DeFranco 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.Ultrasound Obstet Gynecol. 2007; 30: 697-705Crossref PubMed Scopus (211) Google Scholar, 11Facchinetti F. Paganelli S. Comitini G. Dante G. Volpe A. Cervical length changes during preterm cervical ripening: effects of a 17-a-hydrosyprogesterone caproate.Am J Obstet Gynecol. 2007; 196: 453.e1-453.e4Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 12Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1328) Google Scholar, 13da 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.Am J Obstet Gynecol. 2003; 188: 419-424Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar 6 metaanalyses,14Sanchez-Ramos L. Kaunitz A.M. Delke I. Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials.Am J Obstet Gynecol. 2005; 105: 273-279Crossref Scopus (144) Google Scholar, 15Dodd J.M. Crowther C.A. Cincotta R. Flenady V. Robinson J.S. Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.Acta Obstet Gynecol Scand. 2005; 84: 526-533Crossref PubMed Google Scholar, 16Dodd J.M. Flenady V. Cincotta R. Crowther C.A. Prenatal administration of progesterone for preventing preterm birth [review].Cochrane Database Syst Rev. 2006; 2 (CD004947)Crossref Google Scholar, 17Mackenzie 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.Am J Obstet Gynecol. 2006; 194: 1234-1242Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 18Coomarasamy A. Thangaratinam S. Gee H. Khan K.S. Progesterone for the prevention of preterm birth: a critical evaluation of evidence.Eur J Obstet Gynecol Reprod Biol. 2006; 129: 111-118Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 19Dodd J.M. Flenady V.J. Cincotta R. Crowther C.A. Progesterone for the prevention of preterm birth.Obstet Gynecol. 2008; 112: 127-134Crossref PubMed Scopus (109) Google Scholar and 3 reports of national recommendations or guidelines.4American College of Obstetricians and GynecologistUse of progesterone to reduce preterm birth: ACOG committee opinion No. 2919.Obstet Gynecol. 2003; 102: 1115-1116Crossref PubMed Scopus (87) Google Scholar, 5Farine D. Mundle W.R. Dodd J. The use of progesterone for prevention of preterm birth.J Obstet Gynaecol Can. 2008; 30: 67-71Abstract Full Text PDF PubMed Scopus (46) Google Scholar, 20American College of Obstetricians and GynecologistUse of progesterone to reduce preterm birth: ACOG committee opinion No. 419.Obstet Gynecol. 2008; 112: 963Crossref PubMed Google Scholar 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. Among the 8 clinical trials identified,6Borna S. Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.Aust N Z J Obstet Gynaecol. 2008; 48: 58-63Crossref PubMed Scopus (97) Google Scholar, 7Rouse D.J. Caritis S.N. Peaceman A. et al.A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.N Engl J Med. 2007; 357: 454-461Crossref PubMed Scopus (317) Google Scholar, 8Fonseca E.B. Celik E. Parra M. Singh M. Nicolaides K.H. Progesterone and the risk of preterm birth among women with a short cervix.N Engl J Med. 2007; 357: 462-469Crossref PubMed Scopus (848) Google Scholar, 9O'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.Ultrasound Obstet Gynecol. 2007; 30: 687-696Crossref PubMed Scopus (239) Google Scholar, 10DeFranco 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.Ultrasound Obstet Gynecol. 2007; 30: 697-705Crossref PubMed Scopus (211) Google Scholar, 11Facchinetti F. Paganelli S. Comitini G. Dante G. Volpe A. Cervical length changes during preterm cervical ripening: effects of a 17-a-hydrosyprogesterone caproate.Am J Obstet Gynecol. 2007; 196: 453.e1-453.e4Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 12Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1328) Google Scholar, 13da 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.Am J Obstet Gynecol. 