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New International Study Indicates Vaginal Progesterone Reduces Rate of Preterm Birth by 45%

Major New International Study Shows the Effectiveness and Safety of Vaginal Progesterone in the Prevention of Preterm Birth


Click to read article from AJOG 

 

 
   
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-prong 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 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 30,000 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.”

 

 

 

 

Saving Lives, Reducing Costs

  Preterm Infants: Giving Hope Through Research 
   
  by Ernie Branson, photographer 
  Eunice Kennedy Shriver National Institute of Child Health and Human Development, Dr. Alan Guttmacher, Director. Taken at the NICHD’s Perinatology Research Branch, located at the Detroit Medical Center, this photo represents giving hope through research to infants born prematurely that they can achieve their full potential for healthy and productive lives.”

It’s one of the grimmest – and most heartbreaking – statistics in all of medicine. 500,000.

That’s the approximate number of American women who experience premature birth each year…and then look on helplessly, all too often, while their helpless infants endure weeks (and sometimes months) of trauma that can include respiratory distress, nutritional complications, organ failure and even death.

It’s a devastating scenario, to say the least.  But the fearsome physical toll caused by “preterm birth” – a dangerous medical condition in which pregnant mothers deliver their babies ahead of schedule, long before Mother Nature has provided them with all the tools they need to thrive – is only part of this often tragic story.

“How do you quantify the emotional toll?” asks Kara Hamilton, the State Director of Program Services and Public Affairs at the Michigan March of Dimes, which has been a non-profit leader in the battle against premature birth for many years.  “How do you put a number on it, when a mother has to watch her baby suffering in an intensive care unit . . . or when she can’t even hold that struggling infant in her arms, sometimes for weeks or months at a time?

“For both mother and child, preterm birth is often a disaster that destroys quality of life – while also sending shock waves of sadness and heartache through other family members and friends.”


Along with the physical toll from premature birth, says
Hamilton, there are also major financial costs that put a huge burden on the healthcare system and the economy each year.  Some telling examples:

 

  • The annual societal economic cost of premature birth in the U.S. is more than $26.2 billion per year, according to the latest estimates from the U.S. Department of Health and Human Services and other federal agencies. 

  • Because those losses are occurring in an ailing economy where the surging cost of healthcare how accounts for 17 percent of the entire U.S. Gross Domestic Product (GDP), they’re taking a huge toll on the nation’s economic well-being.

  • According to the latest March of Dimes estimates, preterm birth “increases healthcare costs to employers, alone, by more than 300 percent each year.”

  • Reducing the number of premature births (500,000) in the U.S. by only 12 percent could save the nation more than $500 million a year.

Says the Michigan March of Dimes expert: “You don’t need a Ph.D. in math – or in healthcare – to understand that the price we’re all paying for premature birth in this society is absolutely horrific.

           

“But there’s a hopeful side to all of this,” she adds, “which is that we’re getting closer every day to making real inroads on this major world health issue.  If we can continue to make the kind of progress we’ve been making in recent years, the prospects are bright that we’ll be able to spare women and babies from trauma no one should have to face . . . while also helping to lower the cost of everyone’s healthcare.”

Pre-term birth facts

  • “The Global and Regional Toll of Preterm Birth,” a report released by the March of Dimes in late 2009, declared that about one million deaths in the first month of life, or 28 percent of newborn deaths around the world, could be traced to a complication from premature birth.

  • While the majority of women giving birth prematurely did so in Africa and Asia, the United States and Canada recorded a combined 500,000 premature births.

  • Data compiled by the World Health Organization and used for the March of Dimes report indicated that 10.6 percent of births in North America are premature, second only to the 11.9 percent rate of Africa. In the United States, premature births have increased 35 percent in the last quarter century, partly because of the use of assisted reproductive technology.

  • Wherever trend data are available, according to the March of Dimes, the rates of preterm birth are increasing around the world. The U.S. consistently records higher infant mortality rates than most other developed countries. The nation currently ranks 41st in infant mortality rates among industrialized nations.

  • In 2007, nearly seven of every 1,000 American babies died before their first birthday. The U.S. National Center for Health Statistics cited the high rate of premature births as the main reason for the nation’s poor ranking of infant mortality rates.

  • The March of Dimes graded the United States with a “D” in its 2010 report card on preterm births. The organization grades individual states by comparing their premature birth rate to the national objective of 7.6 percent, the rate set by the Healthy People 2010 objective, a report issued every 10 years by the Office of Disease Prevention and Health Promotion, and the U.S. Department of Health and Human Services. In the most recent March of Dimes report card, not a single state met the national objective. In fact, only 17 states received a “C” grade, the highest mark given that year. Twenty states received a “D” and 13 states received an “F” grade. Michigan’s grade was a “D.”

  • In Michigan, the rate of babies born prematurely increased more than 10 percent between 1998 and 2008. One of every eight babies born in Michigan – 295 in an average week -- is born prematurely.

  • Michigan’s rate of preterm birth (12.7 percent) exceeds the national average of 12.3 percent.

  • The U.S. Centers for Disease Control and Prevention reports that preterm births topped the list of the most expensive hospitalizations in Michigan in 2007. Each premature birth in the state costs an average of $102,103 at the time of discharge from the hospital. That is 14 times the cost of a normal birth.



DMC Specialists Leading the Research

Dr. Romero, Principal Investigator of the study, and Sonia S. Hassan, M.D., the lead author of the study and the director of the PRB's Center for Advanced Obstetrical Care and Research housed at the DMC/WSU campus, also pointed out that numerous studies (many by the PRB) over the past decade have shown that ultrasound of the uterine cervix can identify pregnant women who are at high risk for preterm delivery. The ultrasound examination is simple to perform, painless, and can be performed between the 19th and 24th weeks of pregnancy. It also reduced the rate of respiratory distress syndrome, the most common complication of premature babies.

Meet the Doctors


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Roberto Romero, M.D.
is Chief of the Perinatology Research Branch and Head of the Program for Perinatal Research and Obstetrics in the Division of Intramural Research of NICHD/NIH.

Dr. Romero trained at Yale University in Obstetrics and Gynecology and in Maternal-Fetal Medicine. Subsequently, he joined the Yale faculty and became the Director of Perinatal Research. In 1992, he became Professor and Vice Chair of the Department of Obstetrics and Gynecology at Wayne State University and Chief of the Perinatology Research Branch of NICHD/NIH. Click here for more information
 
   


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Sonia S. Hassan, M.D.
is the Associate Dean of Maternal, Perinatal and Child Health and a Professor in the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, at Wayne State University School of Medicine. She is also the Director of the Center for Advanced Obstetrical Care and Research in the Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), of the US Department of Health and Human Services (DHHS). In addition, Dr. Hassan is also the Director of the Perinatology Research Branch/Wayne State University (WSU)/Detroit Medical Center (DMC) Maternal-Fetal Medicine Fellowship and the Associate Director of the Combined Maternal-Fetal Medicine/Medical Genetics Fellowship.  Click here for more information

 

 

 

 

 

 

 


Roberto Romero, MD

Sonia S. Hassan, MD























 

 

 

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