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

doi:10.1016/j.ajog.2011.12.003

American Journal of Obstetrics and Gynecology

Volume 206, Issue 2, February 2012, Pages 124.e1-124.e19

https://doi.org/10.1016/j.ajog.2011.12.003 Get rights and content

Objective

To determine whether the use of vaginal progesterone in asymptomatic women with a sonographic short cervix (≤25 mm) in the midtrimester reduces the risk of preterm birth and improves neonatal morbidity and mortality.

Study Design

Individual patient data metaanalysis of randomized controlled trials.

Results

Five trials of high quality were included with a total of 775 women and 827 infants. Treatment with vaginal progesterone was associated with a significant reduction in the rate of preterm birth <33 weeks (relative risk [RR], 0.58; 95% confidence interval [CI], 0.42–0.80), <35 weeks (RR, 0.69; 95% CI, 0.55–0.88), and <28 weeks (RR, 0.50; 95% CI, 0.30–0.81); respiratory distress syndrome (RR, 0.48; 95% CI, 0.30–0.76); composite neonatal morbidity and mortality (RR, 0.57; 95% CI, 0.40–0.81); birthweight <1500 g (RR, 0.55; 95% CI, 0.38–0.80); admission to neonatal intensive care unit (RR, 0.75; 95% CI, 0.59–0.94); and requirement for mechanical ventilation (RR, 0.66; 95% CI, 0.44–0.98). There were no significant differences between the vaginal progesterone and placebo groups in the rate of adverse maternal events or congenital anomalies.

Conclusion

Vaginal progesterone administration to asymptomatic women with a sonographic short cervix reduces the risk of preterm birth and neonatal morbidity and mortality.

Section snippets

Materials and Methods

The study was conducted based on a prospectively prepared protocol, and is reported using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for metaanalyses of randomized controlled trials¹⁴² and suggested guidelines for IPD metaanalyses.¹⁴¹

Study selection, details, and quality

The searches yielded 2611 citations, of which 10 were considered for potential inclusion (Figure 1). Five studies were excluded.125, 153, 154, 155, 156 Three of these studies evaluated vaginal progesterone in women at high risk for preterm birth (previous preterm birth,125, 154 uterine malformation,¹²⁵ cervical insufficiency,¹²⁵ and twins¹⁵⁵) but none of them measured or collected data on cervical length. Two of these studies125, 154 reported that prophylactic administration of vaginal

Principal findings of this study

Vaginal progesterone administration to asymptomatic women with a sonographic short cervix in the midtrimester was associated with: (1) a significant 42% reduction in the rate of preterm birth <33 weeks (primary outcome); (2) a significant reduction in the risk of preterm birth <35, <34, <30, and <28 weeks and a trend for a reduction in the rate of preterm birth <36 weeks; (3) a significant reduction in the risk of spontaneous preterm birth <33 and <34 weeks; (4) a significantly lower rate of

