Single Course Of Antenatal Corticosteroids Research Articles

Antenatal corticosteroids: the good, the bad and the unknown.

The purpose of this review was to summarize recently published clinical and animal-based studies of antenatal corticosteroids, describe current recommendations for practice, and suggest priority areas for future research. A single course of antenatal corticosteroids is known to improve newborn lung function after preterm birth and to reduce the risk of newborn death. Current evidence from animal and clinical studies suggests that additional numbers of courses do not further improve lung function and are associated with risks of adverse consequences. These risks principally include restricted intrauterine growth, altered brain development, postnatal insulin resistance and changes to the hypothalamic-pituitary-adrenal axis. The research challenges in this field are now centred on uncovering the mechanisms by which cortisol is involved in programming the fetus for its future metabolic life, and discovering ways in which the effectiveness and safety of antenatal glucocorticoids can be enhanced.

Multiple Courses of Antenatal Corticosteroids Are Associated With Early Severe Lung Disease in Preterm Neonates

Administering a single course of antenatal corticosteroids (ANCS) to women at risk of delivering prematurely has numerous positive neonatal effects including decreases in respiratory distress syndrome, intraventricular hemorrhage, and mortality. Although benefit lasts at least 7 to 10 days, there are no trials confirming benefit beyond this time, so that some obstetricians choose to recommend repeated courses of ANCS. The authors reviewed findings of the thyrotropin-releasing hormone (TRH) trial for prevention of lung disease in preterm infants to determine, in 595 trial neonates born at 26 to 32 weeks' gestation, whether three or more courses of ANCS correlated with infant mortality. The trial, using a randomized design, took place at 13 North American centers in the years 1992 to 1996. All participants received a course of ANCS when enrolled, either two 12-mg intramuscular doses of betamethasone given 24 hours apart or four 6-mg doses of dexamethasone at 6-hour intervals. Women randomized to receive TRH or placebo were given repeated courses of ANCS at the direction of the attending obstetrician. Mortality was 9.2% for neonates exposed to three or more courses of maternal ANCS therapy and 4.8% for those whose mothers received one or two courses. The odds ratio for death in the former group was 3.2 after adjusting for gestational age and multiple gestations. The time of delivery after the last steroid dose did not significantly influence mortality. Multicourse ANCS remained significantly associated with mortality after controlling for tocolytic exposure. Whether the mother received TRH or placebo was not a factor. Early severe lung disease (ESLD) correlated with three or more courses of ANCS, but nonrespiratory neonatal morbidity related to prematurity did not. An increased incidence of ESLD explained the association between mortality and multicourse ANCS therapy. Survival time after birth was significantly shorter when three or more courses of ANCS were administered. The present findings suggest that repeat courses are warranted only in the setting of a clinical trial.

Recommendations for repeat courses of antenatal corticosteroids: A decision analysis

Objective: The objective was to review the evidence regarding multiple versus single courses of antenatal corticosteroids (ACS), devise dosing regimens based on this evidence, and then, by using decision analysis, compare 5 ACS regimens: (1) single course, (2) weekly courses, (3) every-other-week dosing, (4) every-other-week dosing with no more than 2 courses, and (5) an every-other-week dosing regimen with no third courses after 30 weeks and no second course after 32 weeks. Study Design: The literature was examined for evidence regarding a dose response of the benefits and detriments of ACS. A decision analytic model was designed by using odds ratios, risks of morbidity and mortality, and birth rates from the literature. Mathematic modeling, based on data in the literature, was used to estimate the number of patients who would present at risk for preterm delivery and at what gestational age they would subsequently be delivered. A sensitivity analysis was performed to account for uncertainties in the data. Results: Of approximately 4 million annual births in the United States, a conservative estimate of 138,000 patients will present between 24 and 34 weeks of gestation at risk for preterm delivery, with 91,915 deliveries. If the 5 different dosing regimens are applied to these patients, strategy 1, the single course of ACS, would result in 30,232 cases of respiratory distress syndrome (RDS) and 4032 neonatal deaths. Three of the other dosing regimens (2, 3, and 5) would all decrease the number of cases of RDS but would concomitantly increase neonatal deaths. Only dosing regimen 4 would decrease the cases of RDS by 2187 without increasing the number of neonatal deaths. Conclusion: There is evidence that there may be a decrease in the incidence of RDS secondary to the use of multiple doses of ACS; however, a concomitant increase in neonatal deaths may also occur. On the basis of our results, we recommend the following: (1) all fetuses between 24 and 34 weeks' gestation at risk for preterm delivery should be given the first course, (2) if there is a persisting risk of preterm delivery subsequent to this, the next course should be given 2 weeks later, and (3) no more than 2 courses should be given. These recommendations need to be examined in a randomized, controlled trial. (Am J Obstet Gynecol 2002;186:1221-9.)