2003; 188: 419-424Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar 1 was a subgroup analysis of another included trial.10DeFranco 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.Ultrasound Obstet Gynecol. 2007; 30: 697-705Crossref PubMed Scopus (211) Google Scholar 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.4American College of Obstetricians and GynecologistUse of progesterone to reduce preterm birth: ACOG committee opinion No. 2919.Obstet Gynecol. 2003; 102: 1115-1116Crossref PubMed Scopus (87) Google Scholar, 5Farine D. Mundle W.R. Dodd J. The use of progesterone for prevention of preterm birth.J Obstet Gynaecol Can. 2008; 30: 67-71Abstract Full Text PDF PubMed Scopus (46) Google Scholar, 20American College of Obstetricians and GynecologistUse of progesterone to reduce preterm birth: ACOG committee opinion No. 419.Obstet Gynecol. 2008; 112: 963Crossref PubMed Google Scholar 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 2000StudyDesignSample SizeProgesterone interventionPopulation (indication)Primary outcome(s)Borna and Sahabi6Borna S. Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.Aust N Z J Obstet Gynaecol. 2008; 48: 58-63Crossref PubMed Scopus (97) Google ScholarRCT (no placebo)70400 mg vaginal suppository dailyArrested (threatened) PTL(1) Latency (days)(2) Recurrence of PTLO'Brien et al9O'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.Ultrasound Obstet Gynecol. 2007; 30: 687-696Crossref PubMed Scopus (239) Google ScholarRCT (placebo controlled)65990 mg vaginal gelPrior SPTB, 18-22 wkPTB ≤ 32 wkFonseca et al8Fonseca E.B. Celik E. Parra M. Singh M. Nicolaides K.H. Progesterone and the risk of preterm birth among women with a short cervix.N Engl J Med. 2007; 357: 462-469Crossref PubMed Scopus (848) Google ScholarRCT (placebo controlled)250200 mg vaginal capsule daily until 34 wkShort cervix ≤ 15 mm at 20-25 wkSpontaneous PTB < 34 wkRouse et al7Rouse D.J. Caritis S.N. Peaceman A. et al.A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.N Engl J Med. 2007; 357: 454-461Crossref PubMed Scopus (317) Google ScholarRCT (placebo controlled661250 mg 17P IM until 35 wkTwins at 16-20 wk(1) PTB < 35 wk or IUFD < 35 wkFacchinetti et al11Facchinetti F. Paganelli S. Comitini G. Dante G. Volpe A. Cervical length changes during preterm cervical ripening: effects of a 17-a-hydrosyprogesterone caproate.Am J Obstet Gynecol. 2007; 196: 453.e1-453.e4Abstract Full Text Full Text PDF PubMed Scopus (120) Google ScholarRCT (no placebo)60341 mg 17P IM twice weeklyArrested PTLChange in cervical lengthMeis et al12Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1328) Google ScholarRCT (placebo controlled)463250 mg 17P IM weeklyPrior SPTB, 16 wkPTB < 37 wkda Fonseca et al13da 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.Am J Obstet Gynecol. 2003; 188: 419-424Abstract Full Text Full Text PDF PubMed Scopus (653) Google ScholarRCT (placebo controlled)142100 mg daily vaginal suppository until 34 wkPrior SPTB, 24 wk onwardPTB < 37 wkIM, 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. Open table in a new tab TABLE 2Metaanalyses of clinical trials of progesterone for preterm birth prevention since 2000StudyNo. of trialsNo. of women (infants)Progesterone interventionPopulation (indication)Primary outcome(s)Dodd et al19Dodd J.M. Flenady V.J. Cincotta R. Crowther C.A. Progesterone for the prevention of preterm birth.Obstet Gynecol. 2008; 112: 127-134Crossref PubMed Scopus (109) Google Scholar112425 (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 handicapCoomarasamy et al18Coomarasamy A. Thangaratinam S. Gee H. Khan K.S. Progesterone for the prevention of preterm birth: a critical evaluation of evidence.Eur J Obstet Gynecol Reprod Biol. 2006; 129: 111-118Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar9 (cumulative metaanalysis)> 1062Any antenatal use(1) Risk factors for PTB excluding multiples(1) PTB < 37 wk(2) PTB < 34 wk(3) RDSMackenzie et al17Mackenzie 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.Am J Obstet Gynecol. 