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Antenatal Corticosteroids Revisited: Repeat Courses

National Institutes of Health
Consensus Development Conference Statement
August 17-18, 2000

Artwork for the conference depicting a woman craddling an infant figure.

Due to the cumulative nature of medical research, some of the information in this statement is likely to be out of date. For more current information on this and other health topics, please visit MedlinePlus, a service of the U.S. National Library of Medicine, National Institutes of Health.

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:

  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

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