Multiple Versus Single Courses of Antenatal Corticosteroids for Preterm Birth: A Pilot Study

Objectives: (1) To determine the feasibility of a multicentre, randomized, double-masked, placebo-controlled trial to investigate the effects of multiple courses of antenatal corticosteroids (ACS) more than 7 days following the initial course of ACS therapy, on perinatal or neonatal mortality or neonatal morbidity. (2) To determine the risk of complications that would require discontinuation of ACS therapy. (3) To determine if multiple courses of ACS have an effect on the concentrations of plasma cortisol and adrenocorticotropin hormone (ACTH) in cord blood and in maternal blood immediately following delivery, compared to a single course of ACS.Methods: Women at 24 to 30 weeks' gestation, at continued increased risk of preterm birth 7 or more days following a single course of ACS were randomized to receive weekly courses of betamethasone or placebo until 33 weeks' gestation or delivery.Results: Women were recruited at two hospitals in Toronto from 01 September 1999 to 31 August 2000. Of the 78 women who were approached and were eligible for the study, 12 (15%) were recruited and 66 (85%) refused to participate. Of the 66 refusals, 38 (58%) did not feel their physicians were supportive of the study, 10 (15%) did not want to be randomized, and 4 (6%) had other personal reasons for refusing to enter the trial. Fourteen women (21%) had physicians who did not allow them to join the study. The lack of physician support was due to concerns related to the potential adverse effects of multiple courses of ACS. There were no complications requiring discontinuation of ACS. Plasma cortisol and ACTH concentrations in cord and maternal blood taken after delivery were not significantly different between ACS and placebo groups.Conclusion: A multicentre randomized controlled trial is required to determine the benefits and risks of multiple versus a single course of ACS. If the study Protocols are supported by physicians and their patients, a multicentre randomized controlled trial is feasible.

Antenatal corticosteroids for preterm birth

A single course of antenatal corticosteroids is a rare example of a treatment that yields both a health benefit and a cost savings. This article reviews the history and background of antenatal corticosteroids, its use in clinical practice and the controversy today regarding the use of multiple courses of antenatal corticosteroids.

Multiple Courses of Antenatal Steroids

In Brief OBJECTIVE To review the existing literature regarding the effect of multiple courses of antenatal corticosteroids in reducing the occurrence of complications arising because of lung immaturity. DATA SOURCES A systematic review of the English-language literature was conducted using a computerized database. We searched the English-language human and animal literature in MEDLINE and PubMed (National Library of Medicine, Bethesda, MD), as well as abstracts from recent meetings of the Society for Gynecologic Investigation and the Society for Maternal-Fetal Medicine. The search terms used were antenatal steroids, prenatal steroids, and respiratory distress syndrome. STUDY SELECTION We screened 2472 abstracts and found 280 relevant articles, which we independently reviewed. Only prospective well-designed animal studies were included. In humans, no well-designed randomized controlled trials (RCTs) were identified. Data that specifically addressed the issue of beneficial and adverse outcome of multiple courses of antenatal corticosteroids were included. TABULATION, INTEGRATION, AND RESULTS Twelve studies and three abstracts concerning animal models were included. These suggest multiple adverse consequences including decrease in birth and lung weights and brain growth restriction. In humans, 14 publications and five abstracts, mostly in the form of retrospective studies, although methodologicaly lacking, were included. Possible beneficial effects include lower rates of respiratory distress syndrome and a decrease in oxygen use, whereas adverse outcomes embody reduction in birth head circumference, birth weights, and increased neonatal and maternal infection rates. CONCLUSION To date, there are no well-designed RCTs in humans that support the advantages of multiple courses over a single course of antenatal corticosteroids. An increasing body of evidence raises the concern of adverse consequences from the use of repeated courses. While awaiting results from RCTs in progress, we recommend that a single course of antenatal corticosteroids be given to all women at risk for preterm birth at 24–34 weeks' gestation. Repeated doses of antenatal steroids for fetal lung maturation may have multiple adverse consequences with no clear benefit over a single course.