2006; 194: 1234-1242Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar3648Second-trimester use(1) Increased risk for SPTBPTB < 37 wkDodd et al16Dodd J.M. Flenady V. Cincotta R. Crowther C.A. Prenatal administration of progesterone for preventing preterm birth [review].Cochrane Database Syst Rev. 2006; 2 (CD004947)Crossref Google Scholar6988Any antenatal useAny pregnancy(1) Perinatal death(2) PTB < 34 wk(3) Neurodevelopmental handicapDodd et al15Dodd J.M. Crowther C.A. Cincotta R. Flenady V. Robinson J.S. Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.Acta Obstet Gynecol Scand. 2005; 84: 526-533Crossref PubMed Google Scholar71020Any antenatal useSingletonsMultiple adverse infant and maternal outcomesSanchez-Ramos et al14Sanchez-Ramos L. Kaunitz A.M. Delke I. Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials.Am J Obstet Gynecol. 2005; 105: 273-279Crossref Scopus (144) Google Scholar101339Any antenatal use (placebo controlled)Women at risk for PTB(1) PTB < 37 wk(2) Perinatal mortalityPTB, 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. Open table in a new tab 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. 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. 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 protocolsTypeRouteDose (mg)TimingReferencesSynthetic 17PIM250Weekly from 16-20 wk7Rouse D.J. Caritis S.N. Peaceman A. et al.A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.N Engl J Med. 2007; 357: 454-461Crossref PubMed Scopus (317) Google Scholar, 12Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1328) Google Scholar, 15Dodd J.M. Crowther C.A. Cincotta R. Flenady V. Robinson J.S. Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.Acta Obstet Gynecol Scand. 2005; 84: 526-533Crossref PubMed Google Scholar, 19Dodd J.M. Flenady V.J. Cincotta R. Crowther C.A. Progesterone for the prevention of preterm birth.Obstet Gynecol. 2008; 112: 127-134Crossref PubMed Scopus (109) Google ScholarIM341Twice weekly11Facchinetti F. Paganelli S. Comitini G. Dante G. Volpe A. Cervical length changes during preterm cervical ripening: effects of a 17-a-hydrosyprogesterone caproate.Am J Obstet Gynecol. 2007; 196: 453.e1-453.e4Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 19Dodd J.M. Flenady V.J. Cincotta R. Crowther C.A. Progesterone for the prevention of preterm birth.Obstet Gynecol. 2008; 112: 127-134Crossref PubMed Scopus (109) Google ScholarIM250Thrice weekly19Dodd J.M. Flenady V.J. Cincotta R. Crowther C.A. Progesterone for the prevention of preterm birth.Obstet Gynecol. 2008; 112: 127-134Crossref PubMed Scopus (109) Google ScholarIM500Weekly15Dodd J.M. Crowther C.A. Cincotta R. Flenady V. Robinson J.S. Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.Acta Obstet Gynecol Scand. 2005; 84: 526-533Crossref PubMed Google ScholarIM250Every 3 days from 28 wk15Dodd J.M. Crowther C.A. Cincotta R. Flenady V. Robinson J.S. Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.Acta Obstet Gynecol Scand. 2005; 84: 526-533Crossref PubMed Google ScholarIM1000Weekly from 16 wk15Dodd J.M. Crowther C.A. Cincotta R. Flenady V. Robinson J.S. Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.Acta Obstet Gynecol Scand. 2005; 84: 526-533Crossref PubMed Google ScholarIM25Every 5 days14Sanchez-Ramos L. Kaunitz A.M. Delke I. Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials.Am J Obstet Gynecol. 