Vaginal Progesterone Cuts Premature Births

Laura Newman, MA

December 20, 2011

December 20, 2011 — Women with a sonographically detected short cervix cut their risk for preterm birth in half with vaginal progesterone, according to a meta-analysis published online December 14 in the American Journal of Obstetrics & Gynecology. The report confirms results from several, prospective, randomized trials showing that progesterone was effective in preventing preterm births.

"The present [individual patient data] meta-analysis provides compelling evidence of the benefit of vaginal progesterone to prevent preterm birth and neonatal morbidity/mortality in women with a short cervix," write Roberto Romero, MD, chief of the Perinatology Research Branch at the Eunice Kennedy Shriver National Institute of Child Health and Development at the National Institutes of Health and colleagues. "This intervention appears to be more effective in patients with a singleton pregnancy and a cervical length between 10 and 20 mm."

The research team, including collaborators from the United States, Austria, Brazil, Denmark, India, South Africa, Turkey, and the United Kingdom, reviewed individual patient data from 5 high-quality randomized trials that tested the efficacy and safety of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality. A total of 775 women and 827 infants participated in the trials and were included in the meta-analysis.

Dr. Romero and colleagues defined a short cervix as a cervix length of 25 mm, determined sonographically during the midtrimester; 25 mm is the length most frequently used in studies evaluating the predictive value of cervical length for preterm birth. The investigators used the rate of preterm birth before 33 weeks of gestation as the primary outcome; secondary outcomes included later preterm births at several cut points, as well as neonatal morbidity and mortality outcomes. Two of the prospective placebo-controlled trials (Fonseca et al, 2007; Hassan et al, 2010) accounted for most of the mothers and infants.

Vaginal progesterone reduced the rate of birth at less than 33 weeks' gestation by 42% (relative risk [RR], 0.58; 95% confidence interval [CI], 0.42 - 0.80). It also reduced the risk for birth at less than 35 weeks' gestation by 31% (RR, 0.69; 95% CI, 0.55 - 0.88), and less than 28 weeks' gestation by 50% (RR, 0.50; 95% CI, 0.30 - 0.81).

Vaginal progesterone also improved the following outcomes: respiratory distress syndrome (RR, 0.48; 95% CI, 0.30 - 0.76), a composite measure of neonatal morbidity and mortality (RR, 0.57; 95% CI, 0.40 - 0.81), birth weight less than 1500 g (RR, 0.55; 95% CI, 0.38 - 0.80), admission to the neonatal intensive care unit (RR, 0.75; 95% CI, 0.59 - 0.94), and the need for mechanical ventilation (RR, 0.66; 95% CI, 0.44 - 0.98).

Despite these statistically significant improvements, 2 commentators do not think the meta-analysis defines a standard of care for progesterone use to prevent premature births in women with a short cervix.

In an interview with Medscape Medical News, Sarah Bradley, MD, clinical assistant professor of obstetrics and gynecology from the University of Wisconsin–Madison, called the meta-analysis "murky."

"The different trials had different standards for a short cervix, and women were included who got both cervical cerclage and vaginal progesterone, making it difficult to disentangle the 2," she added.

"The numbers are not really new," said Aaron B. Caughey, MD, PhD, director of women's health and chair of obstetrics and gynecology, Oregon Health Sciences University, Portland, in an interview with Medscape Medical News. "We already knew these results from the 2 big trials." Dr. Caughey said that the Fonseca et al 2007 and Hassan et al 2011 trials contributed most of the numbers, and that the meta-analysis did not add much.

Additionally, critical information is still missing. "It remains to be defined what is a short cervix," said Dr. Caughey. "Is it 10 mm, 15, or 20?"

In counseling women, Dr. Caughey said, "we explain cerclage and progesterone as treatment options, offering it to women with a cervix shorter than 15 mm. Some women might ask to have both, but one of those treatments is enough." Dr. Caughey also sees more research as essential to developing optimal interventions for preventing prematurity.

Stratifying women by race, ethnicity, socioeconomic status, and maternal age should be priorities in future research, he explained.

The 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. One coauthor had disclosed participating in studies of progesterone gel for preterm birth prevention sponsored by Columbia Laboratories, Inc, the manufacturer of the preparation used in the PREGNANT trial and a prior trial of vaginal progesterone in women at risk for preterm delivery. He also serves on the advisory board and is a consultant for Watson Pharmaceuticals, a company with a financial interest in marketing vaginal progesterone gel for the prevention of preterm birth. Another coauthor is an employee of Columbia Laboratories, Inc. Some of the authors are listed in the patent on the use of all progesterone compounds to prevent preterm birth. Dr. Caughey and Dr. Bradley have disclosed no relevant financial relationships.

Am J Obstet Gynecol. 2011. Published online December 12, 2011. Full text

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