|
Antenatal Corticosteroids Revisited: Repeat
Courses
National Institutes of
Health
Consensus Development Conference Statement
August 17-18, 2000
This statement is more
than five years old and is provided solely for historical purposes. Due to
the cumulative nature of medical research, new knowledge has inevitably
accumulated in this subject area in the time since the statement was
initially prepared. Thus some of the material is likely to be out of date,
and at worst simply wrong. For reliable, current information on this and
other health topics, we recommend consulting the National Institutes of
Health's MedlinePlus http://www.nlm.nih.gov/medlineplus/.
This statement was originally published as:
Antenatal Corticosteroids Revisited: Repeat Courses. NIH Consens
Statement 2000 August 17-18; 17(2): 1-10.
For making bibliographic reference to consensus statement no. 112 in
the electronic form displayed here, it is recommended that the following
format be used:
Antenatal Corticosteroids Revisited: Repeat Courses. NIH Consens
Statement Online 2000 August 17-18; [cited year, month, day]; 17(2):
1-10.
Introduction
Preterm delivery remains a major cause of illness and death in infants.
Corticosteroid treatment of pregnant women who deliver prematurely was
first introduced in 1972 to enhance fetal lung maturity. Subsequent
research focused on the ability of corticosteroids to reduce mortality and
brain injury in preterm neonates.
In 1994, the National Institutes of Health sponsored a Consensus
Development Conference on the Effect of Corticosteroids for Fetal
Maturation on Perinatal Outcomes to assess the effectiveness of antenatal
corticosteroid therapy. The consensus panel concluded that giving a single
course of corticosteroids to pregnant women at risk for preterm delivery
reduces the risk of death, respiratory distress syndrome, and
intraventricular hemorrhage in their preterm infants.
The 1994 panel noted that optimal benefit of antenatal corticosteroid
therapy lasts 7 days. The panel also noted that the potential benefits and
risks of repeated administration of antenatal corticosteroids 7 days after
the initial course are unknown and called for additional research on this
issue. However, during recent years the use of repeat courses of antenatal
corticosteroids has become widespread in the United States, England, and
Australia. Such courses include weekly dosages, occasional dosages, or
rescue therapy (single-course steroids) given on an as-needed basis for
planned or imminent delivery.
The NIH organized this 1? day conference to present research on repeat
courses of antenatal corticosteroid therapy. After a day of presentations
and audience discussion, an independent, non-Federal consensus development
panel weighed the scientific evidence and wrote a draft statement that was
presented to the audience on the second day. The consensus statement
addressed these three questions:
- Is the evidence on benefits and risks of repeat courses of antenatal
corticosteroids sufficient to permit consensus recommendations?
- If so, what are the recommendations?
- If not, what additional information should be obtained?
The primary sponsors of this meeting were the National Institute of
Child Health and Human Development and the NIH Office of Medical
Applications of Research. The National Institute of Nursing Research and
the National Heart, Lung, and Blood Institute were co-sponsors.
1. Is the evidence on benefits
and risks of repeat courses of antenatal corticosteroids sufficient to
permit consensus recommendations?
Studies of single versus repeat courses of antenatal corticosteroids
were evaluated for benefits and risks through a review of published
literature and data presented during the consensus conference.
Benefits
In preterm animals, multiple doses of antenatal corticosteroids improve
lung function when compared with a single dose. These benefits include
improved lung mechanics and gas exchange as well as increased lung volume
and surfactant pools.
No published data on any of the possible benefits to humans of repeat
courses of antenatal corticosteroids were available from randomized
controlled trials, and the data from nonrandomized controlled trials were
limited in quality. Many studies were published as abstracts. The most
common research design was a retrospective evaluation of clinical data;
other studies were retrospective cohort comparisons. Methodologic
inconsistencies, such as variation in latent period from last dose to
delivery, in number of repeat courses compared, and variability of
inclusion of multifetal pregnancies made it difficult to combine data from
multiple studies. Despite their limitations, these studies suggested
possible benefits in reduction of the incidence and severity of
respiratory distress syndrome, and reduction in the incidence of patent
ductus arteriosus. There is little or no evidence to support other
possible benefits, including a reduction in mortality rate or reductions
in the incidence of intraventricular hemorrhage, chronic lung disease,
sepsis, necrotizing enterocolitis, or retinopathy of prematurity.
Risks
Data from studies on both animals and humans raise questions about the
safety of repeat doses of antenatal corticosteroids. Animal studies have
shown that repeat courses of antenatal corticosteroids have deleterious
effects on lung growth and organization, cerebral myelination, the
function of the hypothalamic-pituitary-adrenal axis, and retinal
development. In addition, there is evidence for a dose dependent effect on
fetal growth and persistence of immature lung architecture.
Evidence from human studies on both the short and long-term adverse
effects of repeat doses of corticosteroids is contradictory and therefore
inconclusive. The available human data come from inadequately controlled
observational and retrospective studies, some of which suggest adverse
maternal and fetal effects. Even when studies suggest a deleterious
outcome, they are generally inconsistent. In addition, none of the studies
controlled for postnatal corticosteroid treatment, used widely at the time
of the reports available to the panel. The study populations often
excluded children whose mothers had received repeat courses of
corticosteroids and who delivered late in the preterm period or at term.
