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Kirsten Duckitt
Clinical Lecturer
Nuffield Department of Obstetrics and Gynaecology
Level 3, Women's Centre
John Radcliffe Hospital
Headington
Oxford
OX3 9DU
01865 741166 bleep 1028
>>> perinatl@slip.net 10/08/00 08:51pm >>>
Readers of this forum might wish to go to the following URl:
http://odp.od.nih.gov/consensus/cons/112/112_statement.htm
- - -
Essentially what it says is:
112. Antenatal Corticosteroids Revisited: Repeat
Courses
National Institutes of Health
Consensus Development Conference Statement
August 17-18, 2000
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.
NIH Consensus Statements are prepared by a nonadvocate, non-Federal
panel of experts, based on (1) presentations by investigators working in
areas relevant to the consensus questions during a 2-day public session;
(2) questions and statements from conference attendees during open
discussion periods that are part of the public session; and (3) closed
deliberations by the panel during the remainder of the second day and
morning of the third. This statement is an independent report of the
panel and is not a policy statement of the NIH or the Federal
Government.
Introduction
1. Is the evidence on benefits and risks of repeat courses of antenatal
corticosteroids sufficient to permit consensus recommendations?
2. If so, what are the recommendations?
3. If not, what additional information should be obtained?
Conclusions
Consensus Development Panel
Speakers
Planning Committee
Conference Sponsors
Conference Cosponsors
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:
1.Is the evidence on benefits and risks of repeat courses of antenatal
corticosteroids sufficient to permit consensus recommendations?
2.If so, what are the recommendations?
3.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
