Ultrasound Obstet Gynecol 2014; 43: 596–599 Published online 7 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
Letters to the Editor
Re-analysis of the PREGNANT trial confirms that vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix Two randomized controlled trials reported that vaginal progesterone reduces preterm birth in women with a short cervix1,2 . Progesterone use in women with a midtrimester cervical length of 10–20 mm was associated with reduced preterm birth < 33 weeks and respiratory distress syndrome (RDS). Results of the PREGNANT trial2 were reviewed by the US Food and Drug Administration (FDA) for a New Drug Application. The FDA subsequently issued a document concluding that the data ‘[did] not support the efficacy of progesterone gel.’3 . Given the discrepancy between the FDA findings and the PREGNANT trial, the PREGNANT principal investigator provided the original data and requested an independent re-analysis of the PREGNANT trial, which is reported here. Methodological details are supplied in the supporting information online (Appendix S1). Table S1 describes baseline demographic and treatment characteristics of 458 women randomized to receive progesterone (n = 235) or placebo (n = 223). These 458 women comprised the intention-to-treat (ITT) analysis set. Women allocated to progesterone had a significantly lower rate of preterm birth < 33 weeks than women
administered placebo (8.9% vs 16.1%; relative risk (RR) = 0.55 (95% CI, 0.33–0.92), P = 0.02), even after adjustment for study site and risk strata (RR = 0.54 (95% CI, 0.33–0.89), P = 0.01). The progesterone group also experienced significantly fewer preterm births < 28 weeks and < 35 weeks (Table 1). Neonates in the progesterone group experienced significantly less RDS than those born to mothers given placebo, an effect that persisted after adjustment (RR = 0.40 (95% CI, 0.17–0.94), P = 0.03). The unadjusted risk for any morbidity/mortality event was significantly lower in neonates born to mothers in the progesterone group (RR = 0.57 (95% CI, 0.33–0.99), P = 0.04), as were composite morbidity/mortality scores ‘0–4 scale without NICU’ and ‘0–6 scale without NICU’ (both P = 0.05). Progesterone therapy was associated with a significant reduction in birth weight < 1500 g (RR = 0.47 (95% CI, 0.26–0.85), P = 0.01). Results for all neonatal outcomes are given in Table 1. Logistic regression for preterm birth < 33 weeks in the ITT analysis controlled for pooled study site and other risk factors, but the effect of treatment remained essentially unchanged (odds ratio = 0.48 (95% CI, 0.25–0.91), P = 0.02). Results of the ‘treated-patient analysis set’ and ‘compliant analysis set’ are reported in Tables S2 and S3.
Table 1 Primary and secondary outcomes in progesterone-treated (n = 235) and placebo (n = 233) patients; intent-to-treat analysis set
Outcome Primary outcome Preterm birth < 33 weeks Secondary outcomes Preterm birth < 28 weeks Preterm birth < 35 weeks Preterm birth < 37 weeks Respiratory distress syndrome Bronchopulmonary dysplasia Proven sepsis Necrotizing enterocolitis Intraventricular hemorrhage, Grade III/IV Periventricular leukomalacia Perinatal death Fetal death Neonatal death Composite outcome scores Any morbidity/mortality event 0–4 without NICU 0–4 with NICU 0–6 without NICU Birth weight < 2500 g Birth weight < 1500 g
Vaginal progesterone Placebo group Relative risk group (n (%)) (n (%)) (95% CI)*
P
Adjusted RR (95% CI)‡
P
21/235 (8.9)
36/223 (16.1)
0.55 (0.33–0.92)
0.020 0.54 (0.33–0.89)
0.013
12/235 (5.1) 34/235 (14.5) 71/235 (30.2) 7/235 (3.0) 4/235 (1.7) 7/235 (3.0) 5/235 (2.1) 0/235 (0.0) 0/235 (0.0) 8/235 (3.4) 5/235 (2.1) 3/235 (1.3)
23/223 (10.3) 52/223 (23.3) 76/223 (34.1) 17/223 (7.6) 5/223 (2.2) 6/223 (2.7) 4/223 (1.8) 1/223 (0.4) 0/223 (0.0) 11/223 (4.9) 6/223 (2.7) 5/223 (2.2)
0.50 (0.25–0.97) 0.62 (0.42–0.92) 0.89 (0.68–1.16) 0.39 (0.17–0.92) 0.76 (0.21–2.79) 1.11 (0.38–3.24) 1.19 (0.32–4.36) 0.32 (0.01–7.73)† Not estimable 0.69 (0.28–1.68) 0.79 (0.24–2.55) 0.57 (0.14–2.35)
0.036 0.016 0.376 0.026 0.678 0.853 0.797 0.305 NA 0.413 0.694 0.431
0.044 0.007 0.304 0.029 0.746 0.758 0.763 0.317 NA 0.447 0.740 0.441
18/235 (7.7)
30/223 (13.5)
0.57 (0.33–0.99)
60/234 (25.6) 15/234 (6.4)
68/220 (30.9) 30/220 (13.6)
0.83 (0.62–1.11) 0.47 (0.26–0.85)
0.043 0.59 (0.34–1.02) 0.048 0.068 0.048 0.213 0.83 (0.62–1.11) 0.010 0.49 (0.28–0.87)
