Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial

Authors

  • S. S. Hassan,

    1. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD and Detroit, MI, USA
    2. Department of Obstetrics and Gynecology, Wayne State University/Detroit Medical Center, Hutzel Women's Hospital, Detroit, MI, USA
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  • R. Romero,

    Corresponding author
    1. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD and Detroit, MI, USA
    2. Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
    3. Department of Epidemiology, Michigan State University, East Lansing, MI, USA
    • Chief, Perinatology Research Branch, Program Director for Perinatal Research and Obstetrics Intramural Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, 3990 John R, Detroit, MI 48201, USA
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  • D. Vidyadhari,

    1. Department of Obstetrics and Gynecology, MediCiti Institute of Medical Services, Andhra Pradesh, India
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  • S. Fusey,

    1. Department of Obstetrics and Gynecology, Government Medical College and Hospital, Maharashtra, India
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  • J. K. Baxter,

    1. Thomas Jefferson University, Department of Obstetrics and Gynecology, Philadelphia, PA, USA
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  • M. Khandelwal,

    1. Department of Obstetrics and Gynecology, Cooper University Hospital, Camden, NJ, USA
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  • J. Vijayaraghavan,

    1. Department of Obstetrics and Gynecology, Shri Ramchandra Medical College and Hospital, Tamil Nadu, India
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  • Y. Trivedi,

    1. Department of Gynecology, Sheth L.G. Hospital, Gujarat, India
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  • P. Soma-Pillay,

    1. Department of Obstetrics and Gynaecology, Steve Biko Academic Hospital, Pretoria, South Africa
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  • P. Sambarey,

    1. Department of Obstetrics and Gynecology, B.J. Medical College and Sassoon General Hospital, Maharashtra, India
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  • A. Dayal,

    1. Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
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  • V. Potapov,

    1. Department of Obstetrics and Gynecology of Dnepropetrovsk State Medical Academy, Municipal Establishment ‘City Maternity Hospital # 1’, Dnepropetrovsk, Ukraine
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  • J. O'Brien,

    1. Perinatal Diagnostic Center, Central Baptist Hospital, Lexington, KY, USA
    2. Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY, USA
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  • V. Astakhov,

    1. Department of Obstetrics and Gynecology of M. Gorky Donetsk National Medical University, Municipal Hospital ‘6th Central City Clinical Hospital’, Donetsk, Ukraine
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  • O. Yuzko,

    1. 1st Department of Obstetrics and Gynecology of Ukrainian State Institute of Human Reproductology of P.L. Shupik National Academy of Postgraduate Education, Pechersk Regional ‘1st Antenatal Out-Patients’ Clinic', Kiev, Ukraine
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  • W. Kinzler,

    1. Winthrop University Hospital, Clinical Trials Center, Mineola, NY, USA
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  • B. Dattel,

    1. Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk,VA, USA
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  • H. Sehdev,

    1. University of Pennsylvania Health System, Pennsylvania Hospital, Philadelphia, PA, USA
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  • L. Mazheika,

    1. Public Health Services Establishment Minsk ‘1st City Clinic’, Minsk, Republic of Belarus
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  • D. Manchulenko,

    1. Department of Antenatal Day-Hospital of Municipal Health Care Establishment ‘City Maternity Hospital # 1’, Chernovtsy, Ukraine
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  • M. T. Gervasi,

    1. U.O. Ostetricia/Ginecologia, Azienda Ospedaliera di Padova, Padova, Italy
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  • L. Sullivan,

    1. Department of Biostatistics, Boston University, School of Public Health, Boston, MA, USA
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  • A. Conde-Agudelo,

    1. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD and Detroit, MI, USA
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  • J. A. Phillips,

    1. Sage Statistical Solutions, Inc., Elfand, NC, USA
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  • G. W. Creasy,

    1. Columbia Laboratories, Inc., Livingston, NJ, USA
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  • for the PREGNANT Trial


Abstract

Objectives

Women with a sonographic short cervix in the mid-trimester are at increased risk for preterm delivery. This study was undertaken to determine the efficacy and safety of using micronized vaginal progesterone gel to reduce the risk of preterm birth and associated neonatal complications in women with a sonographic short cervix.

Methods

This was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled asymptomatic women with a singleton pregnancy and a sonographic short cervix (10–20 mm) at 19 + 0 to 23 + 6 weeks of gestation. Women were allocated randomly to receive vaginal progesterone gel or placebo daily starting from 20 to 23 + 6 weeks until 36 + 6 weeks, rupture of membranes or delivery, whichever occurred first. Randomization sequence was stratified by center and history of a previous preterm birth. The primary endpoint was preterm birth before 33 weeks of gestation. Analysis was by intention to treat.

Results

Of 465 women randomized, seven were lost to follow-up and 458 (vaginal progesterone gel, n = 235; placebo, n = 223) were included in the analysis. Women allocated to receive vaginal progesterone had a lower rate of preterm birth before 33 weeks than did those allocated to placebo (8.9% (n = 21) vs 16.1% (n = 36); relative risk (RR), 0.55; 95% CI, 0.33–0.92; P = 0.02). The effect remained significant after adjustment for covariables (adjusted RR, 0.52; 95% CI, 0.31–0.91; P = 0.02). Vaginal progesterone was also associated with a significant reduction in the rate of preterm birth before 28 weeks (5.1% vs 10.3%; RR, 0.50; 95% CI, 0.25–0.97; P = 0.04) and 35 weeks (14.5% vs 23.3%; RR, 0.62; 95% CI, 0.42–0.92; P = 0.02), respiratory distress syndrome (3.0% vs 7.6%; RR, 0.39; 95% CI, 0.17–0.92; P = 0.03), any neonatal morbidity or mortality event (7.7% vs 13.5%; RR, 0.57; 95% CI, 0.33–0.99; P = 0.04) and birth weight < 1500 g (6.4% (15/234) vs 13.6% (30/220); RR, 0.47; 95% CI, 0.26–0.85; P = 0.01). There were no differences in the incidence of treatment-related adverse events between the groups.

Conclusions

The administration of vaginal progesterone gel to women with a sonographic short cervix in the mid-trimester is associated with a 45% reduction in the rate of preterm birth before 33 weeks of gestation and with improved neonatal outcome. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

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