Nevertheless, some studies suggest matters of
concern. For the mother, these include increased maternal infection and
suppression of the maternal hypothalamic-pituitary-adrenal axis.
Fetal/neonatal effects include decreased somatic and brain growth, adrenal
suppression, neonatal sepsis, chronic lung disease, and mortality. No
consistent effect on intraventricular hemorrhage was apparent from the
available data. Although no increase in the incidence of cerebral palsy
was noted, neurodevelopmental followup studies suggest an increase in
psychomotor delay and behavioral problems. Concern about the effects of
repeated corticosteroids on the central nervous system is heightened by
the fact that randomized controlled trials of postnatal corticosteroids
have found adverse neurologic effects in infants of gestational age
similar to those treated in utero.
Summary
Data from currently available studies assessing benefits and risks are
inadequate to argue for or against the use of repeat or rescue courses of
antenatal corticosteroids for fetal maturation.
2. If so, what are the
recommendations?
Clinical Recommendations
- All pregnant women between 24 and 34 weeks gestation who are at risk
of preterm delivery within 7 days should be considered candidates for
antenatal treatment with a single course of corticosteroids.
- Treatment consists of two doses of 12 mg of betamethasone given
intramuscularly 24 hours apart or four doses of 6 mg of dexamethasone
given intramuscularly 12 hours apart, as recommended by the consensus
panel in 1994. There is no proof of efficacy for any other regimen.
- Because of insufficient scientific data from randomized clinical
trials regarding efficacy and safety, repeat courses of
corticosteroids should not be used routinely. In general, it should be
reserved for patients enrolled in randomized controlled trials.
Several randomized trials are in progress.
3. If not, what additional
information should be obtained?
- The following research is recommended:
- Well-designed randomized clinical trials which are of sufficient
power to evaluate efficacy and safety are needed.
- In light of the possible risks, the design of randomized
clinical trials should minimize the exposure of mothers and
fetuses while protecting the integrity of the research design.
- These trials should assess:
- Clinically important neonatal morbidities, such as respiratory
distress syndrome, chronic lung disease, and brain injury.
- Clinically important maternal morbidities, such as infection and
adrenal suppression.
- The effects of repeat courses of corticosteroids on patterns of
fetal and postnatal growth.
- The potential effects of incremental courses on benefits and
risks, since the benefits of repeat courses of antenatal
corticosteroids are likely to decrease with advancing gestational
age.
- The efficacy and safety of rescue therapy.
- The interaction of repeat courses of antenatal corticosteroids
with postnatal corticosteroid therapy.
- Long-term growth and neuropsychological outcome up to at least
school age, using state-of-the-art techniques.
- In addition:
- Animal studies should evaluate the pathophysiologic and
metabolic mechanisms of potential benefits and risks, including
the effects of repeat corticosteroids on central nervous system
myelination and brain development.
Conclusions
- The collective international data continue to support unequivocally
the use and efficacy of a single course of antenatal corticosteroids
using the dosage and interval of administration specified in the 1994
Consensus Development Conference report.
- The current benefit and risk data are insufficient to support
routine use of repeat or rescue courses of antenatal corticosteroids
in clinical practice.
- Clinical trials are in progress to assess potential benefits and
risks of various regimens of repeat courses. Until data establish a
favorable benefit-to-risk ratio, repeat courses of antenatal
corticosteroids, including rescue therapy, should be reserved for
patients enrolled in clinical trials.
Consensus Development Panel
Larry C. Gilstrap III, M.D.
Panel and Conference Chairperson
Emma Sue Hightower Chairman and Professor
Department of Obstetrics, Gynecology, and Reproductive Sciences
University of Texas-Houston Medical School
Houston, Texas
William H. Clewell, M.D.
Associate Director
Department of Maternal-Fetal Medicine
Good Samaritan Regional Medical Center
Phoenix, Arizona
Mary E. D'Alton, M.D.
Virgil G. Damon Professor of Obstetrics and Gynecology
Director, Division of Maternal-Fetal Medicine
Columbia University
College of Physicians and Surgeons
New York Presbyterian Hospital
New York, New York
Marilyn B. Escobedo, M.D.
Professor, Department of Pediatrics,
Division of Neonatology
Medical Director, University Hospital
Newborn Intensive Care Unit
University of Texas Health Science Center at San Antonio
San Antonio, Texas
Joel Frader, M.D.
Professor of Pediatrics
Program in Medical Ethics and Humanities
Northwestern University Medical School
Attending Physician
Co-Director, Hospice and Palliative Care Program
Chair, Institutional Review Board
Children's Memorial Hospital
Chicago, Illinois
Dwenda K. Gjerdingen, M.D.
Associate Professor
Department of Family Practice and Community Health
University of Minnesota Medical School
St. Paul, Minnesota
Jan Goddard-Finegold, M.D.