0.51 (0.27–1.00) 0.59 (0.40–0.87) 0.87 (0.67–1.13) 0.40 (0.17–0.94) 0.81 (0.23–2.90) 1.18 (0.40–3.47) 1.21 (0.34–4.31) 0.33 (0.01–7.80)† Not estimable 0.71 (0.29–1.75) 0.82 (0.25–2.70) 0.58 (0.14–2.38)
0.054 0.065 0.069 0.065 0.203 0.013
*Unadjusted relative risks (RR) and 95% CI calculated using the Cochran–Mantel–Haenszel (CMH) test. †Based on logit estimator with continuity correction. ‡Adjusted RR and 95% CI calculated using CMH test, adjusted for pooled study site and risk strata. Note, adjusted RRs were not reported in the original table reported by the PREGNANT trial. NICU, neonatal intensive care unit.
Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.
LETTERS TO THE EDITOR
Letters to the Editor
597
Re-analysis of the PREGNANT trial by independent academic investigators has replicated in every respect the original results2 , which are also consistent with an individual patient data meta-analysis based on five randomized trials including PREGNANT4 . We calculate the risk difference (RD) in the meta-analysis for early preterm delivery to be RD = −0.09 (95% CI, −0.14 to 0.04), with number needed to treat = 11 (95% CI, 7–25). One observation in the FDA report merits further comment5 . The Cochran–Mantel–Haenszel (CMH) test used in the original analysis2 was considered inappropriate owing to ‘insufficient sample size’ in each stratum and ‘inconsistent treatment effects among strata’5 . We disagree. The CMH test in SAS used by us is equivalent to the Mantel–Haenszel conditional test, both providing identical results and a valid stratified analysis even when sample sizes within strata are small6 . Given the persistently high prevalence of preterm delivery, there is substantial evidence that administration of vaginal progesterone to women with an asymptomatic sonographic short cervix promises considerable public health benefit.
Acknowledgments This study was performed through subcontract N01HD23342 between Wayne State University and Yale University, funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. We are grateful to Livia Kidd for technical assistance in the preparation of this manuscript. The authors declare no conflicts of interest. L. A. McKay†‡, T. R. Holford†‡ and M. B. Bracken*†‡§ †Yale School of Public Health, New Haven, CT, USA; ‡Yale Center for Perinatal, Pediatric and Environmental Epidemiology, New Haven, CT, USA; §School of Medicine, Yale University, New Haven, CT, USA *Correspondence. (e-mail: [email protected])
3. NDA 022139, Progesterone gel 8% (Background Document for Meeting of Advisory Committee for Reproductive Health Drugs). Prepared by the Division of Reproductive and Urologic Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration. December 22, 2011. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugs AdvisoryCommittee/UCM287987.pdf. 4. Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O’Brien JM, Cetingoz E, Da Fonseca E, Creasy GW, Klein K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, Hassan SS. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012; 206: 124.e1–19. 5. NDA 22–139 for Progesterone Gel 8% (Briefing Materials for Advisory Committee for Reproductive Health Drugs). Prepared by Columbia Laboratories, Inc. December 15, 2011. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/Committe esMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisory Committee/UCM287988.pdf. 6. Holford TR. Multivariate Methods in Epidemiology. Oxford University Press: Oxford, 2002; 66.
SUPPORTING INFORMATION ON THE INTERNET The following supporting information may be found in the online version of this article: Appendix S1 Details of the methodology used to re-analyze data from the PREGNANT trial, additional results and supplementary references Table S1 Baseline and treatment characteristics of the population (n = 458) Table S2 Primary and secondary outcomes in progesterone (n = 235) and placebo (n = 224) patients; treated patient analysis set Table S3 Primary and secondary outcomes in progesterone (n = 194) and placebo (n = 193) patients; compliant analysis set
DOI: 10.1002/uog.13331
References 1. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007; 357: 462–469. 2. Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, Vijayaraghavan J, Trivedi Y, Soma-Pillay P, Sambarey P, Dayal A, Potapov V, O’Brien J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H, Mazheika L, Manchulenko D, Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011; 38: 18–31.
Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.