2005; 105: 273-279Crossref Scopus (144) Google ScholarNatural progesteroneVaginal200Nightly, 24-33 wk8Fonseca E.B. Celik E. Parra M. Singh M. Nicolaides K.H. Progesterone and the risk of preterm birth among women with a short cervix.N Engl J Med. 2007; 357: 462-469Crossref PubMed Scopus (848) Google Scholar, 19Dodd J.M. Flenady V.J. Cincotta R. Crowther C.A. Progesterone for the prevention of preterm birth.Obstet Gynecol. 2008; 112: 127-134Crossref PubMed Scopus (109) Google ScholarVaginal400Daily, 18 wk to delivery6Borna S. Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.Aust N Z J Obstet Gynaecol. 2008; 48: 58-63Crossref PubMed Scopus (97) Google Scholar, 19Dodd J.M. Flenady V.J. Cincotta R. Crowther C.A. Progesterone for the prevention of preterm birth.Obstet Gynecol. 2008; 112: 127-134Crossref PubMed Scopus (109) Google ScholarVaginal100Daily capsules to 34 wk13da 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.Am J Obstet Gynecol. 2003; 188: 419-424Abstract Full Text Full Text PDF PubMed Scopus (653) Google ScholarVaginal90Daily, 18 wk to delivery9O'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.Ultrasound Obstet Gynecol. 2007; 30: 687-696Crossref PubMed Scopus (239) Google ScholarOral900-1600Daily, from onset of PTL18Coomarasamy A. Thangaratinam S. Gee H. Khan K.S. Progesterone for the prevention of preterm birth: a critical evaluation of evidence.Eur J Obstet Gynecol Reprod Biol. 2006; 129: 111-118Abstract Full Text Full Text PDF PubMed Scopus (39) Google ScholarIM, intramuscular; PTL, preterm labor; 17P, 17-alpha-hydroxyprogesterone.Tita. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol 2009. Open table in a new tab IM, intramuscular; PTL, preterm labor; 17P, 17-alpha-hydroxyprogesterone. Tita. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol 2009. 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.18Coomarasamy A. Thangaratinam S. Gee H. Khan K.S. Progesterone for the prevention of preterm birth: a critical evaluation of evidence.Eur J Obstet Gynecol Reprod Biol. 2006; 129: 111-118Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar 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.8Fonseca E.B. Celik E. Parra M. Singh M. Nicolaides K.H. Progesterone and the risk of preterm birth among women with a short cervix.N Engl J Med. 2007; 357: 462-469Crossref PubMed Scopus (848) Google Scholar, 9O'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.Ultrasound Obstet Gynecol. 2007; 30: 687-696Crossref PubMed Scopus (239) Google Scholar 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.9O'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.Ultrasound Obstet Gynecol. 2007; 30: 687-696Crossref PubMed Scopus (239) Google Scholar, 21Miles 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.Fertil Steril. 1994; 62: 485-490Abstract Full Text PDF PubMed Google Scholar This is attributed to direct transport of progesterone from vagina to the uterus: the so-called uterine first-pass effect.22Cicinelli E. de Ziegler D. Bulletti C. Matteo M.G. Schonauer L.M. Galantino P. Direct transport of progesterone from vagina to uterus.Obstet Gynecol. 2000; 95: 403-406Crossref PubMed Scopus (209) Google Scholar 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).7Rouse D.J. Caritis S.N. Peaceman A. et al.A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.N Engl J Med. 2007; 357: 454-461Crossref PubMed Scopus (317) Google Scholar, 12Meis P.J. Klebanoff M. Thom E. et al.Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385Crossref PubMed Scopus (1328) Google Scholar 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.23Northen 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.Obstet Gynecol. 2007; 110: 865-872Crossref PubMed Scopus (106) Google Scholar 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,13da 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.Am J Obstet Gynecol. 2003; 188: 419-424Abstract Fu
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