Antenatal corticosteroids revisited: repeat courses— National Institutes of Health Consensus Development Conference Statement, August 17–18, 2000

Objective: To provide health care providers, patients, and the general public with a responsible assessment of currently available data regarding the benefits and risks of repeat courses of antenatal corticosteroids. Participants: A non-Federal, non-advocate, 16-member panel representing the fields of obstetrics and gynecology, pediatrics, maternal and fetal medicine, neonatology, medical ethics, community health, pharmacology, psychology, and reproductive biology. In addition, 13 experts in these same fields presented data to the panel and to a conference audience of approximately 200. Evidence: The literature was searched using MEDLINE and an extensive bibliography of references was provided to the panel. Experts prepared abstracts of their conference presentations with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience. Consensus Process: The panel, answering predefined questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. The draft statement was made available on the World Wide Web immediately following its release at the conference and was updated with the panel’s final revisions. 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.

Clinical use of antenatal corticosteroids: benefits and risks.

After completing this article, readers should be able to: 1. Describe the rationale for the use of antenatal corticosteroids for human fetal maturation. 2. Delineate recommendations of the 1994 National Institutes of Health Consensus Conference on Antenatal Corticosteroids. 3. Review areas of controversy in the clinical use of antenatal corticosteroids. 4. Describe the potential risks of multiple courses of antenatal corticosteroids. 5. Delineate current recommendations for clinical use of antenatal corticosteroids to promote fetal maturation. Glucocorticoid administration initially was appreciated as a method for accelerating development of the intestine more than 40 years ago. Since that time, developmental effects of these agents have been defined in at least 16 tissues of mammals. More than 30 years ago, while studying the mechanism of initiation of labor in sheep, Liggins made the observation that infusion of corticosteroids into fetal lambs was associated with improved survival and decreased lung disease in animals delivered preterm. Subsequently, numerous studies in cell culture, animal models, and human fetal tissue have delineated the multiple effects of glucocorticoids on the developing lung. These include increases in both the total tissue and alveolar surfactant pools; a decrease in vascular permeability, with less protein leak into the alveolar spaces; enhanced clearance of lung water; maturation of parenchymal structure; increase in lung compliance and maximal lung volume; enhanced response to surfactant treatment; and improvement in respiratory function, outcome, and survival. (See accompanying article on scientific rationale for use of antenatal glucocorticoids.) In 1972, the first randomized clinical trial of administration of antenatal corticosteroids (ANCS) in humans demonstrated decreased mortality and a decreased incidence of respiratory distress syndrome (RDS) in preterm infants born at less than 34 weeks’ gestation, who were treated with betamethasone for at least 24 hours before delivery. Over the ensuing 20 years, multiple clinical investigations continued to document the effectiveness of ANCS on …

Effect of single versus multiple courses of antenatal corticosteroids on maternal and neonatal outcome