Ultrasound Obstet Gynecol 2014; 43: 596–599.
Letters to the Editor
Re-analysis of the PREGNANT trial confirms that vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix Two randomized controlled trials reported that vaginal progesterone reduces preterm birth in women with a short cervix1,2 . Progesterone use in women with a midtrimester cervical length of 10–20 mm was associated with reduced preterm birth < 33 weeks and respiratory distress syndrome (RDS). Results of the PREGNANT trial2 were reviewed by the US Food and Drug Administration (FDA) for a New Drug Application. The FDA subsequently issued a document concluding that the data ‘[did] not support the efficacy of progesterone gel.’3 . Given the discrepancy between the FDA findings and the PREGNANT trial, the PREGNANT principal investigator provided the original data and requested an independent re-analysis of the PREGNANT trial, which is reported here. Methodological details are supplied in the supporting information online (Appendix S1). Table S1 describes baseline demographic and treatment characteristics of 458 women randomized to receive progesterone (n = 235) or placebo (n = 223). These 458 women comprised the intention-to-treat (ITT) analysis set. Women allocated to progesterone had a significantly lower rate of preterm birth < 33 weeks than women
administered placebo (8.9% vs 16.1%; relative risk (RR) = 0.55 (95% CI, 0.33–0.92), P = 0.02), even after adjustment for study site and risk strata (RR = 0.54 (95% CI, 0.33–0.89), P = 0.01). The progesterone group also experienced significantly fewer preterm births < 28 weeks and < 35 weeks (Table 1). Neonates in the progesterone group experienced significantly less RDS than those born to mothers given placebo, an effect that persisted after adjustment (RR = 0.40 (95% CI, 0.17–0.94), P = 0.03). The unadjusted risk for any morbidity/mortality event was significantly lower in neonates born to mothers in the progesterone group (RR = 0.57 (95% CI, 0.33–0.99), P = 0.04), as were composite morbidity/mortality scores ‘0–4 scale without NICU’ and ‘0–6 scale without NICU’ (both P = 0.05). Progesterone therapy was associated with a significant reduction in birth weight < 1500 g (RR = 0.47 (95% CI, 0.26–0.85), P = 0.01). Results for all neonatal outcomes are given in Table 1. Logistic regression for preterm birth < 33 weeks in the ITT analysis controlled for pooled study site and other risk factors, but the effect of treatment remained essentially unchanged (odds ratio = 0.48 (95% CI, 0.25–0.91), P = 0.02). Results of the ‘treated-patient analysis set’ and ‘compliant analysis set’ are reported in Tables S2 and S3.
Table 1 Primary and secondary outcomes in progesterone-treated (n = 235) and placebo (n = 233) patients; intent-to-treat analysis set
Outcome Primary outcome Preterm birth < 33 weeks Secondary outcomes Preterm birth < 28 weeks Preterm birth < 35 weeks Preterm birth < 37 weeks Respiratory distress syndrome Bronchopulmonary dysplasia Proven sepsis Necrotizing enterocolitis Intraventricular hemorrhage, Grade III/IV Periventricular leukomalacia Perinatal death Fetal death Neonatal death Composite outcome scores Any morbidity/mortality event 0–4 without NICU 0–4 with NICU 0–6 without NICU Birth weight < 2500 g Birth weight < 1500 g
Vaginal progesterone Placebo group Relative risk group (n (%)) (n (%)) (95% CI)*
P
Adjusted RR (95% CI)‡
P
21/235 (8.9)
36/223 (16.1)
0.55 (0.33–0.92)
0.020 0.54 (0.33–0.89)
0.013
12/235 (5.1) 34/235 (14.5) 71/235 (30.2) 7/235 (3.0) 4/235 (1.7) 7/235 (3.0) 5/235 (2.1) 0/235 (0.0) 0/235 (0.0) 8/235 (3.4) 5/235 (2.1) 3/235 (1.3)
23/223 (10.3) 52/223 (23.3) 76/223 (34.1) 17/223 (7.6) 5/223 (2.2) 6/223 (2.7) 4/223 (1.8) 1/223 (0.4) 0/223 (0.0) 11/223 (4.9) 6/223 (2.7) 5/223 (2.2)
0.50 (0.25–0.97) 0.62 (0.42–0.92) 0.89 (0.68–1.16) 0.39 (0.17–0.92) 0.76 (0.21–2.79) 1.11 (0.38–3.24) 1.19 (0.32–4.36) 0.32 (0.01–7.73)† Not estimable 0.69 (0.28–1.68) 0.79 (0.24–2.55) 0.57 (0.14–2.35)
0.036 0.016 0.376 0.026 0.678 0.853 0.797 0.305 NA 0.413 0.694 0.431
0.044 0.007 0.304 0.029 0.746 0.758 0.763 0.317 NA 0.447 0.740 0.441
18/235 (7.7)
30/223 (13.5)
0.57 (0.33–0.99)
60/234 (25.6) 15/234 (6.4)
68/220 (30.9) 30/220 (13.6)
0.83 (0.62–1.11) 0.47 (0.26–0.85)
0.043 0.59 (0.34–1.02) 0.048 0.068 0.048 0.213 0.83 (0.62–1.11) 0.010 0.49 (0.28–0.87)
0.51 (0.27–1.00) 0.59 (0.40–0.87) 0.87 (0.67–1.13) 0.40 (0.17–0.94) 0.81 (0.23–2.90) 1.18 (0.40–3.47) 1.21 (0.34–4.31) 0.33 (0.01–7.80)† Not estimable 0.71 (0.29–1.75) 0.82 (0.25–2.70) 0.58 (0.14–2.38)
0.054 0.065 0.069 0.065 0.203 0.013
*Unadjusted relative risks (RR) and 95% CI calculated using the Cochran–Mantel–Haenszel (CMH) test. †Based on logit estimator with continuity correction. ‡Adjusted RR and 95% CI calculated using CMH test, adjusted for pooled study site and risk strata. Note, adjusted RRs were not reported in the original table reported by the PREGNANT trial. NICU, neonatal intensive care unit.
Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.
LETTERS TO THE EDITOR
Letters to the Editor
597
Re-analysis of the PREGNANT trial by independent academic investigators has replicated in every respect the original results2 , which are also consistent with an individual patient data meta-analysis based on five randomized trials including PREGNANT4 . We calculate the risk difference (RD) in the meta-analysis for early preterm delivery to be RD = −0.09 (95% CI, −0.14 to 0.04), with number needed to treat = 11 (95% CI, 7–25). One observation in the FDA report merits further comment5 . The Cochran–Mantel–Haenszel (CMH) test used in the original analysis2 was considered inappropriate owing to ‘insufficient sample size’ in each stratum and ‘inconsistent treatment effects among strata’5 . We disagree. The CMH test in SAS used by us is equivalent to the Mantel–Haenszel conditional test, both providing identical results and a valid stratified analysis even when sample sizes within strata are small6 . Given the persistently high prevalence of preterm delivery, there is substantial evidence that administration of vaginal progesterone to women with an asymptomatic sonographic short cervix promises considerable public health benefit.
Acknowledgments This study was performed through subcontract N01HD23342 between Wayne State University and Yale University, funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. We are grateful to Livia Kidd for technical assistance in the preparation of this manuscript. The authors declare no conflicts of interest. L. A. McKay†‡, T. R. Holford†‡ and M. B. Bracken*†‡§ †Yale School of Public Health, New Haven, CT, USA; ‡Yale Center for Perinatal, Pediatric and Environmental Epidemiology, New Haven, CT, USA; §School of Medicine, Yale University, New Haven, CT, USA *Correspondence. (e-mail: [email protected])
3. NDA 022139, Progesterone gel 8% (Background Document for Meeting of Advisory Committee for Reproductive Health Drugs). Prepared by the Division of Reproductive and Urologic Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration. December 22, 2011. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugs AdvisoryCommittee/UCM287987.pdf. 4. Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O’Brien JM, Cetingoz E, Da Fonseca E, Creasy GW, Klein K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, Hassan SS. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012; 206: 124.e1–19. 5. NDA 22–139 for Progesterone Gel 8% (Briefing Materials for Advisory Committee for Reproductive Health Drugs). Prepared by Columbia Laboratories, Inc. December 15, 2011. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/Committe esMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisory Committee/UCM287988.pdf. 6. Holford TR. Multivariate Methods in Epidemiology. Oxford University Press: Oxford, 2002; 66.
SUPPORTING INFORMATION ON THE INTERNET The following supporting information may be found in the online version of this article: Appendix S1 Details of the methodology used to re-analyze data from the PREGNANT trial, additional results and supplementary references Table S1 Baseline and treatment characteristics of the population (n = 458) Table S2 Primary and secondary outcomes in progesterone (n = 235) and placebo (n = 224) patients; treated patient analysis set Table S3 Primary and secondary outcomes in progesterone (n = 194) and placebo (n = 193) patients; compliant analysis set
DOI: 10.1002/uog.13331
References 1. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007; 357: 462–469. 2. Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, Vijayaraghavan J, Trivedi Y, Soma-Pillay P, Sambarey P, Dayal A, Potapov V, O’Brien J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H, Mazheika L, Manchulenko D, Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011; 38: 18–31.
Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd.
Ultrasound Obstet Gynecol 2014; 43: 596–599.
