Vaginal progesterone reduces rate of preterm birth and neonatal complications

A team of investigators of the National Institutes of Health housed at the Detroit Medical Center (DMC) and Wayne State University (WSU) published today that performing a cervical ultrasound in all pregnant women and treating those with a short cervix with vaginal progesterone reduces the rate of preterm birth and neonatal complications. The study is based on the analysis of all randomized clinical trials of vaginal progesterone conducted worldwide.

The problem: Preterm birth is a major health care problem. Approximately 12.9 million births worldwide are preterm (<37 weeks of gestation); 11 million occur in Africa and Asia, 900,000 in Latin America and the Caribbean, and 500,000 each in Europe and the United States. The highest rates of preterm birth are in Africa (11.9 percent) and in the U.S. (12 percent).

• Preterm birth is the leading cause of infant mortality (death by the age of one year), a standard indicator of health and disease of a community or society
• Every five minutes, 50 preterm babies are born worldwide
• Preterm births are at increased risk of death and long-term disability (such as cerebral palsy, autism spectrum disorders and developmental delays)
• In developing countries, many premature babies gasp for air because of respiratory immaturity, and due to a limited number of respirators and medications (surfactant) to support respiratory function, some die in this process
• The cost of preterm birth to society has been estimated to be $26 billion per year (2005 dollars) in the United States alone

The challenge: Despite decades of clinical and basic research, there has not been much progress in the prevention of premature birth. There is a need for a strategy to identify the pregnant mother at risk for premature birth and to implement interventions to reduce prematurity. Efforts such as bed rest, nutritional supplementation, vitamins, antibiotics and medications to stop the uterus from contracting have not reduced the rate of preterm birth.

A solution at last: The most significant advance to prevent preterm birth consists of a two-pronged strategy in which all pregnant women undergo a measurement of the cervical length, and those with a short cervix (at risk for preterm birth) would be treated with vaginal progesterone. Two major studies (one from the U.S. with centers around the world, led by the PRB/WSU/DMC, and one from the United Kingdom) have provided evidence that this approach works.

What is new: A study published in the authoritative American Journal of Obstetrics & Gynecology reported the combined results of several randomized clinical trials using the "gold standard" for combining such studies: a meta-analysis of individual patient data.

The key findings of the study were:

• The vaginal application of progesterone reduces the rate of preterm birth in women at less than 33 weeks of gestation, but also is effective at less than 28, 32 and 35 weeks. This means that vaginal progesterone reduces both "early" and "late" preterm births. Early preterm births (< 32 weeks) are associated with a high rate of neonatal complications and long-term neurologic disability. Late preterm births (34-36 6/7 weeks) represent 70 percent of all preterm births, and although they have a lower rate of complications than early preterm births, they are still a major health care problem.   
• Vaginal progesterone administration to women with a short cervix detected by ultrasound reduced the rate of: 1) admission to the newborn intensive care unit; 2) respiratory distress syndrome; 3) the need for mechanical ventilation; and 4) a composite score of complications that included intracranial hemorrhage, bowel problems, respiratory difficulties, infection and death.
• Vaginal progesterone was effective in women with a short cervix and whether or not they had experienced a previous preterm birth.
• The benefits of progesterone administration were observed in women who had a cervical length of 25 mm or less.
• This is the first study to show that vaginal progesterone is effective in reducing the rate of neonatal complications in twin gestations. Previous studies of natural and synthetic progestins have been negative. This study found that progesterone benefits women with a twin gestation and a short cervix.
• There was remarkable consistency of the magnitude of the effect of vaginal progesterone in the prevention of preterm birth among studies conducted in different parts of the world.

Health care implications of this study in the U.S.: It is now possible to offer all pregnant women a method to determine whether they are at risk for preterm birth (i.e. transvaginal cervical ultrasound) and prevent a large fraction of preterm births in women with a short cervix using vaginal progesterone. Progesterone is a natural hormone produced by the ovary and the placenta. This hormone favors continuation of pregnancy to term, and it has been used to support pregnancies conceived after in vitro fertilization for more than 15 years.

Universal implementation of cervical ultrasound and vaginal progesterone is estimated to result in the prevention of approximately 45,000 preterm births at <35 weeks in the U.S. per year, with an annual savings of more than $500 million in health care costs. 

"The results of this study provide compelling evidence that vaginal progesterone administration to women with a short cervix is an effective strategy to reduce preterm birth," said Dr. Roberto Romero, Chief of the Perinatology Research Branch (PRB) of the National Institutes of Health. "Our new study indicates that to prevent one case of preterm birth at <33 weeks of gestation, only 13 mothers with a short cervix would need to be treated, and 11 to prevent one preterm birth at <35 weeks of gestation. This makes progesterone the most powerful strategy to reduce preterm birth developed thus far.

"Of great interest is that this study provides the first evidence that vaginal progesterone administration may also reduce the rate of preterm birth in twin gestations with a short cervix by 30 percent, and decrease the rate of neonatal complications in twin gestations," Dr. Romero continued. "Previous studies using progesterone or a synthetic progestational agent had yielded negative results, but this is because the focus was not on women who could benefit from progesterone (those with a short cervix)."

"Once again, the Perinatology Research Branch has made a pioneering contribution that can give hope to expectant mothers," said DMC President and CEO Michael Duggan. "We're also glad to have played a key role in the basic building blocks of this study, as patients from the Detroit Medical Center participated in the key trial, which is the basis for this analysis. In this holiday season, especially, it's gratifying to know that the Detroit Medical Center has helped to create such a precious health care gift."

Dr. Sonia S. Hassan, Director of the PRB's Center for Advanced Obstetrical Care and Research, Associate Dean for Maternal, Perinatal and Child Health at Wayne State University School of Medicine and a co-author, suggested that "physicians and health care professionals caring for all pregnant women should counsel patients that there is a test to identify patients at risk for preterm birth. Pregnant women should be advised to undergo a transvaginal ultrasound to detect a short cervix between 19 and 24 weeks. Patients found to have a short cervix should be considered for progesterone therapy (typically 90 mg/day) from 20 to 36 and six-sevenths weeks. Our recommendation of using 90 mg/day is based on the analysis of the study published today, indicating that there is no difference in the effectiveness of progesterone if we use 90-100 mg/day versus 200 mg/day. As a general principle, we prefer to use the lowest effective dose of any compound during pregnancy."

Dr. Hassan emphasized "preterm birth is the leading cause of perinatal morbidity and mortality worldwide. The work that has led to this treatment strategy has the potential to improve the outcome of pregnancies worldwide. We're proud of this achievement and what has been accomplished by working together with our partners."

The study is titled Vaginal Progesterone in Women with an Asymptomatic Sonographic Short Cervix in the Midtrimester Decreases Preterm Delivery and Neonatal Morbidity: A Systematic Review and Meta-Analysis of Individual Patient Data, published in the American Journal of Obstetrics and Gynecology.     

Dr. Valerie Parisi, Dean of the Wayne State University School of Medicine and an obstetrician, said that "this publication represents the highest quality of evidence in support of the efficacy and safety of progesterone to prevent preterm birth." She highlighted the importance of the historical partnership between the PRB of the NICHD/NIH, the DMC and the Wayne State University Medical School in a long-standing effort to reduce the rate of preterm birth. "We are very proud of the contributions of our partnership with NIH to improve the health care of mothers and children."