Objective: Treatment of pregnant mothers with a single course of antenatal corticosteroids significantly reduces neonatal mortality and morbidity. Multiple weekly courses are often given. However, the safety and efficacy of repeated courses of antenatal corticosteroids have not been adequately studied. Study Design: A retrospective study was performed for 609 mothers and their 713 infants who were treated with 1 to 12 courses of antenatal corticosteroids. Data for 369 singleton preterm infants born at ≤34 weeks’ gestation, 210 multiple gestations, and 134 infants delivered at ≥35 weeks’ gestation were analyzed separately. Results: The incidence of respiratory distress syndrome was 45% for single-course and 35% for multiple-course groups ( P = .005; odds ratio, 0.44; 95% confidence interval, 0.25-0.79). The multiple-course group also had significantly less patent ductus arteriosus (20% vs 13%; P = .016). Incidence of death before discharge and other neonatal morbidities were similar. The multiple-course group had a reduction of 0.46 ± 0.19 cm in head circumference at birth ( P = .013) when adjusted for gestational age and preeclampsia. The 2 groups had similar birth weights. Infants born at ≥35 weeks’ gestation, multiple-gestation infants, and infants who were born >7 days after the last corticosteroid dose had similar outcomes, regardless of the number of courses they received. Mothers treated with multiple courses compared with a single course had a significantly higher incidence of postpartum endometritis ( P = .013), even though they had a lower incidence of prolonged rupture of membranes (24% vs 33%, P = .06) and similar cesarean delivery rates. Conclusion: Exposure to multiple courses of antenatal corticosteroids compared with a single course resulted in a significant reduction in the incidence of respiratory distress syndrome in singleton preterm infants delivered within a week of the last corticosteroid dose. This was associated with a reduction in birth head circumference and an increased incidence of maternal endometritis. Whether the potential benefits of repeated therapy clearly outweigh the risks will ultimately be determined in randomized prospective controlled trials. (Am J Obstet Gynecol 2000;182:1243-9.)

Multiple Courses of Antenatal Corticosteroids for Preterm Birth

a single course of antenatal corticosteroids (ACS) reduces the risks of neonatal death, respiratory distress syndrome (RDS) and possibly intraventricular haemorrhage (IVH) in preterm infants. Because the maximum benefit of therapy appears to occur between 24 hours and seven days following the initial treatment, some physicians have suggested that repeated courses of ACS be administered at weekly intervals to women who remain at increased risk of preterm delivery. In some centres, this approach has become routine, despite the fact that repeated courses of ACS have not been evaluated in a randomized fashion. There are limited numbers of small human studies which have reported that multiple courses of ACS are associated with a decreased risk of RDS. They also have reported a slightly higher risk of necrotizing enterocolitis (NEC) and neonatal mortality, and a reduction in birth head circumference and birthweight. In animals, multiple courses of ACS have been associated with a progressive improvement in post-natal lung function. However, infant growth restriction and alteration of central nervous system myelination have also been shown as adverse effects. The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study (MACS) has been proposed as a multicentre, double-blind, randomized controlled trial of multiple courses versus a single course of ACS for women at increased risk of preterm birth. Centres in Canada, the USA and Israel have been invited to participate. Prior to MACS, a pilot study will be undertaken at Sunnybrook and Women’s College Health Science Centre and Mount Sinai Hospital in Toronto, to determine the feasibility of MACS.

Multiple Courses of Antenatal Corticosteroids (ANCS): Effect on Respiratory Morbidity, Mortality and Growth in Preterm Infants. † 956

Many obstetricians treat women in preterm labor with repeated courses of ANCS. However, it is unknown whether additional courses of ANCS are beneficial or potentially deleterious for growth or development of these fetuses. In the North American Thyrotropin Releasing Hormone (TRH) trial, women presenting at< 30 weeks gestation in preterm labor received TRH or placebo in combination with ANCS. All women received one course of ANCS. Subsequent courses were given at the discretion of individual obstetricians. Of 1132 infants delivered in the trial, 616 (55%) received one course, 218 (19%) received two courses, 201 (18%) received 3-5 courses and 76 (7%) received 6-13 courses of ANCS. Adjusting for gestational age, we compared the mortality and respiratory outcomes for infants of 25-32 wk gestation who received one course vs. two or more courses of ANCS (90% power to detect 10% difference in outcomeα = 0.05). Among infants born at 25 to < 28 wk, the incidence of RDS was 85% (194/229) for those who received 1 course of ANCS and 85% (89/105) for those who received 2 or more courses (p = 1.00). The incidence of RDS at 28-32 wk was 51% (92/181) for 1 course and 45% (85/191) for 2 or more courses (p = 0.22). The number of courses of ANCS was not associated with birth weight, the incidence of death, chronic lung disease at 28 days or at 36 weeks post-menstrual age, or with other morbidities of prematurity (PDA, IVH, NEC, ROP). There was no association between TRH and any of these outcomes. We conclude from this retrospective analysis that there is no evidence that multiple courses of ANCS are associated with either additional benefit to respiratory outcomes or deleterious effects on growth, when compared to a single course of ANCS. A prospective randomized trial would be necessary to definitively answer this question.