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Considering the available information, the results of elective cerclage seem to be more beneficial for the patient than those of emergency cerclage. Therefore, it would be more reasonable to perform elective cerclage in patients with mid-trimester or preterm miscarriage and concomitant cervical shortening before emergency cerclage is required. Furthermore, the benefit of progestin, in addition after surgical intervention, has not been established.
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Preterm birth remains one of the most urgent unresolved medical problems in obstetrics, yet only 2 therapeutics for preventing preterm birth have ever been approved by the United States Food and Drug Administration, and neither remains on the market. The recent withdrawal of 17-hydroxyprogesterone caproate (17-OHPC, Makena) marks a new but familiar era for obstetrics with no Food and Drug Administration–approved pharmaceuticals to address preterm birth. The lack of pharmaceuticals reflects a broad and ineffective pipeline hindered by extensive regulatory hurdles, soaring costs of performing drug research, and concerns regarding adverse effects among a particularly vulnerable population. The pharmaceutical industry has historically limited investments in research for diseases with similarly small markets, such as cystic fibrosis, given their rarity and diminished projected financial return. The Orphan Drug Act, however, incentivizes drug development for “orphan diseases”, defined as affecting <200,000 people in the United States annually. Although the total number of preterm births in the United States exceeds this threshold annually, the early subset of preterm birth (<34 weeks’ gestation) would qualify, which is predominantly caused by inflammation and infection. The scientific rationale for classifying preterm birth into early and late subsets is strong given that their etiologies differ, and therapeutics that may be efficacious for one subset may not work for the other. For example, antiinflammatory therapeutics would be expected to be highly effective for early but not late preterm birth. A robust therapeutic pipeline of antiinflammatory drugs already exists, which could be used to target spontaneous early preterm birth, in combination with antibiotics shown to sterilize the amniotic cavity. New applications for therapeutics targeting spontaneous early preterm birth could categorize as orphan disease drugs, which could revitalize the preterm birth therapeutic pipeline. Herein, we describe why drugs targeting early preterm birth should qualify for orphan status, which may increase pharmaceutical interest for this vitally important obstetrical condition.
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Spontaneous preterm birth (sPTB) stands as a leading cause of neonatal mortality. Consequently, preventing sPTB has emerged as a paramount concern in healthcare. Therefore, our study aimed to develop a nomogram, encompassing patient characteristics and cervical elastography, to predict sPTB in singleton pregnancies. Specifically, we targeted those with a short cervix length (CL), no history of sPTB, and who were receiving vaginal progesterone therapy.
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: The majority of the authors report no conflict of interest except as stated in this paragraph. J.M.O'B. was involved in studies of progesterone gel treatment for preterm birth prevention sponsored by Columbia Laboratories Inc, the manufacturer of the preparation used in the PREGNANT Trial and a previous trial of vaginal progesterone in women at risk for preterm delivery. J.M.O'B. serves on advisory boards and is a consultant for Watson Pharmaceuticals, a company with a financial interest in marketing vaginal progesterone gel for the prevention of preterm birth. He and others are listed in the patent on the use of all progesterone compounds to prevent preterm birth (US Patent No. 7,884,093: Progesterone for the Treatment and Prevention of Spontaneous Preterm Birth). G.W.C. is an employee of Columbia Laboratories Inc.

: This research was supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services.

: Reprints not available from the authors

: Cite this article as: Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012;206:124.e1-19.

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Reports of major impactVaginal 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

Objective

Study Design

Results

Conclusion

Section snippets

Materials and Methods

Study selection, details, and quality

Principal findings of this study

Lancet

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Reprod Biomed Online

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Lancet

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Obstet Gynecol

Eur J Obstet Gynecol Reprod Biol

Am J Obstet Gynecol

Am J Obstet Gynecol

Cell

Best Pract Res Clin Obstet Gynaecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Trends Pharmacol Sci

Prostaglandins

Trends Pharmacol Sci

Mol Cell Endocrinol

Trends Neurosci

Life Sci

J Steroid Biochem Mol Biol

Steroids

J Biol Chem

J Steroid Biochem

Am J Obstet Gynecol

Infant mortality statistics from the 2002 period: linked birth/infant death data set

Natl Vital Stat Rep

The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity

Bull World Health Organ

Births: final data for 2007

Natl Vital Stat Rep

Epidemiology of preterm birth and its clinical subtypes

J Matern Fetal Neonatal Med

Trends in twin preterm birth subtypes in the United States, 1989 through 2000: impact on perinatal mortality

Am J Obstet Gynecol

Prevention of prematurity by single embryo transfer

J Perinat Med

Modification of assisted reproduction techniques to prevent preterm birth

Clin Obstet Gynecol

Spontaneous preterm delivery in primiparous women at low risk in Denmark: population based study

BMJ

Prenatal medicine: the child is the father of the man 1996

J Matern Fetal Neonatal Med

The great obstetrical syndromes

J Matern Fetal Neonatal Med

The preterm labor syndrome

Ann N Y Acad Sci

Antibiotic administration to patients with preterm premature rupture of membranes does not eradicate intra-amniotic infection

J Matern Fetal Neonatal Med

Reports of major impact
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