Associate Professor of Pediatrics and Pathology
Division of Pediatric Neurology
Baylor College of Medicine and Texas Children's Hospital
Houston, Texas
Robert L. Goldenberg, M.D.
Charles E. Flowers Professor
Department of Obstetrics and Gynecology
University of Alabama School of Medicine
Birmingham, Alabama
Maureen Hack, MBChB
Professor of Pediatrics and Reproductive Biology
Rainbow Babies and Children's Hospital of University Hospitals of
Cleveland
Case Western Reserve University
Cleveland, Ohio
Thomas N. Hansen, M.D.
Chairman, Department of Pediatrics
Ohio State University
Chief Executive Officer
Children's Hospital
Columbus, Ohio
Ralph E. Kauffman, M.D.
Marion Merrell Dow/Missouri Chair in Medical Research
Professor of Pediatrics and Pharmacology
University of Missouri-Kansas City
Children's Mercy Hospital
Kansas City, Missour
Emmett B. Keeler, Ph.D.
Senior Mathematician
Health Program
The RAND Graduate School
Santa Monica, California
William Oh, M.D.
Sylvia Kay Hassenfeld Professor of Pediatrics
Chairman, Department of Pediatrics
Brown University School of Medicine
Pediatrician-in-Chief, Rhode Island Hospital
Medical Director, Hasbro Children's Hospital
Providence, Rhode Island
E. Albert Reece, M.D.
Abraham Roth Professor and Chairman
Department of Obstetrics, Gynecology, and Reproductive Sciences
Temple University School of Medicine
Philadelphia, Pennsylvania
Elizabeth J. Susman, Ph.D., R.N.
Jean Phillips Shibley Professor
Department of Biobehavioral Health
Pennsylvania State University
University Park, Pennsylvania
Marlyn G. Vogel, Ed.D.
Licensed Psychologist
Limekiln Simmons
Special Services
School District of Hatboro-Horsham
Ambler, Pennsylvania
Speakers
Beverly Banks, M.D., Ph.D.
Neonatologist
Division of Neonatology
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania
M. Sean Esplin, M.D.
Assistant Professor
Division of Maternal-Fetal Medicine
Department of Obstetrics and Gynecology
University of Utah Health Sciences Center
Salt Lake City, Utah
Noel French, MBChB, FRACP
Head of Neonatal Followup
King Edward Memorial Hospital
Subiaco, Perth
Australia
Debra Guinn, M.D.
Assistant Professor
Department of Obstetrics and Gynecology
University of Colorado Health Sciences
Center and Denver Health Medical Center
Denver, Colorado
Alan Jobe, M.D., Ph.D.
Professor of Pediatrics
Children's Hospital Medical Center of Cincinnati
Cincinnati, Ohio
Brian Mercer, M.D.
Director
Maternal-Fetal Medicine
Department of Obstetrics and Gynecology
MetroHealth Medical Center
Cleveland, Ohio
Kellie E. Murphy, M.D., M.Sc., FRCSC
Assistant Professor
University of Toronto
Department of Obstetrics and Gynecology
Mount Sinai Hospital
Toronto, Ontario
Canada
James F. Padbury, M.D.
Professor and Vice Chairman
Department of Pediatrics
Brown University School of Medicine
Pediatrician-in-Chief
Women and Infants Hospital of Rhode Island
Providence, Rhode Island
James R. Scott, M.D.
Professor
Department of Obstetrics and Gynecology
University of Utah Health Sciences Center
Salt Lake City, Utah
John C. Sinclair, M.D.
Professor
Department of Pediatrics
McMaster University Medical Center
Hamilton, Ontario
Canada
Michael Socol, M.D.
Vice Chair and Professor
Head, Section of Maternal-Fetal Medicine
Department of Obstetrics and Gynecology
Northwestern University Medical School
Chicago, Illinois
Ronald J. Wapner, M.D.
Director
Division of Maternal-Fetal Medicine
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Robert M. Ward, M.D., FAAP, F.C.P.
Professor
Director, Pediatric Pharmacology Program
Department of Pediatrics
University of Utah School of Medicine
Salt Lake City, Utah
Planning Committee
Duane Alexander, M.D.
Planning Committee Chairperson
Director
National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland
John A. Bowersox
Communications Specialist
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
Jerry M. Elliott
Program Analysis and Management Officer
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
Barnett S. Kramer, M.D., M.P.H.
Director
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
Catherine Y. Spong, M.D.
Pregnancy and Perinatology Branch
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland
Judith M. Whalen, M.P.A.
Associate Director for Science Policy, Analysis, and Communication
National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland
Linda Wright, M.D.
Special Assistant to the Director
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland
Conference Sponsors
National Institute of Child Health and Human Development
Duane Alexander, M.D.
Director
Office of Medical Applications of Research
Barnett S. Kramer, M.D., M.P.H.
Director
Conference Cosponsors
National Institute of Nursing Research
Patricia A. Grady, Ph.D., R.N., F.A.A.N.
Director
National Heart, Lung, and Blood Institute
Mary Anne Berberich, Ph.D.
Scientific Research Group Leader
|
